Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: S([O:5][C:6]1[CH:11]=[CH:10][C:9]([NH:12][CH3:13])=[CH:8][CH:7]=1)(O)(=O)=O.[C:14]([NH:17][C:18]1[CH:23]=[CH:22][C:21]([S:24](Cl)(=[O:26])=[O:25])=[CH:20][CH:19]=1)(=[O:16])[CH3:15].C(N(CC)CC)C>C(O)C>[OH:5][C:6]1[CH:7]=[CH:8][C:9]([N:12]([CH3:13])[S:24]([C:21]2[CH:20]=[CH:19][C:18]([NH:17][C:14](=[O:16])[CH3:15])=[CH:23][CH:22]=2)(=[O:26])=[O:25])=[CH:10][CH:11]=1
Reactant: CNc1ccc(OS(=O)(=O)O)cc1
Reactant: CC(=O)Nc1ccc(S(=O)(=O)Cl)cc1
Solvent: CCN(CC)CC
Solvent: CCO
Product: CC(=O)Nc1ccc(S(=O)(=O)N(C)c2ccc(O)cc2)cc1

Procedure:
4-Methylaminophenol sulfate and equivalent 4-acetamidobenzenesulfonyl chloride and double equivalent triethylamine were reacted in ethanol at room temperature for 4 hours. After the solvent was removed in vacuo, the residue was extracted with diethyl ether. The ether layer was washed successively with 2 N hydrochloric acid, saturated aqueous NaHCO3 solution and water, then dried over anhydrous Na2SO4 The solvent was removed and the residue was recrystallized from ethanol to give N-(4-hydroxyphenyl)-N-methyl-4-acetamidobenzenesulfonamide, mp 202-203° C.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH2:9][C:10]([OH:12])=[O:11])[CH:6]=[CH:7][CH:8]=1.Cl[CH2:14][C:15](=O)[CH3:16].C(=O)([O-])[O-].[K+].[K+]>C(#N)C.C(OCC)(=O)C>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([C:9]2[C:10](=[O:12])[O:11][CH2:14][C:15]=2[CH3:16])[CH:6]=[CH:7][CH:8]=1
Reactant: COc1cccc(CC(=O)O)c1
Reactant: CC(=O)CCl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Solvent: CCOC(C)=O
Product: COc1cccc(C2=C(C)COC2=O)c1
Yield: 78.3 %

Procedure:
A mixture of 3-methoxyphenylacetic acid (3.32 g, 20 mmol), chloroacetone (2.02 g, 22 mmol) and potassium carbonate (6.07 g, 44 mmol) in acetonitrile (30 mL) was heated at reflux for 5 hours. The resultant mixture was cooled to room temperature, diluted with ethyl acetate (60 ml), filtered through a silica gel pad, and washed with ethyl acetate (2×50 mL). The filtrate was concentrated in vacuo and the residue was treated with ether and hexanes to give a yellowish solid (3.2 g, 78% yield). 1H NMR (CDCl3):2.22 (s, 3H), 3.84 (s, 3H), 4.79 (s, 2H), 6.92 (m, 1H), 7.05 (m, 2H), 7.36 (m, 1H).
Reaction SMILES: [Cl:1][C:2]1[C:7]([C:8]2[C:13]([F:14])=[CH:12][C:11]([O:15][CH2:16][CH2:17][CH2:18][O:19]CC3C=CC(OC)=CC=3)=[CH:10][C:9]=2[F:29])=[C:6]([CH:30]2[CH2:36][CH2:35][CH2:34][CH2:33][CH2:32][CH2:31]2)[N:5]2[N:37]=[CH:38][N:39]=[C:4]2[N:3]=1.ClC1C(=O)C(C#N)=C(C#N)C(=O)C=1Cl>C(Cl)Cl.O>[Cl:1][C:2]1[C:7]([C:8]2[C:13]([F:14])=[CH:12][C:11]([O:15][CH2:16][CH2:17][CH2:18][OH:19])=[CH:10][C:9]=2[F:29])=[C:6]([CH:30]2[CH2:36][CH2:35][CH2:34][CH2:33][CH2:32][CH2:31]2)[N:5]2[N:37]=[CH:38][N:39]=[C:4]2[N:3]=1
Reactant: COc1ccc(COCCCOc2cc(F)c(-c3c(Cl)nc4ncnn4c3C3CCCCCC3)c(F)c2)cc1
Agent: N#CC1=C(C#N)C(=O)C(Cl)=C(Cl)C1=O
Solvent: ClCCl
Solvent: O
Product: OCCCOc1cc(F)c(-c2c(Cl)nc3ncnn3c2C2CCCCCC2)c(F)c1
Temperature: 25 °C
Reaction time: 0.33 h
Yield: 77.8 %

Procedure:
To a solution of 5-chloro-7-cycloheptyl-6-(2,6-difluoro-4-{3-[(4-methoxybenzyl)oxy]propoxy}phenyl)[1,2,4]triazolo[1,5-a]pyrimidine (56 mg, 0.1 mmol) in 4 mL of methylene chloride and 0.2 mL of water is added 2,3-dichloro-5,6-dicyano-1,4-bezoquinone (100 mg, 0.44 mmol). The mixture is stirred at room temperature for 20 minutes, then washed with saturated aqueous sodium bicarbonate solution (x2), dried over magnesium sulfate, and concentrated to a residue. The residue is chromatographed over silica gel, eluting with a gradient of 33% ethyl acetate in hexanes to 66% ethyl acetate in hexanes. Concentration provides 3-[4-(5-chloro-7-cycloheptyl[1,2,4]triazolo[1,5-a]pyrimidin-6-yl)-3,5-difluorophenoxy]propan-1-ol as a light yellow solid (34 mg). MS: m/z 437.2 (M+H).
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[C:12](=[O:13])[CH2:11][C@H:10]([C:14]([OH:16])=[O:15])[CH2:9]2)=[CH:4][CH:3]=1.S(=O)(=O)(O)O.[CH3:22]OC(OC)(C)C.O>CO>[CH3:22][O:15][C:14]([C@H:10]1[CH2:11][C:12](=[O:13])[N:8]([C:5]2[CH:4]=[CH:3][C:2]([OH:1])=[CH:7][CH:6]=2)[CH2:9]1)=[O:16]
Reactant: O=C(O)[C@H]1CC(=O)N(c2ccc(O)cc2)C1
Reactant: COC(C)(C)OC
Agent: O=S(=O)(O)O
Solvent: CO
Solvent: O
Product: COC(=O)[C@H]1CC(=O)N(c2ccc(O)cc2)C1
Yield: 86 %

Procedure:
A mixture of 26 g (117.5 mmol) of (S)-1-(4-hydroxy-phenyl)-5-oxo-pyrrolidine-3-carboxylic acid, 0.66 ml of sulfuric acid, and 100 ml of dimethoxypropane in 700 ml of methanol are heated to reflux for 3 hours. For the working-up, the reaction mixture is reduced to ⅘ of its volume, then the residue is added under stirring to a mixture of ice and water. The precipitated product is collected on a filter funnel, washed with cold water and finally dried under high vacuum to yield 23.7 g (86% of theory) of (S)-1-(4-hydroxy-phenyl)-5-oxo-pyrrolidine-3-carboxylic acid methyl ester as a white solid; MS: m/e=234 (M−H)+; optical integrity: 97.4% e.e. .
Reaction SMILES: C(N(CC)CC)C.[NH2:8][C:9]1[CH:10]=[C:11]([CH:16]=[CH:17][C:18]=1[NH:19][CH2:20][CH2:21][N:22]([CH3:24])[CH3:23])[C:12]([NH:14][CH3:15])=[O:13].[C:25](Cl)(=O)[CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][CH2:36][CH2:37][CH2:38][CH2:39][CH2:40][CH2:41][CH3:42]>C(Cl)(Cl)Cl>[CH3:24][N:22]([CH3:23])[CH2:21][CH2:20][N:19]1[C:18]2[CH:17]=[CH:16][C:11]([C:12]([NH:14][CH3:15])=[O:13])=[CH:10][C:9]=2[N:8]=[C:42]1[CH2:41][CH2:40][CH2:39][CH2:38][CH2:37][CH2:36][CH2:35][CH2:34][CH2:33][CH2:32][CH2:31][CH2:30][CH2:29][CH2:28][CH2:27][CH2:26][CH3:25]
Reactant: CNC(=O)c1ccc(NCCN(C)C)c(N)c1
Reactant: CCCCCCCCCCCCCCCCCC(=O)Cl
Solvent: ClC(Cl)Cl
Solvent: CCN(CC)CC
Product: CCCCCCCCCCCCCCCCCc1nc2cc(C(=O)NC)ccc2n1CCN(C)C
Reaction time: 2.5 h

Procedure:
Triethylamine (1.00 ml) was added to a solution containing 3-amino-4-{[2-(dimethylamino)ethyl]amino}-N-methylbenzamide (1.500 g) in chloroform (15 ml), and then stearoyl chloride (2.20 mnl) was added thereto while being cooled with ice. After being stirred for 2.5 hours, the reaction mixture was diluted with chloroform, washed with saturated sodium hydrogencarbonate aqueous solution and saturated brine successively, dried over sodium sulfate anhydride, and concentrated. Concentrated hydrochloric acid (5.3 ml) was added to a solution containing the residue (3.030 g) in ethanol (30 ml). After being stirred for 1.5 hours at 90° C., the reaction mixture was concentrated. The residue, with ethyl acetate added thereto, was washed with 1N sodium hydroxide aqueous solution and saturated brine successively, dried over sodium sulfate anhydride, and concentrated. The residue (3.737 g) was purified by silica gel column chromatography (silica gel 75 g, chloroform:methanol=50:1-30:1), thereby yielding the entitled compound (2.225 g) as pale yellow solid.
Reaction SMILES: [NH:1]([C:10]([O:12][C:13]([CH3:16])([CH3:15])[CH3:14])=[O:11])[C@H:2]([C:7]([OH:9])=O)[CH2:3][CH2:4][S:5][CH3:6].CN(C)C=O.[NH2:22][C@H:23]([C:28]([O:30][CH3:31])=[O:29])[CH2:24][CH:25]([CH3:27])[CH3:26].C1(P(N=[N+]=[N-])(C2C=CC=CC=2)=O)C=CC=CC=1>C(N(CC)CC)C>[NH:1]([C:10]([O:12][C:13]([CH3:16])([CH3:15])[CH3:14])=[O:11])[C@H:2]([C:7]([NH:22][C@H:23]([C:28]([O:30][CH3:31])=[O:29])[CH2:24][CH:25]([CH3:27])[CH3:26])=[O:9])[CH2:3][CH2:4][S:5][CH3:6]
Reactant: CSCC[C@H](NC(=O)OC(C)(C)C)C(=O)O
Reactant: COC(=O)[C@@H](N)CC(C)C
Agent: [N-]=[N+]=NP(=O)(c1ccccc1)c1ccccc1
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: COC(=O)[C@H](CC(C)C)NC(=O)[C@H](CCSC)NC(=O)OC(C)(C)C
Temperature: 0 °C
Reaction time: 3 h

Procedure:
6.225 g. (25 mole) of BOC-L-Met was dissolved in 160 ml. of degassed dimethylformamide and cooled under nitrogen to 0° C. 4.55 g. (25 mmole) of L-Leu-OMe was dissolved in 80 ml. of dimethylformamide and set aside. To the BOC-L-Met was added 5.38 ml. of diphenylphosphorylazide in 10% excess followed by 3.48 ml. of triethylamine in 10% excess, followed by the L-Leu-OMe. The reaction mixture was stirred at 0° C. for 3 hrs., then at room temperature for 16 hrs. The solution was concentrated and treated with 3:1 dimethylformamide/water and mixed bed resin, whereupon it crystallized out on the resin. The resin and crystals were filtered and the resin washed with dimethylformamide to isolate the product. The filtrate was then concentrated and recrystallized from ethyl acetate/hexane. 7.74 g. of product was obtained.
Reaction SMILES: FC(F)(F)S(O[C@H:7]([C:12]1[CH:17]=[CH:16][C:15]([Cl:18])=[C:14]([Cl:19])[CH:13]=1)[C:8]([F:11])([F:10])[F:9])(=O)=O.C([O-])([O-])=O.[K+].[K+].[CH3:28][O:29][C:30]1[CH:31]=[C:32]([CH2:38][NH2:39])[CH:33]=[CH:34][C:35]=1[O:36][CH3:37].O>C1CCCCC1>[Cl:19][C:14]1[CH:13]=[C:12]([CH:7]([NH:39][CH2:38][C:32]2[CH:33]=[CH:34][C:35]([O:36][CH3:37])=[C:30]([O:29][CH3:28])[CH:31]=2)[C:8]([F:11])([F:10])[F:9])[CH:17]=[CH:16][C:15]=1[Cl:18]
Reactant: O=S(=O)(O[C@H](c1ccc(Cl)c(Cl)c1)C(F)(F)F)C(F)(F)F
Reactant: COc1ccc(CN)cc1OC
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: C1CCCCC1
Product: COc1ccc(CNC(c2ccc(Cl)c(Cl)c2)C(F)(F)F)cc1OC
Yield: 36.1 %

Procedure:
A solution of 144 (10.9 g, 28.9 mmol), K2CO3 (5.99 g, 43.4 mmol) and (3,4-dimethoxyphenyl)methanamine (6.77 g, 40.5 mmol) in cyclohexane (200 mL) and heated to 65° C. for 24 h. Water was added and the organic layer was concentrated and the crude product was purified by SiO2 chromatography eluting with EtOAc/hexane (5 to 20% EtOAc) to afford 4.11 g (36.1%) of 1-(3,4-dichlorophenyl)-N-(3,4-dimethoxybenzyl)-2,2,2-trifluoroethanamine (146).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([NH2:9])=[CH:5][C:4]=1[C:10]([F:13])([F:12])[F:11].[Cl-].Cl[CH2:16][CH2:17][NH2+:18][CH2:19][CH2:20]Cl>C(O)CCC>[CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([N:9]2[CH2:20][CH2:19][NH:18][CH2:17][CH2:16]2)=[CH:5][C:4]=1[C:10]([F:11])([F:12])[F:13]
Reactant: ClCC[NH2+]CCCl
Reactant: COc1ccc(N)cc1C(F)(F)F
Agent: [Cl-]
Solvent: CCCCO
Product: COc1ccc(N2CCNCC2)cc1C(F)(F)F
Temperature: 25 °C

Procedure:
A mixture of 4-methoxy-3-trifluoromethylphenylamine (12 g; 0.0627 mol) and bis(2-chloroethyl) ammonium chloride (11.2 g; 0.0627 mol) in n-butanol (120 ml) was refluxed for 10 hours. The reaction mixture was cooled at room temperature and the crude title compound precipitated as hydrochloride salt overnight. The solid was collected and crystallized from acetone. 7 g; m.p. 244-245° C.
Reaction SMILES: [CH:1]1([N:6]2[C:14](=[O:15])[NH:13][C:12]3[C:7]2=[N:8][C:9]([C:21]2[CH:26]=[CH:25][CH:24]=[C:23]([OH:27])[CH:22]=2)=[N:10][C:11]=3[C:16]([O:18]CC)=O)[CH2:5][CH2:4][CH2:3][CH2:2]1.[NH2:28]C1C(C(OCC)=O)=NC(C2C=CC=C(O)C=2)=NC=1NC1CCCC1.C(N1C=CN=C1)(N1C=CN=C1)=O>C(Cl)Cl>[CH:1]1([N:6]2[C:14](=[O:15])[NH:13][C:12]3[C:7]2=[N:8][C:9]([C:21]2[CH:26]=[CH:25][CH:24]=[C:23]([OH:27])[CH:22]=2)=[N:10][C:11]=3[C:16]([NH2:28])=[O:18])[CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: CCOC(=O)c1nc(-c2cccc(O)c2)nc(NC2CCCC2)c1N
Reactant: CCOC(=O)c1nc(-c2cccc(O)c2)nc2c1[nH]c(=O)n2C1CCCC1
Agent: O=C(n1ccnc1)n1ccnc1
Solvent: ClCCl
Product: NC(=O)c1nc(-c2cccc(O)c2)nc2c1[nH]c(=O)n2C1CCCC1
Temperature: 25 °C
Reaction time: 120 h
Yield: 60 %

Procedure:
Ethyl 9-cyclopentyl-2-(3-hydroxyphenyl)-8-oxo-8,9-dihydro-7H-purine-6-carboxylate. Ethyl 5-amino-6-(cyclopentylamino)-2-(3-hydroxyphenyl)pyrimidine-4-carboxylate (76.3 mg, 0.223 mmol) was dissolved in methylene chloride (5 ml) and 1,1′-carbonyldiimidazole (361.6 mg, 2.23 mmol) was added. The reaction was refluxed for 1H and then stirred at room temperature for 5 days. The solvent was removed under reduced pressure and the crude material was purified by column chromatography (50% ethyl acetate in hexanes) to provide the title compound (49.7 mg, 0.135 mmol, 60% yield). MS (ESI) m/z 369.4 [M+1]+.
Reaction SMILES: [CH3:1][C:2](OCC1C2C(=CC=CC=2)C(COC(C)=O)=C2C=1C=CC=C2)=[O:3].[Cl:25][C:26]1[N:30]2[N:31]=[C:32]([NH2:35])[CH:33]=[CH:34][C:29]2=[N:28][N:27]=1.C(OC(=O)C)(=O)C>N1C=CC=CC=1>[Cl:25][C:26]1[N:30]2[N:31]=[C:32]([NH:35][C:2](=[O:3])[CH3:1])[CH:33]=[CH:34][C:29]2=[N:28][N:27]=1
Reactant: CC(=O)OCc1c2ccccc2c(COC(C)=O)c2ccccc12
Reactant: Nc1ccc2nnc(Cl)n2n1
Solvent: CC(=O)OC(C)=O
Solvent: c1ccncc1
Product: CC(=O)Nc1ccc2nnc(Cl)n2n1
Reaction time: 6 h

Procedure:
0.11 cm3 of acetic anhyhdride is added to a mixture of 202 mg of 3-chloro[1,2,4]triazolo[4,3-b]pyridazin-6-amine in 5 cm3 of pyridine at 0° C. The temperature is allowed to rise to 20° C. over 6 h, then 0.05 cm3 of acetic anhydride is again added and stirring is maintained for 24 h. The precipitate formed is spin-filter-dried and then washed with ethyl ether and pentane. This solid is purified by chromatography on Biotage Quad 12/25 (KP-SIL, 60 A; 32-63 μM), elution being carried out with a gradient of dichloromethane/methanol of 100/0 to 90/10. 41 mg of N-(3-chloro[1,2,4]triazolo[4,3-b]pyridazin-6-yl)acetamide are thus obtained in the form of a white powder, the characteristics of which are as follows:
Reaction SMILES: F[C:2]1[CH:3]=[C:4]([Cl:10])[CH:5]=[C:6]([CH:9]=1)[C:7]#[N:8].[CH3:11][N:12]1[CH2:17][CH2:16][NH:15][CH2:14][CH2:13]1.C(OCC)C>CS(C)=O.Cl>[Cl:10][C:4]1[CH:5]=[C:6]([CH:9]=[C:2]([N:15]2[CH2:16][CH2:17][N:12]([CH3:11])[CH2:13][CH2:14]2)[CH:3]=1)[C:7]#[N:8]
Reactant: N#Cc1cc(F)cc(Cl)c1
Reactant: CN1CCNCC1
Agent: Cl
Solvent: CS(C)=O
Solvent: CCOCC
Product: CN1CCN(c2cc(Cl)cc(C#N)c2)CC1
Temperature: 80 °C
Yield: 92.8 %

Procedure:
5-Fluoro-3-chloro-benzonitrile (Ig, 6.4 mmol) was dissolved in DMSO (20 ml) followed by addition OfK2CO3 (1.3 g, 9.6 mmol) and 1-methyl piperazine (1.4 ml, 12.8 mmol). The reaction mixture was heated at 80° C. for 20 hours. Diethyl ether was added to the crude material (10 ml) then acidified with IN HCl. A precipitate was filtered off from the crude reaction mixture to give 3-chloro-5-(4-methyl-ρiρerazin-1-yl)-benzonitrile (1.4 g, 93% yield) as a white solid (LC/MS: Rt 1.83 [M+H]+ 236, acidic method).
Reaction SMILES: [CH3:1][O:2][C:3]1[C:4]([NH:9][CH2:10][CH:11]2[CH2:16][CH2:15][NH:14][CH2:13][CH2:12]2)=[N:5][CH:6]=[CH:7][N:8]=1.[CH3:17][C:18]1[CH:35]=[CH:34][C:21]([CH2:22][O:23][C:24](=O)[O:25]N2C(=O)CCC2=O)=[CH:20][CH:19]=1>CN(C=O)C.C(OCC)(=O)C>[CH3:17][C:18]1[CH:35]=[CH:34][C:21]([CH2:22][O:23][C:24]([N:14]2[CH2:15][CH2:16][CH:11]([CH2:10][NH:9][C:4]3[C:3]([O:2][CH3:1])=[N:8][CH:7]=[CH:6][N:5]=3)[CH2:12][CH2:13]2)=[O:25])=[CH:20][CH:19]=1
Reactant: COc1nccnc1NCC1CCNCC1
Reactant: Cc1ccc(COC(=O)ON2C(=O)CCC2=O)cc1
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: COc1nccnc1NCC1CCN(C(=O)OCc2ccc(C)cc2)CC1
Temperature: 25 °C
Reaction time: 18 h

Procedure:
A mixture of 4-[(3-methoxy-pyrazin-2-ylamino)-methyl]-piperidine (EXAMPLE 127, STEP 3) (0.093 g, 0.00042 mol) and N-(4-methylbenzyloxycarbonyloxy)succinimide (INTERMEDIATE 1A)(118 mg) in DMF (2 mL) was stirred at rt for 18 h. The reaction was diluted with ethyl acetate (30 mL), washed with 10% aqueous sodium bicarbonate (20 mL) followed by brine (10 mL), concentrated in vacuo and chromatographed on silica using a gradient elution of 5–15% acetone/dichloromethane. Concentration in vacuo followed by crystallization from ether/hexane gave the title compound. M.S.(M+1): 371.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:23]=[CH:22][C:6]([CH2:7][NH:8][CH2:9][CH:10]([Se:15][C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)[C:11]([O:13]C)=O)=[CH:5][CH:4]=1.[Br:24][C:25]1[CH:30]=[CH:29][CH:28]=[C:27]([N:31]=[C:32]=[O:33])[C:26]=1[CH3:34].C([O-])([O-])=O.[K+].[K+]>CN(C=O)C>[Br:24][C:25]1[C:26]([CH3:34])=[C:27]([N:31]2[C:11](=[O:13])[CH:10]([Se:15][C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=3)[CH2:9][N:8]([CH2:7][C:6]3[CH:5]=[CH:4][C:3]([O:2][CH3:1])=[CH:23][CH:22]=3)[C:32]2=[O:33])[CH:28]=[CH:29][CH:30]=1
Reactant: COC(=O)C(CNCc1ccc(OC)cc1)[Se]c1ccccc1
Reactant: Cc1c(Br)cccc1N=C=O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: COc1ccc(CN2CC([Se]c3ccccc3)C(=O)N(c3cccc(Br)c3C)C2=O)cc1
Temperature: 65 °C
Yield: 100 %

Procedure:
A mixture of methyl 3-((4-methoxybenzyl)amino)-2-(phenylselanyl)propanoate (3.68 g, 9.73 mmol), 1-bromo-3-isocyanato-2-methylbenzene (2.27 g, 10.7 mmol), and K2CO3 (0.672 g, 4.86 mmol) in DMF (49 mL) was heated at 65° C. for 5 h. The cooled mixture was partitioned between water and EtOAc. And the organic phase was washed with brine, dried and concentrated to provide 3-(3-bromo-2-methylphenyl)-1-(4-methoxybenzyl)-5-(phenylselanyl)dihydropyrimidine-2,4(1H,3H)-dione as a light brown solid (5.43 g), used without further purification. Mass spectrum m/z 557, 559, 561 (M+H)+.
Reaction SMILES: [CH2:1]([C:3]1[N:4]=[C:5]([CH:19]2[CH2:24][CH2:23][NH:22][CH2:21][CH2:20]2)[N:6]2[C:11]=1[C:10](=[O:12])[NH:9][C:8]([C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1)=[N:7]2)[CH3:2].[CH:25]1([C:30](Cl)=[O:31])[CH2:29][CH2:28][CH2:27][CH2:26]1>>[CH:25]1([C:30]([N:22]2[CH2:23][CH2:24][CH:19]([C:5]3[N:6]4[C:11]([C:10](=[O:12])[NH:9][C:8]([C:13]5[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=5)=[N:7]4)=[C:3]([CH2:1][CH3:2])[N:4]=3)[CH2:20][CH2:21]2)=[O:31])[CH2:29][CH2:28][CH2:27][CH2:26]1
Reactant: CCc1nc(C2CCNCC2)n2nc(-c3ccccc3)[nH]c(=O)c12
Reactant: O=C(Cl)C1CCCC1
Product: CCc1nc(C2CCN(C(=O)C3CCCC3)CC2)n2nc(-c3ccccc3)[nH]c(=O)c12

Procedure:
In analogy to the procedure for Example 103 Step (b), 30 mg (0.09 mmol) 5-ethyl-2-phenyl-7-(4-piperidinyl)imidazo[5,1-f][1,2,4]triazin-4(3H)-one, 14 mg (0.10 mmol) cyclopentanecarbonyl chloride are stirred at room temperature overnight, proportionate amounts of the solvents are used.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:12]2[O:16][N:15]=[C:14]([C:17]3[C:27]4[CH2:26][CH2:25][NH:24][CH2:23][CH2:22][C:21]=4[CH:20]=[CH:19][CH:18]=3)[N:13]=2)[CH:5]=[CH:6][C:7]=1[O:8][CH:9]([CH3:11])[CH3:10].C(=O)([O-])[O-].[K+].[K+].Br[CH2:35][CH2:36][C:37]([O:39][C:40]([CH3:43])([CH3:42])[CH3:41])=[O:38]>C(Cl)Cl>[Cl:1][C:2]1[CH:3]=[C:4]([C:12]2[O:16][N:15]=[C:14]([C:17]3[C:27]4[CH2:26][CH2:25][N:24]([CH2:35][CH2:36][C:37]([O:39][C:40]([CH3:43])([CH3:42])[CH3:41])=[O:38])[CH2:23][CH2:22][C:21]=4[CH:20]=[CH:19][CH:18]=3)[N:13]=2)[CH:5]=[CH:6][C:7]=1[O:8][CH:9]([CH3:10])[CH3:11]
Reactant: CC(C)(C)OC(=O)CCBr
Reactant: CC(C)Oc1ccc(-c2nc(-c3cccc4c3CCNCC4)no2)cc1Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: ClCCl
Product: CC(C)Oc1ccc(-c2nc(-c3cccc4c3CCN(CCC(=O)OC(C)(C)C)CC4)no2)cc1Cl
Temperature: 100 °C
Yield: 25.4 %

Procedure:
In a 5 ml microwave reaction vessel was added 6-(5-{3-chloro-4-[(1-methyl ethyl)oxy]phenyl}-1,2,4-oxadiazol-3-yl)-2,3,4,5-tetrahydro-1H-3-benzazepine (Free base of Example 8, obtained by standard methods e.g. partitioning between organic and basic aqueous solvents and collecting organic solvent) (70 mg) in DMF (3 ml) to give a brown solution. Then potassium carbonate (101 mg) was added followed by 1,1-dimethylethyl 3-bromopropanoate (38.1 mg, 0.182 mmol). The reaction mixture was heated at 100° C. for 10 minutes. The cooled reaction mixture was diluted with DCM (5 ml) and purified by SCX (washing with methanol and eluting the crude amino ester with methanolic ammonia). Purification by MDAP yielded the amino ester, 1,1-dimethylethyl 3-[6-(5-{3-chloro-4-[(1-methylethyl)oxy]phenyl}-1,2,4-oxadiazol-3-yl)-1,2,4,5-tetrahydro-3H-3-benzazepin-3-yl]propanoate (25 mg, 0.046 mmol, 25.4% yield) isolated as a light yellow oil. MS (ES) C28H3435ClN3O4 requires 511; found 512 [M+H]+.
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[CH:7]=[N:8][NH:9][CH:10]=1)=[O:5])[CH3:2].[H-].[Na+].[CH2:13](I)[CH:14]([CH3:16])[CH3:15].O>CN(C=O)C>[CH2:1]([O:3][C:4]([C:6]1[CH:7]=[N:8][N:9]([CH2:13][CH:14]([CH3:16])[CH3:15])[CH:10]=1)=[O:5])[CH3:2]
Reactant: CCOC(=O)c1cn[nH]c1
Reactant: CC(C)CI
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: CCOC(=O)c1cnn(CC(C)C)c1
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
1H-Pyrazole-4-carboxylic acid ethyl ester (5.0 g) was dissolved in DMF (50 mL), 60% sodium hydride (1.57 g) was added, and the mixture was stirred at 0° C. for 30 min. Then, isobutyl iodide (4.7 mL) was added, and the mixture was stirred for 14 hr. Water was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer was washed with water, dried over magnesium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel chromatography (elution solvent; hexane:ethyl acetate=8:2) to give 1-(2-methylpropyl)-1H-pyrazole-4-carboxylic acid ethyl ester (6.0 g) as an oil. The obtained compound was subjected to reactions in the same manner as in Reference Examples 17 to 18 to give the title compound.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[C:12]([CH2:13][O:14][C:15]3[CH:23]=[CH:22][C:18]([C:19]([OH:21])=O)=[CH:17][N:16]=3)=[C:11]([CH3:24])[N:10]=[N:9]2)=[CH:4][CH:3]=1.[NH2:25][N:26]1[CH2:31][CH2:30][O:29][CH2:28][CH2:27]1>>[F:1][C:2]1[CH:3]=[CH:4][C:5]([N:8]2[C:12]([CH2:13][O:14][C:15]3[CH:23]=[CH:22][C:18]([C:19]([NH:25][N:26]4[CH2:31][CH2:30][O:29][CH2:28][CH2:27]4)=[O:21])=[CH:17][N:16]=3)=[C:11]([CH3:24])[N:10]=[N:9]2)=[CH:6][CH:7]=1
Reactant: Cc1nnn(-c2ccc(F)cc2)c1COc1ccc(C(=O)O)cn1
Reactant: NN1CCOCC1
Product: Cc1nnn(-c2ccc(F)cc2)c1COc1ccc(C(=O)NN2CCOCC2)cn1
Yield: 78 %

Procedure:
As described for example 61b, 6-[3-(4-fluoro-phenyl)-5-methyl-3H-[1,2,3]triazol-4-ylmethoxy]-nicotinic acid (83 mg, 0.25 mmol) was converted, using 4-aminomorpholine instead of 4-aminotetrahydropyran, to the title compound (81 mg, 78%) which was obtained as a white solid. MS: m/e=413.3 [M+H]+.
Reaction SMILES: [CH3:1][C:2]1[C:11]2[CH:12]=[C:13]([C:14]([O:16][CH2:17][CH3:18])=[O:15])[N:9]3[C:10]=2[C:5]([C:6](=[O:19])[CH2:7][CH2:8]3)=[CH:4][CH:3]=1.O1CCCC1.[BH4-].[Na+]>C(O)C>[OH:19][CH:6]1[C:5]2[C:10]3=[C:11]([CH:12]=[C:13]([C:14]([O:16][CH2:17][CH3:18])=[O:15])[N:9]3[CH2:8][CH2:7]1)[C:2]([CH3:1])=[CH:3][CH:4]=2
Reactant: CCOC(=O)c1cc2c(C)ccc3c2n1CCC3=O
Agent: [BH4-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CCO
Product: CCOC(=O)c1cc2c(C)ccc3c2n1CCC3O
Temperature: 0 °C
Reaction time: 1 h
Yield: 79.1 %

Procedure:
Ethyl 5,6-dihydro-9-methyl-6-oxo-4H-pyrrolo [3,2,1-ij]quinoline-2-carboxylate (3.00 g, 11.7 mmol) was added to a mixture of tetrahydrofuran (20 ml) and ethanol (80 ml), and the reaction mixture was cooled to 0° C. Then, sodium borohydride (0.44 g, 11.7 mmol) was added and the resulting mixture was stirred at 0° C. for 1 hour. The reaction mixture was concentrated under reduced pressure, and ethyl acetate and then a 5% aqueous sodium hydroxide solution were added to the residue. After being separated, the aqueous layer was further extracted twice with ethyl acetate, and the combined organic layer was washed with a 5% aqueous sodium chloride solution and dried over anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure and the resulting residue was purified by a silica gel column chromatography (eluent: ethyl acetate/n-hexane= 1/9) to obtain 2.40 g of ethyl 5,6-dihydro-6-hydroxy-9-methyl-4H-pyrrolo [3,2,1-ij]-quinoline-2-carboxylate.
Reaction SMILES: O=P(Cl)(Cl)Cl.[O:6]1[C:10]2[CH:11]=[CH:12][C:13]([C:15]3([C:18]([NH:20][C:21]4[CH:22]=[C:23]5[C:27](=[CH:28][CH:29]=4)[NH:26][C:25]([C:30]([CH3:33])([CH3:32])[CH3:31])=[CH:24]5)=[O:19])[CH2:17][CH2:16]3)=[CH:14][C:9]=2[O:8][CH2:7]1.CN([CH:37]=[O:38])C>>[O:6]1[C:10]2[CH:11]=[CH:12][C:13]([C:15]3([C:18]([NH:20][C:21]4[CH:22]=[C:23]5[C:27](=[CH:28][CH:29]=4)[NH:26][C:25]([C:30]([CH3:33])([CH3:32])[CH3:31])=[C:24]5[CH:37]=[O:38])=[O:19])[CH2:17][CH2:16]3)=[CH:14][C:9]=2[O:8][CH2:7]1
Reactant: CC(C)(C)c1cc2cc(NC(=O)C3(c4ccc5c(c4)OCO5)CC3)ccc2[nH]1
Reactant: CN(C)C=O
Solvent: O=P(Cl)(Cl)Cl
Product: CC(C)(C)c1[nH]c2ccc(NC(=O)C3(c4ccc5c(c4)OCO5)CC3)cc2c1C=O
Temperature: 0 °C
Reaction time: 1 h
Yield: 61 %

Procedure:
POCl3 (12 g, 80 mmol) was added dropwise to DMF (40 mL) held at −20° C. After the addition was complete, the reaction mixture was allowed to warm to 0° C. and was stirred for 1 h. 1-(Benzo[d][1,3]dioxol-5-yl)-N-(2-tert-butyl-1H-indol-5-yl)cyclopropanecarbox amide (3.0 g, 8.0 mmol) was added and the mixture was warmed to 25° C. After stirring for 30 minutes the reaction mixture was poured over ice and stirred for 2 h. The mixture was then heated at 100° C. for 30 min. The mixture was cooled and the solid precipitate was collected and washed with water. The solid was then dissolved in 200 mL dichloromethane and washed with 200 mL of a saturated aq. NaHCO3. The organics were dried over Na2SO4 and evaporated to yield 1-(benzo[d][1,3]dioxol-5-yl)-N-(2-tert-butyl-3-formyl-1H-indol-5-yl)cyclopropane-carboxamide (2.0 g, 61%). ESI-MS m/z calc. 404.5, found 405.5 (M+1)+; retention time 3.30 minutes. 1H NMR (400 MHz, DMSO-d6) δ 11.48 (s, 1H), 10.39 (5, 1H), 8.72 (s, 1H), 8.21 (s, 1H), 7.35-7.31 (m, 2H), 7.04-7.03 (m, 1H), 6.97-6.90 (m, 2H), 6.03 (s, 2H), 1.53 (s, 9H), 1.42-1.39 (m, 2H), 1.05-1.03 (m, 2H).