Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br[C:2]1[CH:3]=[CH:4][C:5]([Cl:22])=[C:6]([CH:21]=1)[C:7]([NH:9][CH2:10][C:11]12[CH2:20][CH:15]3[CH2:16][CH:17]([CH2:19][CH:13]([CH2:14]3)[CH2:12]1)[CH2:18]2)=[O:8].[CH2:23](C([Sn])=C(CCCC)CCCC)[CH2:24]CC.[F-].[Cs+]>C1(C)C=CC=CC=1.CC(C)=O.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[Cl:22][C:5]1[CH:4]=[CH:3][C:2]([CH:23]=[CH2:24])=[CH:21][C:6]=1[C:7]([NH:9][CH2:10][C:11]12[CH2:20][CH:15]3[CH2:16][CH:17]([CH2:19][CH:13]([CH2:14]3)[CH2:12]1)[CH2:18]2)=[O:8]
Reactant: CCCCC([Sn])=C(CCCC)CCCC
Reactant: O=C(NCC12CC3CC(CC(C3)C1)C2)c1cc(Br)ccc1Cl
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: [Cs+]
Agent: [F-]
Solvent: CC(C)=O
Solvent: Cc1ccccc1
Product: C=Cc1ccc(Cl)c(C(=O)NCC23CC4CC(CC(C4)C2)C3)c1
Temperature: 25 °C

Procedure:
A solution of 5-bromo-2-chloro-N-(tricyclo[3.3.1.13,7]dec-1-ylmethyl)benzamide (prepared as described in WO 00/61569) (1.0 g), tetrakis(triphenylphosphine)palladium(0) (96 mg) and tributylvinyltin (1.15 mL) in toluene (15 mL) was heated at reflux for 3 hours, then cooled to room temperature, diluted with acetone (30 mL) and treated with cesium fluoride (10% aq, 10 mL) at room temperature for 2 hours. The resulting mixture was filtered through celite with further washing with toluene and concentrated. Water was added and the mixture was extracted with ethyl acetate. The combined organic phases were washed with water, dried over anhydrous magnesium sulfate and concentrated. The resulting oil was purified by column chromatography (ethyl acetate:isohexane 100:1 to 80:20) to give the sub-titled compound as a white solid (0.87 g).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:13]=[C:12]([C:14]([F:17])([F:16])[F:15])[N:11]3[N:18]=[CH:19][C:20]([C:21](O)=[O:22])=[C:10]3[N:9]=2)=[CH:4][C:3]=1[CH3:24].[NH2:25][C:26]1[N:31]=[CH:30][C:29]([C:32]([NH:34]O)=[NH:33])=[CH:28][N:27]=1>>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:13]=[C:12]([C:14]([F:17])([F:15])[F:16])[N:11]3[N:18]=[CH:19][C:20]([C:21]4[O:22][N:34]=[C:32]([C:29]5[CH:28]=[N:27][C:26]([NH2:25])=[N:31][CH:30]=5)[N:33]=4)=[C:10]3[N:9]=2)=[CH:4][C:3]=1[CH3:24]
Reactant: Cc1cc(-c2cc(C(F)(F)F)n3ncc(C(=O)O)c3n2)ccc1Cl
Reactant: N=C(NO)c1cnc(N)nc1
Product: Cc1cc(-c2cc(C(F)(F)F)n3ncc(-c4nc(-c5cnc(N)nc5)no4)c3n2)ccc1Cl

Procedure:
The title compound was prepared from 5-(4-chloro-3-methyl-phenyl)-7-trifluoromethyl-pyrazolo[1,5-a]pyrimidine-3-carboxylic acid (example C.6) (178 mg, 0.5 mmol) and 2-amino-N-hydroxy-pyrimidine-5-carboxamidine (example B.5) (115 mg, 0.75 mmol) according to general procedure II. Obtained after flash chromatography on silica gel (ethyl acetate/heptane) and further purification by crystallization (dichloromethane/hexane) as a yellow solid (54 mg, 23%). MS (EI) 472.1 [(M)+]; mp 272° C.
Reaction SMILES: [C:1]1([NH:7][CH2:8][CH2:9][OH:10])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[O:11]1[C:15]([C:16]2[CH:21]=[CH:20][C:19]([NH:22][C:23]3[N:24]=[C:25](OS(C(F)(F)F)(=O)=O)[C:26]4[CH2:32][N:31]([C:33]([O:35][C:36]([CH3:39])([CH3:38])[CH3:37])=[O:34])[CH2:30][CH2:29][C:27]=4[N:28]=3)=[CH:18][CH:17]=2)=[CH:14][N:13]=[CH:12]1.O>CS(C)=O>[OH:10][CH2:9][CH2:8][N:7]([C:1]1[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1)[C:25]1[C:26]2[CH2:32][N:31]([C:33]([O:35][C:36]([CH3:39])([CH3:38])[CH3:37])=[O:34])[CH2:30][CH2:29][C:27]=2[N:28]=[C:23]([NH:22][C:19]2[CH:18]=[CH:17][C:16]([C:15]3[O:11][CH:12]=[N:13][CH:14]=3)=[CH:21][CH:20]=2)[N:24]=1
Reactant: CC(C)(C)OC(=O)N1CCc2nc(Nc3ccc(-c4cnco4)cc3)nc(OS(=O)(=O)C(F)(F)F)c2C1
Reactant: OCCNc1ccccc1
Solvent: CS(C)=O
Solvent: O
Product: CC(C)(C)OC(=O)N1CCc2nc(Nc3ccc(-c4cnco4)cc3)nc(N(CCO)c3ccccc3)c2C1
Temperature: 70 °C
Yield: 76.7 %

Procedure:
2-(Phenylamino)ethanol (0.051 g, 0.37 mmol) was added to tert-butyl 2-(4-(oxazol-5-yl)phenylamino)-4-(trifluoromethylsulfonyloxy)-7,8-dihydropyrido[4,3-d]pyrimidine-6(5H)-carboxylate (0.2 g, 0.37 mmol, Example 1b) in DMSO (3 mL). The reaction mixture was heated in a microwave reactor at 70° C. for 3 h. Water (1 mL) was added to the solution and the precipitate was washed with water and filtered to give tert-butyl 4-((2-hydroxyethyl)(phenyl)amino)-2-(4-(oxazol-5-yl)phenylamino)-7,8-dihydropyrido[4,3-d]pyrimidine-6(5H)-carboxylate (150 mg, 77%). No further purification. MS (ESI+)/(ESI−) m/z 529/527
Reaction SMILES: [N:1]1[CH:6]=[CH:5][C:4]([C:7]2[C:8]3[N:9]([CH:16]=[C:17]([OH:19])[CH:18]=3)[C:10]3[C:15]=2[CH2:14][CH2:13][CH2:12][CH:11]=3)=[CH:3][CH:2]=1.[CH2:20]([O:22][C:23](=[O:28])[C:24](Br)([CH3:26])[CH3:25])[CH3:21]>>[CH2:20]([O:22][C:23](=[O:28])[C:24]([O:19][C:17]1[CH:18]=[C:8]2[C:7]([C:4]3[CH:5]=[CH:6][N:1]=[CH:2][CH:3]=3)=[C:15]3[C:10](=[CH:11][CH2:12][CH2:13][CH2:14]3)[N:9]2[CH:16]=1)([CH3:26])[CH3:25])[CH3:21]
Reactant: Oc1cc2c(-c3ccncc3)c3c(n2c1)=CCCC3
Reactant: CCOC(=O)C(C)(C)Br
Product: CCOC(=O)C(C)(C)Oc1cc2c(-c3ccncc3)c3c(n2c1)=CCCC3

Procedure:
The above compound was prepared from 7,8-dihydro-9-(4-pyridyl)-6H-pyrrolo[1,2-a]-indole-2-ol and 2-bromo-2-methyl-propanoic acid ethylester using a procedure analogous to that of Example 10.
Reaction SMILES: [OH:1][CH:2]1[CH:7]([C:8]2[CH:13]=[CH:12][C:11]([O:14][CH2:15][CH2:16][CH2:17][O:18][CH2:19][C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][C:21]=3[O:26][CH3:27])=[CH:10][CH:9]=2)[CH2:6][CH2:5][N:4]([C:28]([O:30][C:31]([CH3:34])([CH3:33])[CH3:32])=[O:29])[CH2:3]1.[CH2:35]([C@@H:37]1[O:39][CH2:38]1)Cl>>[CH3:27][O:26][C:21]1[CH:22]=[CH:23][CH:24]=[CH:25][C:20]=1[CH2:19][O:18][CH2:17][CH2:16][CH2:15][O:14][C:11]1[CH:12]=[CH:13][C:8]([CH:7]2[CH2:6][CH2:5][N:4]([C:28]([O:30][C:31]([CH3:34])([CH3:33])[CH3:32])=[O:29])[CH2:3][CH:2]2[O:1][CH2:35][CH:37]2[CH2:38][O:39]2)=[CH:9][CH:10]=1
Reactant: ClC[C@H]1CO1
Reactant: COc1ccccc1COCCCOc1ccc(C2CCN(C(=O)OC(C)(C)C)CC2O)cc1
Product: COc1ccccc1COCCCOc1ccc(C2CCN(C(=O)OC(C)(C)C)CC2OCC2CO2)cc1

Procedure:
Analogously to Method D, 5.60 g of tert-butyl 3-hydroxy-4-{4-[3-(2-methoxybenzyloxy)-propoxy]phenyl}piperidine-1-carboxylate and 2.05 ml of (R)-(−)-epichlorohydrin are reacted. The title compound is obtained as a colourless oil. Rf=0.12 (1:3 EtOAc-heptane); Rt=5.55.
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[C:7]([F:12])[CH:8]=[CH:9][CH:10]=2)[N:5]=[CH:4][N:3]=1.[F:13][C:14]([F:32])([F:31])[C:15]1[CH:16]=[CH:17][C:18]([O:21][C:22]2[CH:27]=[CH:26][C:25]([CH2:28][CH2:29][NH2:30])=[CH:24][CH:23]=2)=[N:19][CH:20]=1.C(N(CC)CC)C>C(O)C>[F:12][C:7]1[CH:8]=[CH:9][CH:10]=[C:11]2[C:6]=1[N:5]=[CH:4][N:3]=[C:2]2[NH:30][CH2:29][CH2:28][C:25]1[CH:24]=[CH:23][C:22]([O:21][C:18]2[CH:17]=[CH:16][C:15]([C:14]([F:32])([F:13])[F:31])=[CH:20][N:19]=2)=[CH:27][CH:26]=1
Reactant: NCCc1ccc(Oc2ccc(C(F)(F)F)cn2)cc1
Reactant: Fc1cccc2c(Cl)ncnc12
Solvent: CCN(CC)CC
Solvent: CCO
Product: Fc1cccc2c(NCCc3ccc(Oc4ccc(C(F)(F)F)cn4)cc3)ncnc12
Yield: 58.4 %

Procedure:
A mixture of 4-chloro-8-fluoroquinazoline (1.82 g, 0.01 mol), 2-(4-(5-trifluoromethyl-2-pyridinyloxy)-phenyl)ethylamine (2.82 g, 0.01 mol), triethylamine (1.1 g, 0.011 mol) and ethanol (50 mL) was heated under reflux for three hours and allowed to cool. Solvent was evaporated under reduced pressure, and the residue dissolved in dichloromethane. This was washed with 0.5M sodium hydroxide solution and water, and dried over anhydrous sodium sulphate. Evaporation of the solvent under reduced pressure and recrystallization from ethyl acetate:hexane gave 2.5 g of product. MP 152° C.
Reaction SMILES: Cl[O-:2].[Li+].[C:4]([C:7]1[S:8][C:9]([O:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH3:30])=[CH:10][CH:11]=1)(=[O:6])C.[OH-].[K+]>>[CH2:13]([O:12][C:9]1[S:8][C:7]([C:4]([OH:6])=[O:2])=[CH:11][CH:10]=1)[CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH3:30]
Reactant: CCCCCCCCCCCCCCCCCCOc1ccc(C(C)=O)s1
Reactant: [O-]Cl
Agent: [K+]
Agent: [Li+]
Agent: [OH-]
Product: CCCCCCCCCCCCCCCCCCOc1ccc(C(=O)O)s1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
When in Example 3, 1-bromooctadecane is substituted for 1-bromohexadecane, 2-octadecyloxythiophene is obtained. A mixture of 35.3 g (0.1 mole) of 2-octadecyloxythiophene and 12.3 g (0.12 mole) of acetic anhydride is cooled in an ice bath. While rapidly stirring this mixture, 1.4 g of boron trifluoride etherate is added, and the mixture is heated to 100° C with stirring for 1 hour after which it is cooled to room temperature. Ice water is added, and the mixture is extracted with chloroform. The chloroform solution is evaporated to dryness under reduce pressure to give 2-acetyl-5-octadecyloxythiophene. In 500 ml of 10% aqueous potassium hydroxide 2-acetyl-5-octadecyloxythiophene is combined with 35.0 g (0.6 mole) of lithium hypochlorite. The mixture is stirred vigorously on a steam bath overnight, then allowed to cool to room temperature and extracted with ether. The aqueous extract is acidified with hydrochloric acid to precipitate 5-octadecyloxy-2-thiophenecarboxylic acid
Reaction SMILES: [OH:1][CH2:2][C@@H:3]1[CH2:8][N:7]([C:9]([C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)[C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)[CH2:6][C@H:5]([N:28]2[CH:33]=[CH:32][C:31]([NH:34][C:35](=[O:42])[C:36]3[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=3)=[N:30][C:29]2=[O:43])[O:4]1.[C:44]1(=[O:50])[O:49][C:47](=[O:48])[CH2:46][CH2:45]1.CO>CN(C)C1C=CN=CC=1.ClCCl>[C:35]([NH:34][C:31]1[CH:32]=[CH:33][N:28]([C@H:5]2[CH2:6][N:7]([C:9]([C:22]3[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=3)([C:10]3[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=3)[C:16]3[CH:17]=[CH:18][CH:19]=[CH:20][CH:21]=3)[CH2:8][C@@H:3]([CH2:2][O:1][C:44](=[O:50])[CH2:45][CH2:46][C:47]([OH:49])=[O:48])[O:4]2)[C:29](=[O:43])[N:30]=1)(=[O:42])[C:36]1[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=1
Reactant: O=C(Nc1ccn([C@H]2CN(C(c3ccccc3)(c3ccccc3)c3ccccc3)C[C@@H](CO)O2)c(=O)n1)c1ccccc1
Reactant: O=C1CCC(=O)O1
Agent: CN(C)c1ccncc1
Solvent: ClCCl
Solvent: CO
Product: O=C(O)CCC(=O)OC[C@@H]1CN(C(c2ccccc2)(c2ccccc2)c2ccccc2)C[C@H](n2ccc(NC(=O)c3ccccc3)nc2=O)O1
Temperature: 25 °C
Reaction time: 3 h
Yield: 100.2 %

Procedure:
Under argon atmosphere, 22.0 g of N-{1-[(2R,6S)-6-(hydroxymethyl)-4-tritylmorpholin-2-yl]-2-oxo-1,2-dihydropyrimidin-4-yl}benzamide and 7.04 g of 4-dimethylaminopyridine (4-DMAP) were suspended in 269 mL of dichloromethane, and 5.76 g of succinic anhydride was added to the suspension, followed by stirring at room temperature for 3 hours. To the reaction solution was added 40 mL of methanol, and the mixture was concentrated under reduced pressure. The residue was extracted using ethyl acetate and 0.5M aqueous potassium dihydrogenphosphate solution. The resulting organic layer was washed sequentially with 0.5M aqueous potassium dihydrogenphosphate solution, water and brine in the order mentioned. The resulting organic layer was dried over sodium sulfate and concentrated under reduced pressure to give 25.9 g of the product.
Reaction SMILES: [F:1][C:2]1[CH:3]=[CH:4][C:5]2[N:9]=[C:8]([C@@H:10]([NH:14][C:15]3[N:23]=[CH:22][N:21]=[C:20]4[C:16]=3[N:17]=[CH:18][N:19]4C3CCCCO3)[CH2:11][O:12][CH3:13])[N:7]([C:30]3[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=3)[C:6]=2[C:36]=1[F:37].Cl>CO.O1CCOCC1>[F:1][C:2]1[CH:3]=[CH:4][C:5]2[N:9]=[C:8]([CH:10]([NH:14][C:15]3[N:23]=[CH:22][N:21]=[C:20]4[C:16]=3[N:17]=[CH:18][NH:19]4)[CH2:11][O:12][CH3:13])[N:7]([C:30]3[CH:31]=[CH:32][CH:33]=[CH:34][CH:35]=3)[C:6]=2[C:36]=1[F:37]
Reactant: COC[C@H](Nc1ncnc2c1ncn2C1CCCCO1)c1nc2ccc(F)c(F)c2n1-c1ccccc1
Agent: Cl
Solvent: CO
Solvent: C1COCCO1
Product: COCC(Nc1ncnc2[nH]cnc12)c1nc2ccc(F)c(F)c2n1-c1ccccc1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 46.2 %

Procedure:
To a solution of [(R)-1-(6,7-difluoro-1-phenyl-1H-benzoimidazol-2-yl)-2-methoxyethyl]-[9-(tetrahydro-pyran-2-yl)-9H-purin-6-yl]amine (290 mg, 0.57 mmol) in methanol (5 mL) was added HCl in dioxane (0.5 mL, 4M) and the reaction stirred at RT for 30 min. The reaction mixture was concentrated in vacuo and the resultant residue dissolved in EtOAc (10 mL). The solution was washed with sat. aq. NaHCO3 and the product extracted with EtOAc (3×10 mL). The combined organic extracts were washed with brine, dried (MgSO4) and concentrated in vacuo. The resultant residue was triturated with diethyl ether, collected by filtration and dried in vacuo to yield 190 as a white solid (111 mg, 46%). 1H NMR 400 MHz (DMSO-d6): δ 8.13-7.98 (2H, m), 7.89 (1H, br s), 7.74-7.58 (2H, m), 7.59-7.39 (4H, m), 7.29-7.14 (1H, m), 5.47 (1H, br s), 3.87-3.77 (2H, m), 3.11 (3H, s). LCMS (Method K): RT=3.72 min, [M+H]+=422
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([OH:11])[CH:5]=[CH:6][C:7]=1[N+:8]([O-:10])=[O:9].[F:12][C:13]1[CH:18]=[CH:17][C:16]([CH2:19]Cl)=[CH:15][CH:14]=1.C(=O)([O-])[O-].[K+].[K+]>C(C(C)=O)C>[F:1][C:2]1[CH:3]=[C:4]([O:11][CH2:19][C:16]2[CH:17]=[CH:18][C:13]([F:12])=[CH:14][CH:15]=2)[CH:5]=[CH:6][C:7]=1[N+:8]([O-:10])=[O:9]
Reactant: O=[N+]([O-])c1ccc(O)cc1F
Reactant: Fc1ccc(CCl)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCC(C)=O
Product: O=[N+]([O-])c1ccc(OCc2ccc(F)cc2)cc1F
Temperature: 70 °C
Yield: 18.6 %

Procedure:
A stirred mixture of 10.0 g (0.063 mole) of 3-fluoro-4-nitrophenol, 17.0 g (0.090 mole) of 4-fluorophenylmethyl chloride, and 12.42 g (0.090 mole) of anhydrous potassium carbonate in 80 mL of methyl ethyl ketone was heated at 70° C. for approximately 17 hours. The reaction mixture was then cooled and filtered and the filtrate evaporated under reduced pressure, leaving 3.10 g of 4-fluorophenylmethyl 3-fluoro-4-nitrophenyl ether as a solid; m.p. 90°-91° C.
Reaction SMILES: Cl.[NH2:2][CH:3]([CH2:16][C:17]1[C:25]2[C:20](=[CH:21][CH:22]=[CH:23][CH:24]=2)[NH:19][CH:18]=1)[C:4]([O:6][CH2:7][C:8]1[CH:13]=[C:12]([CH3:14])[CH:11]=[C:10]([CH3:15])[CH:9]=1)=[O:5].C(N(CC)CC)C.[C:33]1([S:39](Cl)(=[O:41])=[O:40])[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=1>O1CCCC1>[C:33]1([S:39]([NH:2][CH:3]([CH2:16][C:17]2[C:25]3[C:20](=[CH:21][CH:22]=[CH:23][CH:24]=3)[NH:19][CH:18]=2)[C:4]([O:6][CH2:7][C:8]2[CH:9]=[C:10]([CH3:15])[CH:11]=[C:12]([CH3:14])[CH:13]=2)=[O:5])(=[O:41])=[O:40])[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=1
Reactant: Cc1cc(C)cc(COC(=O)C(N)Cc2c[nH]c3ccccc23)c1
Reactant: O=S(=O)(Cl)c1ccccc1
Agent: Cl
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: Cc1cc(C)cc(COC(=O)C(Cc2c[nH]c3ccccc23)NS(=O)(=O)c2ccccc2)c1
Reaction time: 0.25 h

Procedure:
3,5-Dimethylbenzyl 2-amino-3-(3-indolyl)propionate hydrochloride (1.0 g) was suspended in tetrahydrofuran (10 ml). Triethylamine (0.38 ml) was added and the solution was stirred for 15 mins. Benzenesulphonyl chloride (0.35 ml) was added and the solution was stirred at room temperature for 1 hour. Work-up as for Example 14 gave a solid which was recrystallised from ethanol to yield the title compound, 0.85 g, m.p. 114°-116° C. 1H NMR (360 MHz, CDCl3) δ7.98 (1H, s), 7.72 (2H, d, J=7 Hz), 7.54-7.30 (5H, m), 7.17 (1H, t, J=7 Hz), 7.06 (1H, t. J=7 Hz), 6.94 (1H, s), 6.89 (1H, s), 6.62 (2H, s), 5.17 (1H, d, J=9.2 Hz), 4.68 (2H, ABq, J=11.9 Hz), 4.33 (1H, m), 3.27 (2H, m), 2.27 (6H, s).
Reaction SMILES: [CH3:1][N:2]([CH3:12])[N:3]1[C:7](=[O:8])[CH:6]([CH3:9])[S:5][C:4]1=[N:10][OH:11].[CH3:13][N:14]=[C:15]=[O:16]>CC(C)=O.C(N(CC)CC)C>[CH3:12][N:2]([CH3:1])[N:3]1[C:7](=[O:8])[CH:6]([CH3:9])[S:5][C:4]1=[N:10][O:11][C:15](=[O:16])[NH:14][CH3:13]
Reactant: CN=C=O
Reactant: CC1SC(=NO)N(N(C)C)C1=O
Solvent: CCN(CC)CC
Solvent: CC(C)=O
Product: CNC(=O)ON=C1SC(C)C(=O)N1N(C)C
Reaction time: 24 h
Yield: 325.6 %

Procedure:
A solution of 1.18 g of 3-dimethylamino-5-methyl-2-oximino-4-thiazolidinone in 50 ml acetone, 1.0 g methylisocyanate and 2 drops of triethylamine was placed in a pressure bottle and left standing at room temperature. After 20 hours additional 0.75 ml of methylisocyanate and 2 drops of triethylamine were added and left standing for 24 hours. Concentration yielded 5.0 g of crude product. Crystallized from methylene chloride and isopropyl ether, m.p. 110°-113°C.
Reaction SMILES: [CH:1]1([C:4](Cl)=[O:5])[CH2:3][CH2:2]1.[NH2:7][C:8]1[CH:20]=[CH:19][C:11]([C:12]([CH2:14][CH2:15][C:16]([OH:18])=[O:17])=[O:13])=[CH:10][CH:9]=1>O1CCCC1>[CH:1]1([C:4]([NH:7][C:8]2[CH:9]=[CH:10][C:11]([C:12]([CH2:14][CH2:15][C:16]([OH:18])=[O:17])=[O:13])=[CH:19][CH:20]=2)=[O:5])[CH2:3][CH2:2]1
Reactant: Nc1ccc(C(=O)CCC(=O)O)cc1
Reactant: O=C(Cl)C1CC1
Solvent: C1CCOC1
Product: O=C(O)CCC(=O)c1ccc(NC(=O)C2CC2)cc1
Reaction time: 7 h
Yield: 75.4 %

Procedure:
3.2 g (30.6 millimoles) of cyclopropanecarboxylic acid chloride, dissolved in 20 ml of absolute tetrahydrofuran, are added dropwise, at room temperature, to a stirred solution of 5.0 g (25.9 millimoles) of 3-(p-aminobenzoyl)-propionic acid in 100 ml of absolute tetrahydrofuran; a precipitate forms. The reaction mixture is then kept for 7 hours under reflux. The product is filtered off at 10° C., washed with water and dried under reduced pressure at 50° C. 5.1 g (75% of theory) of 3-(p-cyclopropylcarbonylaminobenzoyl)-propionic acid are obtained as yellow crystals, of melting point 229°-230° C. (after recrystallization from ethanol/water).
Reaction SMILES: C([Li])(C)(C)C.[CH3:6][O:7][C:8]1[CH:17]=[CH:16][C:15]2[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=2)[N:9]=1.[CH:18]1[C:31]2[C:30]3([CH2:33][N:34]4[CH2:39][CH2:38][C:37](=[O:40])[CH2:36][CH2:35]4)[CH2:32][CH:23]([C:24]4[C:29]3=[CH:28][CH:27]=[CH:26][CH:25]=4)[C:22]=2[CH:21]=[CH:20][CH:19]=1.[Li]C1C=CC2C(=CC=CC=2)N=1>O1CCCC1.C(NC(C)C)(C)C>[CH:28]1[C:29]2[C:30]3([CH2:33][N:34]4[CH2:39][CH2:38][C:37]([C:17]5[C:8]([O:7][CH3:6])=[N:9][C:10]6[C:15]([CH:16]=5)=[CH:14][CH:13]=[CH:12][CH:11]=6)([OH:40])[CH2:36][CH2:35]4)[CH2:32][CH:23]([C:22]4[C:31]3=[CH:18][CH:19]=[CH:20][CH:21]=4)[C:24]=2[CH:25]=[CH:26][CH:27]=1
Reactant: O=C1CCN(CC23CC(c4ccccc42)c2ccccc23)CC1
Reactant: COc1ccc2ccccc2n1
Agent: [Li]C(C)(C)C
Agent: [Li]c1ccc2ccccc2n1
Solvent: C1CCOC1
Solvent: CC(C)NC(C)C
Product: COc1nc2ccccc2cc1C1(O)CCN(CC23CC(c4ccccc42)c2ccccc23)CC1
Temperature: -72 °C
Reaction time: 1 h
Yield: 65.5 %

Procedure:
To a cooled solution (-72° C.) or t-butyllithium (1.7M in pentane, limiting reagent, 1.90 mL, 3.19 mmol) in tetrahydrofuran (24 mL) under nitrogen was added several drops of diisopropylamine (catalytic amount). This was followed by 2-methoxyquinoline (0.69 mL, 4.39 mmol, 1.38 eq). The reaction was stirred at -72° C. for 1 h, warmed to 0° C. and stirred at this temperature for 3 h. After recooling to -72 ° C., a solution of 1-(9,10-dihydro-9,10-methanoanthracen-9-ylmethyl)-4-piperidinone (described in example 5d) (1.00 g, 3.30 mmol, 1.03 eq) in tetrahydrofuran (3.0 mL) was added dropwise to the lithioquinoline solution. The reaction was stirred at room temperature for 18 h and quenched with water (10 mL). The aqueous phase was extracted with ethyl acetate (200 mL). The organic extract was washed with water (2×200 mL), dried with anhydrous sodium sulfate and reduced to an oil. The reaction mixture was purified by flash chromatography over silica gel (100 mL; eluent: 25% ethyl acetate in hexane) to obtain 1.00 g (66%) of the title compound as a white solid. TLC analysis (Rf 0.19, 25% ethyl acetate in hexane). 1H NMR (CDCl3, 250 MHz) 7.89 (s, 1H), 7.81 (d, J=8.4 Hz, 1H), 7.88 (d, J=7.7 Hz, 1H), 7.59 (dd, J=6.8, 7.3 Hz, 1H), 7.38 (dd, J=7.4, 7.5 Hz, 1H), 7.23 (m, 4H), 6.93 (m, 4H), 4.27 (s, 1H), 4.16 (s, 3H), 3.80 (s, 1H), 3.49 (s, 2H), 2.87 (m, 4H), 2.63 (s, 2H), 2.09 (m, 4H) MS (CI, CH4) m/z 463 (M+1,100), 491 (M+29,19), 445 (23). The free base was dissolved in methylene chloride, treated with ethereal HCl, and the hydrochloride salt was precipitated with ether dilution. The solid was filtered, rinsed with fresh diethyl ether and dried in vacuo (50° C., 10 pascal, 18 h) to yield a white solid, mp 213°-217° C. (dec).
Reaction SMILES: [Cl:1][C:2]1[CH:16]=[CH:15][C:14]2[C:7]3[N:8]=[C:9]([NH:11][C:12]#[N:13])[S:10][C:6]=3[CH2:5][C:4]=2[CH:3]=1.[NH2:17][C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1>C(O)C>[Cl:1][C:2]1[CH:16]=[CH:15][C:14]2[C:7]3[N:8]=[C:9]([NH:11][C:12]([NH:17][C:18]4[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=4)=[NH:13])[S:10][C:6]=3[CH2:5][C:4]=2[CH:3]=1
Reactant: N#CNc1nc2c(s1)Cc1cc(Cl)ccc1-2
Reactant: Nc1ccccc1
Solvent: CCO
Product: N=C(Nc1ccccc1)Nc1nc2c(s1)Cc1cc(Cl)ccc1-2

Procedure:
0.26 g of 6-chloro-8H-indeno[1,2-d]thiazol-2-yl-cyanamide is suspended in 10 ml of ethanol at room temperature and, after addition of 0.1 of aniline, heated to reflux for 6 h. The reaction mixture is concentrated in vacuo, and the residue is purified by chromatography on silica gel with 5/1 dichloromethane/ethyl acetate. N-(6-Chloro-8H-indeno[1,2-d]thiazol-2-yl)-N′-phenylguanidine is obtained and melts with decomposition at 210° C.
Reaction SMILES: [Cl:1][C:2]1[CH:11]=[C:10]2[C:5]([N:6]=[CH:7][C:8]([NH:12][C@H:13]3[CH2:16][C@H:15]([NH:17][C:18]4[C:23]([NH2:24])=[CH:22][CH:21]=[CH:20][N:19]=4)[CH2:14]3)=[N:9]2)=[CH:4][CH:3]=1.[C:25](OC)(OC)(OC)[O:26][CH3:27].C(O)(=O)CC>O>[Cl:1][C:2]1[CH:11]=[C:10]2[C:5]([N:6]=[CH:7][C:8]([NH:12][C@H:13]3[CH2:16][C@H:15]([N:17]4[C:18]5=[N:19][CH:20]=[CH:21][CH:22]=[C:23]5[N:24]=[C:25]4[O:26][CH3:27])[CH2:14]3)=[N:9]2)=[CH:4][CH:3]=1
Reactant: Nc1cccnc1N[C@H]1C[C@H](Nc2cnc3ccc(Cl)cc3n2)C1
Reactant: COC(OC)(OC)OC
Solvent: O
Solvent: CCC(=O)O
Product: COc1nc2cccnc2n1[C@H]1C[C@H](Nc2cnc3ccc(Cl)cc3n2)C1
Temperature: 100 °C
Reaction time: 2 h

Procedure:
N2-(trans-3-((7-chloroquinoxalin-2-yl)amino)cyclobutyl)pyridine-2,3-diamine (118 mg, 0.346 mmol), tetramethyl orthocarbonate (922 μl, 6.92 mmol) and propionic acid (12.91 μl, 0.173 mmol) were combined under nitrogen. The reaction mixture was stirred at 100° C. for 2 hours. The reaction mixture was diluted with water and extracted with dichloromethane. The organic extract was washed with saturated ammonium chloride and dried over magnesium sulfate. The solution was concentrated in vacuo to give the crude material as a off-white solid. It was absorbed onto a plug of silica gel and purified by chromatography through a Redi-Sep pre-packed silica gel column (4 g), eluting with a hexane to ethyl acetate gradient, to provide 7-chloro-N-(trans-3-(2-methoxy-3H-imidazo[4,5-b]pyridin-3-yl)cyclobutyl)quinoxalin-2-amine (85 mg, 0.223 mmol, 64.5% yield). M+1: 380.9.
Reaction SMILES: [NH2:1][C:2]1[CH:9]=[C:8](F)[C:5]([C:6]#[N:7])=[CH:4][N:3]=1.[CH3:11][O:12][CH:13]([CH3:16])[CH2:14][NH2:15]>>[NH2:1][C:2]1[CH:9]=[C:8]([NH:15][CH2:14][CH:13]([O:12][CH3:11])[CH3:16])[C:5]([C:6]#[N:7])=[CH:4][N:3]=1
Reactant: COC(C)CN
Reactant: N#Cc1cnc(N)cc1F
Product: COC(C)CNc1cc(N)ncc1C#N

Procedure:
From intermediate 21 and racemic 2-methoxypropan-1-amine, reacted in an analogous manner to the preparation of intermediate 49. (UPLC-MS 3) tR 0.39 min; ESI-MS 207.1 [M+H]+.
Reaction SMILES: [C:1]12([C:11](Cl)=[O:12])[CH2:10][CH:5]3[CH2:6][CH:7]([CH2:9][CH:3]([CH2:4]3)[CH2:2]1)[CH2:8]2.[NH2:14][C:15]1[CH:16]=[N:17][C:18]2[C:23]([CH:24]=1)=[CH:22][CH:21]=[CH:20][CH:19]=2.N1C=CC=CC=1>O>[N:17]1[C:18]2[C:23](=[CH:22][CH:21]=[CH:20][CH:19]=2)[CH:24]=[C:15]([NH:14][C:11]([C:1]23[CH2:10][CH:5]4[CH2:6][CH:7]([CH2:9][CH:3]([CH2:4]4)[CH2:2]2)[CH2:8]3)=[O:12])[CH:16]=1
Reactant: Nc1cnc2ccccc2c1
Reactant: O=C(Cl)C12CC3CC(CC(C3)C1)C2
Solvent: O
Solvent: c1ccncc1
Product: O=C(Nc1cnc2ccccc2c1)C12CC3CC(CC(C3)C1)C2
Yield: 28.3 %

Procedure:
Prepared from 1-adamantanecarbonyl chloride (0.75 g, 3.8 mmol), 3-aminoquinoline (0.60 g, 4.2 mmol), pyridine (10 mL), and water (100 mL) yielding 0.33 g (29%) of (86):