Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl[C:2]1[CH:7]=[C:6]([Cl:8])[N:5]=[C:4]([CH3:9])[N:3]=1.[CH3:10][C:11]1[N:12]=[C:13]([NH2:19])[S:14][C:15]=1[C:16]([OH:18])=[O:17].[H-].[Na+].Cl>O1CCCC1.CN(C)C(=O)C>[CH3:10][C:11]1[N:12]=[C:13]([NH:19][C:2]2[CH:7]=[C:6]([Cl:8])[N:5]=[C:4]([CH3:9])[N:3]=2)[S:14][C:15]=1[C:16]([OH:18])=[O:17]
Reactant: Cc1nc(Cl)cc(Cl)n1
Reactant: Cc1nc(N)sc1C(=O)O
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: CC(=O)N(C)C
Solvent: C1CCOC1
Product: Cc1nc(Cl)cc(Nc2nc(C)c(C(=O)O)s2)n1
Reaction time: 3 h
Yield: 87.3 %

Procedure:
In a reaction flask, 49.49 g 4,6-dichloro-2-methylpyrimidine (0.303 mol), 40.00 g methyl 2-aminothiazol-5-carboxylic acid (0.253 mol), and 200 ml N,N-dimethylacetamide were charged, the temperature was brought to −5° C. and 18.20 g sodium hydride (0.455 mol) in 90 ml tetrahydrofuran were added dropwise and the reaction mixture was kept under these conditions for about three hours. At the end of the reaction, 250 ml of a solution of hydrochloric acid 2N were added, the temperature was brought to the room value, the formed solid was filtered and washed with water (4×200 ml) and dried in oven under vacuum at a temperature of 55° C. for about eight hours, to give 62.89 g methyl 2-(6-chloro-2-methylpyrimidin-4-yl-amino)thiazol-5-carboxylic acid.
Reaction SMILES: [Br:1][C:2]1[C:3]([CH3:12])=[C:4]([CH:9]=[CH:10][CH:11]=1)[C:5]([O:7][CH3:8])=[O:6].[Br:13]N1C(=O)CCC1=O.N(C(C)(C)C#N)=NC(C)(C)C#N>C(Cl)(Cl)(Cl)Cl>[Br:1][C:2]1[C:3]([CH2:12][Br:13])=[C:4]([CH:9]=[CH:10][CH:11]=1)[C:5]([O:7][CH3:8])=[O:6]
Reactant: COC(=O)c1cccc(Br)c1C
Reactant: O=C1CCC(=O)N1Br
Agent: CC(C)(C#N)N=NC(C)(C)C#N
Solvent: ClC(Cl)(Cl)Cl
Product: COC(=O)c1cccc(Br)c1CBr
Yield: 96 %

Procedure:
A solution of methyl 3-bromo-2-methylbenzoate (1.00 g), N-bromosuccinimide (855 mg) and 2,2′-azobis(isobutyronitrile) (71.8 mg) in carbon tetrachloride (50 ml) was heated under reflux for 8 h. The reaction mixture was concentrated, and the residue was diluted with ethyl acetate, washed with saturated aqueous sodium hydrogen carbonate and saturated brine and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure and the residue was purified by column chomatography (eluent; hexane:ethyl acetate=20:1) to give the title compound (1.29 g) as a colorless oil.
Reaction SMILES: [Cl:1][C:2]1[C:11]([O:12]C(C)C)=[C:10]2[C:5]([CH:6]=[CH:7][CH:8]=[N:9]2)=[C:4]([C:16]2[CH:17]=[N:18][CH:19]=[CH:20][CH:21]=2)[CH:3]=1.B(Cl)(Cl)Cl>>[Cl:1][C:2]1[C:11]([OH:12])=[C:10]2[C:5]([CH:6]=[CH:7][CH:8]=[N:9]2)=[C:4]([C:16]2[CH:17]=[N:18][CH:19]=[CH:20][CH:21]=2)[CH:3]=1
Reactant: CC(C)Oc1c(Cl)cc(-c2cccnc2)c2cccnc12
Agent: ClB(Cl)Cl
Product: Oc1c(Cl)cc(-c2cccnc2)c2cccnc12
Yield: 94.6 %

Procedure:
Cleavage of the isopropyl ether 22 (20 mg, 0.07 mmol) with boron trichloride following the method outlined in Example 8, gave 7-chloro-5-(pyridin-3-yl)-quinolin-8-ol (PBT 1057) as a pale straw-coloured solid (17 mg, 94%). 1H NMR (CD3OD, 400 MHz): δ 9.16 (m, 2H), 9.04 (d, J=5.8, 1 H), 8.93 (dd, J=1.2 and 8.6, 1 H), 8.84 (m, 1H), 8.30 (dd, J=5.8 and 8.1, 1 H), 8.09 (s, 1H), 8.08 (dd, J=5.1 and 8.6, 1 H).
Reaction SMILES: [NH2:1][CH2:2][CH2:3][CH:4]1[C:13]2[C:8](=[CH:9][CH:10]=[C:11]([O:14][CH3:15])[CH:12]=2)[CH2:7][CH2:6][CH2:5]1.C(N(CC)CC)C.[CH:23]1([C:26](Cl)=[O:27])[CH2:25][CH2:24]1.O>C1COCC1>[CH:23]1([C:26]([NH:1][CH2:2][CH2:3][CH:4]2[C:13]3[C:8](=[CH:9][CH:10]=[C:11]([O:14][CH3:15])[CH:12]=3)[CH2:7][CH2:6][CH2:5]2)=[O:27])[CH2:25][CH2:24]1
Reactant: O=C(Cl)C1CC1
Reactant: COc1ccc2c(c1)C(CCN)CCC2
Solvent: O
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: COc1ccc2c(c1)C(CCNC(=O)C1CC1)CCC2
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 76 %

Procedure:
To a solution of (1,2,3,4-tetrahydro-7-methoxy-1-naphthylidene)acetonitrile (1.0 g, 5.02 mmol) in ethanol (10 ml) were added a saturated ammonia/ethanol solution (5 ml) and Raney nickel (W-2, 1 g). The mixture was stirred for 4 hours at 50° C. under hydrogen atmosphere (3-4 kgf/cm2). The Raney nickel was filtered off and, then, the solvent was distilled off under reduced pressure to give 1-(2-aminoethyl)-7-methoxy-1,2,3,4-tetrahydronaphthalene. To a solution of this 1-(2-aminoethyl)-7-methoxy-1,2,3,4-tetrahydronaphthalene and triethylamine (0.76 g, 7.53 mmol) in THF (20 ml) was gradually added dropwise, under ice-cooling, cyclopropanecarbonyl chloride (0.63 g, 6.02 mmol). The mixture was stirred for 30 minutes at room temperature. The reaction mixture was poured into water. The organic layer was subjected to extraction with chloroform. The extract solution was washed with brine and water, which was then dried over anhydrous magnesium sulfate, followed by distilling off the solvent. The residue was purified by means of a silica gel column chromatography (ethyl acetate:hexane=2:8) to give the above-titled compound (1.04 g, yield 76%, oil).
Reaction SMILES: [OH:1][CH2:2][CH2:3][N:4]([CH2:17][C:18]([F:21])([F:20])[F:19])[C:5]1[CH:12]=[CH:11][C:8]([C:9]#[N:10])=[C:7]([C:13]([F:16])([F:15])[F:14])[CH:6]=1.O[C:23]1[CH:28]=[CH:27][C:26]([N:29]2[CH2:33][CH2:32][CH2:31][C:30]2=[O:34])=[CH:25][CH:24]=1>>[O:34]=[C:30]1[CH2:31][CH2:32][CH2:33][N:29]1[C:26]1[CH:27]=[CH:28][C:23]([O:1][CH2:2][CH2:3][N:4]([CH2:17][C:18]([F:19])([F:20])[F:21])[C:5]2[CH:12]=[CH:11][C:8]([C:9]#[N:10])=[C:7]([C:13]([F:15])([F:16])[F:14])[CH:6]=2)=[CH:24][CH:25]=1
Reactant: O=C1CCCN1c1ccc(O)cc1
Reactant: N#Cc1ccc(N(CCO)CC(F)(F)F)cc1C(F)(F)F
Product: N#Cc1ccc(N(CCOc2ccc(N3CCCC3=O)cc2)CC(F)(F)F)cc1C(F)(F)F

Procedure:
Synthesized as described in Example 27B from 4-[(2-hydroxyethyl)(2,2,2-trifluoroethyl)amino]-2-(trifluoromethyl)benzonitrile (Example 15B) and 1-(4-hydroxyphenyl)-2-pyrrolidinone (step A above): MS (APCI) m/z 472 (M+1).
Reaction SMILES: [CH2:1]([NH:8][C@H:9]([CH3:16])[C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C([Li])CCC.[CH2:22]([O:24][C:25](=[O:41])[CH:26]=[CH:27][C:28]1[CH:33]=[CH:32][C:31]([C:34]2[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=2)=[C:30]([F:40])[CH:29]=1)[CH3:23]>C1COCC1>[CH2:22]([O:24][C:25](=[O:41])[CH2:26][CH:27]([N:8]([CH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1)[C@@H:9]([C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1)[CH3:16])[C:28]1[CH:33]=[CH:32][C:31]([C:34]2[CH:35]=[CH:36][CH:37]=[CH:38][CH:39]=2)=[C:30]([F:40])[CH:29]=1)[CH3:23]
Reactant: C[C@@H](NCc1ccccc1)c1ccccc1
Reactant: CCOC(=O)C=Cc1ccc(-c2ccccc2)c(F)c1
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: CCOC(=O)CC(c1ccc(-c2ccccc2)c(F)c1)N(Cc1ccccc1)[C@H](C)c1ccccc1
Temperature: -78 °C
Reaction time: 0.17 h

Procedure:
A cooled (0° C.) solution of N-benzyl-(R)-α-methylbenzylamine (8.9 mL, 42.6 mmol) in THF (100 mL) was treated with n-butyllithium (26.6 mL of a 1.6 M soln in hexanes; 42.6 mmol). After stirring for 10 min, the purple solution was cooled to −78° C. and treated with a solution of ester 13-2 (5.76 g, 21.3 mmol) in THF (10 mL). After stirring for 20 min, the solution was quenched with satd aq NH4Cl soln (5 mL), and the cold bath removed. The reaction mixture was diluted with Et2O (100 mL), and washed with 10% aq citric acid (50 mL), satd aq NaHCO3 (50 mL), 5% aq acetic acid (30 mL), 10% aq K2CO3 (50 mL), and brine (50 mL). The solution was dried over MgSO4, filtered and concentrated. The residue was purified by flash chromatography (90:10 hexanes/EtOAc) to give adduct 13-3.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:12]=1[O:13][CH3:14])[N:9]=[CH:8][CH:7]=[C:6]2[O:15][C:16]1[C:22]([CH3:23])=[CH:21][C:19]([NH2:20])=[C:18]([CH3:24])[CH:17]=1.C(N(CC)CC)C.ClC(Cl)(O[C:36](=[O:42])OC(Cl)(Cl)Cl)Cl.[CH2:44]([N:46]([CH2:50][CH3:51])[CH2:47][CH2:48][NH2:49])[CH3:45]>C(Cl)(Cl)Cl.O>[CH2:44]([N:46]([CH2:50][CH3:51])[CH2:47][CH2:48][NH:49][C:36]([NH:20][C:19]1[CH:21]=[C:22]([CH3:23])[C:16]([O:15][C:6]2[C:5]3[C:10](=[CH:11][C:12]([O:13][CH3:14])=[C:3]([O:2][CH3:1])[CH:4]=3)[N:9]=[CH:8][CH:7]=2)=[CH:17][C:18]=1[CH3:24])=[O:42])[CH3:45]
Reactant: O=C(OC(Cl)(Cl)Cl)OC(Cl)(Cl)Cl
Reactant: CCN(CC)CCN
Reactant: COc1cc2nccc(Oc3cc(C)c(N)cc3C)c2cc1OC
Solvent: CCN(CC)CC
Solvent: O
Solvent: ClC(Cl)Cl
Product: CCN(CC)CCNC(=O)Nc1cc(C)c(Oc2ccnc3cc(OC)c(OC)cc23)cc1C
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 9.7 %

Procedure:
4-[(6,7-Dimethoxy-4-quinolyl)oxy]-2,5-dimethylaniline (50 mg) was dissolved in chloroform (5 ml), and triethylamine (0.5 ml) to prepare a solution. A solution of triphosgene (68 mg) in chloroform was then added to the solution, and the mixture was stirred at room temperature for 10 min. Next, N1,N1-diethyl-1,2-ethanediamine (27 mg) was added thereto, and the mixture was further stirred at room temperature for one hr. Water was added to stop the reaction, and the reaction solution was then extracted with chloroform, followed by concentration. The residue was purified on a column using chloroform/methanol to give the title compound (7 mg, yield 10%).
Reaction SMILES: [F:1][C:2]1[C:7]([CH:8]([CH2:14][N+:15]([O-])=O)[CH2:9][C:10](OC)=[O:11])=[CH:6][CH:5]=[CH:4][N:3]=1.[BH4-].[Na+]>CCO.[Ni](Cl)Cl>[F:1][C:2]1[C:7]([CH:8]2[CH2:14][NH:15][C:10](=[O:11])[CH2:9]2)=[CH:6][CH:5]=[CH:4][N:3]=1
Reactant: COC(=O)CC(C[N+](=O)[O-])c1cccnc1F
Agent: Cl[Ni]Cl
Agent: [BH4-]
Agent: [Na+]
Solvent: CCO
Product: O=C1CC(c2cccnc2F)CN1
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 22.8 %

Procedure:
To a solution of methyl 3-(2-fluoropyridin-3-yl)-4-nitrobutanoate (0.991 g, 4.09 mmol) in EtOH (20 mL) at 0° C. was added nickel chloride (0.532 g, 4.10 mmol) and sodium borohydride (1.60 g, 42.3 mmol). The reaction mixture was stirred at 0° C. for 30 min, warmed to room temperature over 30 min, and stirred at room temperature for 30 min. The reaction mixture was quenched with saturated aqueous KH2PO4 and diluted with water and EtOAc. The mixture was filtered through a pad of Celite. The filtrate was extracted with EtOAc (6×) and the combined organic extracts were washed with brine (1×), dried over MgSO4, filtered, and concentrated. Purification by flash column chromatography on silica gel (5% to 10% MeOH in DCM) gave 4-(2-fluoropyridin-3-yl)pyrrolidin-2-one (0.168 g, 0.932 mmol, 23% yield) as a colorless oil. MS (ESI, pos. ion) m/z: 181.1 (M+1).
Reaction SMILES: C(=O)([O-])[O-].[K+].[K+].[N+:7]([C:10]1[CH:15]=[CH:14][C:13]([N:16]2[CH2:20][CH2:19][NH:18][C:17]2=[S:21])=[CH:12][CH:11]=1)([O-:9])=[O:8].IC.[C:24](OCC)(=O)C>CC(C)=O.O>[CH3:24][S:21][C:17]1[N:16]([C:13]2[CH:14]=[CH:15][C:10]([N+:7]([O-:9])=[O:8])=[CH:11][CH:12]=2)[CH:20]=[CH:19][N:18]=1
Reactant: O=[N+]([O-])c1ccc(N2CCNC2=S)cc1
Reactant: CCOC(C)=O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CI
Solvent: CC(C)=O
Product: CSc1nccn1-c1ccc([N+](=O)[O-])cc1

Procedure:
To a stirred suspension of potassium carbonate(40.07 g, 22.60 mmol) in 175 mL acetone was added 1-(4-nitrophenyl) imidazoline-2-thione(5.0 g,22.60 mmol). Dripped iodomethane (1.44 mL,23.05 mmol) into reaction mixture and heated to reflux temperature for 20 h. Concentrated reaction mixture under reduced pressure and took up resulting solid in 200 mL water. Extracted aqueous three times with ethyl acetate. Combined extracts, dried over magnesium sulfate and concentrated in vacuo to give 5.29 g of crude 4-(2'-methylthioimidazol-1-yl)nitrobenzene. 1HNMR(DMSO-d6) δ: 10.45 (s, 1 H) 8.06 (dd, 1 H, J1 =2.0 Hz, J2 =8.0 Hz), 8.38-8.33 (m, 2 H), 7.77-7.72 (m, 2 H), 7.61 (d, 1 H, J=1.5 Hz), 7.14 (d, 1 H, J=1.5 Hz), 2.52 (s, 3 H). ESI mass spectrum analysis m/z(relative intensity) 236 (M+H,100).
Reaction SMILES: [CH2:1]([C:5]1[C:9]([CH2:10][O:11][C:12]2[CH:20]=[CH:19][C:15]([C:16]([OH:18])=O)=[CH:14][N:13]=2)=[C:8]([CH2:21][OH:22])[O:7][N:6]=1)[CH2:2][CH2:3][CH3:4].[CH:23]1([NH2:27])[CH2:26][CH2:25][CH2:24]1.F[B-](F)(F)F.N1(OC(N(C)C)=[N+](C)C)C2C=CC=CC=2N=N1.C(N(C(C)C)C(C)C)C>CN(C=O)C>[CH2:1]([C:5]1[C:9]([CH2:10][O:11][C:12]2[CH:20]=[CH:19][C:15]([C:16]([NH:27][CH:23]3[CH2:26][CH2:25][CH2:24]3)=[O:18])=[CH:14][N:13]=2)=[C:8]([CH2:21][OH:22])[O:7][N:6]=1)[CH2:2][CH2:3][CH3:4]
Reactant: CCCCc1noc(CO)c1COc1ccc(C(=O)O)cn1
Reactant: NC1CCC1
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[B-](F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: CCCCc1noc(CO)c1COc1ccc(C(=O)NC2CCC2)cn1
Temperature: 25 °C
Reaction time: 17 h
Yield: 62.6 %

Procedure:
To a solution of 6-[3-butyl-5-hydroxymethyl-isoxazol-4-ylmethoxy]-nicotinic acid (49 mg, 0.16 mmol) in DMF (2 mL) was added cyclobutylamine (25 mg, 0.35 mmol), O-(benzotriazol-1-yl)-N,N,N′,N′-tetramethyluronium tetrafluoroborate (82 mg, 0.26 mmol) and N-ethyldiisopropylamine (136 μL, 0.80 mmol) with DMF (1 mL). The reaction mixture was stirred for 17 h at room temperature. The reaction was partitioned between water and ethyl acetate. The aqueous phase was extracted two times with ethyl acetate and the combined organic phases were washed with brine, dried over sodium sulfate and concentrated to a yellow oil. The crude material was purified by chromatography (silica, dichloromethane:methanol 100:0 to 97:3) to afford the title compound (36 mg, 63%) as a colorless gum. MS: m/e=360.3 [M+H]+.
Reaction SMILES: C(N(C(C)C)CC)(C)C.[Cl:10][C:11]1[CH:15]=[N:14][N:13]([CH3:16])[C:12]=1[C:17]([OH:19])=O.CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.[B-](F)(F)(F)F.[C:42]1([C:48]2[N:49]=[C:50]3[CH:55]=[C:54]([NH2:56])[N:53]=[CH:52][N:51]3[CH:57]=2)[CH:47]=[CH:46][CH:45]=[CH:44][CH:43]=1>CN(C=O)C>[C:42]1([C:48]2[N:49]=[C:50]3[CH:55]=[C:54]([NH:56][C:17]([C:12]4[N:13]([CH3:16])[N:14]=[CH:15][C:11]=4[Cl:10])=[O:19])[N:53]=[CH:52][N:51]3[CH:57]=2)[CH:43]=[CH:44][CH:45]=[CH:46][CH:47]=1
Reactant: Cn1ncc(Cl)c1C(=O)O
Reactant: Nc1cc2nc(-c3ccccc3)cn2cn1
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[B-](F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: Cn1ncc(Cl)c1C(=O)Nc1cc2nc(-c3ccccc3)cn2cn1
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 6.7 %

Procedure:
DMF (8 ml) and diisopropylethylamine (738 mg) were added to 4-chloro-2-methyl-2H-pyrazole-3-carboxylic acid (916 mg, 5.7 mmol) and TBTU (1.83 g), and the mixture was stirred at r.t. (10 min). 2-Phenyl-imidazo[1,2-c]pyrimidin-7-ylamine (400 mg, 1.9 mmol) was added and the mixture was stirred at r.t. overnight. The reaction mixture was then poured on water (35 ml), and the mixture was extracted with ethyl acetate. The combined organic layers were dried (Na2SO4) and evaporated. The title compound (45 mg, 6.7%) was isolated from the residue by column chromatography (silica gel, heptane:ethyl acetate=100:0-60:40), followed by preparative, inverse-phase HPLC (Agilent Zorbax XdB-C18 column, time per run ˜7 min, flow rate 30 ml/min, solvent gradient H2O/CH3CN=95:5-5:95). MS (m/e)=353.1 [M+H+].
Reaction SMILES: [Cl:1][C:2]1[C:3](F)=[C:4]([F:19])[CH:5]=[C:6]2[C:11]=1[N:10]([CH:12]1[CH2:14][CH2:13]1)[CH:9]=[C:8]([C:15]([OH:17])=[O:16])[C:7]2=[O:18].N12CCCN=C1CCCCC2.Cl.Cl.[CH:34]12[NH:42][CH2:41][CH:38]([NH:39][CH2:40]1)[CH2:37][CH2:36][CH2:35]2>C(#N)C>[Cl:1][C:2]1[C:3]([N:39]2[CH2:40][CH:34]3[NH:42][CH2:41][CH:38]2[CH2:37][CH2:36][CH2:35]3)=[C:4]([F:19])[CH:5]=[C:6]2[C:11]=1[N:10]([CH:12]1[CH2:14][CH2:13]1)[CH:9]=[C:8]([C:15]([OH:17])=[O:16])[C:7]2=[O:18]
Reactant: C1CC2CNC(C1)CN2
Reactant: O=C(O)c1cn(C2CC2)c2c(Cl)c(F)c(F)cc2c1=O
Agent: Cl
Solvent: C1CCC2=NCCCN2CC1
Solvent: CC#N
Product: O=C(O)c1cn(C2CC2)c2c(Cl)c(N3CC4CCCC3CN4)c(F)cc2c1=O
Temperature: 25 °C
Reaction time: 8 h
Yield: 60.5 %

Procedure:
A suspension of 1.0 g (3.34 mmol) of 8-chloro-1-cyclopropyl-6,7-difluoro-1,4-dihydro-4-oxo-3-quinolinecarboxylic acid, 30 ml of acetonitrile, 1.52 g (10.0 mmol) of 1,8-diazabicyclo[5.4.0]undec7-ene, and 0.72 g (3.62 mmol) of 6,8-diazabicyclo [3.2.2]nonane, dihydrochloride was heated under reflux for 3 hr, then stirred at room temperature overnight. The precipitate was removed by filtration and washed with acetonitrile and ether to give 0.82 g of the title compound, mp 217°-220° C.
Reaction SMILES: [CH:1]1([C:4]2[C:5]([O:13][CH2:14][C:15]([F:18])([F:17])[F:16])=[N:6][CH:7]=[C:8]([CH:12]=2)[C:9]([OH:11])=O)[CH2:3][CH2:2]1.[O:19]=[S:20]1(=[O:27])[CH2:25][CH2:24][N:23]([NH2:26])[CH2:22][CH2:21]1>>[CH:1]1([C:4]2[C:5]([O:13][CH2:14][C:15]([F:18])([F:17])[F:16])=[N:6][CH:7]=[C:8]([CH:12]=2)[C:9]([NH:26][N:23]2[CH2:24][CH2:25][S:20](=[O:27])(=[O:19])[CH2:21][CH2:22]2)=[O:11])[CH2:2][CH2:3]1
Reactant: NN1CCS(=O)(=O)CC1
Reactant: O=C(O)c1cnc(OCC(F)(F)F)c(C2CC2)c1
Product: O=C(NN1CCS(=O)(=O)CC1)c1cnc(OCC(F)(F)F)c(C2CC2)c1

Procedure:
The title compound was synthesized in analogy to the procedure described in Example 34 c), using 5-cyclopropyl-6-(2,2,2-trifluoro-ethoxy)-nicotinic acid (example 34b) and 1,1-dioxo-1λ6-thiomorpholin-4-ylamine as starting materials (CAN 26494-76-8); MS (ESI) 394.4 (M+H)+.
Reaction SMILES: C(O[C:6](=O)[N:7]([C:9]1[N:14]=[C:13]2[NH:15][C:16]([C:18]3[CH:23]=[CH:22][CH:21]=[C:20]([CH2:24][CH2:25][NH:26][C:27](=[O:29])[CH3:28])[N:19]=3)=[CH:17][C:12]2=[C:11]2[N:30]([CH3:33])[CH:31]=[N:32][C:10]=12)C)(C)(C)C.FC(F)(F)C(O)=O.CN1C(=O)CCC1>C(Cl)Cl>[CH3:33][N:30]1[C:11]2=[C:12]3[CH:17]=[C:16]([C:18]4[N:19]=[C:20]([CH2:24][CH2:25][NH:26][C:27](=[O:29])[CH3:28])[CH:21]=[CH:22][CH:23]=4)[NH:15][C:13]3=[N:14][C:9]([NH:7][CH3:6])=[C:10]2[N:32]=[CH:31]1
Reactant: CC(=O)NCCc1cccc(-c2cc3c(nc(N(C)C(=O)OC(C)(C)C)c4ncn(C)c43)[nH]2)n1
Solvent: CN1CCCC1=O
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CNc1nc2[nH]c(-c3cccc(CCNC(C)=O)n3)cc2c2c1ncn2C
Reaction time: 0.25 h

Procedure:
A450.4 (147 mg, 0.30 mmol), was dissolved in DMA (5 mL) and the solution heated to 77° C. One equivalent of 1.0M potassium t-butoxide in THF (0.3 ml, 0.30 mmol) was quickly added and the reaction heated at 70° C. for thirty minutes. A second equivalent of 1.0M potassium t-butoxide in THF (0.3 ml, 0.30 mmol) was quickly added and the reaction mixture stirred an additional thirty minutes. The reaction mixture was concentrated in vacuo. The crude product residue was purified by Silica Gel (230-400 Mesh) chromatography eluting with 2-5% MeOH/CH2Cl2 to give the Boc-protected intermediate, tert-butyl-7-(6-(2-acetamidoethyl)pyridin-2-yl)-1-methyl-1,6-dihydroimidazo[4,5-d]pyrrolo[2,3-b]pyridine-4-yl(methyl)carbamate as an off-white solid. (76 mg, 52% yield). The solid was dissolved in methylene chloride (0.5 mL) and trifluoroacetic acid (0.5 mL) was added and the reaction mixture stirred for 0.25 h. The solvent was evaporated under reduced pressure to provide A450 (37 mg, 63%). M+H+=364.26. 1H NMP (400 MHz) MEOD δ 8.14 (s, 1H), 7.84 (m, 2H), 7.52 (s, 1H), 7.30 (m, 1H), 4.18 (s, 3H), 3.77 (m, 2H), 3.29 (s, 3H), 3.11 (m, 2H), 1.94 (s, 3H).
Reaction SMILES: [Cl:1][C:2]1[C:7]([Cl:8])=[CH:6][N:5]=[C:4]([NH2:9])[CH:3]=1.[C:10](N1C=CC=CC1=O)(N1C=CC=CC1=O)=[S:11]>ClCCl>[Cl:1][C:2]1[C:7]([Cl:8])=[CH:6][N:5]=[C:4]([N:9]=[C:10]=[S:11])[CH:3]=1
Reactant: Nc1cc(Cl)c(Cl)cn1
Reactant: O=c1ccccn1C(=S)n1ccccc1=O
Solvent: ClCCl
Product: S=C=Nc1cc(Cl)c(Cl)cn1
Temperature: 40 °C
Reaction time: 3 h
Yield: 83 %

Procedure:
To 4,5-dichloropyridin-2-amine (0.25 g, 1.53 mmol) in dichloromethane (25 mL) was added 1,1′-thiocarbonyldipyridin-2(1H)-one (0.36 g, 1.56 mmol). The reaction was stirred at 40° C. for 3 hours, then cooled to room temperature. The crude material was purified by chromatography (Biotage: 25-100% ethyl acetate/hexane) to yield 4,5-dichloro-2-isothiocyanatopyridine (0.26 g, 1.27 mmol, 83% yield) as a yellow powder. The product was carried directly to the next step.
Reaction SMILES: [C:1]1([N:7]2[C:11](=[O:12])[CH:10]([C:13](=O)[CH2:14][C:15](=O)[CH3:16])[C:9]([CH3:19])=[N:8]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH3:20][NH:21][NH2:22]>>[CH3:20][N:21]1[C:13]([C:10]2[C:9]([CH3:19])=[N:8][N:7]([C:1]3[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=3)[C:11]=2[OH:12])=[CH:14][C:15]([CH3:16])=[N:22]1
Reactant: CNN
Reactant: CC(=O)CC(=O)C1C(=O)N(c2ccccc2)N=C1C
Product: Cc1cc(-c2c(C)nn(-c3ccccc3)c2O)n(C)n1

Procedure:
Prepare the title compound from 1-[1-phenyl-3-methyl-5-oxo-4,5-dihydro-1H-pyrazol-4-yl]-butane-1,3-dione and methylhydrazine according to the procedure of Example 28.
Reaction SMILES: Br[C:2]1[CH:11]=[CH:10][C:9]2[N:8]=[CH:7][C:6]3[N:12]([CH3:23])[C:13](=[O:22])[N:14]([C:15]4[CH:16]=[N:17][N:18]([CH3:21])[C:19]=4[CH3:20])[C:5]=3[C:4]=2[CH:3]=1.[CH3:24][O:25][C:26]1[CH:27]=[C:28](B(O)O)[CH:29]=[CH:30][C:31]=1[O:32][CH3:33]>CN(C=O)C.C([O-])([O-])=O.[K+].[K+].CO.CC(N(C)C)=O.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>[CH3:24][O:25][C:26]1[CH:27]=[C:28]([C:2]2[CH:11]=[CH:10][C:9]3[N:8]=[CH:7][C:6]4[N:12]([CH3:23])[C:13](=[O:22])[N:14]([C:15]5[CH:16]=[N:17][N:18]([CH3:21])[C:19]=5[CH3:20])[C:5]=4[C:4]=3[CH:3]=2)[CH:29]=[CH:30][C:31]=1[O:32][CH3:33]
Reactant: COc1ccc(B(O)O)cc1OC
Reactant: Cc1c(-n2c(=O)n(C)c3cnc4ccc(Br)cc4c32)cnn1C
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(=O)N(C)C
Solvent: CO
Solvent: CN(C)C=O
Product: COc1ccc(-c2ccc3ncc4c(c3c2)n(-c2cnn(C)c2C)c(=O)n4C)cc1OC
Temperature: 105 °C
Reaction time: 1.5 h

Procedure:
A mixture of 8-bromo-1-(1,5-dimethyl-1H-pyrazol-4-yl)-3-methyl-1,3-dihydro-imidazo[4,5-c]quinolin-2-one (Intermediate J, 50 mg, 0.132 mmol), 3,4-dimethoxyphenylboronic acid (Aldrich, Buchs, Switzerland, 29 mg, 0.156 mmol) and PdCl2(PPh3)2 (6 mg, 0.0085 mmol) in DMF (1.2 ml) and 1 M aqueous K2CO3 (0.329 ml) was stirred under argon at 105° C. for 1.5 h. Then the RM was cooled to rt, diluted with MeOH/DMA+3 drops TFA and purified directly by Prep. HPLC (H2O (0.1% TFA)/CH3CN 95:5 to 55:45). The fractions containing product were collected together and basified with NaHCO3 (0.3 g), before being concentrated. The resulting suspension was filtered and the cake was washed with water, before being dried under high vacuum to give the title compound as an off-white solid. (HPLC: tR 2.66 min (Method A); M+H=430 MS-ES; 1H-NMR (d6-DMSO, 400 MHz) 8.92 (s, 1H), 8.08-8.01 (m, 1H), 7.95-7.88 (m, 1H), 7.76 (s, 1H), 7.60-7.55 (m, 1H), 7.13-7.08 (m, 1H), 7.05-7.00 (m, 1H), 6.99-6.94 (m, 1H), 3.88-382 (m, 6H), 3.78 (s, 3H), 3.56 (s, 3H), 2.11 (s, 3H))
Reaction SMILES: C1C=CC2N(O)N=NC=2C=1.CCN=C=NCCCN(C)C.Cl.[CH2:23]([O:25][C:26]1[CH:27]=[C:28]([CH:32]=[C:33]([O:41][CH2:42][CH3:43])[C:34]=1[C:35]1[CH:36]=[N:37][N:38]([CH3:40])[CH:39]=1)[C:29]([OH:31])=O)[CH3:24].Cl.[CH3:45][C:46]([CH3:73])([CH3:72])[C:47]([O:49][CH2:50][N:51]1[N:55]=[N:54][C:53]([C:56]2[CH:57]=[C:58]3[C:68](=[CH:69][CH:70]=2)[O:67][C:61]2([CH2:66][CH2:65][NH:64][CH2:63][CH2:62]2)[CH2:60][C:59]3=[O:71])=[N:52]1)=[O:48]>O.CN(C=O)C.CCN(CC)CC>[CH3:45][C:46]([CH3:73])([CH3:72])[C:47]([O:49][CH2:50][N:51]1[N:55]=[N:54][C:53]([C:56]2[CH:57]=[C:58]3[C:68](=[CH:69][CH:70]=2)[O:67][C:61]2([CH2:62][CH2:63][N:64]([C:29]([C:28]4[CH:32]=[C:33]([O:41][CH2:42][CH3:43])[C:34]([C:35]5[CH:36]=[N:37][N:38]([CH3:40])[CH:39]=5)=[C:26]([O:25][CH2:23][CH3:24])[CH:27]=4)=[O:31])[CH2:65][CH2:66]2)[CH2:60][C:59]3=[O:71])=[N:52]1)=[O:48]
Reactant: CCOc1cc(C(=O)O)cc(OCC)c1-c1cnn(C)c1
Reactant: CC(C)(C)C(=O)OCn1nnc(-c2ccc3c(c2)C(=O)CC2(CCNCC2)O3)n1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Solvent: O
Product: CCOc1cc(C(=O)N2CCC3(CC2)CC(=O)c2cc(-c4nnn(COC(=O)C(C)(C)C)n4)ccc2O3)cc(OCC)c1-c1cnn(C)c1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
Et3N (223 μL), HOBT (123 mg) and WSC hydrochloride (154 mg) were added to a DMF (8 mL) solution of 3,5-diethoxy-4-(1-methyl-1H-pyrazol-4-yl)benzoic acid (194 mg) and [5-(4-oxospiro[chroman-2,4′-piperidin]-6-yl)-2H-tetrazol-2-yl]methyl 2,2-dimethylpropanoate hydrochloride (349 mg), and stirred overnight at room temperature. The reaction liquid was poured into saturated saline water, extracted with ethyl acetate, and the organic layer was washed with water and saturated saline water. The organic layer was dried with sodium sulfate, filtered, concentrated, and purified through silica gel column chromatography (hexane/EtOAc) to obtain the title compound. 1H-NMR (400 MHz, CDCl3) δ: 8.69 (1H, d, J=4.0 Hz), 8.32 (1H, dd, J=8.0, 4.0 Hz), 8.14 (1H, s), 7.97 (1H, s), 7.17 (1H, d, J=8.0 Hz), 6.64 (2H, s), 6.50 (2H, s), 4.32-4.18 (1H, m), 4.08 (4H, q, J=8.0 Hz), 3.94 (3H, s), 3.64-3.20 (3H, m), 2.97 (2H, s), 2.10-1.75 (4H, m), 1.37 (6H, t, J=8.0 Hz), 1.22 (9H, s). MS [M+H]+=672.