Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1C(C#N)=[N:4][CH:5]=[CH:6][CH:7]=1.[CH3:10][Mg]I.C([O:15][CH2:16][CH3:17])C.Cl>C1COCC1>[C:16]([C:17]1[C:2]([Cl:1])=[CH:7][CH:6]=[CH:5][N:4]=1)(=[O:15])[CH3:10]
Reactant: N#Cc1ncccc1Cl
Reactant: C[Mg]I
Reactant: CCOCC
Agent: Cl
Solvent: C1CCOC1
Product: CC(=O)c1ncccc1Cl
Reaction time: 2 h

Procedure:
Dissolve 3-chloro-2-cyanopyridine (10.0 g, 0.072 mol, Chem. Pharm. Bull. (1985) 33:565-571) in anhydrous THF (200 mL) under N2 atmosphere and cool in an ice bath. Add drop wise 3.0 M MeMgI in diethyl ether (48 ml, 0.14 mol) to the reaction mixture and stir in an ice bath for 2 hours. Pour the reaction mixture over ice cold water, acidify the mixture with 2.0 N aq. HCl to pH 2 to 3. Extract the reaction mixture with EtOAc (3×100 mL) and dry over anhydrous MgSO4. Filter, concentrate under vacuum and then filter through a pad of silica gel using 20% ethyl acetate/hexane as eluent. Removal of solvent under reduced pressure gives pure 2-acetyl-3-chloropyridine as oil.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([NH:11][C@H:12]([C:27]([OH:29])=[O:28])[CH2:13][CH2:14][CH2:15][NH:16][S:17]([C:20]2[CH:25]=[CH:24][C:23]([Br:26])=[CH:22][CH:21]=2)(=[O:19])=[O:18])(=[O:10])=[O:9])=[CH:4][CH:3]=1.[H-].[Na+].[H][H].[F:34][C:35]1[CH:42]=[CH:41][C:38]([CH2:39]Br)=[CH:37][CH:36]=1.Cl>CN(C=O)C>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([NH:11][C@H:12]([C:27]([OH:29])=[O:28])[CH2:13][CH2:14][CH2:15][N:16]([S:17]([C:20]2[CH:21]=[CH:22][C:23]([Br:26])=[CH:24][CH:25]=2)(=[O:19])=[O:18])[CH2:39][C:38]2[CH:41]=[CH:42][C:35]([F:34])=[CH:36][CH:37]=2)(=[O:10])=[O:9])=[CH:4][CH:3]=1
Reactant: O=C(O)[C@H](CCCNS(=O)(=O)c1ccc(Br)cc1)NS(=O)(=O)c1ccc(Br)cc1
Reactant: [H][H]
Reactant: Fc1ccc(CBr)cc1
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: O=C(O)[C@H](CCCN(Cc1ccc(F)cc1)S(=O)(=O)c1ccc(Br)cc1)NS(=O)(=O)c1ccc(Br)cc1
Reaction time: 1 h
Yield: 83.7 %

Procedure:
To a stirred solution of Nα,Nδ-di-(4-bromobenzenesulfonyl)-L-ornithine (145 mg, 0.25 mmol) in DMF (2.5 mL) was added NaH. The reaction was stirred at room temperature until the hydrogen evolution stoped. 4-fluorobenzyl bromide (57 mg, 0.3 mmol) in solution in DMF (0.5 mL) was added and the mixture was allowed to stirr at room temperature for 1 h. HCl (1N) was added until acidic pH (˜3) and the reaction was extracted with EtOAc. The organic layer was dried (MgSO4) and concentrated. The crude material was purified by flash chromatography eluting with hexanes:EtOAc:AcOH, 50:50:00; 25:75:00 and then 25:70:0.5 to afford 142 mg (84%) of the title compound.
Reaction SMILES: [C:1]([O:5][C:6](=[O:14])[NH:7][C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)([CH3:4])([CH3:3])[CH3:2].[Li]C(C)(C)C.[C:20]1(=[O:24])[CH2:23][CH2:22][CH2:21]1>CCOCC>[C:1]([O:5][C:6](=[O:14])[NH:7][C:8]1[CH:9]=[CH:10][CH:11]=[CH:12][C:13]=1[C:20]1([OH:24])[CH2:23][CH2:22][CH2:21]1)([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)Nc1ccccc1
Reactant: O=C1CCC1
Agent: [Li]C(C)(C)C
Solvent: CCOCC
Product: CC(C)(C)OC(=O)Nc1ccccc1C1(O)CCC1
Temperature: 25 °C
Reaction time: 3 h
Yield: 31.4 %

Procedure:
To phenyl-carbamic acid tert-butyl ester (2 g, 10.4 mmol) in ether (30 mL) at 0° C. was added t-BuLi (15 mL, 26 mmol, 1.7 M) and the reaction solution stirred for 3 hours prior to the addition of cyclobutanone (1.2 mL, 15.6 mmol). The reaction mixture was allowed to warm to room temperature. Upon completion by thin-layer chromatography (TLC), the reaction was poured into ice-cold saturated ammonium chloride (100 mL) and extracted with ethyl acetate (50 mL). The organics were dried over sodium sulfate, concentrated, and purified on a silica gel column (10% ethyl acetate/hexane) to give tert-butyl[2-(1-hydroxycyclobutyl)phenyl]carbamate (0.86 g, 32%) as a white solid. 1H NMR (DMSO-d6): δ 8.48 (s, 1H), 7.8 (d, 1H, J=7.92 Hz), 7.35 (dd, 1H, J=7.7, 1.4 Hz), 7.25 (td, 1H, J=7.5, 1.6 Hz), 7.03 (td, 1H, J=7.5, 1.3 Hz), 2.51–2.49 (m, 2H), 2.43–2.39 (m, 2H), 2.28–2.25 (m, 2H), 1.45 (s, 9H). MS (ESI) m/z 190 ([M+H]+); MS (ESI) m/z 188 ([M−H]−);
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([C@@H:9]2[C@@H:14]([O:15][CH2:16][C:17]3[CH:18]=[CH:19][C:20]4[O:25][CH2:24][CH2:23][N:22]([CH2:26][CH2:27][CH2:28][O:29][CH3:30])[C:21]=4[CH:31]=3)[CH2:13][N:12]([S:32]([C:35]3[CH:40]=[CH:39][C:38]([CH3:41])=[CH:37][CH:36]=3)(=[O:34])=[O:33])[C@@H:11]([CH2:42][C:43](=[O:46])[CH:44]=[CH2:45])[CH2:10]2)=[CH:5][CH:4]=1.C(N1CCN2CCN(C(CC)C)P1N(C(CC)C)CC2)(CC)C.[CH3:70][OH:71]>Cl>[CH3:70][O:71][CH2:45][CH2:44][C:43](=[O:46])[CH2:42][C@H:11]1[CH2:10][C@H:9]([C:6]2[CH:7]=[CH:8][C:3]([O:2][CH3:1])=[CH:4][CH:5]=2)[C@@H:14]([O:15][CH2:16][C:17]2[CH:18]=[CH:19][C:20]3[O:25][CH2:24][CH2:23][N:22]([CH2:26][CH2:27][CH2:28][O:29][CH3:30])[C:21]=3[CH:31]=2)[CH2:13][N:12]1[S:32]([C:35]1[CH:40]=[CH:39][C:38]([CH3:41])=[CH:37][CH:36]=1)(=[O:34])=[O:33]
Reactant: C=CC(=O)C[C@H]1C[C@H](c2ccc(OC)cc2)[C@@H](OCc2ccc3c(c2)N(CCCOC)CCO3)CN1S(=O)(=O)c1ccc(C)cc1
Reactant: CO
Agent: CCC(C)N1CCN2CCN(C(C)CC)P1N(C(C)CC)CC2
Agent: Cl
Product: COCCCN1CCOc2ccc(CO[C@H]3CN(S(=O)(=O)c4ccc(C)cc4)[C@@H](CC(=O)CCOC)C[C@@H]3c3ccc(OC)cc3)cc21
Temperature: 35 °C

Procedure:
To a stirred solution of 0.5 g of 1-[(2R,4R,5R)-4-(4-methoxy-phenyl)-5-[4-(3-methoxy-propyl)-3,4-dihydro-2H-benzo[1,4]oxazin-6-ylmethoxy]-1-(toluene-4-sulfonyl)-piperidin-2-yl]-but-3-en-2-one in 1.5 ml of methanol is added 38 mg of 2,8,9-tri-sec-butyl-2,5,8,9-tetraaza-1-phospha-bicyclo[3.3.3]undecane and the reaction mixture is heated to 35° C. for 1 day. The reaction mixture is diluted with 1N hydrochloric acid solution and extracted with ethyl acetate. The organic phases are combined, dried and concentrated under reduced pressure to afford the crude title compound. The residue is purified by flash chromatography (SiO2 60 F) to afford the title compound as a yellow oil. Rf=0.25 (EtOAc-heptane 2:3); Rt=5.16.
Reaction SMILES: [N+:1]([C:4]1[CH:11]=[CH:10][C:7]([CH:8]=O)=[CH:6][CH:5]=1)([O-:3])=[O:2].[C:12]([O:18][CH3:19])(=[O:17])[CH2:13][C:14]([CH3:16])=[O:15].N1CCCCC1.C(O)(=O)C>CC(O)C>[N+:1]([C:4]1[CH:11]=[CH:10][C:7]([CH:8]=[C:13]([C:14](=[O:15])[CH3:16])[C:12]([O:18][CH3:19])=[O:17])=[CH:6][CH:5]=1)([O-:3])=[O:2]
Reactant: O=Cc1ccc([N+](=O)[O-])cc1
Reactant: COC(=O)CC(C)=O
Solvent: C1CCNCC1
Solvent: CC(=O)O
Solvent: CC(C)O
Product: COC(=O)C(=Cc1ccc([N+](=O)[O-])cc1)C(C)=O
Temperature: 25 °C
Reaction time: 48 h

Procedure:
A mixture of 4-nitrobenzaldehyde (15.1 g, 0.1 mol), methyl acetoacetate (12.773 g, 0.11 mol), piperidine (0.41 g, 476 mL, 4.8 mmol), and acetic acid (0.288 g, 274 mL, 4.8 mmol) in 2-propanol (400 mL) was stirred at room temperature for 48 hours. The white solid, methyl 2-{(4-nitrophenyl)methylene}-3-oxobutyrate, formed was filtered, washed with 2-propanol (2×50 mL) and dried (21.80 g, 93%).
Reaction SMILES: [CH:1](=O)[CH3:2].[C:4](O)(=O)[CH3:5].[N+:8]([C:11]1[CH:12]=[C:13]2[C:19]([NH2:20])=[N:18][NH:17][C:14]2=[N:15][CH:16]=1)([O-:10])=[O:9].[BH-](OC(C)=O)(OC(C)=O)OC(C)=O.[Na+]>C1COCC1.ClC(Cl)C.C(OCC)(=O)C>[CH2:4]([N:20]([CH2:1][CH3:2])[C:19]1[C:13]2[C:14](=[N:15][CH:16]=[C:11]([N+:8]([O-:10])=[O:9])[CH:12]=2)[NH:17][N:18]=1)[CH3:5]
Reactant: Nc1n[nH]c2ncc([N+](=O)[O-])cc12
Reactant: CC(=O)O
Reactant: CC=O
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CC(Cl)Cl
Solvent: C1CCOC1
Product: CCN(CC)c1n[nH]c2ncc([N+](=O)[O-])cc12
Reaction time: 60 h
Yield: 16 %

Procedure:
Acetaldehyde (0.258 g, 5.86 mmol) and a drop of acetic acid were added to a solution of 5-nitro-1H-pyrazolo[3,4-b]pyridin-3-amine (0.105 g, 0.586 mmol) in THF/dichloroethane (“DCE”) (12 mL, 1:1). NaBH(OAc)3 (1.24 g, 5.86 mmol) was added, and the mixture was left at room temperature for 60 hours. The reaction mixture was diluted with ethyl acetate (50 mL) and quenched with water (10 mL). The aqueous layer was extracted with ethyl acetate (2×50 mL). The combined organic layers were dried, filtered and concentrated. The crude product was purified by column chromatography, eluting with hexanes/ethyl acetate (9:1), hexanes/ethyl acetate (4:1) to give N,N-diethyl-5-nitro-1H-pyrazolo[3,4-b]pyridin-3-amine (22 mg, 16% yield) as a solid.
Reaction SMILES: [OH:1][C:2]1[CH:14]=[CH:13][C:12]([N+:15]([O-])=O)=[CH:11][C:3]=1[C:4]([CH2:6][CH2:7][C:8]([OH:10])=[O:9])=[O:5]>[OH-].[NH4+].O>[NH2:15][C:12]1[CH:13]=[CH:14][C:2]([OH:1])=[C:3]([CH:11]=1)[C:4]([CH2:6][CH2:7][C:8]([OH:10])=[O:9])=[O:5]
Reactant: O=C(O)CCC(=O)c1cc([N+](=O)[O-])ccc1O
Agent: [NH4+]
Agent: [OH-]
Solvent: O
Product: Nc1ccc(O)c(C(=O)CCC(=O)O)c1
Reaction time: 1 h
Yield: 45.7 %

Procedure:
A solution of 3-(2-hydroxy-5-nitrobenzoyl)propionic acid (5.5 g) in ammonium hydroxide solution (5N; 100 ml) was added to a stirred, boiling solution of ferrous sulphate heptahydrate (45 g) in water (200 ml). Stirring under reflux was continued for a further 60 minutes, ammonium hydroxide solution was added until the mixture had pH 9, the reaction mixture filtered through Kieselguhr and the filtrate evaporated to dryness. The solid residue was crystallised from ethanol to give pale yellow needles of 3-(5-amino-2-hydroxybenzoyl)propionic acid (2.2 g, 46%, m.p. 158°-160°C; M+, 209, M, 209).
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([C:8]2[C:16]([C:17]3[C:22]([F:23])=[CH:21][N:20]=[C:19]([NH:24][C:25]4[CH:34]=[C:33]5[C:28]([CH2:29][CH2:30][N:31]([CH3:35])[CH2:32]5)=[CH:27][CH:26]=4)[N:18]=3)=[C:11]3[CH:12]=[CH:13][CH:14]=[CH:15][N:10]3[N:9]=2)[CH:5]=[CH:6][CH:7]=1.[F:36][C:37]1[CH:45]=[CH:44][CH:43]=[C:42]([F:46])[C:38]=1[C:39](Cl)=[O:40]>C1COCC1.CO>[F:36][C:37]1[CH:45]=[CH:44][CH:43]=[C:42]([F:46])[C:38]=1[C:39]([NH:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([C:8]2[C:16]([C:17]3[C:22]([F:23])=[CH:21][N:20]=[C:19]([NH:24][C:25]4[CH:34]=[C:33]5[C:28]([CH2:29][CH2:30][N:31]([CH3:35])[CH2:32]5)=[CH:27][CH:26]=4)[N:18]=3)=[C:11]3[CH:12]=[CH:13][CH:14]=[CH:15][N:10]3[N:9]=2)[CH:3]=1)=[O:40]
Reactant: CN1CCc2ccc(Nc3ncc(F)c(-c4c(-c5cccc(N)c5)nn5ccccc45)n3)cc2C1
Reactant: O=C(Cl)c1c(F)cccc1F
Solvent: CO
Solvent: C1CCOC1
Product: CN1CCc2ccc(Nc3ncc(F)c(-c4c(-c5cccc(NC(=O)c6c(F)cccc6F)c5)nn5ccccc45)n3)cc2C1
Temperature: 25 °C
Reaction time: 0.33 h
Yield: 23.1 %

Procedure:
To a solution of N-{4-[2-(3-aminophenyl)pyrazolo[1,5-a]pyridin-3-yl]-5-fluoro-2-pyrimidinyl}-2-methyl-1,2,3,4-tetrahydro-7-isoquinolinamine (50 mg, 0.11 mmol) in THF (5 mL) was added 2,6-difluorobenzoyl chloride (20 mg, 0.11 mmol) and the reaction mixture stirred at rt for 20 min. The reaction was diluted with MeOH, adsorbed onto silica gel, and purified by column chromatography (0-10% MeOH/DCM+1% NH4OH) to afford the title compound (15.4 mg, 24%) as a pale yellow solid. 1H NMR (400 MHz, DMSO-d6) δ 10.86 (s, 1H), 9.52 (s, 1H), 8.86 (d, J=7.69 Hz, 1H), 8.45-8.46 (m, 1H), 8.06 (s, 1H), 7.89 (d, J=8.61 Hz, 1H), 7.71-7.73 (m, 1H), 7.54-7.58 (m, 1H), 7.30-7.47 (m, 4H), 7.20-7.24 (m, 3H), 7.08-7.12 (m, 1H), 6.86 (d, J=8.42 Hz, 1H), 3.26 (s, 2H), 2.66-2.69 (m, 2H), 2.49-2.51 (m, 2H), 2.26 (s, 3H). ES-LC/MS m/z=606 [M+H]+.
Reaction SMILES: [C:1]([C:3]1[CH:4]=[CH:5][C:6]2[O:10][C:9]([C:11]([C:13]3[C:21]([O:22][CH3:23])=[CH:20][C:19]([CH3:24])=[C:18]4[C:14]=3[CH:15]=[CH:16][N:17]4[C:25]([O:27][C:28]([CH3:31])([CH3:30])[CH3:29])=[O:26])=O)=[N:8][C:7]=2[CH:32]=1)#[N:2].[CH3:33][C:34]([S:37]([NH2:39])=[O:38])([CH3:36])[CH3:35]>C1(C)C=CC=CC=1.CCOC(C)=O.[Cl-].[Na+].O>[C:34]([S:37]([N:39]=[C:11]([C:9]1[O:10][C:6]2[CH:5]=[CH:4][C:3]([C:1]#[N:2])=[CH:32][C:7]=2[N:8]=1)[C:13]1[C:21]([O:22][CH3:23])=[CH:20][C:19]([CH3:24])=[C:18]2[C:14]=1[CH:15]=[CH:16][N:17]2[C:25]([O:27][C:28]([CH3:30])([CH3:31])[CH3:29])=[O:26])=[O:38])([CH3:36])([CH3:35])[CH3:33]
Reactant: COc1cc(C)c2c(ccn2C(=O)OC(C)(C)C)c1C(=O)c1nc2cc(C#N)ccc2o1
Reactant: CC(C)(C)S(N)=O
Agent: [Cl-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: Cc1ccccc1
Solvent: O
Product: COc1cc(C)c2c(ccn2C(=O)OC(C)(C)C)c1C(=NS(=O)C(C)(C)C)c1nc2cc(C#N)ccc2o1

Procedure:
To a solution of tert-butyl 4-(5-cyanobenzo[d]oxazole-2-carbonyl)-5-methoxy-7-methyl-1H-indole-1-carboxylate (Example 126-A) (711 mg, 1.648 mmol) and 2-methyl-2-propanesulfinamide (599 mg, 4.94 mmol) in toluene (16.5 mL), Zr(O-t-Bu)4 (4.33 mL, 8.24 mmol) was added at room temperature. After 2 hours the reaction mixture was diluted with EtOAc and brine. The resulting mixture was filtered through Celite® and the organic layer of the filtrate was dried over MgSO4, filtered, and concentrated. The resulting residue was purified by flash chromatography (0-80% EtOAc:Heptanes) to provide the title compound. MS (ESI+) m/z 535.2 (M+H).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:9]2[CH:13]([NH:14][CH3:15])[CH2:12][N:11]([C:16]([CH:18]3[CH2:23][CH2:22][N:21]([C:24]([C:26]4([CH3:29])[CH2:28][CH2:27]4)=[O:25])[CH2:20][CH2:19]3)=[O:17])[CH2:10]2)[CH:5]=[CH:6][C:7]=1[Cl:8].[F:30][C:31]1[CH:36]=[CH:35][C:34]([CH:37]([CH:41]([CH3:43])[CH3:42])[C:38]([OH:40])=O)=[CH:33][CH:32]=1>>[Cl:1][C:2]1[CH:3]=[C:4]([CH:9]2[CH2:10][N:11]([C:16]([CH:18]3[CH2:19][CH2:20][N:21]([C:24]([C:26]4([CH3:29])[CH2:27][CH2:28]4)=[O:25])[CH2:22][CH2:23]3)=[O:17])[CH2:12][CH:13]2[N:14]([CH3:15])[C:38](=[O:40])[CH:37]([C:34]2[CH:33]=[CH:32][C:31]([F:30])=[CH:36][CH:35]=2)[CH:41]([CH3:43])[CH3:42])[CH:5]=[CH:6][C:7]=1[Cl:8]
Reactant: CNC1CN(C(=O)C2CCN(C(=O)C3(C)CC3)CC2)CC1c1ccc(Cl)c(Cl)c1
Reactant: CC(C)C(C(=O)O)c1ccc(F)cc1
Product: CC(C)C(C(=O)N(C)C1CN(C(=O)C2CCN(C(=O)C3(C)CC3)CC2)CC1c1ccc(Cl)c(Cl)c1)c1ccc(F)cc1

Procedure:
In analogy to the procedure described for the synthesis of example 97, the title compound N-{(3RS,4SR)-4-(3,4-dichloro-phenyl)-1-[1-(1-methyl-cyclopropanecarbonyl)-piperidine-4-carbonyl]-pyrrolidin-3-yl}-2-(4-fluoro-phenyl)-3,N-dimethyl-butyramide was prepared from {4-[(3SR,4RS)-3-(3,4-dichloro-phenyl)-4-methylamino-pyrrolidine-1-carbonyl]-piperidin-1-yl}-(1-methyl-cyclopropyl)-methanone using 2-(4-fluoro-phenyl)-3-methyl-butyric acid instead of 4-chloro-3-(trifluoromethyl)benzoic acid and was obtained as a light brown oil. MS m/e: 616.4 [M]+.
Reaction SMILES: [CH2:1]([O:4][C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][C:6]=1[C:11]1[NH:20][C:19](=[O:21])[C:18]2[C:13](=[C:14](I)[CH:15]=[CH:16][CH:17]=2)[N:12]=1)[CH2:2][CH3:3].[C:23]1([CH2:29][CH2:30][CH:31]=[CH:32][CH3:33])[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1>>[CH2:1]([O:4][C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][C:6]=1[C:11]1[NH:20][C:19](=[O:21])[C:18]2[C:13](=[C:14]([C:31](=[CH:30][CH2:29][C:23]3[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=3)[CH2:32][CH3:33])[CH:15]=[CH:16][CH:17]=2)[N:12]=1)[CH2:2][CH3:3]
Reactant: CCCOc1ccccc1-c1nc2c(I)cccc2c(=O)[nH]1
Reactant: CC=CCCc1ccccc1
Product: CCCOc1ccccc1-c1nc2c(C(=CCc3ccccc3)CC)cccc2c(=O)[nH]1
Yield: 64.6 %

Procedure:
The title compounds are prepared analogously to the method of Example 1, starting with the compound from Example III and 5-phenyl-2-pentene.
Reaction SMILES: [NH2:1][C@H:2]([C:4]1[N:9]([C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)[C:8](=[O:16])[C:7]2=[C:17]([CH3:20])[CH:18]=[CH:19][N:6]2[N:5]=1)[CH3:3].Cl[C:22]1[C:23]2[CH:31]=[CH:30][S:29][C:24]=2[N:25]=[C:26]([CH3:28])[N:27]=1.C(N(CC)C(C)C)(C)C>>[CH3:20][C:17]1[CH:18]=[CH:19][N:6]2[C:7]=1[C:8](=[O:16])[N:9]([C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1)[C:4]([C@@H:2]([NH:1][C:22]1[C:23]3[CH:31]=[CH:30][S:29][C:24]=3[N:25]=[C:26]([CH3:28])[N:27]=1)[CH3:3])=[N:5]2
Reactant: Cc1ccn2nc([C@H](C)N)n(-c3ccccc3)c(=O)c12
Reactant: Cc1nc(Cl)c2ccsc2n1
Solvent: CCN(C(C)C)C(C)C
Product: Cc1nc(N[C@@H](C)c2nn3ccc(C)c3c(=O)n2-c2ccccc2)c2ccsc2n1
Yield: 40.5 %

Procedure:
(S)-2-(1-Aminoethyl)-5-methyl-3-phenylpyrrolo[2,1-f][1,2,4]triazin-4(3H)-one (50 mg, 0.16 mmol) was treated with 4-chloro-2-methylthieno[2,3-d]pyrimidine (45 mg, 0.25 mmol), N,N-diisopropylethylamine (257 μl, 1.48 mmol) according to the method described in Example 17. The crude was purified using SP1® Purification System by reverse phase to give 27 mg (40% yield) of the title compound as a white solid. Purity 100%.
Reaction SMILES: C[C:2]([CH3:5])([O-:4])C.[K+].[CH2:7]([O:14][C:15]1[CH:22]=[CH:21][C:18]([CH:19]=O)=[CH:17][CH:16]=1)[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1.C1C[O:26][CH2:25][CH2:24]1>>[CH2:7]([O:14][C:15]1[CH:22]=[CH:21][C:18](/[CH:19]=[CH:24]/[C:25]([O:4][CH2:2][CH3:5])=[O:26])=[CH:17][CH:16]=1)[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1
Reactant: CC(C)(C)[O-]
Reactant: C1CCOC1
Reactant: O=Cc1ccc(OCc2ccccc2)cc1
Agent: [K+]
Product: CCOC(=O)/C=C/c1ccc(OCc2ccccc2)cc1
Temperature: 0 °C
Reaction time: 0.62 h
Yield: 95 %

Procedure:
Triethyl phosphonoacetate (259 mL, 1.3 mol) was added slowly drop wise to a solution of Potassium-tert-butoxide (145 g, 1.29 mol) in dry THF (2 L) at −5° C. and stirred for 30-45 mins. Then a solution of 4-(benzyloxy)benzaldehyde (Intermediate P, 230 g, 1.08 mol) in dry THF (1.5 L) was added slowly drop wise at −10° C. over a period of 15 mins and stirred for 30 mins. After completion, the reaction mixture was poured into ice water (1 L) and extracted with EtOAc (2×1.5 L). The combined organic extracts were washed with sat NaHCO3 solution (1 L), water (1 L), brine (1 L), dried over anhydrous Na2SO4, filtered and evaporated to get crude (E)-ethyl 3-(4-(benzyloxy)phenyl)acrylate (290 g, 95%). The crude was carried to next step without further purification.
Reaction SMILES: N#N.[F:3][C:4]([C:7]1[O:8][CH:9]=[C:10]([CH2:12][OH:13])[N:11]=1)([F:6])[CH3:5].CCN(CC)CC.[S:21](Cl)([CH3:24])(=[O:23])=[O:22]>C(Cl)Cl.CN(C1C=CN=CC=1)C>[CH3:24][S:21]([O:13][CH2:12][C:10]1[N:11]=[C:7]([C:4]([F:6])([F:3])[CH3:5])[O:8][CH:9]=1)(=[O:23])=[O:22]
Reactant: CC(F)(F)c1nc(CO)co1
Reactant: CS(=O)(=O)Cl
Agent: CN(C)c1ccncc1
Agent: N#N
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CC(F)(F)c1nc(COS(C)(=O)=O)co1
Temperature: 0 °C
Reaction time: 1.5 h
Yield: 92.9 %

Procedure:
In a flame dried round-bottomed flask equipped with a magnetic stir bar and under inert atmosphere (N2), a solution of (2-(1,1-difluoroethyl)oxazol-4-yl)methanol (505 mg, 3.10 mmol) in dry CH2Cl2 (15 mL) was treated at 0° C. with Et3N (0.56 mL, 4.03 mmol) followed by DMAP (38 mg, 0.31 mmol) and Ms-Cl (0.31 mL, 3.91 mmol). After stirring at 0° C. for 1.5 h, the reaction was quenched with water. The layers were separated and the aq. layer extracted with CH2Cl2 (3×) The org. layer was dried over Na2SO4, filtered, and the solvents were removed under reduced pressure to give 695 mg of crude (2-(1,1-difluoroethyl)oxazol-4-yl)methyl methanesulfonate as a yellow solid. A solution of this crude material in DMF (8 mL) was added to a solution of 4-nitro-2H-[1,2,3]triazole (3.08 g of a 10% solution in acetone, 2.70 mmol) in DMF (10 mL) pre-treated for 30 min with DIPEA (0.9 mL, 5.39 mmol) and the reaction mixture was stirred overnight at 50° C. Water (30 mL), followed by EA (50 mL) were added. The aq. layer was extracted with EA (50 mL) and the combined org. extracts were dried over Na2SO4, filtered, and the solvents were removed under reduced pressure. Purification of the residue by FC (5:1→2:1 hept-EA) gave the title compound as a yellow solid: TLC:rf (1:2 hept-EA)=0.4. LC-MS-conditions 01: tR=0.89 min, [M]+=259.11.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:15])[C:4]1[CH:13]=[C:12](Br)[CH:11]=[C:6]([C:7]([O:9][CH3:10])=[O:8])[CH:5]=1.[CH:16]([C:18]1[CH:23]=[CH:22][N:21]=[CH:20][CH:19]=1)=[CH2:17].C1(C)C=CC=CC=1P(C1C=CC=CC=1C)C1C=CC=CC=1C>CCN(CC)CC.CC([O-])=O.CC([O-])=O.[Pd+2]>[CH3:1][O:2][C:3](=[O:15])[C:4]1[CH:13]=[C:12]([CH:17]=[CH:16][C:18]2[CH:23]=[CH:22][N:21]=[CH:20][CH:19]=2)[CH:11]=[C:6]([C:7]([O:9][CH3:10])=[O:8])[CH:5]=1
Reactant: C=Cc1ccncc1
Reactant: COC(=O)c1cc(Br)cc(C(=O)OC)c1
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: Cc1ccccc1P(c1ccccc1C)c1ccccc1C
Solvent: CCN(CC)CC
Product: COC(=O)c1cc(C=Cc2ccncc2)cc(C(=O)OC)c1
Yield: 65 %

Procedure:
A solution of 5-bromoisophthalic acid dimethylester (542 mg, 2 mmol) and 4-vinylpyridine (206 mg, 2 mmol), Pd(OAc)2 (8 mg), tri-o-tolylphosphine (30 mg) in 5 ml Et3N (5 ml) was stirred at 80° C. for overnight. The reaction mixture was purified by silica gel column eluted by 50% EtOAc in hexane to afford the product (65% yield). MS+=297. 1H NMR (CDCl3, 400 MHz) 8.64 (s, 1H), 8.61 (d, 2H), 8.38 (d, 2H), 7.40 (m, 2H), 7.35 (m, 1H), 7.21 (m, 1H), 4.02 (s, 6H);
Reaction SMILES: Cl.[N:2]1([C:8]([CH2:10][C:11]2[C:19]3[C:14](=[CH:15][CH:16]=[C:17]([C:20]#[N:21])[CH:18]=3)[NH:13][CH:12]=2)=[O:9])[CH2:7][CH2:6][NH:5][CH2:4][CH2:3]1.C(N([CH2:27][CH3:28])CC)C.[C:29]1(C)[C:30]([S:35](Cl)(=[O:37])=[O:36])=[CH:31][CH:32]=C[CH:34]=1>C(Cl)(Cl)Cl>[C:27]1([CH3:28])[CH:32]=[CH:31][C:30]([S:35]([N:5]2[CH2:6][CH2:7][N:2]([C:8]([CH2:10][C:11]3[C:19]4[C:14](=[CH:15][CH:16]=[C:17]([C:20]#[N:21])[CH:18]=4)[NH:13][CH:12]=3)=[O:9])[CH2:3][CH2:4]2)(=[O:37])=[O:36])=[CH:29][CH:34]=1
Reactant: CCN(CC)CC
Reactant: N#Cc1ccc2[nH]cc(CC(=O)N3CCNCC3)c2c1
Reactant: Cc1ccccc1S(=O)(=O)Cl
Agent: Cl
Solvent: ClC(Cl)Cl
Product: Cc1ccc(S(=O)(=O)N2CCN(C(=O)Cc3c[nH]c4ccc(C#N)cc34)CC2)cc1
Temperature: 25 °C
Reaction time: 18 h
Yield: 85 %

Procedure:
To a stirred solution of 3-(piperazinecarbonyl)methyl-5-cyanoindole hydrochloride (200 mg, 0.66 mmol) and triethylamine (134 mg, 185 μL) in chloroform was added toluenesulfonylchloride (126 mg, 0.66 mmol). After stirring for 18 h at rt under a nitrogen atmosphere, the reaction was quenched with water, extracted with chloroform, washed with 1N HCl, sat sodium bicarbonate, and brine, dried with sodium sulfate, filtered and concentrated in vacuo to afford 237 mg of product. LRMS (M+H)+ 423.
Reaction SMILES: [CH:1]([O:4][C:5]1[NH:9][N:8]=[C:7]([NH2:10])[CH:6]=1)([CH3:3])[CH3:2].[Cl:11][C:12]1[N:19]=[C:18](Cl)[C:17]([F:21])=[CH:16][C:13]=1[C:14]#[N:15].C(N(CC)CC)C>C1COCC1>[Cl:11][C:12]1[N:19]=[C:18]([NH:10][C:7]2[CH:6]=[C:5]([O:4][CH:1]([CH3:3])[CH3:2])[NH:9][N:8]=2)[C:17]([F:21])=[CH:16][C:13]=1[C:14]#[N:15]
Reactant: N#Cc1cc(F)c(Cl)nc1Cl
Reactant: CC(C)Oc1cc(N)n[nH]1
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: CC(C)Oc1cc(Nc2nc(Cl)c(C#N)cc2F)n[nH]1
Temperature: 25 °C
Yield: 49.7 %

Procedure:
A solution of 5-isopropoxy-1H-pyrazol-3-amine (0.96 g, 6.8 mmol), 2,6-dichloro-5-fluoronicotinonitrile (1.3 g, 6.8 mmol), and triethylamine (0.9 g, 8.8 mmol) in THF (30 ml) was heated to 60° C. for 4 days, and then cooled to 25° C., at which point the product precipitated. The resulting solid was filtered and washed with hexanes (100 ml) to give the title compound (1.0 g, 50%). MS: Calcd.: 295. Found: [M+H]+ 296.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]([CH2:10]C=O)=N)=[CH:4][CH:3]=1.[NH2:13][C:14]([NH2:16])=[O:15].Cl.[CH2:18](O)C>>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[CH:10]=[N:13][C:14]([OH:15])=[N:16][CH:18]=2)=[CH:6][CH:7]=1
Reactant: NC(N)=O
Reactant: N=C(CC=O)c1ccc(Cl)cc1
Reactant: CCO
Agent: Cl
Product: Oc1ncc(-c2ccc(Cl)cc2)cn1

Procedure:
A mixture of 20.0 g. of (p-chlorophenyl)formimidoylacetaldehyde and 5.0 g. of urea is heated under reflux in 50 ml. of ethanol and 10 ml. of concentrated hydrochloric acid for 5 hours. The reaction mixture is worked up as described in Example 4 and the product is crystallized from ethanol to give 13.0 g. of a solid. The solid in 260 ml. of ethanol and 13 ml. of concentrated hydrochloric acid is heated under reflux for 16 hours. The reaction mixture is cooled and the material which is separated is collected and dissolved in a minimum of dimethyl sulfoxide. Dilute ammonium hydroxide (20%) is added and the product is collected, washed with water, ethanol, and ether to yield 8.78 g. of the product of the Example, m.p. 324°-327° C.