Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[CH:9][CH:8]=[CH:7][C:3]=1[C:4]([NH2:6])=[O:5].C(Cl)(=O)[C:12](Cl)=[O:13]>ClCCCl>[Cl:1][C:2]1[CH:10]=[CH:9][CH:8]=[CH:7][C:3]=1[C:4]([N:6]=[C:12]=[O:13])=[O:5]
Reactant: NC(=O)c1ccccc1Cl
Reactant: O=C(Cl)C(=O)Cl
Solvent: ClCCCl
Product: O=C=NC(=O)c1ccccc1Cl
Temperature: 100 °C
Reaction time: 8 h

Procedure:
0.23 g (1.5 mmol) of 2-chlorobenzamide and 0.19 g (1.6 mmol, 1.1 eq) of oxalyl chloride were added to 10 ml of 1,2-dichloroethane and then the mixture was stirred for 8 hours at 100° C. The reaction solution was cooled down to room temperature. The reaction solvent and excessive oxalyl chloride were removed by distillation under reduced pressure to obtain 2-chlorobenzoyl isocyanate in an oily state. 10 ml of fresh 1,2-dichloroethane and 0.28 g (1.5 mmol) of 2,5-dichloro-4-cyano aniline were successively added thereto, reacted for 2 hours and filtered to obtain 0.43 g (Yield 78%) of the title compound as a solid.
Reaction SMILES: C(OC([N:8]1[CH2:17][CH2:16][C:15]2[C:11](=[C:12](OS(C(F)(F)F)(=O)=O)[N:13]([CH:18]([CH3:20])[CH3:19])[N:14]=2)[CH2:10][CH2:9]1)=O)(C)(C)C.[CH:29]([C:32]1[CH:37]=[CH:36][C:35](B(O)O)=[CH:34][CH:33]=1)([CH3:31])[CH3:30]>>[CH:18]([N:13]1[C:12]([C:35]2[CH:36]=[CH:37][C:32]([CH:29]([CH3:31])[CH3:30])=[CH:33][CH:34]=2)=[C:11]2[C:15]([CH2:16][CH2:17][NH:8][CH2:9][CH2:10]2)=[N:14]1)([CH3:19])[CH3:20]
Reactant: CC(C)n1nc2c(c1OS(=O)(=O)C(F)(F)F)CCN(C(=O)OC(C)(C)C)CC2
Reactant: CC(C)c1ccc(B(O)O)cc1
Product: CC(C)c1ccc(-c2c3c(nn2C(C)C)CCNCC3)cc1
Yield: 94.2 %

Procedure:
The title compound (177 mg) was prepared according to Example 189 using 270 mg of 2-isopropyl-3-trifluoromethanesulfonyloxy-4,5,7,8-tetrahydro-2H-1,2,6-triaza-azulene-6-carboxylic acid tert-butyl ester (Example 189, Step A) and 311 mg of 4-isopropylphenylboronic acid. MS (ESI): exact mass calculated for C19H27N3, 297.44; found, m/z 298.5 [M+H]+. 1H NMR (500 MHz, CD3OD): 7.35-7.34 (m, 2H), 7.19-7.17 (m, 2H), 4.57 (br s, 1H), 4.38-4.32 (m, 1H), 3.36-3.34 (m, 1H), 3.15-3.13 (m, 1H), 2.90 (m, 1H), 2.79-2.70 (m, 2H), 1.31 (d, J=13.3 Hz, 6H), 1.20 (d, J=6.9 Hz, 6H).
Reaction SMILES: CS(Cl)(=O)=O.[OH:6][CH2:7][CH:8]1[CH2:13][CH2:12][N:11]([C:14]([O:16][C:17]([CH3:20])([CH3:19])[CH3:18])=[O:15])[CH2:10][CH2:9]1.C(N(CC)CC)C.[Br:28][C:29]1[N:34]=[CH:33][C:32](O)=[CH:31][CH:30]=1.C([O-])([O-])=O.[K+].[K+]>O.CN(C=O)C.C(Cl)Cl>[Br:28][C:29]1[N:34]=[CH:33][C:32]([O:6][CH2:7][CH:8]2[CH2:13][CH2:12][N:11]([C:14]([O:16][C:17]([CH3:20])([CH3:19])[CH3:18])=[O:15])[CH2:10][CH2:9]2)=[CH:31][CH:30]=1
Reactant: CC(C)(C)OC(=O)N1CCC(CO)CC1
Reactant: Oc1ccc(Br)nc1
Agent: CS(=O)(=O)Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CC(C)(C)OC(=O)N1CCC(COc2ccc(Br)nc2)CC1
Temperature: 0 °C
Reaction time: 1 h
Yield: 42.3 %

Procedure:
Methanesulfonyl chloride (1.8 mL, 23.4 mmol) was added to a mixture of 1,1-dimethylethyl 4-(hydroxymethyl)-1-piperidinecarboxylate (4.8 g, 22.3 mmol), triethylamine (3.4 mL, 24.5 mmol), and CH2Cl2 (100 mL) at 0° C. The mixture stirred at 0° C. for 1 h. The mixture was washed with water. The organics were dried over MgSO4, filtered, and the filtrate was concentrated. The resulting residue was charged with 6-bromo-3-pyridinol (3.88 g, 22.3 mmol), K2CO3 (6.16 g, 44.6 mmol), DMF (50 mL), and was stirred at 90° C. overnight. The mixture was cooled to ambient temperature, and was set at ambient temperature overnight. The mixture was charged with water, and was stirred at ambient temperature for 4 h. The resulting tan precipitate was filtered, washed with water, and air-dried. The precipitate was purified by chromatography on a silica gel column using 0 to 10% MeOH/CH2Cl2 to give 3.6 g (43%) of 1,1-dimethylethyl 4-{[(6-bromo-3-pyridinyl)oxy]methyl}-1-piperidinecarboxylate as a white solid, and 3.5 g of 1,1-dimethylethyl 4-{[(6-bromo-3-pyridinyl)oxy]methyl}-1-piperidinecarboxylate that contained impurities. The impure batch was repurified by chromatography on a silica gel column using 0 to 2.5% MeOH/CH2Cl2 to give 2.8 g (34%) of 1,1-dimethylethyl 4-{[(6-bromo-3-pyridinyl)oxy]methyl}-1-piperidinecarboxylate as an off-white solid which still contained a ˜17% impurity. 1H NMR (400 MHz, CDCl3): δ 8.02 (d, 1H, J=3.0 Hz), 7.34 (d, 1H, J=8.7 Hz), 7.06 (dd, 1H, Ja=8.7 Hz, Jb=3.1 Hz), 4.15 (d, 2H, J=10.3 Hz), 3.80 (d, 2H, J=6.3 Hz), 2.72 (t, 2H, J=12.4 Hz), 2.01-1.85 (m, 1H), 1.79 (d, 2H, J=12.8 Hz), 1.44 (s, 9H), 1.32-1.13 (m, 2H); LRMS (ESI), m/z 371/373 (M+H).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[C:12]([CH3:13])=[C:11]([C:14](Cl)=[O:15])[CH:10]=[N:9]2)=[CH:4][CH:3]=1.[NH2:17][C:18]1[CH:19]=[CH:20][C:21]([O:26][CH2:27][CH2:28][N:29]2[CH2:34][CH2:33][O:32][CH2:31][CH2:30]2)=[C:22]([CH:25]=1)[C:23]#[N:24]>>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[C:12]([CH3:13])=[C:11]([C:14]([NH:17][C:18]3[CH:19]=[CH:20][C:21]([O:26][CH2:27][CH2:28][N:29]4[CH2:30][CH2:31][O:32][CH2:33][CH2:34]4)=[C:22]([C:23]#[N:24])[CH:25]=3)=[O:15])[CH:10]=[N:9]2)=[CH:4][CH:3]=1
Reactant: Cc1c(C(=O)Cl)cnn1-c1ccc(Cl)cc1
Reactant: N#Cc1cc(N)ccc1OCCN1CCOCC1
Product: Cc1c(C(=O)Nc2ccc(OCCN3CCOCC3)c(C#N)c2)cnn1-c1ccc(Cl)cc1
Yield: 85.9 %

Procedure:
By the reaction and treatment in the same manner as in Example 150 using 1-(4-chlorophenyl)-5-methylpyrazole-4-carboxylic chloride (0.65 g) and 5-amino-2-(2-morpholinoethoxy)benzonitrile (0.95 g), the title compound (1.02 g) was obtained, melting point: 187–189° C.
Reaction SMILES: [CH3:1][C:2]1[C:3]([N:7]=[C:8]=[S:9])=[CH:4][S:5][CH:6]=1.[NH2:10][C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=1[NH2:17]>>[NH2:10][C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=1[NH:17][C:8]([NH:7][C:3]1[C:2]([CH3:1])=[CH:6][S:5][CH:4]=1)=[S:9]
Reactant: Cc1cscc1N=C=S
Reactant: Nc1ccccc1N
Product: Cc1cscc1NC(=S)Nc1ccccc1N

Procedure:
is obtained analogously to the reaction described in example 1 b) from 4-methyl-3-thienyl isothiocyanate and 1,2-diaminobenzene. Crystalline solid having a 1st m.p. of 177-182° C., followed by another crystallization and 2nd m.p. 285-290° C.
Reaction SMILES: [OH:1][C:2]1[C:11]2[C:6](=[C:7]([C:12]([F:15])([F:14])[F:13])[CH:8]=[CH:9][CH:10]=2)[N:5]=[C:4]([C@@H:16]([NH:19]C(=O)OC(C)(C)C)[CH2:17][CH3:18])[C:3]=1[C:27]([NH:29][C:30]1[S:31][CH:32]=[CH:33][N:34]=1)=[O:28].C(Cl)Cl.FC(F)(F)C(O)=O.C(=O)(O)[O-].[Na+]>O.C(#N)C>[NH2:19][C@H:16]([C:4]1[C:3]([C:27]([NH:29][C:30]2[S:31][CH:32]=[CH:33][N:34]=2)=[O:28])=[C:2]([OH:1])[C:11]2[C:6](=[C:7]([C:12]([F:13])([F:15])[F:14])[CH:8]=[CH:9][CH:10]=2)[N:5]=1)[CH2:17][CH3:18]
Reactant: CC[C@H](NC(=O)OC(C)(C)C)c1nc2c(C(F)(F)F)cccc2c(O)c1C(=O)Nc1nccs1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O=C(O)C(F)(F)F
Solvent: O
Solvent: ClCCl
Product: CC[C@H](N)c1nc2c(C(F)(F)F)cccc2c(O)c1C(=O)Nc1nccs1
Temperature: 25 °C
Reaction time: 2 h
Yield: 62.6 %

Procedure:
A mixture of 6.5 g of the product of Example 7, 130 ml of methylene chloride and 65 ml of trifluoroacetic acid was stirred for 2 hours at ambient temperature and then the methylene chloride and trifluoroacetic acid were eliminated under reduced pressure. The residue was taken up in iced water and the pH was adjusted to 7 with a solution of sodium bicarbonate. The mixture was filtered and the product was washed and dried under reduced pressure at 100° C. The product obtained was dissolved at reflux in 120 ml of acetonitrile and the solution was filtered. The filtrate was concentrated to 100 ml and the crystals obtained were frozen, separated, washed and dried under reduced pressure at 100° C. to obtain 3.25 g of 2-[(S) 1-aminopropyl]-4-hydroxy-N-(2-thiazolyl)-8-trifluoromethyl-3-quinoline-carboxamide melting at 206° C. and having a specific rotation of [α]D =+177°±2.5° (c=0.8% in CH3COOH).
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][C:6]([CH3:11])=[C:5]2[C:12]([O:14][CH2:15][CH3:16])=[O:13].C(=O)([O-])[O-].[K+].[K+].[CH3:23][C:24]([CH3:26])=[O:25]>>[CH2:15]([O:14][C:12]([C:5]1[C:4]2[C:8](=[CH:9][CH:10]=[C:2]([O:1][CH2:23][CH:24]3[CH2:26][O:25]3)[CH:3]=2)[NH:7][C:6]=1[CH3:11])=[O:13])[CH3:16]
Reactant: CCOC(=O)c1c(C)[nH]c2ccc(O)cc12
Reactant: CC(C)=O
Agent: O=C([O-])[O-]
Agent: [K+]
Product: CCOC(=O)c1c(C)[nH]c2ccc(OCC3CO3)cc12
Temperature: 25 °C

Procedure:
A solution of 2.19 g (10 mmol) of ethyl 5-hydroxy-2-methyl-indole-3-carboxylate, 2.6 g (10 mmol) of 2S(+)glycidyl-3-nitrobenzenesulfonate and 1.5 g (11 mmol) of potassium carbonate in 25 mL reagent grade acetone was refluxed overnight. The mixture was then allowed to cool to room temperature and the solids were removed by vacuum filtration. The filtrate was concentrated in vacuo and the residue was dissolved in ethyl acetate. The organics were washed once with water, twice with brine, dried over sodium sulfate and concentrated in vacuo. Then the solid was dried under vacuum to give 2.65 g of the title compound as a dull tan solid; mp 93–94° C.; 1H NMR (300 MHz, CDCl3) δ 1.44 (t, J=5.3 Hz, 3H), 2.71 (s, 3H), 2.74–2.80 (m, 1H), 2.92 (t, J=4.7 Hz, 1H), 3.37–3.43 (m, 1H), 4.00–4.06 (m, 1 H), 4.27–4.31 (m, 1H), 4.37 (q, J=5.3 Hz, 2H), 6.86 (dd, J=5.5, 3.0 Hz, 1H), 7.18 (d, J=8.7 Hz, 1H), 7.67 (d, J=3.0 Hz, 1H), 8.32 (s, 1H); MS (ES) m/z: 275.9 (MH+); HRMS Calcd. for C15H18NO4(MH+): 276.1236. Found: 276.1228.
Reaction SMILES: [O:1]=[C:2]1[CH:11]=[C:10]([CH:12]([CH3:16])[C:13]([OH:15])=[O:14])[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[NH:3]1.[N+:17]([O-])([OH:19])=[O:18]>O>[N+:17]([C:7]1[CH:8]=[C:9]2[C:4](=[CH:5][CH:6]=1)[NH:3][C:2](=[O:1])[CH:11]=[C:10]2[CH:12]([CH3:16])[C:13]([OH:15])=[O:14])([O-:19])=[O:18]
Reactant: CC(C(=O)O)c1cc(=O)[nH]c2ccccc12
Reactant: O=[N+]([O-])O
Solvent: O
Product: CC(C(=O)O)c1cc(=O)[nH]c2ccc([N+](=O)[O-])cc12
Temperature: 5 °C
Reaction time: 0.67 h
Yield: 90 %

Procedure:
α-(1,2-Dihydro-2-oxo-quinol-4-yl)propionic acid (15 g.) was added in portions to stirred fuming nitric acid cooled to 5° C. The rate of addition was such that the reaction temperature remained between 5° and 10° C. After the addition was complete, the mixture was stirred at ambient temperature for 40 minutes and was then poured into water (1.2 l.). The resultant solid was separated by filtration, washed with water and dried in vacuo to give α-(6-nitro-1,2-dihydro-2-oxo-quinol-4-yl)propionic acid as a white solid (90% yield), with m.p. 276°-278° C. (decomposition).
Reaction SMILES: [OH:1][C:2]1[CH:9]=[CH:8][C:5]([CH:6]=[O:7])=[CH:4][C:3]=1[CH3:10].C([O-])([O-])=O.[K+].[K+].Cl[C:18]1[CH:25]=[CH:24][C:21]([C:22]#[N:23])=[CH:20][N:19]=1.O>CN(C=O)C>[CH:6]([C:5]1[CH:8]=[CH:9][C:2]([O:1][C:18]2[CH:25]=[CH:24][C:21]([C:22]#[N:23])=[CH:20][N:19]=2)=[C:3]([CH3:10])[CH:4]=1)=[O:7]
Reactant: Cc1cc(C=O)ccc1O
Reactant: N#Cc1ccc(Cl)nc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: Cc1cc(C=O)ccc1Oc1ccc(C#N)cn1
Temperature: 25 °C
Yield: 97.1 %

Procedure:
Combine 4-hydroxy-3-methyl-benzaldehyde (401 mg, 2.94 mmol), K2CO3 (570 mg, 4.12 mmol) and 6-chloronicotinonitrile (408 mg, 2.94 mmol) in DMF (6 ml), heat at 100° C. After 4 h cool to ambient temperature and pour into water. Extract the aqueous layer with EtOAc. Dry the organic layer over Na2SO4 and eliminate the solvent. Dry under vacuum at 45° C. overnight to get the title compound (680 mg, 97%). 1H-NMR (CDCl3, 400 MHz): 9.99 (s, 1H), 8.43 (d, 1H, J=2.5 Hz), 7.97 (dd, 1H, J=2.5 and 8.8 Hz), 7.84 (bs, 1H), 7.80 (dd, 1H, J=2.5 and 8.8 Hz), 7.22 (d, 1H, J=8.4 Hz), 7.11 (d, 1H, J=8.4 Hz), 2.24 (s, 3H).
Reaction SMILES: C([O:8][C:9]1[CH:10]=[C:11]2[C:15](=[CH:16][CH:17]=1)[N:14]([S:18]([C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1)(=[O:20])=[O:19])[CH:13]=[CH:12]2)C1C=CC=CC=1.C1CCCCC=1.Cl>CCO.[Pd]>[C:21]1([S:18]([N:14]2[C:15]3[C:11](=[CH:10][C:9]([OH:8])=[CH:17][CH:16]=3)[CH:12]=[CH:13]2)(=[O:19])=[O:20])[CH:22]=[CH:23][CH:24]=[CH:25][CH:26]=1
Reactant: O=S(=O)(c1ccccc1)n1ccc2cc(OCc3ccccc3)ccc21
Agent: [Pd]
Agent: Cl
Solvent: C1=CCCCC1
Solvent: CCO
Product: O=S(=O)(c1ccccc1)n1ccc2cc(O)ccc21
Temperature: 150 °C

Procedure:
To a solution of 5-(benzyloxy)-1-(phenylsulfonyl)-1H-indole (0.50 g, 1.37 mmol; Intermediate 86) in EtOH (3 mL), Pd/C (30 wt %, 0.15 g), cyclohexene (1 mL), and HCl (1 mL) and was added. The reaction mixture was warmed to 150° C. for 1 h using microwave heating. The Pd/C was filtered off and the solvent was removed under reduced pressure. The product (about 95% pure) was used without further purification.
Reaction SMILES: FC(F)C1N2N=C(N3CCNCC3)C=CC2=NN=1.[F:19][CH:20]([F:48])[C:21]1[C:46]([F:47])=[CH:45][CH:44]=[CH:43][C:22]=1[CH2:23][N:24]1[CH2:29][CH2:28][N:27]([C:30]2[CH:31]=[CH:32][C:33]3[N:34]([C:36]([C:39](F)([F:41])[F:40])=[N:37][N:38]=3)[N:35]=2)[CH2:26][CH2:25]1>>[F:41][CH:39]([F:40])[C:36]1[N:34]2[N:35]=[C:30]([N:27]3[CH2:26][CH2:25][N:24]([CH2:23][C:22]4[CH:43]=[CH:44][CH:45]=[C:46]([F:47])[C:21]=4[CH:20]([F:19])[F:48])[CH2:29][CH2:28]3)[CH:31]=[CH:32][C:33]2=[N:38][N:37]=1
Reactant: Fc1cccc(CN2CCN(c3ccc4nnc(C(F)(F)F)n4n3)CC2)c1C(F)F
Agent: FC(F)c1nnc2ccc(N3CCNCC3)nn12
Product: Fc1cccc(CN2CCN(c3ccc4nnc(C(F)F)n4n3)CC2)c1C(F)F
Yield: 39 %

Procedure:
Obtained in 39% yield by General Synthetic Method 5, starting from 3-(difluoromethyl)-6-(piperazin-1-yl)-[1,2,4]triazolo[4,3-b]pyridazine (obtained as described in Examples 248-263, preparation of starting materials) and 2-difluoromethyl-3-fluorobenzaldehyde (obtained as described in Example 781, preparation of starting materials).
Reaction SMILES: C([O:3][C:4](=[O:27])[CH2:5][N:6]1[C:11]2[N:12]=[CH:13][CH:14]=[CH:15][C:10]=2[C:9](=[O:16])[N:8]=[C:7]1[CH2:17][CH2:18][C:19]1[CH:24]=[CH:23][C:22]([F:25])=[CH:21][C:20]=1[F:26])C.[OH-].[Li+]>C(O)C.O>[F:26][C:20]1[CH:21]=[C:22]([F:25])[CH:23]=[CH:24][C:19]=1[CH2:18][CH2:17][C:7]1[N:6]([CH2:5][C:4]([OH:27])=[O:3])[C:11]2[N:12]=[CH:13][CH:14]=[CH:15][C:10]=2[C:9](=[O:16])[N:8]=1
Reactant: CCOC(=O)Cn1c(CCc2ccc(F)cc2F)nc(=O)c2cccnc21
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: CCO
Product: O=C(O)Cn1c(CCc2ccc(F)cc2F)nc(=O)c2cccnc21
Reaction time: 2 h
Yield: 76.6 %

Procedure:
Ethyl[2-[2-(2,4-difluorophenyl)ethyl]-4-oxopyrido[2,3-d]pyrimidin-1(4H)-yl]acetate (Int. C1) (32.76 g, 1 equiv) was dissolved in ethanol (350 ml) and water (70 ml), cooled in ice, then aqueous lithium hydroxide (2M solution, 43.42 ml, 0.99 equiv) was added. Stirring was continued for 2 h at room temperature. The solution was concentrated in vacuo and the residue was redissolved in water (700 ml) and saturated aqueous sodium bicarbonate (50 ml), then washed with ethyl acetate (200 ml). The aqueous layer was acidified to pH 2 with 2M hydrochloric acid, and the precipitate was filtered off, washed with ice water (50 ml) and dried in vacuo (50° C., 16 h) to obtain the desired product (23.2 g).
Reaction SMILES: [CH3:1][C:2]([CH2:9][C:10]1[CH:15]=[CH:14][C:13]([N+:16]([O-])=O)=[CH:12][CH:11]=1)([C:6]([NH2:8])=[O:7])[C:3]([NH2:5])=[O:4]>[Pd].C(OCC)(=O)C.C(O)C>[NH2:16][C:13]1[CH:12]=[CH:11][C:10]([CH2:9][C:2]([CH3:1])([C:3]([NH2:5])=[O:4])[C:6]([NH2:8])=[O:7])=[CH:15][CH:14]=1
Reactant: CC(Cc1ccc([N+](=O)[O-])cc1)(C(N)=O)C(N)=O
Agent: [Pd]
Solvent: CCOC(C)=O
Solvent: CCO
Product: CC(Cc1ccc(N)cc1)(C(N)=O)C(N)=O
Reaction time: 6 h
Yield: 46.2 %

Procedure:
A 250-mL round bottom flask was charged with 2-methyl-2-(4-nitrobenzyl)malonamide (0.69 g, 2.74 mmol) and 10% palladium on carbon (0.17 g) in 1:2 ethyl acetate/ethanol (30 mL). This mixture was vigorously stirred under H2 (1 atm) for 6 h. The mixture was then filtered through celite to afford the title compound (0.28 g, 46%) as an off-white solid. MW=221.26. 1H NMR (DMSO-d6, 300 MHz) δ 7.15 (s, 2H), 7.08 (s, 2H), 6.80 (d, J=8.1 Hz, 2H), 6.41 (d, J=8.1 Hz, 2H), 4.87 (s, 2H), 2.86 (s, 2H), 1.07 (s, 3H).
Reaction SMILES: [H-].[Na+].Cl.[F:4][C:5]1[CH:13]=[CH:12][C:8]([C:9]([NH2:11])=[NH:10])=[CH:7][CH:6]=1.[CH:14]([CH:16]([CH3:21])[C:17](OC)=O)=[O:15]>C(O)C>[F:4][C:5]1[CH:13]=[CH:12][C:8]([C:9]2[NH:11][C:14](=[O:15])[C:16]([CH3:21])=[CH:17][N:10]=2)=[CH:7][CH:6]=1
Reactant: N=C(N)c1ccc(F)cc1
Reactant: COC(=O)C(C)C=O
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: CCO
Product: Cc1cnc(-c2ccc(F)cc2)[nH]c1=O
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
Sodium hydride (0.52 g, 13 mmol) is added to 20 mL of anhydrous ethanol and stirred for 30 minutes at ambient temperature. To this, 4-fluorobenzamidine hydrochloride (1.47 g, 8.5 mmol) (from example 40) is added and the mixture is stirred for further 30 minutes. Methyl 2-formylpropionate (1 g, 10.6 mmol) is added dropwise and the reaction mixture is left for 4 days under stirring at ambient temperature.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C@@:8]1([NH:19][C:20]([NH:22][C:23](=[O:30])[C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)=[S:21])[C@H:12]([CH2:13]O)[C@@H:11]([C:15]([F:18])([F:17])[F:16])[O:10][CH2:9]1.N1C=CC=CC=1.FC(F)(F)S(OS(C(F)(F)F)(=O)=O)(=O)=O.[NH4+].[Cl-]>C(Cl)Cl.O>[F:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C@:8]12[CH2:9][O:10][C@H:11]([C:15]([F:16])([F:17])[F:18])[C@H:12]1[CH2:13][S:21][C:20]([NH:22][C:23](=[O:30])[C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1)=[N:19]2
Reactant: O=C(NC(=S)N[C@@]1(c2ccccc2F)CO[C@H](C(F)(F)F)[C@H]1CO)c1ccccc1
Agent: O=S(=O)(OS(=O)(=O)C(F)(F)F)C(F)(F)F
Agent: [Cl-]
Agent: [NH4+]
Solvent: ClCCl
Solvent: O
Solvent: c1ccncc1
Product: O=C(NC1=N[C@@]2(c3ccccc3F)CO[C@H](C(F)(F)F)[C@H]2CS1)c1ccccc1
Temperature: -20 °C
Reaction time: 0.5 h
Yield: 100.9 %

Procedure:
A solution of N-((3S,4R,5S)-3-(2-fluorophenyl)-4-(hydroxymethyl)-5-(trifluoromethyl)-tetrahydrofuran-3-ylcarbamothioyl)benzamide (258.3 g, 583.8 mmol) in CH2Cl2 (1.55 L) was cooled to −19.4° C. Pyridine (118 mL, 1.46 mol) was added while maintaining temperature at −20° C., and then the reaction mixture was cooled to −24° C. In another nitrogen purged vessel, CH2Cl2 (258 mL) was added followed by trifluoromethanesulfonic anhydride (108.0 mL, 642.2 mmol). The resulting solution was added to the reaction mixture over 30 min, while maintaining temperature <−19.7° C. Upon completed addition, the reaction mixture was stirred for 30 min at −20° C. to −15° C., and then warmed to −11° C. over 20 min. Saturated aq. NH4Cl (646 mL) and water (390 mL) was added. The mixture was warmed to ambient temperature and the aq. layer was removed. The organics were washed with premixed saturated aq. NH4Cl (646 mL) and water (390 mL). The aq. layers were combined, and extracted once with CH2Cl2 (520 mL). The organics were combined, and concentrated under vacuum to afford a light orange foam (250 g, 100%). The residue was used in the next stage without purification. 1H NMR (500 MHz, CDCl3) δ ppm 8.03 (d, J=6.7 Hz, 2H), 7.52 (t, J=7.0 Hz, 1H), 7.48-7.31 (m, 4H), 7.20 (t, J=7.4 Hz, 1H), 7.12 (dd, J=12.0, 8.4 Hz, 1H), 4.82-4.73 (m, 1H), 4.60 (d, J=8.9 Hz, 1H), 4.03 (d, J=8.3 Hz, 1H), 3.57 (d, J=2.7 Hz, 1H), 3.20 (d, J=13.6 Hz, 1H), 2.81 (dd, J=13.8, 2.5 Hz, 1H); 13C NMR (125 MHz, CDCl3) δ ppm 171.50, 159.57 (d, JCF=247.2 Hz), 134.62, 132.49, 130.65 (d, JCF J=8.8 Hz), 129.77, 128.51, 128.45, 125.14 (q, JCF=281.8 Hz), 124.97 (d, JCF=3.0 Hz), 124.66 (d, JCF=10.3 Hz), 117.05 (d, JCF=23.5 Hz), 66.81 (d, JCF=5.2 Hz), 38.90, 23.20.
Reaction SMILES: Cl[C:2]1[N:10]=[C:9]2[C:5]([N:6]=[C:7]([CH2:12][N:13]3[CH2:18][CH2:17][N:16]([S:19]([CH3:22])(=[O:21])=[O:20])[CH2:15][CH2:14]3)[N:8]2[CH3:11])=[C:4]([N:23]2[CH2:28][CH2:27][O:26][CH2:25][CH2:24]2)[N:3]=1.CC1(C)C(C)(C)OB([C:37]2[CH:38]=[CH:39][C:40]([NH2:43])=[N:41][CH:42]=2)O1>>[CH3:11][N:8]1[C:7]([CH2:12][N:13]2[CH2:14][CH2:15][N:16]([S:19]([CH3:22])(=[O:20])=[O:21])[CH2:17][CH2:18]2)=[N:6][C:5]2[C:9]1=[N:10][C:2]([C:37]1[CH:38]=[CH:39][C:40]([NH2:43])=[N:41][CH:42]=1)=[N:3][C:4]=2[N:23]1[CH2:24][CH2:25][O:26][CH2:27][CH2:28]1
Reactant: CC1(C)OB(c2ccc(N)nc2)OC1(C)C
Reactant: Cn1c(CN2CCN(S(C)(=O)=O)CC2)nc2c(N3CCOCC3)nc(Cl)nc21
Product: Cn1c(CN2CCN(S(C)(=O)=O)CC2)nc2c(N3CCOCC3)nc(-c3ccc(N)nc3)nc21

Procedure:
4-(2-Chloro-9-methyl-8-((4-(methylsulfonyl)piperazin-1-yl)methyl)-9H-purin-6-yl)morpholine (50 mg) was reacted with 5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridin-2-amine via General Procedure A and purified via reverse phase HPLC to give 29.1 mg 135 as a white solid. MS (Q1) 488.3 (M)+.
Reaction SMILES: Br[CH2:2][C:3]([C:5]1[CH:6]=[N:7][C:8]([Cl:11])=[CH:9][CH:10]=1)=[O:4].ClCC(C1C=NC(Cl)=CC=1)=O.[BH4-].[Na+].C[O-].[Na+]>C(O)C.CCOC(C)=O>[Cl:11][C:8]1[CH:9]=[CH:10][C:5]([CH:3]2[CH2:2][O:4]2)=[CH:6][N:7]=1
Reactant: O=C(CBr)c1ccc(Cl)nc1
Agent: C[O-]
Agent: O=C(CCl)c1ccc(Cl)nc1
Agent: [BH4-]
Solvent: CCOC(C)=O
Solvent: CCO
Product: Clc1ccc(C2CO2)cn1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a stirred solution of the mixture of 2-bromo-1-(6-chloropyridin-3-yl)ethanone and 2-chloro-1-(6-chloropyridin-3-yl)ethanone (5.6 g) in ethanol (100 ml) at 5° C. was added portionwise over 5 min NaBH4 (904 mg). The reaction mixture was then stirred at room temperature for 1 hour to afford a light yellow solution. TLC analysis showed the reaction was complete. Sodium methoxide (645 mg) was then added and the reaction mixture was stirred at room temperature overnight. TLC analysis showed a small amount of starting material remaining and so the reaction mixture was stirred at 50° C. for 1 h. The reaction mixture was then poured into EtOAc and washed with saturated brine. The organic phase was dried over Na2SO4 and concentrated in vacuo to afford (RS)-2-chloro-5-(oxiran-2-yl)pyridine (4.04 g) as a yellow oil which was used in the next step without further purification. MS (ISP): 158.0 ([{37Cl}M+H]+), 156.0 ([{35Cl}M+H]+).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[N:4][C:5]([N:11]2[CH2:14][CH:13]([O:15][C:16]3[CH:21]=[CH:20][CH:19]=[C:18]([F:22])[CH:17]=3)[CH2:12]2)=[C:6]([CH:10]=1)[C:7]([OH:9])=O.Cl.[NH2:24][C:25]1([C:28]2[CH:37]=[CH:36][C:31]([C:32]([O:34][CH3:35])=[O:33])=[CH:30][CH:29]=2)[CH2:27][CH2:26]1>>[Cl:1][C:2]1[CH:3]=[N:4][C:5]([N:11]2[CH2:12][CH:13]([O:15][C:16]3[CH:21]=[CH:20][CH:19]=[C:18]([F:22])[CH:17]=3)[CH2:14]2)=[C:6]([CH:10]=1)[C:7]([NH:24][C:25]1([C:28]2[CH:37]=[CH:36][C:31]([C:32]([O:34][CH3:35])=[O:33])=[CH:30][CH:29]=2)[CH2:27][CH2:26]1)=[O:9]
Reactant: COC(=O)c1ccc(C2(N)CC2)cc1
Reactant: O=C(O)c1cc(Cl)cnc1N1CC(Oc2cccc(F)c2)C1
Agent: Cl
Product: COC(=O)c1ccc(C2(NC(=O)c3cc(Cl)cnc3N3CC(Oc4cccc(F)c4)C3)CC2)cc1
Yield: 52.3 %

Procedure:
The title compound (D151) (56 mg) was prepared according to the experimental procedure described in Description 146 starting from 5-chloro-2-(3-(3-fluorophenoxy)azetidin-1-yl)nicotinic acid (D103) (70 mg, 0.216 mmol) and methyl 4-(1-aminocyclopropyl)benzoate (D7) (49.18 mg, 0.216 mmol).
Reaction SMILES: [OH:1][CH:2]1[C:12]2[C:7](=[N:8][CH:9]=[C:10]([C:13]3[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=3)[CH:11]=2)[CH:6]=[CH:5][C:4]2[CH:19]=[CH:20][C:21]([NH:23][S:24]([CH3:27])(=[O:26])=[O:25])=[CH:22][C:3]1=2.[CH3:28][C:29](OC(C)=O)=[O:30]>CC(O)=O>[C:29]([O:1][CH:2]1[C:12]2[C:7](=[N:8][CH:9]=[C:10]([C:13]3[CH:14]=[CH:15][CH:16]=[CH:17][CH:18]=3)[CH:11]=2)[CH:6]=[CH:5][C:4]2[CH:19]=[CH:20][C:21]([NH:23][S:24]([CH3:27])(=[O:26])=[O:25])=[CH:22][C:3]1=2)(=[O:30])[CH3:28]
Reactant: CC(=O)OC(C)=O
Reactant: CS(=O)(=O)Nc1ccc2c(c1)C(O)c1cc(-c3ccccc3)cnc1C=C2
Solvent: CC(=O)O
Product: CC(=O)OC1c2cc(NS(C)(=O)=O)ccc2C=Cc2ncc(-c3ccccc3)cc21
Temperature: 120 °C

Procedure:
To a stirred solution of N-(5-hydroxy-3-phenyl-5H-benzo[4,5]cyclohepta[1,2-b]pyridin-7-yl)methanesulfonamide (50 mg, 0.13 mmol) in AcOH (1 mL) was added Ac2O (0.5 mL). The reaction mixture was heated to 120° C. for 1 d, concentrated, and purified by flash chromatography to afford the title compound. 1H NMR (600 MHz, CDCl3) δ 8.83 (s, 1H); 8.11 (s, 1H); 7.18-7.63 (m, 10H); 6.75 (s, 1H); 3.03 (s, 3H); 2.23 (br s, 3H). LRMS (APCI) calc'd for (C23H21N2O4S) [M+H]+, 421.1; found 421.1.