Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[CH:9][C:8]([Cl:11])=[CH:7][C:3]=1[C:4]([OH:6])=O.[NH2:12][C:13]1[CH:14]=[C:15]2[C:19](=[CH:20][CH:21]=1)[C:18](=[O:22])[CH2:17][CH2:16]2.C(N(CC)CC)C>S(Cl)(Cl)=O.C1COCC1>[Cl:1][C:2]1[CH:10]=[CH:9][C:8]([Cl:11])=[CH:7][C:3]=1[C:4]([NH:12][C:13]1[CH:14]=[C:15]2[C:19](=[CH:20][CH:21]=1)[C:18](=[O:22])[CH2:17][CH2:16]2)=[O:6]
Reactant: O=C(O)c1cc(Cl)ccc1Cl
Reactant: Nc1ccc2c(c1)CCC2=O
Solvent: O=S(Cl)Cl
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: O=C(Nc1ccc2c(c1)CCC2=O)c1cc(Cl)ccc1Cl
Yield: 18 %

Procedure:
Reaction of 2,5dichlorobenzoic acid (287 mg, 1.50 mmol) in thionyl chloride (3.5 mL) then with 5-amino-indan-1-one (74 mg, 0.50 mmol) in presence of triethylamine (0.5 mL) in THF (6 mL) according to method B gave 2,5-dichloro-N-(1-oxo-indan-5-yl)-benzamide (33 mg, 0.09 mmol, 35% yield) as a green powder after purification by chromatography on silica gel (eluent: DCM).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:19])[C:4]1[CH:9]=[CH:8][CH:7]=[C:6]([S:10][C:11]2[CH:12]=[N:13][CH:14]=[C:15]([CH2:17][OH:18])[CH:16]=2)[CH:5]=1.[OH:20][C:21]1[C:26]([CH2:27][CH2:28][CH3:29])=[C:25](O)[CH:24]=[CH:23][C:22]=1[C:31](=[O:33])[CH3:32]>>[CH3:1][O:2][C:3](=[O:19])[C:4]1[CH:9]=[CH:8][CH:7]=[C:6]([S:10][C:11]2[CH:12]=[N:13][CH:14]=[C:15]([CH2:17][O:18][C:25]3[CH:24]=[CH:23][C:22]([C:31](=[O:33])[CH3:32])=[C:21]([OH:20])[C:26]=3[CH2:27][CH2:28][CH3:29])[CH:16]=2)[CH:5]=1
Reactant: COC(=O)c1cccc(Sc2cncc(CO)c2)c1
Reactant: CCCc1c(O)ccc(C(C)=O)c1O
Product: CCCc1c(OCc2cncc(Sc3cccc(C(=O)OC)c3)c2)ccc(C(C)=O)c1O
Yield: 62.7 %

Procedure:
Using the procedure essentially of Preparation 117 using 3-(5-hydroxymethyl-pyridin-3-ylsulfanyl)-benzoic acid methyl ester (370 mg, 1.34 mmol), 1-(2,4-dihydroxy-3-propyl-phenyl)-ethanone (261 mg, 1.34 mmol) provides the title compound as colorless oil (379 mg, 0.84 mmol): MS (m/z): 452 (M+1).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:6]=[CH:7][C:8]=1[O:9][C:10]1[CH:15]=[CH:14][C:13]([O:16][CH3:17])=[CH:12][CH:11]=1)[NH2:5].[CH3:18][CH:19]([C:25]([CH3:27])=O)[C:20](OCC)=[O:21].ClC1C(OC2C=CC(OC)=CC=2)=CC=C2C=1C(O)=C(C)C(C)=N2>C(O)C>[Cl:1][C:2]1[CH:3]=[C:4]2[C:6]([C:20]([OH:21])=[C:19]([CH3:18])[C:25]([CH3:27])=[N:5]2)=[CH:7][C:8]=1[O:9][C:10]1[CH:15]=[CH:14][C:13]([O:16][CH3:17])=[CH:12][CH:11]=1
Reactant: COc1ccc(Oc2ccc(N)cc2Cl)cc1
Reactant: CCOC(=O)C(C)C(C)=O
Agent: COc1ccc(Oc2ccc3nc(C)c(C)c(O)c3c2Cl)cc1
Solvent: CCO
Product: COc1ccc(Oc2cc3c(O)c(C)c(C)nc3cc2Cl)cc1
Temperature: 150 °C
Yield: 100 %

Procedure:
A mixture composed of 2.9 g of 3-chloro-4-(4-methoxyphenoxy)-aniline, 2.9 g of ethyl 2-methylacetoacetate, and 0.5 mL of ethanol was added dropwise to 4.2 g of polyphosphoric acid heated to 150° C. This reaction solution was stirred at 140 to 150° C. while removing ethanol by evaporation for 3 hr and was then poured into 195 mL of iced water containing 2 mL of concentrated hydrochloric acid. The crystals were collected by filtration and were washed with n-hexane to give 3.29 g of a mixture of 5-chloro-6-(4-methoxyphenoxy)-4-hydroxy-2,3-dimethyl-quinoline with 7-chloro-6-(4-methoxyphenoxy)-4-hydroxy-2,3-dimethyl-quinoline (yield 100%).
Reaction SMILES: [CH3:1][C:2]1([CH3:23])[C:11]2[C:6](=[CH:7][CH:8]=[C:9]([C:12]([F:15])([F:14])[F:13])[CH:10]=2)[NH:5][CH:4]([C:16]2[CH:22]=[CH:21][CH:20]=[CH:19][C:17]=2[NH2:18])[CH2:3]1.N1C=CC=CC=1.[C:30]1([S:36](Cl)(=[O:38])=[O:37])[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1>O>[CH3:1][C:2]1([CH3:23])[C:11]2[C:6](=[CH:7][CH:8]=[C:9]([C:12]([F:13])([F:15])[F:14])[CH:10]=2)[NH:5][CH:4]([C:16]2[CH:22]=[CH:21][CH:20]=[CH:19][C:17]=2[NH:18][S:36]([C:30]2[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=2)(=[O:38])=[O:37])[CH2:3]1
Reactant: O=S(=O)(Cl)c1ccccc1
Reactant: CC1(C)CC(c2ccccc2N)Nc2ccc(C(F)(F)F)cc21
Solvent: O
Solvent: c1ccncc1
Product: CC1(C)CC(c2ccccc2NS(=O)(=O)c2ccccc2)Nc2ccc(C(F)(F)F)cc21
Temperature: 25 °C
Reaction time: 3 h

Procedure:
To a solution of 2-(4,4-dimethyl-6-(trifluoromethyl)-1,2,3,4-tetrahydroquinolin-2-yl)aniline (150 mg) and pyridine (3 mL) was added benzenesulfonyl chloride (60 μL) at ice-bath under nitrogen. After addition, the resulting mixture was stirred at room temperature for 3 h. The reaction mixture was diluted with water, and extracted with ethyl acetate. The combined organic layer was dried over anhydrous sodium sulfate, concentrated. The residue was purified by HPLC to give N-[2-(4,4-dimethyl-6-trifluoromethyl-1,2,3,4-tetrahydro-quinolin-2-yl)-phenyl]-benzenesulfonamide. LC/MS m/e obsd. (ESI−) [(M−H)−] 459.3.
Reaction SMILES: [F:1][C:2]([F:32])([F:31])[C:3]1[CH:4]=[CH:5][C:6]([O:9][C:10]2[CH:11]=[C:12]([C:16](=[C:18]3[CH2:23][CH2:22][N:21](C(OC(C)(C)C)=O)[CH2:20][CH2:19]3)[CH3:17])[CH:13]=[CH:14][CH:15]=2)=[N:7][CH:8]=1.[C:33]([OH:39])([C:35]([F:38])([F:37])[F:36])=[O:34]>C(Cl)Cl>[F:36][C:35]([F:38])([F:37])[C:33]([OH:39])=[O:34].[NH:21]1[CH2:22][CH2:23][C:18](=[C:16]([C:12]2[CH:11]=[C:10]([CH:15]=[CH:14][CH:13]=2)[O:9][C:6]2[CH:5]=[CH:4][C:3]([C:2]([F:32])([F:1])[F:31])=[CH:8][N:7]=2)[CH3:17])[CH2:19][CH2:20]1
Reactant: CC(=C1CCN(C(=O)OC(C)(C)C)CC1)c1cccc(Oc2ccc(C(F)(F)F)cn2)c1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CC(=C1CCNCC1)c1cccc(Oc2ccc(C(F)(F)F)cn2)c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 97 %

Procedure:
To a solution of tert-butyl 4-(1-(3-(5-(trifluoromethyl)pyridin-2-yloxy)phenyl)ethylidene)piperidine-1-carboxylate (265 mg, 0.591 mmol) in CH2Cl2 (8 mL) was added TFA (2 mL). The reaction was stirred at RT overnight and concentrated to give an oil. This was redissolved in CH2Cl2 and concentrated to give the title compound as an oil (275 mg, 97% yield).
Reaction SMILES: C([O:5][C:6]([C@H:8]([N:10]1[C:15](=[O:16])[C@H:14]([OH:17])[C@H:13]([OH:18])[CH2:12][O:11]1)[CH3:9])=[O:7])(C)(C)C>C(Cl)Cl.FC(F)(F)C(O)=O>[C:6]([C@H:8]([N:10]1[C:15](=[O:16])[C@H:14]([OH:17])[C@H:13]([OH:18])[CH2:12][O:11]1)[CH3:9])([OH:7])=[O:5]
Reactant: C[C@H](C(=O)OC(C)(C)C)N1OC[C@@H](O)[C@@H](O)C1=O
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: C[C@H](C(=O)O)N1OC[C@@H](O)[C@@H](O)C1=O
Temperature: 0 °C
Reaction time: 1 h
Yield: 80.3 %

Procedure:
To a cooled (ca. 0° C.) stirred solution of the tert-butyl ester 8b (0.0467 g, 0.179 mmol) in CH2Cl2 (0.9 ml), trifluoroacetic acid (0.9 mL) was added in one portion. The reaction mixture was kept for 1 hour at room temperature and was evaporated in vacuo to dryness. The semisolid residue was triturated with dry ether and dried in vacuo to afford 0.0295 g (80%) of the product 9b as a white solid. 1H NMR (400 MHz) in CD3CN (J, Hz): δ 1.41 (3H, d, 3J=7.3, α-MeCH), 3.60 (2H, br. s, OH, OH, COOH), 4.14 (1H, dd, 2J=−11.6, 3J=2.3, 6-HA), 4.34 (1H, d, 3J=4.1, 4-H), 4.40 (1H, dd, 2J=−11.6, 3J=7.4, 6-HB), 4.49-4.45 (2H, m, 5-H), 5.01 (1H, q, 3J=7.3, α-CH), 5.31 (1H, br. s, COOH). 13C (100 MHz) in CD3CN: δ 14.45, 54.48, 70.05, 70.99, 77.77, 167.30, 171.82.
Reaction SMILES: [C:1]([C:3]1[CH:4]=[CH:5][C:6]([O:14][CH3:15])=[C:7](/[CH:9]=[CH:10]/[C:11]([OH:13])=O)[CH:8]=1)#[N:2].C(N(CC)CC)C.F[B-](F)(F)F.N1(OC(N(C)C)=[N+](C)C)C2C=CC=CC=2N=N1.[CH2:45]([O:52][C:53](=[O:72])[CH2:54][C@@H:55]([NH2:71])[CH2:56][N:57]1[CH2:62][CH2:61][CH:60]([O:63][C:64]2[CH:69]=[CH:68][C:67]([F:70])=[CH:66][CH:65]=2)[CH2:59][CH2:58]1)[C:46]1[CH:51]=[CH:50][CH:49]=[CH:48][CH:47]=1>C(Cl)Cl>[CH2:45]([O:52][C:53](=[O:72])[CH2:54][C@@H:55]([NH:71][C:11](=[O:13])/[CH:10]=[CH:9]/[C:7]1[CH:8]=[C:3]([C:1]#[N:2])[CH:4]=[CH:5][C:6]=1[O:14][CH3:15])[CH2:56][N:57]1[CH2:58][CH2:59][CH:60]([O:63][C:64]2[CH:65]=[CH:66][C:67]([F:70])=[CH:68][CH:69]=2)[CH2:61][CH2:62]1)[C:46]1[CH:51]=[CH:50][CH:49]=[CH:48][CH:47]=1
Reactant: COc1ccc(C#N)cc1/C=C/C(=O)O
Reactant: N[C@H](CC(=O)OCc1ccccc1)CN1CCC(Oc2ccc(F)cc2)CC1
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[B-](F)(F)F
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: COc1ccc(C#N)cc1/C=C/C(=O)N[C@H](CC(=O)OCc1ccccc1)CN1CCC(Oc2ccc(F)cc2)CC1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
A solution of (E)-3-(5-cyano-2-methoxy-phenyl)-acrylic acid (0.916 g, 4.51 mmol), triethylamine (1.257 ml, 9.02 mmol) and 2-(1H-benzotriazol-1-yl)-1,1,3,3-tetramethyluronium tetrafluoroborate (1.44 g, 4.51 mmol) in DCM (10 ml) is treated with (R)-3-amino-4-[4-(4-fluoro-phenoxy)-piperidin-1-yl]-butyric acid benzyl ester. The reaction mixture is stirred at ambient temperature for 2 hours, then is washed with water, dried over MgSO4 and evaporated. The crude product is purified by flash silica chromatography (elution with 2:1 ethylacetate:hexane) to afford (R)-3-[(E)-3-(5-cyano-2-methoxy-phenyl)-acryloylamino]-4-[4-(4-fluoro-phenoxy)-piperidin-1-yl]-butyric acid benzyl ester. [MH]+ 572.1.
Reaction SMILES: [Cl:1][C:2]1[N:3]([CH2:10][C@:11]2([CH3:14])[CH2:13][O:12]2)[CH:4]=[C:5]([N+:7]([O-:9])=[O:8])[N:6]=1.[NH:15]1[CH2:20][CH2:19][CH:18]([NH:21][C:22]2[CH:27]=[CH:26][C:25]([O:28][C:29]([F:32])([F:31])[F:30])=[CH:24][CH:23]=2)[CH2:17][CH2:16]1>>[Cl:1][C:2]1[N:3]([CH2:10][C@@:11]([CH3:14])([OH:12])[CH2:13][N:15]2[CH2:20][CH2:19][CH:18]([NH:21][C:22]3[CH:23]=[CH:24][C:25]([O:28][C:29]([F:30])([F:31])[F:32])=[CH:26][CH:27]=3)[CH2:17][CH2:16]2)[CH:4]=[C:5]([N+:7]([O-:9])=[O:8])[N:6]=1
Reactant: C[C@@]1(Cn2cc([N+](=O)[O-])nc2Cl)CO1
Reactant: FC(F)(F)Oc1ccc(NC2CCNCC2)cc1
Product: C[C@](O)(CN1CCC(Nc2ccc(OC(F)(F)F)cc2)CC1)Cn1cc([N+](=O)[O-])nc1Cl
Yield: 88 %

Procedure:
Using (R)-2-chloro-1-(2-methyloxiran-2-yl-methyl)-4-nitroimidazole prepared in Example 12 and N-(piperidin-4-yl)-4-trifluoromethoxyaniline gave (S)-1-(2-chloro-4-nitroimidazol-1-yl)-2-methyl-3-[4-(4-trifluoromethoxyphenylamino)piperidin-1-yl]propan-2-ol (1.36 g, yield 88%) as a yellow oil in the same manner as in Example 254.
Reaction SMILES: [Cl:1][C:2]1[CH:31]=[CH:30][C:5]([CH2:6][N:7]2[CH2:12][CH2:11][N:10]([C:13]([O:15][CH2:16][C@@:17]([OH:29])([CH3:28])[CH2:18][N:19]3[CH:23]=[C:22]([N+:24]([O-:26])=[O:25])[N:21]=[C:20]3Cl)=[O:14])[CH2:9][CH2:8]2)=[CH:4][CH:3]=1.[H-].[Na+]>CN(C=O)C>[Cl:1][C:2]1[CH:31]=[CH:30][C:5]([CH2:6][N:7]2[CH2:12][CH2:11][N:10]([C:13]([O:15][CH2:16][C@:17]3([CH3:28])[O:29][C:20]4=[N:21][C:22]([N+:24]([O-:26])=[O:25])=[CH:23][N:19]4[CH2:18]3)=[O:14])[CH2:9][CH2:8]2)=[CH:4][CH:3]=1
Reactant: C[C@](O)(COC(=O)N1CCN(Cc2ccc(Cl)cc2)CC1)Cn1cc([N+](=O)[O-])nc1Cl
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: C[C@]1(COC(=O)N2CCN(Cc3ccc(Cl)cc3)CC2)Cn2cc([N+](=O)[O-])nc2O1
Temperature: 0 °C
Reaction time: 1 h
Yield: 27.4 %

Procedure:
To the solution of (R)-3-(2-chloro-4-nitroimidazol-1-yl)-2-hydroxy-2-methylpropyl 4-(4-chlorobenzyl)piperazine-1-carboxylate prepared in Example 90 (1.82 g, 3.85 mmol) in DMF (10 ml), sodium hydride (0.31 g, 7.70 mmol) was added followed by stirring for 1 hour with cooling on ice-bath. To the reaction mixture, ice-water was added, and the precipitates were filtered off and washed with isopropanol to afford (R)-2-methyl-6-nitro-2,3-dihydroimidazo[2,1-b]oxazol-2-ylmethyl 4-(4-chlorobenzyl)piperazine-1-carboxylate (0.46 g, yield 28%) as a light yellow solid.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([N+:18]([O-])=O)[C:5]([N:8]2[CH2:12][CH2:11][CH2:10][C@H:9]2[C:13](OCC)=[O:14])=[N:6][CH:7]=1.P(OC1C=CC=CC=1)(OC1C=CC=CC=1)OC1C=CC=CC=1>ClCCl.[NH4+].[O-][V](=O)=O.[Pt]>[Br:1][C:2]1[CH:7]=[N:6][C:5]2[N:8]3[CH2:12][CH2:11][CH2:10][C@H:9]3[C:13](=[O:14])[NH:18][C:4]=2[CH:3]=1
Reactant: CCOC(=O)[C@@H]1CCCN1c1ncc(Br)cc1[N+](=O)[O-]
Agent: O=[V](=O)[O-]
Agent: [Pt]
Agent: [NH4+]
Solvent: ClCCl
Product: O=C1Nc2cc(Br)cnc2N2CCC[C@@H]12
Reaction time: 4 h
Yield: 42.8 %

Procedure:
(S)-ethyl 1-(5-bromo-3-nitropyridin-2-yl)pyrrolidine-2-carboxylate (8.6 g, 24.99 mmol) was dissolved in dichloromethane (Volume: 125 ml) and to this solution was added triphenyl phosphite (0.078 g, 0.250 mmol), ammonium metavanadate (0.175 g, 1.499 mmol) and Pt/C (5% wt.) (0.975 g, 0.250 mmol). The reaction mixture was hydrogenated at 80 psi at 25° C. for 4 h. The reaction mixture was filtered through celite using DCM and MeOH to complete the transfer and wash the celite plug. The combined filtrates and washes were concentrated in vacuo and crystallized with ethyl ether (75 mL). The precipitate was filtered and dried in vacuum to afford (S)-3-bromo-6a,7,8,9-tetrahydropyrido[3,2-e]pyrrolo[1,2-a]pyrazin-6(5H)-one (2.87 g, 10.70 mmol, 42.8% yield) as a pale beige solid. 1H NMR (400 MHz, DMSO-d6) δ ppm 1.82-2.03 (m, 3H) 2.11-2.26 (m, 1H) 3.27-3.47 (m, 1H) 3.49-3.63 (m, 1H) 4.01-4.11 (m, 1H) 7.06 (d, J=2.27 Hz, 1H) 7.77 (d, J=2.02 Hz, 1H) 10.57 (s, 1H). [M+H] calc'd for C10H10BrN3O, 268. found, 268.
Reaction SMILES: [CH:1]1([CH2:6][CH:7]([C:11]2[CH:16]=[CH:15][C:14]([S:17]([CH2:20][C:21](=[O:23])[CH3:22])(=[O:19])=[O:18])=[CH:13][CH:12]=2)[C:8](O)=[O:9])[CH2:5][CH2:4][CH2:3][CH2:2]1.C1C=CC2N(O)N=NC=2C=1.CCN=C=NCCCN(C)C.Cl.Cl.[CH3:47][O:48][C:49]1[N:54]=[C:53]2[S:55][C:56]([NH2:58])=[N:57][C:52]2=[CH:51][CH:50]=1.CCN(C(C)C)C(C)C.C(=O)(O)[O-].[Na+]>C(Cl)Cl>[CH:1]1([CH2:6][CH:7]([C:11]2[CH:12]=[CH:13][C:14]([S:17]([CH2:20][C:21](=[O:23])[CH3:22])(=[O:18])=[O:19])=[CH:15][CH:16]=2)[C:8]([NH:58][C:56]2[S:55][C:53]3[C:52]([N:57]=2)=[CH:51][CH:50]=[C:49]([O:48][CH3:47])[N:54]=3)=[O:9])[CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: CC(=O)CS(=O)(=O)c1ccc(C(CC2CCCC2)C(=O)O)cc1
Reactant: COc1ccc2nc(N)sc2n1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: O=C([O-])O
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: COc1ccc2nc(NC(=O)C(CC3CCCC3)c3ccc(S(=O)(=O)CC(C)=O)cc3)sc2n1
Temperature: 25 °C
Reaction time: 24 h

Procedure:
To a solution of the title D compound, 3-cyclopentyl-2-[4-(2-oxo-propylsulfonyl)-phenyl]-propionic acid (400 mg, 0.0011 mol) in 50 mL of DCM, HOBt (250 mg, 0.0018 mol), EDCl hydrochloride (340 mg, 0.0017 mol) and 5-methoxy-thiazolo[5,4-b]pyridin-2ylamine (235 mg, 0.0012 mol) are added followed by the addition of 0.66 mL (0.0037 mol) of DIEA. The reaction is stirred at 25° C. for 24 h, then worked up by treating it with saturated aqueous sodium bicarbonate solution. The resulting organic layer is washed with 1 N aqueous hydrochloric acid solution, followed by water and brine washings. The organic layer is dried over sodium sulfate, filtered and then evaporated under vacuum to give a brown solid. The reaction product is purified by column chromatography over Silica gel (60-120 mesh) using 80% hexane in ethyl acetate as an eluent to give 3-cyclopentyl-N-(5-methoxy-thiazolo[5,4-b]pyridin-2-yl)-2-[4-(2-oxo-propane-1-sulfonyl)-phenyl]-propionamide as a brown solid: MS e/z (ES) 502 (M+1+, 100%); m.p. 67-71° C.; 1H NMR δ 12.71 (s, 1H), 8.02 (d, J=8.8, 1H), 7.65-7.90 (m, 4H), 6.91 (d, J=8.8, 1H), 4.69 (s, 2H), 4.08-4.12 (m, 1H), 3.90 (s, 3H), 2.19 (s, 3H), 1.78-1.82 (m, 1H), 1.60-1.75 (m, 2H), 1.43-1.55 (m, 3H), 1.30-1.42 (m, 3H), 1.00-1.20 (m 2H).
Reaction SMILES: Br[CH2:2][C:3]([C:5]1[CH:10]=[CH:9][C:8]([Br:11])=[CH:7][CH:6]=1)=O.[NH2:12][C:13]1[CH:18]=[C:17]([CH3:19])[CH:16]=[CH:15][N:14]=1>C(O)C>[Br:11][C:8]1[CH:9]=[CH:10][C:5]([C:3]2[N:12]=[C:13]3[CH:18]=[C:17]([CH3:19])[CH:16]=[CH:15][N:14]3[CH:2]=2)=[CH:6][CH:7]=1
Reactant: O=C(CBr)c1ccc(Br)cc1
Reactant: Cc1ccnc(N)c1
Solvent: CCO
Product: Cc1ccn2cc(-c3ccc(Br)cc3)nc2c1
Temperature: 25 °C
Yield: 56.8 %

Procedure:
A mixture of 2,4′-dibromoacetophenone (22.4 g) and 2-amino-4-picoline (8.68 g) in ethanol (80 mL) was heated at reflux temperature for 3 hours. The reaction mixture was cooled to ambient temperature and the crystalline solid-isolated by filtration, washed with ethanol and dried in vacuo to give the title compound (13.1 g).
Reaction SMILES: [O:1]=[S:2]1(=[O:27])[CH2:7][CH2:6][N:5]([C:8]2[N:13]=[C:12]3[N:14]([Si](C(C)C)(C(C)C)C(C)C)[CH:15]=[CH:16][C:11]3=[CH:10][CH:9]=2)[CH2:4][CH2:3]1.[CH3:28][N:29](C=O)C.ClS(N=C=O)(=O)=O.CCOC(C)=O>C(#N)C>[O:27]=[S:2]1(=[O:1])[CH2:3][CH2:4][N:5]([C:8]2[N:13]=[C:12]3[NH:14][CH:15]=[C:16]([C:28]#[N:29])[C:11]3=[CH:10][CH:9]=2)[CH2:6][CH2:7]1
Reactant: CC(C)[Si](C(C)C)(C(C)C)n1ccc2ccc(N3CCS(=O)(=O)CC3)nc21
Reactant: CN(C)C=O
Agent: O=C=NS(=O)(=O)Cl
Solvent: CC#N
Solvent: CCOC(C)=O
Product: N#Cc1c[nH]c2nc(N3CCS(=O)(=O)CC3)ccc12
Temperature: -20 °C
Reaction time: 0.08 h
Yield: 56 %

Procedure:
In a 25 mL round-bottomed flask 6-(1,1-Dioxo-1lambda*6*-thiomorpholin-4-yl)-1-triisopropylsilanyl-1H-pyrrolo[2,3-b]pyridine (322 mg, 790 μmol, Eq: 1.00) was combined with DMF (11.9 ml) to give a colorless solution. The reaction mixture was cooled to −20° C. and stirred for 5 min. Chlorosulfonyl isocyanate (335 mg, 206 μl, 2.37 mmol, Eq: 3) in acetonitrile (11.9 ml) was added dropwise and the resultant cooled reaction was stirred at −20° C. and stirred for 3 hrs The reaction mixture was poured into 25 mL EtOAc and washed with sat NaCl (3×20 mL). After evaporation, crude material was purified by flash chromatography (silica gel, 12 g, 5% to 10% MeOH in DCM) to obtain 6-(1,1-dioxo-1lambda*6*-thiomorpholin-4-yl)-1H-pyrrolo[2,3-b]pyridine-3-carbonitrile (122 mg, 56%).
Reaction SMILES: [F:1][C:2]1[CH:10]=[C:9]2[C:5]([CH:6]=[N:7][NH:8]2)=[CH:4][C:3]=1[C:11]#N.[H-].C([Al+]CC(C)C)C(C)C.C(OCC)(=[O:25])C.C(O)(=O)C(C(C(O)=O)O)O>C1(C)C=CC=CC=1>[F:1][C:2]1[CH:10]=[C:9]2[C:5]([CH:6]=[N:7][NH:8]2)=[CH:4][C:3]=1[CH:11]=[O:25]
Reactant: N#Cc1cc2cn[nH]c2cc1F
Reactant: CCOC(C)=O
Agent: CC(C)C[Al+]CC(C)C
Agent: O=C(O)C(O)C(O)C(=O)O
Agent: [H-]
Solvent: Cc1ccccc1
Product: O=Cc1cc2cn[nH]c2cc1F
Temperature: -40 °C
Reaction time: 3 h

Procedure:
A slurry of 4.8 g (30 mmol) 6-fluoro-1H-indazole-5-carbonitrile [commercially available; preparation given in EP 1 510 516-A1 (production example 82)] in anhydrous toluene (150 ml) was cooled to −40° C. Under inert gas atmosphere, 48 ml (72 mmol) diisobutylaluminium hydride solution (1.5 M in toluene) were added over 30 min, and the resulting mixture was stirred at −40° C. for 3 h. Then, ethyl acetate (30 ml) was added, and the mixture was stirred for further 20 min at −40° C. followed by dropwise addition of aqueous tartaric acid (1 M, 30 ml). The mixture was allowed to warm to 0° C. and filtered at this temperature. The filtrate was extracted with ethyl acetate several times, and the combined organic phases were subsequently washed with saturated aqueous sodium hydrogencarbonate and with brine, dried over sodium sulfate, filtered and concentrated under reduced pressure. The crude product thus obtained (2.60 g, 53% of th.) was used in the next step without further purification.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:11]=[CH:10][C:6]([C:7]([OH:9])=[O:8])=[C:5]([N+:12]([O-:14])=[O:13])[CH:4]=1.[CH2:15]1CCN2C(=NCCC2)CC1.IC.O>CN(C=O)C>[CH3:1][O:2][C:3]1[CH:11]=[CH:10][C:6]([C:7]([O:9][CH3:15])=[O:8])=[C:5]([N+:12]([O-:14])=[O:13])[CH:4]=1
Reactant: C1CCC2=NCCCN2CC1
Reactant: COc1ccc(C(=O)O)c([N+](=O)[O-])c1
Solvent: O
Solvent: CN(C)C=O
Solvent: CI
Product: COC(=O)c1ccc(OC)cc1[N+](=O)[O-]
Temperature: 0 °C
Reaction time: 0.25 h
Yield: 100 %

Procedure:
To a solution of 4-methoxy-2-nitrobenzoic acid (10.0 g, 50.7 mmol) in DMF (200 mL) at 0° C. was added DBU (15.2 mL, 101 mmol) followed by iodomethane (9.47 mL, 152 mmol). The reaction mixture was allowed to stir at 0° C. for 15 min then at rt overnight. The mixture was poured into water and extracted with EtOAc. The organic solutions were combined, washed with brine and dried over MgSO4. The residue was purified by column chromatography to give methyl 4-methoxy-2-nitrobenzoate (50.7 mmol, 85%) as a yellow solid. LCMS (FA): m/z=212.1 (M+H).
Reaction SMILES: [Cl:1][CH2:2][CH2:3][N:4]([CH2:24][CH2:25][Cl:26])[C:5]1[CH:10]=[CH:9][C:8]([NH:11][C:12]([NH:14][C:15]2[CH:20]=[CH:19][CH:18]=[C:17]([N+:21]([O-])=O)[CH:16]=2)=[O:13])=[CH:7][CH:6]=1>C(OCC)(=O)C.[Pd]>[NH2:21][C:17]1[CH:16]=[C:15]([NH:14][C:12]([NH:11][C:8]2[CH:9]=[CH:10][C:5]([N:4]([CH2:3][CH2:2][Cl:1])[CH2:24][CH2:25][Cl:26])=[CH:6][CH:7]=2)=[O:13])[CH:20]=[CH:19][CH:18]=1
Reactant: O=C(Nc1ccc(N(CCCl)CCCl)cc1)Nc1cccc([N+](=O)[O-])c1
Agent: [Pd]
Solvent: CCOC(C)=O
Product: Nc1cccc(NC(=O)Nc2ccc(N(CCCl)CCCl)cc2)c1

Procedure:
The solution of compound 45a (3.5 g, 8.8 mmol) in ethyl acetate (100 mL) was hydrogenated with H2 gas in Parr hydrogenator using 10% Pd—C (0.8 g) as a catalyst at 30-35 psi for 6-7 hours. After completion of the reaction, the mixture was filtered through celite pad and filtrate was evaporated to dryness under reduced pressure to afford 1-(3-aminophenyl)-3-(4-(bis(2-chloroethyl)amino)phenyl)urea (46a), 3.0 g (93%); mp 182-183° C. 1H NMR (DMSO-d6) δ: 3.66-3.72 (8H, m, CH2), 5.22 (2H, brs, NH2), 6.17-6.19 (1H, d, J=8.0 Hz, Ar—H), 6.54-6.56 (1H, d, J=7.9 Hz, Ar—H), 6.69-6.71 (2H, d, J=9.0 Hz, Ar—H), 6.86 (1H, s, Ar—H), 6.88-6.90 (1H, t, J=8.0 Hz, Ar—H), 7.25-7.28 (2H, d, J=8.9 Hz, Ar—H), 8.27 (2H, br s, NH).
Reaction SMILES: [NH2:1][C:2](=[O:36])[CH:3]([C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][C:6]=1[C:11]#[C:12][C:13]1[C:18]([C:19]([F:22])([F:21])[F:20])=[CH:17][N:16]=[C:15]([NH:23][C:24]2[CH:25]=[N:26][N:27](C(OC(C)(C)C)=O)[CH:28]=2)[N:14]=1)[CH3:4].C(O)(C(F)(F)F)=O>C(Cl)Cl>[NH:26]1[CH:25]=[C:24]([NH:23][C:15]2[N:14]=[C:13]([C:12]#[C:11][C:6]3[CH:7]=[CH:8][CH:9]=[CH:10][C:5]=3[CH:3]([CH3:4])[C:2]([NH2:1])=[O:36])[C:18]([C:19]([F:21])([F:20])[F:22])=[CH:17][N:16]=2)[CH:28]=[N:27]1
Reactant: CC(C(N)=O)c1ccccc1C#Cc1nc(Nc2cnn(C(=O)OC(C)(C)C)c2)ncc1C(F)(F)F
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CC(C(N)=O)c1ccccc1C#Cc1nc(Nc2cn[nH]c2)ncc1C(F)(F)F
Temperature: 25 °C
Reaction time: 2 h

Procedure:
A mixture of tert-butyl 4-((4-((2-(1-amino-1-oxopropan-2-yl)phenyl)ethynyl)-5-(trifluoromethyl)pyrimidin-2-yl)amino)-1H-pyrazole-1-carboxylate A62 (0.31 g, 0.62 mmol) and TFA (0.90 mL, 12 mmol) in DCM (3.0 mL) was stirred for 2 hours at room temperature. The mixture was concentrated under reduced pressure and diluted with water (50 mL) before extracting with DCM (2×50 mL) and EtOAc (50 mL). The combined organic residues were concentrated and purified using silica gel column chromatography (50-100% EtOAc in petroleum benzine 40-60° C. then 0-10% MeOH in EtOAc) to give the title compound A63 (0.211 g, 85%). LCMS-D: rt 3.162 min; m/z 401.2 [M+H]+.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[C:6]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)[N:5]=[C:4]([C:14]2[CH:19]=[CH:18][CH:17]=[C:16]([N+:20]([O-:22])=[O:21])[CH:15]=2)[C:3]=1[C:23]([OH:25])=O.S(Cl)(Cl)=O.[CH3:30][N:31]1[CH2:36][CH2:35][NH:34][CH2:33][CH2:32]1.[OH-].[Na+]>C(Cl)Cl.O.CN(C)C=O>[CH3:1][C:2]1[CH:7]=[C:6]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)[N:5]=[C:4]([C:14]2[CH:19]=[CH:18][CH:17]=[C:16]([N+:20]([O-:22])=[O:21])[CH:15]=2)[C:3]=1[C:23]([N:34]1[CH2:35][CH2:36][N:31]([CH3:30])[CH2:32][CH2:33]1)=[O:25]
Reactant: CN1CCNCC1
Reactant: Cc1cc(-c2ccccc2)nc(-c2cccc([N+](=O)[O-])c2)c1C(=O)O
Agent: [Na+]
Agent: [OH-]
Solvent: ClCCl
Solvent: CN(C)C=O
Solvent: O=S(Cl)Cl
Product: Cc1cc(-c2ccccc2)nc(-c2cccc([N+](=O)[O-])c2)c1C(=O)N1CCN(C)CC1
Reaction time: 2 h
Yield: 55.6 %

Procedure:
To a mixture of 4-methyl-2-(3-nitrophenyl)-6-phenyl-3-pyridinecarboxylic acid (1.4 g), methylene chloride (14 ml) and N,N-dimethylformamide (2.8 ml) was added a solution of thionyl chloride (0.33 ml) in methylene chloride (3 ml) at 7° C. under ice cooling. After stirring for 2 hours at the same condition, a solution of 1-methylpiperazine (1.05 g) in methylene chloride (7 ml) was added thereto and the mixture was stirred for 2 hours at the same temperature. After adding water (100 ml) and methylene chloride (50 ml) thereto, the mixture was adjusted to pH 8.5 with 10% aqueous sodium hydroxide. The organic layer was separated, washed successively with water and saturated brine, dried over magnesium sulfate and evaporated in vacuo. The residue was recrystallized from a mixture of ethanol and diethyl ether to give 4-methyl-3-(4-methylpiperazin-1-ylcarbonyl)-2-(3-nitrophenyl)-6-phenylpyridine (0.97 g).