Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1](Cl)(Cl)=[S:2].[NH:5]1[CH:9]=[CH:8][N:7]=[CH:6]1.[Br:10][C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=1[CH:17]([OH:22])[C:18]([F:21])([F:20])[F:19]>ClCCCl>[Br:10][C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=1[CH:17]([O:22][C:1]([N:5]1[CH:9]=[CH:8][N:7]=[CH:6]1)=[S:2])[C:18]([F:20])([F:21])[F:19]
Reactant: OC(c1ccccc1Br)C(F)(F)F
Reactant: c1c[nH]cn1
Reactant: S=C(Cl)Cl
Solvent: ClCCCl
Product: FC(F)(F)C(OC(=S)n1ccnc1)c1ccccc1Br
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 81.2 %

Procedure:
Thiophosgene (24.0 g, 210.0 mmol) was added portion-wise to a vigorously stirred suspension of imidazole (57.0 g, 840.0 mmol) in 1,2-dichloroethane (500 ml) under an atmosphere of nitrogen. After the addition, the reaction mixture was stirred at room temperature for 30 minutes. 1-(2-Bromophenyl)-2,2,2-trifluoro-ethanol (Preparation 55, 46 g, crude, about 140 mmol) in 1,2-dichloroethane (100 m) was added at room temperature. After the addition, the mixture was heated at reflux for 10 minutes. The reaction mixture was cooled then the solvent was evaporated in vacuo. The crude product was purified by column chromatography on silica gel eluting with petroleum ether, then petroleum ether:ethyl acetate (10:1) to afford the title compound as a yellow oil (41.5 g, 81%).
Reaction SMILES: N(C(OC(C)(C)C)=O)=NC(OC(C)(C)C)=O.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[CH3:36][C:37]1[CH:42]=[C:41]([CH2:43][OH:44])[CH:40]=[CH:39][N:38]=1.[F:45][C:46]1[CH:51]=[CH:50][C:49]([C:52]([N:54]2[CH2:59][CH2:58][N:57]3[N:60]=[C:61](O)[CH:62]=[C:56]3[CH2:55]2)=[O:53])=[CH:48][CH:47]=1>C1COCC1>[F:45][C:46]1[CH:47]=[CH:48][C:49]([C:52]([N:54]2[CH2:59][CH2:58][N:57]3[N:60]=[C:61]([O:44][CH2:43][C:41]4[CH:40]=[CH:39][N:38]=[C:37]([CH3:36])[CH:42]=4)[CH:62]=[C:56]3[CH2:55]2)=[O:53])=[CH:50][CH:51]=1
Reactant: O=C(c1ccc(F)cc1)N1CCn2nc(O)cc2C1
Reactant: Cc1cc(CO)ccn1
Agent: CC(C)(C)OC(=O)N=NC(=O)OC(C)(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: Cc1cc(COc2cc3n(n2)CCN(C(=O)c2ccc(F)cc2)C3)ccn1
Temperature: 130 °C
Reaction time: 0.33 h
Yield: 35.5 %

Procedure:
Di-tert-butyl azodicarboxylate (0.138 g, 0.6 mmol) was added to a stirred solution of triphenylphosphine (0.157 g, 0.6 mmol), (2-methylpyridin-4-yl)methanol (0.074 g, 0.6 mmol) and 5-[(4-fluorophenyl)carbonyl]-4,5,6,7-tetrahydropyrazolo[1,5-a]pyrazin-2-ol (0.157 g, 0.6 mmol) in THF (3 mL) in a sealed tube and under nitrogen. The mixture was stirred at 130° C. for 20 minutes under microwave irradiation and the solvents were evaporated in vacuo. The crude product was purified by flash column chromatography (silica; 7 M solution of ammonia in methanol in DCM 0/100 to 5/95, twice). The desired fractions were collected, the solvents evaporated in vacuo and the residue triturated with DIPE to yield 5-[(4-fluorophenyl)carbonyl]-2-[(2-methylpyridin-4-yl)methoxy]-4,5,6,7-tetrahydropyrazolo[1,5-a]pyrazine (0.078 g, 35% yield) as a white solid. C20H19FN4O2. 1H NMR (400 MHz, CDCl3) δ ppm 2.56 (s, 3 H), 4.08 (br. s., 4 H), 4.74 (br. s., 2 H), 5.17 (s, 2 H), 5.52 (br. s., 1 H), 7.10-7.18 (m, 3 H), 7.21 (br. s, 1 H), 7.45-7.52 (m, 2 H), 8.47 (d, J=5.1 Hz, 1 H).
Reaction SMILES: C([O:3][C:4]([C:6]1[N:7]([CH3:22])[CH:8]=[C:9](/[CH:11]=[CH:12]/[C:13]2[CH:18]=[CH:17][C:16]([N+:19]([O-:21])=[O:20])=[CH:15][CH:14]=2)[CH:10]=1)=[O:5])C.C1COCC1.O.[OH-].[Na+]>C(O)C>[CH3:22][N:7]1[CH:8]=[C:9](/[CH:11]=[CH:12]/[C:13]2[CH:14]=[CH:15][C:16]([N+:19]([O-:21])=[O:20])=[CH:17][CH:18]=2)[CH:10]=[C:6]1[C:4]([OH:5])=[O:3]
Reactant: CCOC(=O)c1cc(/C=C/c2ccc([N+](=O)[O-])cc2)cn1C
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Solvent: CCO
Product: Cn1cc(/C=C/c2ccc([N+](=O)[O-])cc2)cc1C(=O)O
Temperature: 25 °C
Yield: 55.2 %

Procedure:
Ethyl-1-methyl-4-[(E)-2-(4-nitrophenyl)ethenyl]-1H-pyrrole-2-carboxylate (0.100 mg, 0.333 mmol; see step (ii) above) was suspended in ethanol (4 mL), THF (8 mL) and water (20 mL) to which sodium hydroxide solution (NaOH 0.190 g, 4.75 mmol in water 10 mL) was added with stirring. The reaction mixture was heated under reflux for 4 h. The reaction mixture was cooled to room temperature then HCl(conc.) was added dropwise with vigorous stirring until pH 2 was attained. The yellow, solid material was filtered off, washed with water and dried in vacuo at 60° C. to provide the title compound (50 mg, 55%), m.p.=212-215° C. (decomposition).
Reaction SMILES: [F:1][C:2]1([F:29])[CH2:7][CH2:6][N:5]([C:8]([C:10]2[NH:11][C:12]3[C:17]([CH:18]=2)=[CH:16][C:15]([C:19]([N:21]2[CH2:25][CH2:24][CH:23]([N:26]([CH3:28])[CH3:27])[CH2:22]2)=[O:20])=[CH:14][CH:13]=3)=[O:9])[CH2:4][CH2:3]1.[F:30][C:31]([F:42])([F:41])[C:32]1[CH:33]=[C:34](B(O)O)[CH:35]=[CH:36][CH:37]=1.N1C=CC=CC=1>ClCCl.C([O-])(=O)C.[Cu+2].C([O-])(=O)C>[F:29][C:2]1([F:1])[CH2:7][CH2:6][N:5]([C:8]([C:10]2[N:11]([C:36]3[CH:35]=[CH:34][CH:33]=[C:32]([C:31]([F:42])([F:41])[F:30])[CH:37]=3)[C:12]3[C:17]([CH:18]=2)=[CH:16][C:15]([C:19]([N:21]2[CH2:25][CH2:24][CH:23]([N:26]([CH3:27])[CH3:28])[CH2:22]2)=[O:20])=[CH:14][CH:13]=3)=[O:9])[CH2:4][CH2:3]1
Reactant: OB(O)c1cccc(C(F)(F)F)c1
Reactant: CN(C)C1CCN(C(=O)c2ccc3[nH]c(C(=O)N4CCC(F)(F)CC4)cc3c2)C1
Agent: [Cu+2]
Agent: CC(=O)[O-]
Solvent: ClCCl
Solvent: c1ccncc1
Product: CN(C)C1CCN(C(=O)c2ccc3c(c2)cc(C(=O)N2CCC(F)(F)CC2)n3-c2cccc(C(F)(F)F)c2)C1
Yield: 60 %

Procedure:
The title compound was synthesized in analogy to example 66, from (RS)-(4,4-difluoro-piperidin-1-yl)-[5-(3-dimethylamino-pyrrolidine-1-carbonyl)-1H-indol-2-yl]-methanone (example 42, intermediate a)), 3-(trifluoromethyl)phenylboronic acid, copper(II) acetate and pyridine in dichloromethane, to give the desired product as a light brown foam (60%).
Reaction SMILES: [F:1][C:2]([F:12])([F:11])[C:3]1[N:8]=[CH:7][C:6]([CH:9]=O)=[CH:5][N:4]=1.N1C2C(=CC=CC=2)C=[C:15]([CH:23]=[O:24])C=1>>[F:1][C:2]([F:12])([F:11])[C:3]1[N:8]=[CH:7][C:6]([CH:9]=[CH:15][CH:23]=[O:24])=[CH:5][N:4]=1
Reactant: O=Cc1cnc2ccccc2c1
Reactant: O=Cc1cnc(C(F)(F)F)nc1
Product: O=CC=Cc1cnc(C(F)(F)F)nc1

Procedure:
The title compound was prepared by a procedure analogous to Reference Example 7 by substituting 2-trifluoromethyl-5-pyrimidinecarboxaldehyde (prepared as described in WO0066566) for the 3-quinolinecarboxaldehyde of Reference Example 7. MS 203 (M+H)+.
Reaction SMILES: [CH2:1]([O:3][C:4]([N:6]1[C:15]2[C:10](=[N:11][C:12]([O:16][CH3:17])=[CH:13][CH:14]=2)[C@@H:9]([NH:18][C:19]2[C:24]([CH2:25][C:26]3[CH:31]=[C:30]([C:32]([F:35])([F:34])[F:33])[CH:29]=[C:28]([C:36]([F:39])([F:38])[F:37])[CH:27]=3)=[N:23][CH:22]=[C:21](Cl)[N:20]=2)[CH2:8][C@H:7]1[CH2:41][CH3:42])=[O:5])[CH3:2].C(N(C(C)C)CC)(C)C.[NH:52]1[CH2:57][CH2:56][O:55][CH2:54][CH2:53]1>CN1CCN(C)C1=O>[CH2:1]([O:3][C:4]([N:6]1[C:15]2[C:10](=[N:11][C:12]([O:16][CH3:17])=[CH:13][CH:14]=2)[C@@H:9]([NH:18][C:19]2[C:24]([CH2:25][C:26]3[CH:31]=[C:30]([C:32]([F:35])([F:34])[F:33])[CH:29]=[C:28]([C:36]([F:39])([F:38])[F:37])[CH:27]=3)=[N:23][CH:22]=[C:21]([N:52]3[CH2:57][CH2:56][O:55][CH2:54][CH2:53]3)[N:20]=2)[CH2:8][C@H:7]1[CH2:41][CH3:42])=[O:5])[CH3:2]
Reactant: C1COCCN1
Reactant: CCOC(=O)N1c2ccc(OC)nc2[C@@H](Nc2nc(Cl)cnc2Cc2cc(C(F)(F)F)cc(C(F)(F)F)c2)C[C@H]1CC
Solvent: CCN(C(C)C)C(C)C
Solvent: CN1CCN(C)C1=O
Product: CCOC(=O)N1c2ccc(OC)nc2[C@@H](Nc2nc(N3CCOCC3)cnc2Cc2cc(C(F)(F)F)cc(C(F)(F)F)c2)C[C@H]1CC
Temperature: 100 °C
Reaction time: 72 h

Procedure:
(2R*,4S*)-4-{[3,5-Bis(trifluoromethyl)benzyl]-(6-chloropyrazin-2-yl)}amino-2-ethyl-6-methoxy-3,4-dihydro-2H-[1,5]naphthyridine-1-carboxylic acid ethyl ester (300 mg) is dissolved in 1,3-dimethylimidazolidinone (2 ml), then thereto are added diisopropylethylamine (0.13 ml) and morpholine (0.6 ml), and the mixture is heated to 100° C. and stirred for 3 days. After adding distilled water, the mixture is extracted with ether. The organic layer is washed with a saturated brine, dried over magnesium sulfate, and concentrated under reduced pressure. The resulting residue is purified by column chromatography (NH-silica gel; hexane: ethyl acetate=9:1→7:3) to give (2R*,4S*)-4-{[3,5-bis(trifluoromethyl)benzyl]-[6-(morpholin-4-yl)pyrazin-2-yl]}amino-2-ethyl-6-methoxy-3,4-dihydro-2H-[1,5]naphthyridine-1-carboxylic acid ethyl ester (223.2 mg). MS (m/z): 669 [M+H]+
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH2:9][C@H:10]([NH:14][C:15](=[O:21])[O:16][C:17]([CH3:20])([CH3:19])[CH3:18])[C@H:11]2[CH2:13][O:12]2)[CH:5]=[C:6]([F:8])[CH:7]=1.[C@@H:22]1([NH2:32])[C:31]2[C:26](=[CH:27][CH:28]=[CH:29][CH:30]=2)CCC1.C[CH:34]([OH:36])C>>[F:1][C:2]1[CH:3]=[C:4]([CH:5]=[C:6]([F:8])[CH:7]=1)[CH2:9][C@H:10]([NH:14][C:15](=[O:21])[O:16][C:17]([CH3:20])([CH3:19])[CH3:18])[C@H:11]([OH:12])[CH2:13][NH:32][CH2:22][C:31]1[CH:30]=[CH:29][CH:28]=[C:27]([O:36][CH3:34])[CH:26]=1
Reactant: N[C@H]1CCCc2ccccc21
Reactant: CC(C)O
Reactant: CC(C)(C)OC(=O)N[C@@H](Cc1cc(F)cc(F)c1)[C@H]1CO1
Product: COc1cccc(CNC[C@@H](O)[C@H](Cc2cc(F)cc(F)c2)NC(=O)OC(C)(C)C)c1

Procedure:
A mixture of tert-butyl (1S)-2-(3,5-difluorophenyl)-1-[(2S)-oxiranyl]ethylcarbamate (V, 500 mg, 1.67 mmol) and 3-methoxybenzylamine (VI, 0.34g, 2.51 mmol) in 2-propanol (3 mL) is heated at reflux overnight, allowed to cool to 20–25 degrees C., and concentrated under reduced pressure. The residue is crystallized from ethyl acetate/hexanes and collected by filtration to afford tert-butyl (1S,2R)-1-(3,5-difluorobenzyl)-2-hydroxy-3-[(3-methoxybenzyl)amino]propylcarbamate (VII, 575 mg) as a solid: ESI-MS (m/z): 437 [M+H]+.
Reaction SMILES: [Cl:1][C:2]1[N:7]=[C:6]([NH2:8])[C:5]([O:9][CH3:10])=[N:4][CH:3]=1.[Br:11][C:12]1[S:16][C:15]([S:17](Cl)(=[O:19])=[O:18])=[CH:14][CH:13]=1>>[Br:11][C:12]1[S:16][C:15]([S:17]([NH:8][C:6]2[C:5]([O:9][CH3:10])=[N:4][CH:3]=[C:2]([Cl:1])[N:7]=2)(=[O:19])=[O:18])=[CH:14][CH:13]=1
Reactant: COc1ncc(Cl)nc1N
Reactant: O=S(=O)(Cl)c1ccc(Br)s1
Product: COc1ncc(Cl)nc1NS(=O)(=O)c1ccc(Br)s1

Procedure:
Prepared by the method of Example 1 from 6-chloro-3-methoxy-2-pyrazinamine and 5-bromothiophenesulphonyl chloride.
Reaction SMILES: [C-:1]#[N:2].[K+].[Cl-].[NH4+:5].[C:6]1([CH2:12][CH:13]=O)[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1.ClCCl>O.CO>[C:6]1([CH2:12][CH:13]([NH2:5])[C:1]#[N:2])[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1
Reactant: O=CCc1ccccc1
Reactant: [C-]#N
Reactant: [NH4+]
Agent: [Cl-]
Agent: [K+]
Solvent: O
Solvent: CO
Solvent: ClCCl
Product: N#CC(N)Cc1ccccc1
Temperature: 60 °C
Reaction time: 4 h
Yield: 54.7 %

Procedure:
In a 1L 5-necked flask equipped with a mechanical stirrer, thermometer, condenser and a dropping funnel was placed potassium cyanide (71.5 g, 1.1 mol) in water (325 mL). Ammonium chloride (64.2 g, 1.2 mol) was added. The resulting mixture was stirred to get a homogenous solution. A solution of phenylacetaldehyde (132 g of 90% purity, 1.0 mol) in methanol (325 mL) was added over 60 min. The resulting mixture was heated at 60° C. HPLC analysis indicated that the reaction was complete after 4 hr. The reaction mixture was cooled to room temperature and then dichloromethane (250 mL) and water (259 mL) were added. The aqueous layer was separated and extracted with dichloromethane (250 mL). The combined organic layers were washed with water (1×100 mL), and product was extracted with 2N HCl (2×300 mL). The combined acidic layers were back washed with dichloromethane (1×250 mL). Dichloromethane (250 mL) was added to the aqueous acidic layer after which the mixture was cooled in an ice-water bath and basified with concentrated ammonia (150 mL). The organic layer was separated and the aqueous layer was extracted with dichloromethane (2×100 ml). The organic layers were combined and washed with water (1×100 mL) then with brine (1×100 mL) and dried over anhydrous magnesium sulfate (15 g). The magnesium sulfate was filtered and the solution was evaporated under reduced pressure to give 80 g (55% yield) of the aminonitrile 2 as an oil. The oil solidified on standing in the refrigerator overnight. HPLC analysis showed a purity of 99%. NMR (CDCl3) δ 7.5 (s, 5H), 3.7–4.1 (m, 1H), 3.05 (d, 2H), 1.7 (s br, 2H).
Reaction SMILES: [F:1][C:2]([F:32])([F:31])[C:3]1[CH:26]=[C:25]([C:27]([F:30])([F:29])[F:28])[CH:24]=[CH:23][C:4]=1[CH2:5][N:6]1[C:14]2[C:9](=[CH:10][C:11](/[CH:15]=[C:16]3/[C:17](=[O:22])[NH:18][C:19](=[O:21])[S:20]/3)=[CH:12][CH:13]=2)[CH:8]=[CH:7]1.Cl.[CH3:34][N:35]([CH3:39])[CH2:36][CH2:37]Cl>>[F:32][C:2]([F:1])([F:31])[C:3]1[CH:26]=[C:25]([C:27]([F:29])([F:30])[F:28])[CH:24]=[CH:23][C:4]=1[CH2:5][N:6]1[C:14]2[C:9](=[CH:10][C:11](/[CH:15]=[C:16]3/[C:17](=[O:22])[N:18]([CH2:37][CH2:36][N:35]([CH3:39])[CH3:34])[C:19](=[O:21])[S:20]/3)=[CH:12][CH:13]=2)[CH:8]=[CH:7]1
Reactant: O=C1NC(=O)/C(=C/c2ccc3c(ccn3Cc3ccc(C(F)(F)F)cc3C(F)(F)F)c2)S1
Reactant: CN(C)CCCl
Agent: Cl
Product: CN(C)CCN1C(=O)S/C(=C\c2ccc3c(ccn3Cc3ccc(C(F)(F)F)cc3C(F)(F)F)c2)C1=O

Procedure:
(5Z)-5-[(1-{[2,4-Bis(trifluoromethyl)phenyl]methyl}-1H-indol-5-yl)methylidene]-3-[2-(dimethylamino)ethyl]-1,3-thiazolidine-2,4-dione was prepared from [(5Z)-5-({1-[2,4-bis-(trifluoromethyl)benzyl]-1H-indol-5-yl}methylidene)-2,4-dioxo-1,3-thiazolidine (from Example 238) and 2-(dimethylamino)ethyl chloride hydrochloride following General Procedure H.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5](I)=[CH:4][C:3]=1[F:9].CC1(C)C(C)(C)OB([C:18]2[CH:23]=[CH:22][C:21]([CH2:24][CH2:25][CH2:26][OH:27])=[CH:20][CH:19]=2)O1.CCOCC>O.C1COCC1.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>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([C:18]2[CH:23]=[CH:22][C:21]([CH2:24][CH2:25][CH2:26][OH:27])=[CH:20][CH:19]=2)=[CH:4][C:3]=1[F:9]
Reactant: CC1(C)OB(c2ccc(CCCO)cc2)OC1(C)C
Reactant: Fc1cc(I)ccc1Br
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Solvent: C1CCOC1
Solvent: CCOCC
Solvent: O
Product: OCCCc1ccc(-c2ccc(Br)c(F)c2)cc1

Procedure:
18 g (65 mmol) of sodium metaborate octahydrate and 2.8 g (3.9 mmol) of bis(triphenylphosphine)palladium(II) chloride are initially introduced in 200 ml of water and 100 ml of THF, 1-bromo-2-fluoro-4-iodobenzene are added, and a solution of 21.5 g (0.082 mol) of 3-[4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl]propan-1-ol in 100 ml THF is subsequently added dropwise. The batch is heated under reflux overnight, taken up in MTB ether and washed three times with water. The org. phase is dried over sodium sulfate, and the solvent is removed in vacuo. Chromatography of the crude product on silica gel with toluene/ethyl acetate (7:1) gives 3-(4′-bromo-3′-fluorobiphenyl-4-yl)propan-1-ol as a colourless oil.
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[CH:6][CH:7]=[C:8]2[C:12]=1[NH:11][CH:10]=[CH:9]2)([O-:3])=[O:2].[Cl:13]N1C(=O)CCC1=O.C(=O)([O-])O.[Na+]>C(#N)C>[Cl:13][C:9]1[C:8]2[C:12](=[C:4]([N+:1]([O-:3])=[O:2])[CH:5]=[CH:6][CH:7]=2)[NH:11][CH:10]=1
Reactant: O=[N+]([O-])c1cccc2cc[nH]c12
Reactant: O=C1CCC(=O)N1Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CC#N
Product: O=[N+]([O-])c1cccc2c(Cl)c[nH]c12
Temperature: 25 °C
Reaction time: 36 h
Yield: 91.9 %

Procedure:
7-Nitro-1H-indole (1.076 g, 6.64 mmol) was dissolved in 30 ml of acetonitrile, followed by the addition of 920 mg (6.89 mmol) of N-chlorosuccinimide. The obtained mixture was stirred at room temperature for 36 hours. A saturated aqueous solution of sodium hydrogencarbonate was added to the resulting mixture to form a precipitate. The precipitate was recovered by filtration and washed with water to give 1.2 g of powdery 3-chloro-7-nitro-1H-indole. This powder (863 mg, 4.39 mmol) was suspended in 10 ml of ethanol, followed by the addition of 4.95 g (21.9 mmol) of stannous chloride dehydrate and 100 μl concentrated hydrochloric acid. The obtained mixture was heated under reflux for 30 minutes, followed by the addition of a saturated aqueous solution of sodium hydrogencarbonate. The obtained mixture was filtered to remove insolubles. Ethyl acetate was added to the filtrate to conduct extraction. The organic phase was dried over magnesium sulfate and concentrated. The residue was purified by silica gel column chromatography to give 490 mg of the title compound.
Reaction SMILES: [CH3:1][O:2][C:3]([NH:5][C@H:6]([C:10]([OH:12])=O)[CH:7]([CH3:9])[CH3:8])=[O:4].C(Cl)CCl.C1C=CC2N(O)N=NC=2C=1.C(N(CC)CC)C.[CH3:34][N:35]1[CH2:40][CH2:39][N:38]([C:41]2[CH:46]=[CH:45][C:44]([CH2:47][N:48]([NH:61][C:62]([O:64][C:65]([CH3:68])([CH3:67])[CH3:66])=[O:63])[CH2:49][C@H:50]([OH:60])[C@@H:51]([NH2:59])[CH2:52][C:53]3[CH:58]=[CH:57][CH:56]=[CH:55][CH:54]=3)=[CH:43][CH:42]=2)[CH2:37][CH2:36]1>CN(C=O)C>[CH3:34][N:35]1[CH2:36][CH2:37][N:38]([C:41]2[CH:46]=[CH:45][C:44]([CH2:47][N:48]([NH:61][C:62]([O:64][C:65]([CH3:68])([CH3:67])[CH3:66])=[O:63])[CH2:49][C@H:50]([OH:60])[C@@H:51]([NH:59][C:10](=[O:12])[C@H:6]([CH:7]([CH3:8])[CH3:9])[NH:5][C:3]([O:2][CH3:1])=[O:4])[CH2:52][C:53]3[CH:54]=[CH:55][CH:56]=[CH:57][CH:58]=3)=[CH:43][CH:42]=2)[CH2:39][CH2:40]1
Reactant: COC(=O)N[C@H](C(=O)O)C(C)C
Reactant: CN1CCN(c2ccc(CN(C[C@H](O)[C@@H](N)Cc3ccccc3)NC(=O)OC(C)(C)C)cc2)CC1
Agent: On1nnc2ccccc21
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Solvent: ClCCCl
Product: COC(=O)N[C@H](C(=O)N[C@@H](Cc1ccccc1)[C@@H](O)CN(Cc1ccc(N2CCN(C)CC2)cc1)NC(=O)OC(C)(C)C)C(C)C
Reaction time: 0.33 h

Procedure:
1.60 g (9.16 mmol) of N-methoxycarbonyl-(L)-valine, 3.29 g (17.16 mmol) of EDC and 1.54 g (11.4 mmol) of HOBT are dissolved, under a N2 atmosphere, in 49 ml of DMF. After 20 min at RT, 4.8 ml (34.4 mmol) of triethylamine are added. 2.77 g (5.7 mmol) of 1-[p-(4-methylpiperazin-1-yl)phenyl]-4(S)-hydroxy-2-(tert-butyloxycarbonyl)amino-5(S)-amino-6-phenyl-2-azahexane in 24 ml of DMF are then added and the whole is thoroughly stirred overnight. The reaction mixture is evaporated under HV and the residue is dissolved in methylene chloride and a little methanol; this solution is then washed with sat. NaHCO3 solution, water and brine. The aqueous phases are extracted twice with methylene chloride. The combined organic phases are dried (Na2SO4) and concentrated by evaporation. Precipitating with DIPE from a concentrated solution in boiling methylene chloride results in the title compound:
Reaction SMILES: [CH3:1][N:2]1[CH2:9][CH2:8][CH2:7][C@H:3]1[C:4]([OH:6])=[O:5].S(Cl)(Cl)=O.[CH3:14]O>>[CH3:14][O:5][C:4](=[O:6])[C@@H:3]1[CH2:7][CH2:8][CH2:9][N:2]1[CH3:1]
Reactant: CO
Reactant: CN1CCC[C@H]1C(=O)O
Solvent: O=S(Cl)Cl
Product: COC(=O)[C@@H]1CCCN1C
Temperature: 25 °C

Procedure:
To a solution of N-methyl (L)-proline, from step 3a, in methanol at 0° C. is added thionyl chloride (1.1 eq) dropwise, and the reaction mixture is slowly allowed to warm to room temperature. Upon completion of the reaction the solvent is removed in vacuo, and the crude product is dissolved in 10% aq. HCl and washed with ether. The aqueous layer is adjusted to pH ~12 with K2CO3 (solid) and extracted with CH2Cl2. The combined CH2Cl2 layers are dried (MgSO4) and concentrated to afford the crude product as a clear oil.
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[C:5]([C:10]3[CH:11]=[C:12]4[C:16](=[CH:17][CH:18]=3)[NH:15][N:14]=[C:13]4[NH2:19])[CH:6]=[CH:7][CH:8]=2)[CH:3]=[CH:2]1.C([OH:22])C.C(O)(=O)C.[Br-].[Br-].[Br-].[NH+]1C=CC=CC=1.[NH+]1C=CC=CC=1.[NH+]1C=CC=CC=1>CC(O)(C)C.[Zn]>[NH2:19][C:13]1[C:12]2[C:16](=[CH:17][CH:18]=[C:10]([C:5]3[CH:6]=[CH:7][CH:8]=[C:9]4[C:4]=3[CH2:3][C:2](=[O:22])[NH:1]4)[CH:11]=2)[NH:15][N:14]=1
Reactant: CCO
Reactant: Nc1n[nH]c2ccc(-c3cccc4[nH]ccc34)cc12
Agent: [Br-]
Agent: [Zn]
Agent: c1cc[nH+]cc1
Solvent: CC(C)(C)O
Solvent: CC(=O)O
Product: Nc1n[nH]c2ccc(-c3cccc4c3CC(=O)N4)cc12
Temperature: 25 °C
Reaction time: 3 h
Yield: 77 %

Procedure:
To the suspension of 5-(1H-indol-4-yl)-1H-indazol-3-ylamine (0.82 g, 3.33 mmol) in t-BuOH: ethanol: acetic acid (20.5 mL: 12 mL: 6 mL) was added pyridinium tribromide (3.17 g, 9.9 mmol) portionwise. The mixture was stirred at room temperature for 3 hours, it immediately became a dark pink color. Zinc dust (excess) was added to the reaction mixture portionwise. After stirring for one hour, the unreacted zinc was filtered off and the solvent was removed under reduced pressure. The residue was washed with ample of water. The solid was triturated with DCM to give 0.563 g (77%) of 4-(3-amino-1H-indazol-5-yl)-1,3-dihydro-indol-2-one.
Reaction SMILES: [F:1][C:2]([F:12])([F:11])[C:3]1[CH:10]=[CH:9][CH:8]=[CH:7][C:4]=1[CH:5]=O.[CH:13]1[C:22]2[C:17](=[CH:18][CH:19]=[CH:20][CH:21]=2)[CH:16]=[CH:15][C:14]=1[C:23]([NH:25][NH2:26])=[O:24]>C(O)C>[F:1][C:2]([F:12])([F:11])[C:3]1[CH:10]=[CH:9][CH:8]=[CH:7][C:4]=1/[CH:5]=[N:26]/[NH:25][C:23]([C:14]1[CH:15]=[CH:16][C:17]2[C:22](=[CH:21][CH:20]=[CH:19][CH:18]=2)[CH:13]=1)=[O:24]
Reactant: NNC(=O)c1ccc2ccccc2c1
Reactant: O=Cc1ccccc1C(F)(F)F
Solvent: CCO
Product: O=C(N/N=C/c1ccccc1C(F)(F)F)c1ccc2ccccc2c1
Temperature: 70 °C
Reaction time: 2 h

Procedure:
2-(Trifluoromethyl)benzaldehyde (4-B) (135 μL, 1.0 mmol) was added to a partial solution of 2-naphthohydrazide (4-A) (186 mg, 1.0 mmol) in ethanol (4 mL) at 70° C. and the mixture stirred at 70° C. for 2 h. The mixture was cooled and the thick precipitate was filtered, washed with cold ethanol and dried to give N′-{(1E)-[2-(trifluoromethyl)phenyl]-methylene}-2-naphthohydrazide (4-C).
Reaction SMILES: Cl.[Cl:2][C:3]1[N:4]=[C:5]([C:11]2[CH:12]=[N:13][CH:14]=[CH:15][CH:16]=2)[S:6][C:7]=1[NH:8][CH2:9][CH3:10].N1C=CC=CC=1.[CH3:23][CH:24]([CH2:28][S:29][CH3:30])[C:25](Cl)=[O:26]>CN(C1C=CN=CC=1)C.ClCCl>[Cl:2][C:3]1[N:4]=[C:5]([C:11]2[CH:12]=[N:13][CH:14]=[CH:15][CH:16]=2)[S:6][C:7]=1[N:8]([CH2:9][CH3:10])[C:25](=[O:26])[CH:24]([CH3:23])[CH2:28][S:29][CH3:30]
Reactant: CCNc1sc(-c2cccnc2)nc1Cl
Reactant: CSCC(C)C(=O)Cl
Agent: CN(C)c1ccncc1
Agent: Cl
Solvent: c1ccncc1
Solvent: ClCCl
Product: CCN(C(=O)C(C)CSC)c1sc(-c2cccnc2)nc1Cl
Temperature: 35 °C
Yield: 90 %

Procedure:
Into a 500-mL three-necked flask fitted with a J-KEM type-T temperature probe, overhead stirrer, reflux condensor, and nitrogen inlet was added (4-chloro-2-pyridin-3-yl-thiazol-5-yl)-ethyl-amine hydrochloride (20.0 g, 72.4 mmol green solid) and dichloromethane (150 mL). To this suspension was added pyridine (14.32 g, 181 mmol, 2.5 eq) (portionwise over 1 min to form a dark green-black solution. To this solution was added DMAP (4.4 g, 36 mmol) followed by 2-methyl-3-methylthiopropanoyl chloride (16.5 g, 108.6 mmol), which was added portionwise over 1 minute. The reaction exotherm went from 20° C. to 31° C. during the addition of the acid chloride. The reaction was heated to 35° C. for 10 hours then cooled to 25° C. for 14 h. To the dark brown reaction mixture was added dichloromethane (200 mL) and the solution was transferred to a 500 mL separatory funnel. The solution was washed with water (100 mL) and the layers were separated. The brown aqueous layers was extracted with dichloromethane (50 mL) and the dark brown dichloromethane extracts combined, washed with brine (100 mL), dried (MgSO4), filtered and rotary evaporated. This gave 30.49 g (74% pure by HPLC at 254 nm) of a crude black oil. The crude product was purified by silica gel chromatography (0 to 100% ethyl acetate/hexanes) to afford a beige solid (23.2 g, 89%): mp 79-81° C.; 1H NMR (300 MHz, CDCl3) δ 9.11 (d, J=1.7 Hz, 1H), 8.71 (d, J=4.8 Hz, 1H), 8.27-8.13 (m, 1H), 7.42 (dd, J=8.0, 4.9 Hz, 1H), 3.90 (bs, 1H), 3.69 (bs, 1H), 2.80 (bs, 2H), 2.47 (bs, 1H), 2.02 (s, 3H), 1.21 (q, J=7.3 Hz, 6H); ESIMS m/z 356 (M+1).