Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([NH2:8])=[CH:4][C:3]=1[N+:9]([O-:11])=[O:10].C([O:14][C:15](=O)[CH2:16][C:17]([CH3:19])=[O:18])C.C(O)C>ClC1C=CC=CC=1>[NH2:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][C:15](=[O:14])[CH2:16][C:17]([CH3:19])=[O:18])=[CH:4][C:3]=1[N+:9]([O-:11])=[O:10]
Reactant: Nc1ccc(N)c([N+](=O)[O-])c1
Reactant: CCOC(=O)CC(C)=O
Solvent: Clc1ccccc1
Solvent: CCO
Product: CC(=O)CC(=O)Nc1ccc(N)c([N+](=O)[O-])c1

Procedure:
15.3 gm (0.1 mol) of 1,4-diamino-2-nitrobenzene were heated in 50 ml of chlorobenzene together with 20 gm of acetoacetic acid ethyl ester, with the simultaneous distillation of ethanol, formed in the reaction. From the cold reaction mixture the precipitate was suctioned off, washed with dilute methanol and recrystallized from dilute acetic acid. The product had a melting point of 146°-147°C.
Reaction SMILES: [Br:1][C:2]1[CH:6]=[N:5][N:4]([CH3:7])[C:3]=1[C:8]1[CH:9]=[C:10]([NH2:23])[CH:11]=[CH:12][C:13]=1[O:14][CH2:15][CH2:16][N:17]1[CH2:21][CH2:20][C@H:19]([F:22])[CH2:18]1.[F:24][C:25]1[CH:26]=[C:27]([CH:31]=[CH:32][CH:33]=1)[C:28](Cl)=[O:29].C(N(CC)CC)C>C1COCC1>[Br:1][C:2]1[CH:6]=[N:5][N:4]([CH3:7])[C:3]=1[C:8]1[CH:9]=[C:10]([NH:23][C:28](=[O:29])[C:27]2[CH:31]=[CH:32][CH:33]=[C:25]([F:24])[CH:26]=2)[CH:11]=[CH:12][C:13]=1[O:14][CH2:15][CH2:16][N:17]1[CH2:21][CH2:20][C@H:19]([F:22])[CH2:18]1
Reactant: O=C(Cl)c1cccc(F)c1
Reactant: Cn1ncc(Br)c1-c1cc(N)ccc1OCCN1CC[C@H](F)C1
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: Cn1ncc(Br)c1-c1cc(NC(=O)c2cccc(F)c2)ccc1OCCN1CC[C@H](F)C1
Temperature: 25 °C
Reaction time: 0.33 h
Yield: 39.6 %

Procedure:
A mixture of 3-(4-bromo-2-methyl-2H-pyrazol-3-yl)-4-[2-((S)-3-fluoro-pyrrolidin-1-yl)-ethoxy]-phenylamine (76 mg, 0.2 mmol), 3-fluorobenzoyl chloride (32 mg, 0.22 mmol), triethylamine (0.3 mL) in THF (2 mL) was stirred at r.t. for 20 min. The solvent was concentrated in vacuo and the crude was purified by HPLC to give the title compound (40 mg, 40%) as a yellow solid as TFA salt. 1H NMR (DMSO-d6, 400 MHz) δ 1.98-2.10 (m, 2H), 2.90-3.45 (m, 6H), 3.68 (s, 3H), 4.28-4.30 (m, 1H), 4.39-4.42 (m, 1H), 5.28-5.42 (m, 1H), 7.28-7.31 (m, 1H), 7.44-7.49 (m, 1H), 7.57-7.63 (m, 1H), 7.67 (d, 1H), 7.73-7.82 (m, 3H), 7.94 (dd, 1H), 10.4 (s, 2H). Exact mass calculated for C23H23BrF2N4O2 504.1. found 505.5/507.5 (MH+).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]([C:10]2[C:14]([C:15]3[C:16]([CH3:22])=[N:17][O:18][C:19]=3[CH2:20][OH:21])=[CH:13][N:12]([CH3:23])[N:11]=2)=[O:9])=[CH:4][CH:3]=1.C(N(CC)CC)C.[CH3:31][S:32](Cl)(=[O:34])=[O:33].C(=O)(O)[O-].[Na+]>C(Cl)Cl>[CH3:31][S:32]([O:21][CH2:20][C:19]1[O:18][N:17]=[C:16]([CH3:22])[C:15]=1[C:14]1[C:10]([C:8](=[O:9])[C:5]2[CH:6]=[CH:7][C:2]([Cl:1])=[CH:3][CH:4]=2)=[N:11][N:12]([CH3:23])[CH:13]=1)(=[O:34])=[O:33]
Reactant: Cc1noc(CO)c1-c1cn(C)nc1C(=O)c1ccc(Cl)cc1
Reactant: CS(=O)(=O)Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: Cc1noc(COS(C)(=O)=O)c1-c1cn(C)nc1C(=O)c1ccc(Cl)cc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 56 %

Procedure:
To a solution of (4-chlorophenyl)(4-(5-(hydroxymethyl)-3-methylisoxazol-4-yl)-1-methyl-1H-pyrazol-3-yl)methanone (0.05 g, 0.15 mmol) in DCM (10 mL), was added triethylamine (0.1 mL) and methane sulfonyl chloride (0.05 mL) at room temperature. The mixture was stirred for 2 h at room temperature. DCM (50 mL) and saturated sodium bicarbonate solution (20 mL) were added. The combined organic layers were dried over anhydrous sodium sulfate and concentrated to afford the titled product as yellow oil (0.035 g, 56%). LC/MS m/z 409 [M+H]+.
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[CH:12]=[CH:11][C:8]([CH:9]=[O:10])=[CH:7][CH:6]=1)=[O:4].[C:13]([O:17][C:18](=[O:21])[CH:19]=[CH2:20])([CH3:16])([CH3:15])[CH3:14].N12CCN(CC1)CC2>C(OCC)(=O)C.CCCCCC>[C:13]([O:17][C:18](=[O:21])[C:19](=[CH2:20])[CH:9]([OH:10])[C:8]1[CH:11]=[CH:12][C:5]([C:3]([O:2][CH3:1])=[O:4])=[CH:6][CH:7]=1)([CH3:16])([CH3:15])[CH3:14]
Reactant: C=CC(=O)OC(C)(C)C
Reactant: COC(=O)c1ccc(C=O)cc1
Agent: C1CN2CCN1CC2
Solvent: CCOC(C)=O
Solvent: CCCCCC
Product: C=C(C(=O)OC(C)(C)C)C(O)c1ccc(C(=O)OC)cc1
Temperature: 25 °C
Reaction time: 120 h
Yield: 73 %

Procedure:
4-(methoxycarbonyl)benzaldehyde (3.3 g, 20 mM), t-butylacrylate (3.5 ml, 24 mM) and 1,4-diazabicyclo[2,2,2]octane (449 mg, 4 mM) were mixed and stirred in a vessel at room temperature for 5 days. The resulting mixture was extracted with ethyl ether. The organic layer was separated, washed with 2N hydrochloric acid, water and an aqueous sodium bicarbonate solution in order, dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The residue thus obtained was subjected to a silica gel column chromatography (eluent: ethyl acetate/n-hexane=1/19), to obtain 4.1 g of the title compound as a white solid (yield 73%).
Reaction SMILES: [ClH:1].Cl.Cl.C([O:11][C:12]([C:14]1([C:17](=[O:49])[NH:18][C:19]2[CH:24]=[CH:23][C:22]([O:25][C:26]3[CH:31]=[CH:30][N:29]=[C:28]([NH:32][C:33]([N:35]4[CH2:40][CH2:39][CH:38]([N:41]5[CH2:46][CH2:45][N:44]([CH3:47])[CH2:43][CH2:42]5)[CH2:37][CH2:36]4)=[O:34])[CH:27]=3)=[CH:21][C:20]=2[F:48])[CH2:16][CH2:15]1)=[O:13])C1C=CC=CC=1>O.C(O)C.[Pd]>[ClH:1].[ClH:1].[ClH:1].[F:48][C:20]1[CH:21]=[C:22]([O:25][C:26]2[CH:31]=[CH:30][N:29]=[C:28]([NH:32][C:33]([N:35]3[CH2:40][CH2:39][CH:38]([N:41]4[CH2:42][CH2:43][N:44]([CH3:47])[CH2:45][CH2:46]4)[CH2:37][CH2:36]3)=[O:34])[CH:27]=2)[CH:23]=[CH:24][C:19]=1[NH:18][C:17]([C:14]1([C:12]([OH:13])=[O:11])[CH2:16][CH2:15]1)=[O:49]
Reactant: CN1CCN(C2CCN(C(=O)Nc3cc(Oc4ccc(NC(=O)C5(C(=O)OCc6ccccc6)CC5)c(F)c4)ccn3)CC2)CC1
Agent: [Pd]
Agent: Cl
Solvent: O
Solvent: CCO
Product: CN1CCN(C2CCN(C(=O)Nc3cc(Oc4ccc(NC(=O)C5(C(=O)O)CC5)c(F)c4)ccn3)CC2)CC1
Temperature: 25 °C
Reaction time: 7 h
Yield: 291 %

Procedure:
1-[2-Fluoro-4-(2-{[4-(4-methylpiperazin-1-yl)piperidine-1-carbonyl]amino}pyridin-4-yloxy)phenylcarbamoyl]cyclopropanecarboxylic acid benzyl ester trihydrochloride (5 g) was dissolved in a mixed solvent of water (10 ml) and ethanol (20 ml), and palladium on carbon (250 mg) was added, and the mixture was stirred at room temperature under a hydrogen atmosphere (0.2 MPa) for 7 hours and 50 minutes. The reaction mixture was filtered, and the residue was washed with a mixed solvent of water (6 ml) and ethanol (10 ml). Ethanol (50 ml) was added to the filtrate, which was azeotropically distilled off and concentrated, and water (0.6 g) and ethanol (8.3 ml) were added. 2-Propanol (10 ml) was added to the solution, followed by stirring at room temperature for 5 minutes. 1-[2-Fluoro-4-(2-{[4-(4-methylpiperazin-1-yl)piperidine-1-carbonyl]amino}pyridin-4-yloxy)phenylcarbamoyl]cyclopropanecarboxylic acid trihydrochloride (150 mg) was added, followed by stirring for 13 hours and 45 minutes. 2-Propanol (50 ml) was further added, and the mixture was stirred at room temperature for 24 hours and 35 minutes. The crystals were filtered and dried to give the title compound (4.26 g) as a white solid.
Reaction SMILES: [CH3:1][N:2]1[CH:6]=[CH:5][CH:4]=[C:3]1[C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][C:8]=1[OH:13].O=[C:15]1[CH2:20][CH2:19][N:18](C(OC(C)(C)C)=O)[CH2:17][CH2:16]1.O.CC1C=CC(S(O)(=O)=O)=CC=1.ClC(Cl)C.Cl>>[CH3:1][N:2]1[CH:6]=[CH:5][C:4]2[C:15]3([O:13][C:8]4[CH:9]=[CH:10][CH:11]=[CH:12][C:7]=4[C:3]1=2)[CH2:20][CH2:19][NH:18][CH2:17][CH2:16]3
Reactant: CC(C)(C)OC(=O)N1CCC(=O)CC1
Reactant: Cn1cccc1-c1ccccc1O
Agent: Cc1ccc(S(=O)(=O)O)cc1
Agent: Cl
Solvent: O
Solvent: CC(Cl)Cl
Product: Cn1ccc2c1-c1ccccc1OC21CCNCC1
Temperature: 80 °C
Reaction time: 1 h

Procedure:
A mixture of 2-(1-methylpyrrol-2-yl)phenol (1.20 g, 6.90 mmol), tert-butyl 4-oxopiperidine-1-carboxylate (1.38 g, 6.93 mmol), 4-methylbenzenesulfonic acid hydrate (264 mg, 1.39 mmol), and dichloroethane (24 mL) was heated at 80° C. for 2 h. To the mixture was added HCl (1.7 mL of 4.0 M, 6.9 mmol) and the mixture was allowed to stir at 50° C. for 1 h. The mixture was cooled to 25° C. and was concentrated in vacuo. The residue was taken up in dichloromethane and was washed with saturated aqueous NaHCO3. The organic layer was dried over sodium sulfate and concentrated. Column chromatography (0-100% ethyl acetate/hexanes) on the residue gave 1-methyl-1H-spiro[chromeno[4,3-b]pyrrole-4,4′-piperidine]. ESI-MS m/z calc. 254.3. found 255.2 (M+1)+; Retention time: 1.51 minutes (3 min run).
Reaction SMILES: [CH:1]12[N:8]([C:9]3[CH:18]=[N:17][C:16]4[C:11](=[CH:12]C=CC=4)[N:10]=3)[CH2:7][CH:6]1[CH2:5][CH2:4][NH:3][CH2:2]2.[C:19](OC(N1CCC2C(NC2)C1)=O)(C)(C)C.ClC1C(C)=NC=C(C)N=1.ClC1C=NC2C(=CC=CC=2)N=1>>[CH3:19][C:18]1[C:9]([N:8]2[C@@H:1]3[C@@H:6]([CH2:5][CH2:4][NH:3][CH2:2]3)[CH2:7]2)=[N:10][C:11]([CH3:12])=[CH:16][N:17]=1
Reactant: CC(C)(C)OC(=O)N1CCC2CNC2C1
Reactant: c1ccc2nc(N3CC4CCNCC43)cnc2c1
Agent: Cc1cnc(C)c(Cl)n1
Agent: Clc1cnc2ccccc2n1
Product: Cc1cnc(C)c(N2C[C@@H]3CCNC[C@@H]32)n1

Procedure:
The title compound was prepared in a manner analogous to Intermediate 2, substituting (1R,6S)-(3,8-diaza-bicyclo[4.2.0]octane-3-carboxylic acid tert-butyl ester for 3,8-diaza-bicyclo[4.2.0]octane-3-carboxylic acid tert-butyl ester and 3-chloro-2,5-dimethyl-pyrazine for 2-chloro-quinoxaline in Step A. MS (ESI) mass calcd. for C12H18N4, 218.30. The compound was used as such in the subsequent reactions.
Reaction SMILES: CS([O:5][C@@:6]([C:16]1[CH:21]=[C:20]([F:22])[CH:19]=[CH:18][C:17]=1[NH2:23])([C:11]#[C:12][CH:13]1[CH2:15][CH2:14]1)[C:7]([F:10])([F:9])[F:8])(=O)=O.[OH-].[Na+].[C:26]([O-])([O-])=[O:27].[Na+].[Na+].ClC(Cl)(OC(=O)OC(Cl)(Cl)Cl)Cl>>[CH:13]1([C:12]#[C:11][C@:6]2([C:7]([F:10])([F:9])[F:8])[C:16]3[CH:21]=[C:20]([F:22])[CH:19]=[CH:18][C:17]=3[NH:23][C:26](=[O:27])[O:5]2)[CH2:15][CH2:14]1
Reactant: O=C([O-])[O-]
Reactant: CS(=O)(=O)O[C@](C#CC1CC1)(c1cc(F)ccc1N)C(F)(F)F
Agent: O=C(OC(Cl)(Cl)Cl)OC(Cl)(Cl)Cl
Agent: [Na+]
Agent: [OH-]
Product: O=C1Nc2ccc(F)cc2[C@](C#CC2CC2)(C(F)(F)F)O1
Temperature: 15 °C
Reaction time: 0.08 h

Procedure:
(R)-2-(2-Amino-5-fluorophenyl)-4-cyclopropyl-1,1,1-trifluorobut-3-yn-2-ol methanesulfonate (CN46619-MSA) of example 4 (14.0 g, 33.5 mmol) in ethyl acetate/heptanes (40 g, 6/4 v/v) was charged to a jacketed 150 mL-reactor with agitator and off-gas scrubber with caustic soda. After addition of aqueous Na2CO3 (12%-w/w, 26.9 g, 30.3 mmol) the mixture was stirred for 5 min at 15° C. The aqueous phase was separated and discarded. Aqueous Na2CO3 (12%-w/w, 34.1 g, 38.4 mmol) was charged to the organic phase, then triphosgene (3.73 g, 12.6 mmol) was added in portions over a period of 25 min at 10° C. The reaction mixture was stirred for 2 h at 8° C.
Reaction SMILES: [NH2:1][C:2]1[C:3]([C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=2)=[N:4][C:5]([N:18]2[CH:22]=[CH:21][N:20]=[CH:19]2)=[C:6]([C:13](OCC)=[O:14])[C:7]=1[C:8](OCC)=[O:9].O.[NH2:30][NH2:31]>C(O)C>[NH2:1][C:2]1[C:7]2[C:8](=[O:9])[NH:31][NH:30][C:13](=[O:14])[C:6]=2[C:5]([N:18]2[CH:22]=[CH:21][N:20]=[CH:19]2)=[N:4][C:3]=1[C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1
Reactant: NN
Reactant: CCOC(=O)c1c(-n2ccnc2)nc(-c2ccccc2)c(N)c1C(=O)OCC
Solvent: CCO
Solvent: O
Product: Nc1c(-c2ccccc2)nc(-n2ccnc2)c2c(=O)[nH][nH]c(=O)c12

Procedure:
In 10ml of ethanol was dissolved 0.342 g of 3-amino-4,5-diethoxycarbonyl-6-(imidazol-1-yl)-2-phenylpyridine, and 0.5 ml of hydrazine monohydrate was added to the solution. The mixture was heated under reflux for 7 hours. After the reaction mixture was concentrated, the residue was acidified with acetic acid. The resulting precipitate was collected with. filtration and washed with water, followed by reprecipitation from DMF/H2O, to give 0.2 g of the title compound as yellow powder.
Reaction SMILES: F[C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[N+:9]([O-:11])=[O:10].[CH3:12][NH2:13]>>[F:8][C:6]1[CH:5]=[CH:4][C:3]([N+:9]([O-:11])=[O:10])=[C:2]([NH:13][CH3:12])[CH:7]=1
Reactant: O=[N+]([O-])c1ccc(F)cc1F
Reactant: CN
Product: CNc1cc(F)ccc1[N+](=O)[O-]
Reaction time: 1 h
Yield: 59.8 %

Procedure:
To stirred 2,4-difluoronitrobenzene (9.54 g., 60 mmole) was added dropwise an aqueous solution of methylamine (40 wt. %) (11.6 g) in an ice bath. The mixture was stirred for another 1 hour. The yellow precipitate was collected by filtration, washed with water and dried in vacuo to give the compound (7) as yellow crystals (6.1 g., 60%).
Reaction SMILES: C([Li])CCC.CCCCCC.Br[C:13]1[CH:14]=[C:15]([C:21]2[CH:26]=[CH:25][N:24]=[CH:23][CH:22]=2)[CH:16]=[CH:17][C:18]=1[O:19][CH3:20].C([O:29][B:30](OCC)[O:31]CC)C.[Cl-].[NH4+]>O1CCCC1>[CH3:20][O:19][C:18]1[CH:17]=[CH:16][C:15]([C:21]2[CH:26]=[CH:25][N:24]=[CH:23][CH:22]=2)=[CH:14][C:13]=1[B:30]([OH:31])[OH:29]
Reactant: CCOB(OCC)OCC
Reactant: COc1ccc(-c2ccncc2)cc1Br
Agent: [Cl-]
Agent: [Li]CCCC
Agent: [NH4+]
Solvent: CCCCCC
Solvent: C1CCOC1
Product: COc1ccc(-c2ccncc2)cc1B(O)O
Temperature: -80 °C
Reaction time: 0.25 h

Procedure:
A solution of n-butyllithium in hexane (1.7 mL of 2.5 M, 4.25 mmol) is added to a stirred solution of 4-(3-bromo-4-methoxyphenyl)pyridine (Example 1 b; 1.06 g, 4 mmol) and triethylborate (0.62 g, 4.2 mmol) in dry tetrahydrofuran (20 mL) at -85° C. under an argon atmosphere. The mixture is stirred for 15 min at -80° C., then treated with a saturated aqueous solution of ammonium chloride (60 mL) and extracted with ethyl acetate (2×80 mL). The combined extracts are dried (Na2SO4), filtered and the solvent is evaporated off under reduced pressure to yield the crude product which is purified by recrystallisation from ethyl acetate-hexane to give 2-methoxy-5-(pyridin-4-yl)phenylboronic acid as a beige crystalline solid. m.p. 194-200° C. and having the following physical characteristics:
Reaction SMILES: CC(C)N=C=NC(C)C.[C:10]1([SH:16])[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1.[C:17]([O:21][C:22](=[O:35])[C@@H:23]([NH:28][C:29](=[O:34])[CH2:30][CH2:31][CH:32]=[CH2:33])[CH2:24][C:25](O)=[O:26])([CH3:20])([CH3:19])[CH3:18].C(O)(=O)CCC=C>CN(C1C=CN=CC=1)C.C(Cl)Cl>[O:26]=[C:25]([S:16][C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1)[CH2:24][C@H:23]([NH:28][C:29](=[O:34])[CH2:30][CH2:31][CH:32]=[CH2:33])[C:22]([O:21][C:17]([CH3:18])([CH3:19])[CH3:20])=[O:35]
Reactant: C=CCCC(=O)N[C@@H](CC(=O)O)C(=O)OC(C)(C)C
Reactant: Sc1ccccc1
Agent: C=CCCC(=O)O
Agent: CC(C)N=C=NC(C)C
Agent: CN(C)c1ccncc1
Solvent: ClCCl
Product: C=CCCC(=O)N[C@@H](CC(=O)Sc1ccccc1)C(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 4 h
Yield: 79 %

Procedure:
DIC (2.43 ml, 15.6 mmol), DMAP (318 mg, 2.60 mmol) and benzenethiol (1.59 ml, 15.6 mmol) were added to a solution of the mixed crude product A (2.53 g, 13.0 mmol) of (S)-4-(tert-butoxy)-4-oxo-3-(pent-4-enamido)butanoic acid (Compound 1b-I) and pent-4-enoic acid (1:0.8) in CH2Cl2 (35 ml), and the mixture was stirred at room temperature for 4 hours. The reaction mixture was filtered, and the resulting filtrate was concentrated, diluted with ethyl acetate and then washed with a saturated aqueous ammonium chloride solution, saturated aqueous sodium bicarbonate and brine. The organic extract was then dried over magnesium sulfate and concentrated under reduced pressure. The resulting residue was purified by reverse-phase silica gel column chromatography (10 mM aqueous ammonium acetate solution/methanol=70/30→0/100), and the resulting crude product was further purified by silica gel column chromatography (hexane/ethyl acetate=100/0→65/35) to afford (S)-tert-butyl 4-oxo-2-(pent-4-enamido)-4-(phenylthio)butanoate (Compound 1e-IF) (1.99 g, 79%).
Reaction SMILES: [CH3:1][CH:2]1[CH2:7][CH2:6][C:5](=O)[CH:4]([CH2:9][C:10](=O)[C:11]2[S:12][CH:13]=[CH:14][N:15]=2)[CH2:3]1.[NH2:17][C:18]1[CH:26]=[CH:25][C:21]([C:22]([OH:24])=[O:23])=[CH:20][CH:19]=1>>[CH3:1][CH:2]1[CH2:7][CH2:6][C:5]2[N:17]([C:18]3[CH:26]=[CH:25][C:21]([C:22]([OH:24])=[O:23])=[CH:20][CH:19]=3)[C:10]([C:11]3[S:12][CH:13]=[CH:14][N:15]=3)=[CH:9][C:4]=2[CH2:3]1
Reactant: Nc1ccc(C(=O)O)cc1
Reactant: CC1CCC(=O)C(CC(=O)c2nccs2)C1
Product: CC1CCc2c(cc(-c3nccs3)n2-c2ccc(C(=O)O)cc2)C1
Yield: 45 %

Procedure:
Following the general methods as outlined under Intermediate 13, starting from 4-methyl-2-[2-oxo-2-(1,3-thiazol-2-yl)ethyl]cyclohexanone and 4-aminobenzoic acid, the title compound was isolated in 45% yield (94% purity by HPLC). MS(ESI+): 339.5; MS(ESI−): 337.7.
Reaction SMILES: S(Cl)([Cl:3])=O.Cl.[N:6]1([CH2:11][CH:12]([N:14]2[C:27]3[CH:26]=[C:25]([C:28]([OH:30])=O)[CH:24]=[CH:23][C:22]=3[S:21][C:20]3[C:15]2=[CH:16][CH:17]=[CH:18][CH:19]=3)[CH3:13])[CH2:10][CH2:9][CH2:8][CH2:7]1>C(Cl)Cl>[ClH:3].[CH3:24][C:25]([CH3:28])=[CH:26][CH2:27][NH:14][C:28]([C:25]1[CH:24]=[CH:23][C:22]2[S:21][C:20]3[C:15](=[CH:16][CH:17]=[CH:18][CH:19]=3)[N:14]([CH:12]([CH3:13])[CH2:11][N:6]3[CH2:10][CH2:9][CH2:8][CH2:7]3)[C:27]=2[CH:26]=1)=[O:30]
Reactant: CC(CN1CCCC1)N1c2ccccc2Sc2ccc(C(=O)O)cc21
Reactant: O=S(Cl)Cl
Agent: Cl
Solvent: ClCCl
Product: CC(C)=CCNC(=O)c1ccc2c(c1)N(C(C)CN1CCCC1)c1ccccc1S2
Temperature: 5 °C
Reaction time: 0.67 h

Procedure:
Thionyl chloride (0.5 cc) is introduced during 5 minutes and with stirring into a suspension of 10-[(2RS)-1-(1-pyrrolidinyl)-2-propyl]-2-phenothiazinecarboxylic acid hydrochloride (1 g) in methylene chloride (30 cc) while the temperature is maintained in the vicinity of 5° C. Stirring is continued for 40 minutes while heating to a temperature in the region of 30° C., and the yellow solution obtained is concentrated to dryness under reduced pressure (30 mm Hg; 4kPa) at 40° C. The residue is dissolved in methylene chloride (30 cc) and 3-methyl-2butenylamine (0.73 g) and triethylamine (0.84 cc) are added. Stirring is maintained for 30 minutes at 20° C. The reaction mixture is diluted with ethyl acetate (100 cc), washed successively with N aqueous sodium hydroxide solution (50 cc) and then with saturated aqueous sodium chloride solution (2×50 cc), dried over magnesium sulphate, filtered and concentrated to dryness under reduced pressure (30 mm Hg; 4 kPa) at 40° C. The oily orange residue (0.9 g) is dissolved in a mixture (30:70 by volume) (35 cc) of ethyl acetate and isopropyl ether, and a 0.3N solution (5.5 cc) of hydrochloric acid in isopropyl ether is added with stirring at 6° C. After one hour's stirring at 6° C., the solid formed is filtered off, washed with isopropyl ether (5 cc) and dried under reduced pressure (5 mm Hg; 0.67 kPa) at 40° C. to give N-(3-methyl-2-butenyl)-10-[(2RS)-1-(1-pyrrolidinyl)-2-propyl]-2-phenothiazinecarboxamide hydrochloride (0.52 g) in the form of a cream-coloured solid, m.p. about 150° C.
Reaction SMILES: [SH:1][C:2]1[NH:3][C:4]2[CH:10]=[C:9]([O:11][CH3:12])[CH:8]=[CH:7][C:5]=2[N:6]=1.Cl.Cl[CH2:15][C:16]1[CH:22]=[CH:21][CH:20]=[CH:19][C:17]=1[NH2:18]>C(O)(C)C>[CH3:12][O:11][C:9]1[CH:8]=[CH:7][C:5]2[NH:6][C:2]([S:1][CH2:15][C:16]3[CH:22]=[CH:21][CH:20]=[CH:19][C:17]=3[NH2:18])=[N:3][C:4]=2[CH:10]=1
Reactant: Nc1ccccc1CCl
Reactant: COc1ccc2nc(S)[nH]c2c1
Agent: Cl
Solvent: CC(C)O
Product: COc1ccc2[nH]c(SCc3ccccc3N)nc2c1
Yield: 19.5 %

Procedure:
The title compound was prepared by the method of Example 1 using 1.68 g (9.33 mMol) of 2-mercapto-5-methoxybenzimidazole instead of 2-mercaptobenzimidazole and 1.99 g (11.2 mMol) of 2-(chloromethyl)aniline hydrochloride instead of 2-(chloromethyl)-N,N-dimethylaniline in 250 ml of isopropyl alcohol. The basic extraction used 5% sodium hydroxide instead of sodium carbonate. Chromatography on silica gel, followed by crystallization from diethylether, gave 520 mg of pure title compound: m.p. 140-142° C. Anal. Calc'd. for C15H15N3OS: C, 63.14; H, 5.30; N,14.73; S, 11.23. Found: C, 63.44; H, 5.42; N, 14.43; S, 11.07.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:8]=[CH:9][C:10]=1[O:11][CH2:12][CH:13]1[CH2:15][CH2:14]1)[C:5](Cl)=[O:6].O[NH:17][C:18](=[NH:38])[C:19]1[CH:28]=[CH:27][CH:26]=[C:25]2[C:20]=1[CH:21]=[CH:22][N:23]=[C:24]2[CH2:29][CH2:30][C:31]([O:33][C:34]([CH3:37])([CH3:36])[CH3:35])=[O:32].C(N(CC)CC)C>CN(C=O)C>[Cl:1][C:2]1[CH:3]=[C:4]([C:5]2[O:6][N:17]=[C:18]([C:19]3[CH:28]=[CH:27][CH:26]=[C:25]4[C:20]=3[CH:21]=[CH:22][N:23]=[C:24]4[CH2:29][CH2:30][C:31]([O:33][C:34]([CH3:37])([CH3:36])[CH3:35])=[O:32])[N:38]=2)[CH:8]=[CH:9][C:10]=1[O:11][CH2:12][CH:13]1[CH2:15][CH2:14]1
Reactant: CC(C)(C)OC(=O)CCc1nccc2c(C(=N)NO)cccc12
Reactant: O=C(Cl)c1ccc(OCC2CC2)c(Cl)c1
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: CC(C)(C)OC(=O)CCc1nccc2c(-c3noc(-c4ccc(OCC5CC5)c(Cl)c4)n3)cccc12
Reaction time: 1.5 h
Yield: 16.1 %

Procedure:
A solution of 3-chloro-4-[(cyclopropylmethyl)oxy]benzoyl chloride (D16; 73.5 mg, 0.3 mmol) in dry DMF (1.5 ml) was added to a stirred solution of 1,1-dimethylethyl 3-{5-[(hydroxyamino)(imino)methyl]-1-isoquinolinyl}propanoate (D36; 85 mg, 0.270 mmol) and triethylamine (0.063 ml, 0.450 mmol) in dry DMF (1.5 ml) at 0° and the mixture was stirred at 0° for 1.5 h. The mixture was then heated at 100° with stirring under nitrogen for 16 h. The cooled mixture was partitioned between saturated aqueous sodium bicarbonate (30 ml) and ethyl acetate (3×20 ml), and the organic layer was washed with 50:50 brine:water and brine, dried (MgSO4) and evaporated in vacuo to give a brown oil. The crude product was purified by flash chromatography on silica gel, eluting with 0-30% ethyl acetate-cyclohexane. The appropriate fractions were combined and evaporated in vacuo to give the title compound as a white solid (22 mg).
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[NH:7][C:8]1[NH:12][C:11]2[CH:13]=[CH:14][C:15]([C:17]([OH:19])=O)=[CH:16][C:10]=2[N:9]=1.[NH2:20][C:21]1[C:29]2[C:24](=[CH:25][C:26]([NH2:30])=[CH:27][CH:28]=2)[NH:23][N:22]=1.CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F>>[NH2:20][C:21]1[C:29]2[C:24](=[CH:25][C:26]([NH:30][C:17]([C:15]3[CH:14]=[CH:13][C:11]4[NH:12][C:8]([NH:7][C:2]5[CH:3]=[CH:4][CH:5]=[CH:6][N:1]=5)=[N:9][C:10]=4[CH:16]=3)=[O:19])=[CH:27][CH:28]=2)[NH:23][N:22]=1
Reactant: Nc1ccc2c(N)n[nH]c2c1
Reactant: O=C(O)c1ccc2[nH]c(Nc3ccccn3)nc2c1
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Product: Nc1n[nH]c2cc(NC(=O)c3ccc4[nH]c(Nc5ccccn5)nc4c3)ccc12

Procedure:
The carboxylic acid (0.5 mmol) from above was coupled with aforementioned 3,6-diaminoindazole (0.5 mmol) using HBTU as described in general procedure D to afford 2-(pyridin-2-ylamino)-1H-benzimidazole-5-carboxylic acid (3-amino-1H-indazol-6-yl)-amide. MS: m/z 385 (M+H)+.
Reaction SMILES: O[CH2:2][NH:3][C:4](=[O:9])[C:5]([F:8])([F:7])[F:6].[Cl:10][C:11]1[CH:16]=[CH:15][CH:14]=[C:13]([Cl:17])[C:12]=1[N+:18]([O-:20])=[O:19].OS(O)(=O)=O>>[N+:18]([C:12]1[C:11]([Cl:10])=[C:16]([CH:15]=[CH:14][C:13]=1[Cl:17])[CH2:2][NH:3][C:4](=[O:9])[C:5]([F:8])([F:7])[F:6])([O-:20])=[O:19]
Reactant: O=[N+]([O-])c1c(Cl)cccc1Cl
Reactant: O=C(NCO)C(F)(F)F
Agent: O=S(=O)(O)O
Product: O=C(NCc1ccc(Cl)c([N+](=O)[O-])c1Cl)C(F)(F)F
Temperature: 75 °C
Reaction time: 8 h

Procedure:
N-(Hydroxymethyl)trifluoroacetamide (6.6 mmol; 0.946 g) is added to a mixture of 2,6-dichloro-nitrobenzene (0.899 mL; 6.6 mmol) and conc. H2SO4 (15 mL) at 75° C. The mixture is stirred at 75° C. overnight, poured into ice water and stirred for 1 h. The precipitate is collected by filtration and dried. Yield 0.32 g (15%). MS [M−H]−=315, HPLC-method B: Rt=1.43 min.
Reaction SMILES: [H-].[Na+].Cl[CH2:4][CH2:5][S:6](Cl)(=[O:8])=[O:7].[Cl:10][C:11]1[CH:12]=[C:13]([C:18]2[CH:23]=[CH:22][C:21]([O:24][C:25]3[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=3)=[CH:20][CH:19]=2)[C:14]([NH2:17])=[N:15][CH:16]=1.O>C1COCC1>[Cl:10][C:11]1[CH:12]=[C:13]([C:18]2[CH:19]=[CH:20][C:21]([O:24][C:25]3[CH:26]=[CH:27][CH:28]=[CH:29][CH:30]=3)=[CH:22][CH:23]=2)[C:14]2[N:15]([CH:16]=1)[CH2:4][CH2:5][S:6](=[O:8])(=[O:7])[N:17]=2
Reactant: Nc1ncc(Cl)cc1-c1ccc(Oc2ccccc2)cc1
Reactant: O=S(=O)(Cl)CCCl
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: O
Product: O=S1(=O)CCN2C=C(Cl)C=C(c3ccc(Oc4ccccc4)cc3)C2=N1
Temperature: 25 °C
Reaction time: 8 h
Yield: 61.3 %

Procedure:
To a mixture of NaH (60%, 2.59 g) and 2-chloroethanesulfonyl chloride (6.33 g) in THF (dry) (50 mL) was added a solution of 5-chloro-3-(4-phenoxyphenyl)pyridin-2-amine (3.84 g) in THF (dry) (50 mL) at room temperature. The mixture was stirred at room temperature overnight. Water and NH silica gel were added and the mixture was concentrated in vacuo. The residue was purified by column chromatography (NH silica gel, eluted with MeOH in EtOAc) to give the title compound (3.07 g) as a pale yellow solid. The solid was crystallized from DMSO (15 mL)-EtOH (90 mL) to give a white solid.