Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C:2]1[C:10]2[C:5](=[CH:6][CH:7]=[C:8]([NH2:11])[CH:9]=2)[NH:4][N:3]=1.N1C=CC=CC=1.[Cl:18][C:19]1[CH:24]=[CH:23][CH:22]=[C:21]([Cl:25])[C:20]=1[S:26](Cl)(=[O:28])=[O:27]>O1CCCC1>[NH2:1][C:2]1[C:10]2[C:5](=[CH:6][CH:7]=[C:8]([NH:11][S:26]([C:20]3[C:21]([Cl:25])=[CH:22][CH:23]=[CH:24][C:19]=3[Cl:18])(=[O:28])=[O:27])[CH:9]=2)[NH:4][N:3]=1
Reactant: O=S(=O)(Cl)c1c(Cl)cccc1Cl
Reactant: Nc1ccc2[nH]nc(N)c2c1
Solvent: C1CCOC1
Solvent: c1ccncc1
Product: Nc1n[nH]c2ccc(NS(=O)(=O)c3c(Cl)cccc3Cl)cc12
Yield: 18.6 %

Procedure:
N-(3-Amino-1H-indazol-5-yl)-2,6-dichlorobenzenesulfonamide can be obtained as described in Example 39 from 0.8 g of 3,5-diamino-1H-indazole, 8 ml of pyridine, 8 ml of tetrahydrofuran and 1.29 g of 2,6-dichlorobenzenesulfonyl chloride. 350 mg of N-(3-amino-1H-indazol-5-yl)-2,6-dichlorobenzenesulfonamide are thus obtained in the form of a pale yellow solid melting at 250° C. (analysis C13H10Cl2N4O2S % calculated C, 43.71; H, 2.82; Cl, 19.85; N, 15.68; O, 8.96; S, 8.98. % found C, 43.39; H, 2.92; Cl, 19.45; N, 15.31; S, 8.73).
Reaction SMILES: Cl.[CH2:2]([N:8]1[CH2:13][CH:12]2[CH:10]([C:11]2([C:15]2[CH:16]=[C:17]([C:21](=[NH:25])OCC)[CH:18]=[CH:19][CH:20]=2)[CH3:14])[C:9]1=[O:26])[CH2:3][CH2:4][CH2:5][CH2:6][CH3:7].CO[CH:29](OC)[CH2:30][NH2:31]>CO>[NH3:8].[CH2:2]([N:8]1[CH2:13][CH:12]2[CH:10]([C:11]2([C:15]2[CH:20]=[CH:19][CH:18]=[C:17]([C:21]3[NH:31][CH:30]=[CH:29][N:25]=3)[CH:16]=2)[CH3:14])[C:9]1=[O:26])[CH2:3][CH2:4][CH2:5][CH2:6][CH3:7]
Reactant: COC(CN)OC
Reactant: CCCCCCN1CC2C(C1=O)C2(C)c1cccc(C(=N)OCC)c1
Agent: Cl
Solvent: CO
Product: CCCCCCN1CC2C(C1=O)C2(C)c1cccc(-c2ncc[nH]2)c1
Product: N
Temperature: 25 °C
Reaction time: 2 h
Yield: 77.7 %

Procedure:
To a solution of ethyl 3-(3-hexyl-6-methyl-2-oxo-3-azabicyclo[3.1.0]hex-6-yl)benzenecarboximidoate hydrochloride (Preparation 42, 528 mg, 1.45 mmol) in methanol (6 ml) at room temperature was added aminoacetaldehyde dimethylacetal (0.16 g, 1.52 mmol). The mixture was heated under reflux for 90 min, cooled to room temperature and the solvent was removed in vacuo. The crude residue was dissolved in 6N hydrochloric acid (8 ml) and the mixture was heated to 80° C. for 30 min and then left at room temperature for 2 h. The mixture was diluted with water (5 ml), the pH was adjusted to 9 using 5N sodium hydroxide solution and the aqueous solution was extracted with ethyl acetate (3×20 ml). The combined extracts were dried (MgSO4), filtered and concentrated in vacuo. The crude residue was purified by silica column chromatography eluting with ethyl acetate:methanol:ammonia solution (0.880) (90:10:1) to afford the title compound (190 mg, 39%) as a colourless oil.
Reaction SMILES: [C:1]([O:5][C:6](=[O:34])[NH:7][C@H:8]([CH2:26][C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][C:28]=1[F:33])[C@@H:9]([OH:25])[CH2:10][C:11]1[CH:16]=[C:15]([Cl:17])[CH:14]=[CH:13][C:12]=1[C:18](=[O:24])[NH:19][C:20]([CH3:23])([CH3:22])[CH3:21])([CH3:4])([CH3:3])[CH3:2].[H-].[Na+].[CH3:37]I>C1COCC1>[C:1]([O:5][C:6](=[O:34])[NH:7][C@H:8]([CH2:26][C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][C:28]=1[F:33])[C@@H:9]([O:25][CH3:37])[CH2:10][C:11]1[CH:16]=[C:15]([Cl:17])[CH:14]=[CH:13][C:12]=1[C:18](=[O:24])[NH:19][C:20]([CH3:23])([CH3:22])[CH3:21])([CH3:2])([CH3:3])[CH3:4]
Reactant: CI
Reactant: CC(C)(C)NC(=O)c1ccc(Cl)cc1C[C@H](O)[C@@H](Cc1ccccc1F)NC(=O)OC(C)(C)C
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: CO[C@@H](Cc1cc(Cl)ccc1C(=O)NC(C)(C)C)[C@@H](Cc1ccccc1F)NC(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 0.33 h

Procedure:
To a solution of [(1R,2S)-3-(2-tert-Butylcarbamoyl-5-chloro-phenyl)-1-(2-fluoro-benzyl)-2-hydroxy-propyl]-carbamic acid tert-butyl ester (0.40 g, 0.81 mmol) in 5 mL of THF is added a 60% dispersion of sodium hydride in mineral oil (64 mg, 1.6 mmol) and the reaction is allowed to stir for 20 minutes at room temperature. Methyl iodide (0.05 mL, 0.81 mmol) is added and stirring is continued for an additional hour. The reaction is quenched by addition of water and the product is extracted into dichloromethane. The combined organic layers are dried over sodium sulfate, filtered, and concentrated under reduced pressure. Purification of the resultant crude residue by silica gel flash column chromatography gives the title compound.
Reaction SMILES: [C:1]([CH2:3][C:4](O)=[O:5])#[N:2].C(Cl)(=O)C(Cl)=O.[CH2:13]([O:15][C:16](=[O:32])[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=1[NH:23][CH2:24][C:25]1[CH:30]=[CH:29][C:28]([F:31])=[CH:27][CH:26]=1)[CH3:14]>ClCCl.CN(C)C=O.O.C(=O)(O)[O-].[Na+]>[CH2:13]([O:15][C:16](=[O:32])[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=1[N:23]([C:4](=[O:5])[CH2:3][C:1]#[N:2])[CH2:24][C:25]1[CH:30]=[CH:29][C:28]([F:31])=[CH:27][CH:26]=1)[CH3:14]
Reactant: CCOC(=O)c1ccccc1NCc1ccc(F)cc1
Reactant: N#CCC(=O)O
Agent: O=C(Cl)C(=O)Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Solvent: ClCCl
Product: CCOC(=O)c1ccccc1N(Cc1ccc(F)cc1)C(=O)CC#N
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a stirred mixture of commercially available cyanoacetic acid (1 eq, 0.170 g, 2.0 mmole) in dichloromethane was added oxalylchloride (0.253 g, 2.0 mmole, 0.169 mL) and 2 drops dimethylformamide. The reaction was stirred for 2 hours at RT until homogenous solution developed. 2-(4-Fluoro-benzylamino)-benzoic acid ethyl ester (1 eq, 0.500 g, 1.82 mmole) was added and the resulting solution, was allowed to stir at RT overnight. Reaction mixture was diluted with saturated sodium bicarbonate water (20 mL) and extracted with ethyl acetate (25 mL×3). Combined organic phase was washed consecutively with water, brine before drying over sodium sulfate. Organic phase was evaporated and the residue was purified by flash chromatography to afford 2-[(2-Cyano-acetyl)-(4-fluoro-benzyl)-amino]-benzoic acid ethyl ester as an off white solid (0.423 g, 68%, LCMS calc M+H 341, obs M+H 341).
Reaction SMILES: [CH3:1][C:2]1[N:3]=[C:4](SC)[N:5]=[N:6][C:7]=1[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1.[O:16]1[CH:20]=[CH:19][CH:18]=[C:17]1[C:21]([N:23]1[CH2:28][CH2:27][NH:26][CH2:25][CH2:24]1)=[O:22]>C1C=CC=CC=1.C(OCC)(=O)C>[O:16]1[CH:20]=[CH:19][CH:18]=[C:17]1[C:21]([N:23]1[CH2:24][CH2:25][N:26]([C:4]2[N:5]=[N:6][C:7]([C:8]3[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=3)=[C:2]([CH3:1])[N:3]=2)[CH2:27][CH2:28]1)=[O:22]
Reactant: O=C(c1ccco1)N1CCNCC1
Reactant: CSc1nnc(-c2ccccc2)c(C)n1
Solvent: CCOC(C)=O
Solvent: c1ccccc1
Product: Cc1nc(N2CCN(C(=O)c3ccco3)CC2)nnc1-c1ccccc1
Yield: 29 %

Procedure:
A mixture of 5-methyl-3-methylthio-6-phenyl-1,2,4-triazine (9 g) and N-(2-furoyl)piperazine (10 g) was heated at 150° to 160° C. for 89 hours with stirring. The reaction mixture was dissolved in benzene (300 ml) and subjected to chromatography on silica gel (300 g) using a mixture of benzene and ethyl acetate (3:2) as an eluent. The eluate was concentrated to dryness and the resulting solid was recrystallized from a mixture of chloroform and diisopropyl ether to give crystals of 3-[4-(2-furoyl)-1-piperazinyl]-5-methyl-6-phenyl-1,2,4-triazine (4.20 g), mp 141.5°~142.5° C.
Reaction SMILES: [CH2:1]([N:4]1[CH2:9][CH2:8][N:7]([C:10]2[N:15]=[CH:14][C:13]([NH2:16])=[CH:12][CH:11]=2)[CH2:6][CH2:5]1)[CH:2]=[CH2:3].[CH:17]([C:20]1[CH:25]=[CH:24][C:23]([S:26](Cl)(=[O:28])=[O:27])=[CH:22][CH:21]=1)([CH3:19])[CH3:18].C(N(CC)CC)C>O1CCCC1>[CH2:1]([N:4]1[CH2:5][CH2:6][N:7]([C:10]2[N:15]=[CH:14][C:13]([NH:16][S:26]([C:23]3[CH:24]=[CH:25][C:20]([CH:17]([CH3:19])[CH3:18])=[CH:21][CH:22]=3)(=[O:28])=[O:27])=[CH:12][CH:11]=2)[CH2:8][CH2:9]1)[CH:2]=[CH2:3]
Reactant: CC(C)c1ccc(S(=O)(=O)Cl)cc1
Reactant: C=CCN1CCN(c2ccc(N)cn2)CC1
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: C=CCN1CCN(c2ccc(NS(=O)(=O)c3ccc(C(C)C)cc3)cn2)CC1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
1.4 g (7.97 mmol) of 6-(4-allylpiperazin-1-yl)pyridin-3-ylamine from Example 1.2 and 1.74 g (7.97 mmol) of 4-isopropylbenzenesulfonyl chloride were dissolved in 30 ml of tetrahydrofuran at room temperature. 3.3 ml (23.91 mmol) of triethylamine were then added to this mixture. After that, the reaction mixture was stirred overnight at room temperature. After the solvent had been evaporated to dryness, water was added to the residue. The aqueous reaction mixture was made acid with 1N hydrochloric acid and extracted twice with diethyl ether. After that, the aqueous phase was made alkaline (pH 9-10) with a 1N aqueous solution of sodium hydroxide and then extracted twice with diethyl ether. After the combined organic phases had been dried over sodium sulfate, the drying agent had been filtered off and the solvent had been evaporated down to dryness, the resulting residue was chromatographed on silica gel using cyclohexane/ethyl acetate (45:55% to 100% ethyl acetate). The filtrate was evaporated down to dryness. The resulting residue was thoroughly stirred in 10 ml of heptane, filtered off in suction and dried, with 1.93 g (61% of theory) of the title compound being obtained.
Reaction SMILES: [H-].[Na+].[CH2:3]([OH:10])[CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][OH:9].[CH3:11]I>O1CCCC1>[CH3:11][O:9][CH2:8][CH2:7][CH2:6][CH2:5][CH2:4][CH2:3][OH:10]
Reactant: CI
Reactant: OCCCCCCO
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: COCCCCCCO
Reaction time: 8 h

Procedure:
Sodium hydride (NaH) (50%, 6.12 g) suspended in tetrahydrofuran (TEF) (60 ml) was added to a solution of 1,6-hexanediol (15.0 g) in THP (200 ml), and kept at 60° C. until gas evolution stopped. After cooling, a solution of methyl iodide (12 ml) in THF (35 ml) was added and kept overnight at room temperature. The crude product obtaind after the usual work-up was chromatographed to give 6-methoxy-1-hexanol. Yield; 8.16 g
Reaction SMILES: C([Cl:4])(=O)C.C(OC([N:12]1[CH2:17][CH2:16][CH:15]([C:18]2[S:22][C:21]([CH2:23][C:24]3[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=3)=[N:20][CH:19]=2)[CH2:14][CH2:13]1)=O)(C)(C)C>CO>[ClH:4].[ClH:4].[CH2:23]([C:21]1[S:22][C:18]([CH:15]2[CH2:16][CH2:17][NH:12][CH2:13][CH2:14]2)=[CH:19][N:20]=1)[C:24]1[CH:25]=[CH:26][CH:27]=[CH:28][CH:29]=1
Reactant: CC(C)(C)OC(=O)N1CCC(c2cnc(Cc3ccccc3)s2)CC1
Reactant: CC(=O)Cl
Solvent: CO
Product: Cl
Product: c1ccc(Cc2ncc(C3CCNCC3)s2)cc1
Temperature: 25 °C
Reaction time: 3.5 h

Procedure:
Acetyl chloride (0.3 mL) was added dropwise to a solution of 320 mg of 1-t-butyloxycarbonyl-4-(2-benzyl-thiazol-5-yl)piperidine in methanol (2 mL) at ice bath temperature. The reaction mixture was stirred 3.5 hr as it warmed to room temperature. Solvent removal in vacuo gave the desired amine as glassy solid. 1H NMR (CD3OD): 1.94 (m, 2H), 2.24 (m, 2H), 3.1˜3.5 (m, 5H), 4.58 (s, 2H), 7.4 (m, 5H) 8.02(s, 1H).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:9]=[C:10]([NH2:19])[CH:11]=[N:12][C:13]=2[O:14][CH2:15][CH:16]2[CH2:18][CH2:17]2)=[CH:4][CH:3]=1.[C:20](O)(=[O:27])[C:21]1[CH:26]=[CH:25][N:24]=[CH:23][CH:22]=1>>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:9]=[C:10]([NH:19][C:20](=[O:27])[C:21]3[CH:26]=[CH:25][N:24]=[CH:23][CH:22]=3)[CH:11]=[N:12][C:13]=2[O:14][CH2:15][CH:16]2[CH2:18][CH2:17]2)=[CH:4][CH:3]=1
Reactant: O=C(O)c1ccncc1
Reactant: Nc1cnc(OCC2CC2)c(-c2ccc(Cl)cc2)c1
Product: O=C(Nc1cnc(OCC2CC2)c(-c2ccc(Cl)cc2)c1)c1ccncc1

Procedure:
The title compound was synthesized in analogy to Example 1, using 5-(4-chloro-phenyl)-6-cyclopropylmethoxy-pyridin-3-ylamine and isonicotinic acid as starting materials, MS (LC/MS): 380.2 (M+H).
Reaction SMILES: [CH2:1]([N:8]1[CH2:13][CH2:12][N:11]([CH:14]2[CH2:19][CH2:18][CH:17]([O:20][C:21]3[N:22]=[CH:23][N:24]=[C:25]4[C:32]=3[C:31]3[C@@H:30]([CH2:33][C:34]#[N:35])[CH2:29][CH2:28][C:27]=3[S:26]4)[CH2:16][CH2:15]2)[CH2:10][CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[OH:36][Li].O.OO>CO>[CH2:1]([N:8]1[CH2:9][CH2:10][N:11]([CH:14]2[CH2:19][CH2:18][CH:17]([O:20][C:21]3[N:22]=[CH:23][N:24]=[C:25]4[C:32]=3[C:31]3[C@@H:30]([CH2:33][C:34]([NH2:35])=[O:36])[CH2:29][CH2:28][C:27]=3[S:26]4)[CH2:16][CH2:15]2)[CH2:12][CH2:13]1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: N#CC[C@H]1CCc2sc3ncnc(OC4CCC(N5CCN(Cc6ccccc6)CC5)CC4)c3c21
Reactant: [Li]O
Agent: OO
Solvent: CO
Solvent: O
Product: NC(=O)C[C@H]1CCc2sc3ncnc(OC4CCC(N5CCN(Cc6ccccc6)CC5)CC4)c3c21
Temperature: 0 °C
Reaction time: 4 h
Yield: 32.4 %

Procedure:
To a solution of 2-[(3R)-12-[[4-(4-benzylpiperazin-1-yl)cyclohexyl]oxy]-7-thia-9,11-diazatricyclo[6.4.0.0[2,6]]dodeca-1(12),2(6),8,10-tetraen-3-yl]acetonitrile (270 mg, 0.55 mmol, 1.00 equiv) in methanol (25 mL) were added LiOH.H2O (70 mg) and H2O2 (30%) (1.2 mL). The resulting solution was stirred for 4 h at 0° C. in a water/ice bath. The reaction was then quenched by the addition of 100 mL of Na2SO3 (sat.). The resulting solution was extracted with 6×50 mL of dichloromethane and the organic layers combined. After evaporation, the residue was purified by silica gel column with dichloromethane/methanol (4:1). This resulted in 90 mg (32%) of Compound I-122 as a white solid.
Reaction SMILES: C(OC([N:11]1[CH2:15][CH:14]([O:16][C:17]([N:19]2[CH2:24][CH2:23][O:22][CH2:21][CH2:20]2)=[O:18])[CH2:13][N:12]1[C:25](=[O:34])[CH2:26][C:27]1[CH:32]=[CH:31][C:30]([F:33])=[CH:29][CH:28]=1)=O)C1C=CC=CC=1>CO>[F:33][C:30]1[CH:31]=[CH:32][C:27]([CH2:26][C:25]([N:12]2[CH2:13][CH:14]([O:16][C:17]([N:19]3[CH2:24][CH2:23][O:22][CH2:21][CH2:20]3)=[O:18])[CH2:15][NH:11]2)=[O:34])=[CH:28][CH:29]=1
Reactant: O=C(OC1CN(C(=O)Cc2ccc(F)cc2)N(C(=O)OCc2ccccc2)C1)N1CCOCC1
Solvent: CO
Product: O=C(OC1CNN(C(=O)Cc2ccc(F)cc2)C1)N1CCOCC1
Reaction time: 2.5 h

Procedure:
morpholine4-carboxylic acid 1-benzyloxycarbonyl-2-[2-(4-fluorophenyl)acetyl]-pyrazolidin-4-yl ester, 40, (512 mg, 1.09 mmol) is dissolved in methanol (10 mL) and the flask flushed with nitrogen then charged with 10% palladium on carbon (103 mg). The reaction mixture is vigorously stirred and hydrogenated at 1 atmosphere for 2.5 hours at room temperature. The reaction mixture is filtered through a pad of Celite, rinsed with ethyl acetate (100 ml.) and concentrated in vacuo to afford 354 mg of the desired product as a white powder.
Reaction SMILES: [O-]CC.[Na+].[N+:5]([C:8]1[CH:9]=[C:10]([OH:14])[CH:11]=[CH:12][CH:13]=1)([O-:7])=[O:6].C1(C)C=CC(S(O[CH2:25][CH2:26][O:27][CH:28]2[CH2:33][CH2:32][CH2:31][CH2:30][CH2:29]2)(=O)=O)=CC=1>CN(C)C=O.O>[CH:28]1([O:27][CH2:26][CH2:25][O:14][C:10]2[CH:9]=[C:8]([N+:5]([O-:7])=[O:6])[CH:13]=[CH:12][CH:11]=2)[CH2:33][CH2:32][CH2:31][CH2:30][CH2:29]1
Reactant: O=[N+]([O-])c1cccc(O)c1
Reactant: Cc1ccc(S(=O)(=O)OCCOC2CCCCC2)cc1
Agent: CC[O-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: O=[N+]([O-])c1cccc(OCCOC2CCCCC2)c1
Temperature: 100 °C
Yield: 95.6 %

Procedure:
To a solution of 6.8 g of sodium ethoxide and 15 g of m-nitrophenol in 250 ml of dimethylformamide, 28 g of cyclohexyloxyethyl p-toluenesulfonate were added. After heating at 100° C. for 2 hours, the resulting mixture was diluted with water and extracted with benzene. The solvent was removed under reduced pressure, and the residue was purified by vacuum distillation to give 23.8 g of 3-[2-(cyclohexyloxy)ethoxy]nitrobenzene. B.P., 118°-124° C./0.1 mmHg. nD27 1.5380.
Reaction SMILES: FC1C=CC(F)=C[C:3]=1[CH2:4][P:5](=[O:12])([O:9][CH2:10][CH3:11])[O:6][CH2:7][CH3:8].BrCC1[N:25]=[C:24]([Cl:26])[CH:23]=[CH:22][N:21]=1.O.C(O)(C(F)(F)F)=O>CC#N>[CH2:10]([O:9][P:5]([CH2:4][C:3]1[N:25]=[C:24]([Cl:26])[CH:23]=[CH:22][N:21]=1)(=[O:12])[O:6][CH2:7][CH3:8])[CH3:11]
Reactant: CCOP(=O)(Cc1cc(F)ccc1F)OCC
Reactant: Clc1ccnc(CBr)n1
Solvent: CC#N
Solvent: O=C(O)C(F)(F)F
Solvent: O
Product: CCOP(=O)(Cc1nccc(Cl)n1)OCC

Procedure:
Prepared according to the same procedure as diethyl 2,5-difluorobenzylphosphonate, starting with 2-(bromomethyl)-4-chloropyrimidine. Analytical HPLC method: Phenomenex LUNA C18, 50×2 3μ, A=90% H2O/10% CH3CN, B=90% CH3CN/10% H2O, Modifier 0.1% TFA, 0.00 min=0% B, 4.0 min=100% B, 5.0 min=100% B, Flow rate=0.8 mL/min. Mass spec.: 265.1 (MH)+.
Reaction SMILES: C(OC([N:8]1[CH2:13][CH2:12][CH:11]([S:14]([C:17]2[CH:22]=[CH:21][C:20]([NH:23][C:24]3[N:29]=[CH:28][C:27]([NH:30][C:31](=[O:47])[C:32]4[CH:37]=[C:36]([NH:38][C:39]([C:41]5[S:42][CH:43]=[CH:44][CH:45]=5)=[O:40])[CH:35]=[CH:34][C:33]=4[Cl:46])=[CH:26][N:25]=3)=[CH:19][CH:18]=2)(=[O:16])=[O:15])[CH2:10][CH2:9]1)=O)(C)(C)C.[C:48]([OH:54])([C:50]([F:53])([F:52])[F:51])=[O:49]>C(Cl)Cl>[Cl:46][C:33]1[CH:34]=[CH:35][C:36]([NH:38][C:39]([C:41]2[S:42][CH:43]=[CH:44][CH:45]=2)=[O:40])=[CH:37][C:32]=1[C:31](=[O:47])[NH:30][C:27]1[CH:28]=[N:29][C:24]([NH:23][C:20]2[CH:19]=[CH:18][C:17]([S:14]([CH:11]3[CH2:10][CH2:9][NH:8][CH2:13][CH2:12]3)(=[O:15])=[O:16])=[CH:22][CH:21]=2)=[N:25][CH:26]=1.[C:48]([OH:54])([C:50]([F:53])([F:52])[F:51])=[O:49]
Reactant: CC(C)(C)OC(=O)N1CCC(S(=O)(=O)c2ccc(Nc3ncc(NC(=O)c4cc(NC(=O)c5cccs5)ccc4Cl)cn3)cc2)CC1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: O=C(Nc1ccc(Cl)c(C(=O)Nc2cnc(Nc3ccc(S(=O)(=O)C4CCNCC4)cc3)nc2)c1)c1cccs1
Reaction time: 3 h

Procedure:
A stirred suspension of intermediate 26 (Example 37) (0.10 g, 0.143 mmol) in DCM (8 mL) was treated with TFA (0.200 mL) and stirred for 3 h. Solvents were then removed yielding desired product as TFA salt (0.075 g, 87%). 1H NMR (DMSO-d6): δ 1.61-1.70 (m, 2H), 2.01-2.04 (m, 2H), 2.80-2.90 (m, 2H), 7.23-7.27 (m, 1H), 7.58 (d, J=8.8 Hz, 1H), 7.74 (d, J=8.9 Hz, 2H), 7.86-7.91 (m, 2H), 8.04-8.05 (m, 4H), 8.21-8.25 (m, 1H), 8.65-8.69 (m, 1H), 8.9 (s, 2H), 10.37 (s, 1H), 10.53 (s, 1H), 10.79 (s, 1H).
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[CH:3]=[N:2]1.I[C:11]1[CH:12]=[C:13]([CH2:17][OH:18])[CH:14]=[CH:15][CH:16]=1.O.P([O-])([O-])([O-])=O.[K+].[K+].[K+].CN[C@@H]1CCCC[C@H]1NC>O>[N:1]1([C:11]2[CH:12]=[C:13]([CH2:17][OH:18])[CH:14]=[CH:15][CH:16]=2)[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[CH:3]=[N:2]1
Reactant: c1ccc2[nH]ncc2c1
Reactant: OCc1cccc(I)c1
Agent: CN[C@@H]1CCCC[C@H]1NC
Agent: O=P([O-])([O-])[O-]
Agent: [K+]
Solvent: O
Product: OCc1cccc(-n2ncc3ccccc32)c1
Temperature: 135 °C
Reaction time: 8 h
Yield: 74.7 %

Procedure:
To a round bottom flask was added 1H-indazole (0.47 g, 4.0 mmol), (3-iodophenyl)methanol (1.4 g, 6.0 mmol), ferric chloride (0.13 g, 0.8 mmol), and tri-potassium phosphate monohydrate (1.84 g, 8.0 mmol). Degassed water (2 mL) was then added followed by (1R,2R)—N,N′-dimethylcyclohexane-1,2-diamine (0.25 mL, 1.6 mmol). The reaction mixture was then heated to 135° C. and stirred overnight. The mixture was cooled to rt, diluted with water and extracted with EtOAc (2×). The combined organic phases were then washed with water, and brine, dried over anhydrous Na2SO4, filtered and concentrated. The residue was purified by flash silica gel chromatography (0% to 50% EtOAc/hexanes) to afford [3-(1H-indazol-1-yl)phenyl]methanol (0.67 g, 74%). LC-MS: (FA) ES+ 225.
Reaction SMILES: [C:1]([C:4]1[CH:9]=[CH:8][CH:7]=[C:6](Br)[N:5]=1)(=[O:3])[CH3:2].[CH2:11]([OH:14])[C:12]#[CH:13]>C(N(CC)CC)C.O.[Cu]I>[C:1]([C:4]1[CH:9]=[CH:8][CH:7]=[C:6]([CH2:13][C:12]#[C:11][OH:14])[N:5]=1)(=[O:3])[CH3:2]
Reactant: C#CCO
Reactant: CC(=O)c1cccc(Br)n1
Agent: [Cu]I
Solvent: CCN(CC)CC
Solvent: O
Product: CC(=O)c1cccc(CC#CO)n1
Temperature: 25 °C
Reaction time: 6 h
Yield: 49.1 %

Procedure:
A suspension of 3 g (15.1 mmol) of 2-acetyl-6-bromopyridine, 0.89 g (15.9 mmol) of propargyl alcohol, 0.078 g of CuI, 300 mg of PdCl2 (P(Ph)3)2 in 60 ml of triethylamine was stirred under nitrogen at room temperature for 6 h. The mixture was diluted with water, extracted with ether, and the organic layer was washed with water (2x), brine, and dried over magnesium sulfate. The organic solution was concentrated in vacuo and the residue was purified by MPLC (silica gel 60, hexane/ethyl acetate, 1:1) to afford 1.3 g (50%) of 2-acetyl-6-(3-hydroxy-2-propynyl)pyridine, as a solid product.
Reaction SMILES: [Cl:1][C:2]1[C:3]([NH2:9])=[N:4][C:5]([NH2:8])=[CH:6][CH:7]=1.O1CCCC1.C(=O)(O)[O-].[Na+].Cl[C:21]([O:23][CH2:24][CH3:25])=[O:22]>O>[NH2:9][C:3]1[N:4]=[C:5]([NH:8][C:21](=[O:22])[O:23][CH2:24][CH3:25])[CH:6]=[CH:7][C:2]=1[Cl:1]
Reactant: CCOC(=O)Cl
Reactant: Nc1ccc(Cl)c(N)n1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Solvent: C1CCOC1
Product: CCOC(=O)Nc1ccc(Cl)c(N)n1
Temperature: 0 °C

Procedure:
A solution of 3-chloro-2,6-diaminopyridine (129 g. 0.9 mole) in 1000 ml. of tetrahydrofuran and 250 ml. of water containing sodium bicarbonate (84 g., 1.0 mole) is stirred at 0° C. while adding ethyl chloroformate (114 g. 1.05 mole) dropwise over 1/2 hour. The mixture is stirred at 0° C. over night. The dark solution is filtered through activated carbon and the organic layer of the filtrate is separated, dried and concentrated in vacuo. The residual oil is taken up in ether, washed with 5 N sodium hydroxide and with saturated sodium chloride solution, dried and concentrated in vacuo. A light amber oil (162 g.) which solidifies when triturated in petroleum ether is obtained. The solid is purified by extracting into boiling hexane (10×300 ml) and cooling the extracts to give 131.6 g. of white solid, m.p. 66°-70°.
Reaction SMILES: BrCCBr.Cl[Si](C)(C)C.[CH2:10]([C:12]([CH2:14][CH3:15])=[O:13])[CH3:11].Br[C:17]([CH3:24])([CH3:23])[C:18]([O:20][CH2:21][CH3:22])=[O:19]>C1COCC1.B(OC)(OC)OC.[Zn]>[CH3:23][C:17]([CH3:24])([C:12]([CH2:14][CH3:15])([OH:13])[CH2:10][CH3:11])[C:18]([O:20][CH2:21][CH3:22])=[O:19]
Reactant: CCC(=O)CC
Reactant: CCOC(=O)C(C)(C)Br
Agent: COB(OC)OC
Agent: C[Si](C)(C)Cl
Agent: [Zn]
Solvent: BrCCBr
Solvent: C1CCOC1
Product: CCOC(=O)C(C)(C)C(O)(CC)CC
Temperature: 25 °C
Reaction time: 20 h
Yield: 47 %

Procedure:
A suspension of zinc dust (39.2 g, 0.6 mol) in 150 ml of THF and 150 ml of B(OCH3)3 is activated with 1,2 dibromoethane (3.0 ml) and chlorotrimethylsilane (3.0 ml). Diethyl ketone (95.7 ml, 0.9 mol) is added to the activated zinc suspension. Ethyl 2-bromo-2-methylpropanoate (Fuka, Buchs, Schweiz) is added dropwise within 90 min to the mixture. The mixture is stirred at r.t. for 20 h. The reaction is quenched by addition of concentrated aqueous ammonia solution (150 ml) at 0° C. Glycerine (150 ml) and diethyl ether (150 ml) is added and the organic layer is separated. The aqueous layer is extracted twice with diethyl ether. The combined organic layers are dried over magnesium sulfate and concentrated in vacuo. Purfication of the residue by vacuum distillation affords ethyl 2,2-dimethyl-3-ethyl-3-hydroxypentanoate 22 (56.65 g, 47%) as a colourless liquid (b.p. 108-110° C./10 mbar). 13C-NMR (100 MHz, CDCl3): δ=179.2; 76.2; 60.9; 50.3; 28.2; 21.6; 14.1; 8.9
Reaction SMILES: [NH2:1][C:2]1[C:7]([CH:8]=O)=[C:6]([CH:10]2[CH2:15][CH2:14][CH2:13][N:12]([C:16]([O:18][C:19]([CH3:22])([CH3:21])[CH3:20])=[O:17])[CH2:11]2)[CH:5]=[C:4]([C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][C:24]=2[OH:29])[N:3]=1.[C:30](OCC)(=[O:37])[CH2:31][C:32]([O:34][CH2:35][CH3:36])=[O:33].N1CCCCC1>C(O)C>[C:19]([O:18][C:16]([N:12]1[CH2:13][CH2:14][CH2:15][CH:10]([C:6]2[CH:5]=[C:4]([C:23]3[CH:28]=[CH:27][CH:26]=[CH:25][C:24]=3[OH:29])[N:3]=[C:2]3[C:7]=2[CH:8]=[C:31]([C:32]([O:34][CH2:35][CH3:36])=[O:33])[C:30](=[O:37])[NH:1]3)[CH2:11]1)=[O:17])([CH3:21])([CH3:22])[CH3:20]
Reactant: CCOC(=O)CC(=O)OCC
Reactant: CC(C)(C)OC(=O)N1CCCC(c2cc(-c3ccccc3O)nc(N)c2C=O)C1
Solvent: CCO
Solvent: C1CCNCC1
Product: CCOC(=O)c1cc2c(C3CCCN(C(=O)OC(C)(C)C)C3)cc(-c3ccccc3O)nc2[nH]c1=O
Temperature: 25 °C
Yield: 70.5 %

Procedure:
To a suspension of tert-butyl 3-[2-amino-3-formyl-6-(2-hydroxyphenyl)-4-pyridinyl]-1-piperidinecarboxylate (0.86 g, 2.16 mmol) in ethanol (25 mL) were added diethyl malonate (6.93 g, 43.27 mmol) and piperidine (2.14 mL, 21.64 mmol) and, and the mixture was heated at reflux overnight. The mixture was allowed to cool to room temperature, and then diluted with ethanol. The resulting precipitate was collected by filtration, washed with ethanol and dried under reduced pressure to give ethyl 5-[1-(tert-butoxycarbonyl)-3-piperidinyl]-7-(2-hydroxyphenyl)-2-oxo-1,2-dihydro-1,8-naphthyridine-3-carboxylate as a yellow solid (0.752 g, yield; 71%).