Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C(N(CC)CC)C.[C:8]([NH2:17])([C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1)([CH3:10])[CH3:9].[CH3:18][S:19][C:20]1[S:21][CH:22]=[C:23]([C:25](Cl)=[O:26])[N:24]=1>C1COCC1>[CH3:9][C:8]([NH:17][C:25]([C:23]1[N:24]=[C:20]([S:19][CH3:18])[S:21][CH:22]=1)=[O:26])([C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1)[CH3:10]
Reactant: CSc1nc(C(=O)Cl)cs1
Reactant: CC(C)(N)c1ccccc1
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: CSc1nc(C(=O)NC(C)(C)c2ccccc2)cs1
Reaction time: 0.25 h

Procedure:
Triethylamine (2.24 ml) was added to a solution of cumylamine (3.2 ml) in anhydrous THF (30 ml). After stirring for 15 min, a solution of 2-(methylthio)-4 -thiazolecarbonyl chloride (Intermediate 12; 3.1 g) in anhydrous THF was added and the reaction mixture was concentrated in vacuo after 15 min. The residue was partitioned with EtOAc and water, dried with MgSO4, and concentrated to an orange oil. Flash purification on silica gel with isocratic elution of DCM yielded the product as a yellow oil (3.7 g). MS (ES) MH+: 293 for C14H16N2OS2; NMR: 1.68 (s, 6H), 2.76 (s, 3H), 7.20 (d, J=7.16 Hz, 1H), 7.29 (t, J=7.54 Hz, 2H), 7.36-7.41 (m, 2H), 8.04 (s, 1H), 8.08 (s, 1H).
Reaction SMILES: [C:1]1([C:7]2[NH:8][C:9]3[C:14]([CH:15]=2)=[CH:13][CH:12]=[CH:11][CH:10]=3)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[Cl-].[Cl:17][C:18]1[CH:30]=[CH:29][CH:28]=[CH:27][C:19]=1[CH:20]=[N+:21]1[CH2:26][CH2:25][CH2:24][CH2:23][CH2:22]1>>[Cl:17][C:18]1[CH:30]=[CH:29][CH:28]=[CH:27][C:19]=1[CH:20]([N:21]1[CH2:26][CH2:25][CH2:24][CH2:23][CH2:22]1)[C:15]1[C:14]2[C:9](=[CH:10][CH:11]=[CH:12][CH:13]=2)[NH:8][C:7]=1[C:1]1[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: c1ccc(-c2cc3ccccc3[nH]2)cc1
Reactant: Clc1ccccc1C=[N+]1CCCCC1
Agent: [Cl-]
Product: Clc1ccccc1C(c1c(-c2ccccc2)[nH]c2ccccc12)N1CCCCC1

Procedure:
The preparation was carried out in accordance with general synthesis instructions 4 from 2-phenyl-1H-indole and 1-(2-chloro-benzylidene)-piperidinium chloride, which had been prepared in accordance with example 26.
Reaction SMILES: [H-].[K+].[CH2:3]([SH:10])[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1.[CH3:11][C:12]1[C:13]([N+]([O-])=O)=[C:14]([CH:21]=[CH:22][CH:23]=1)[C:15]([O:17][CH:18]([CH3:20])[CH3:19])=[O:16]>O1CCCC1>[CH3:11][C:12]1[C:13]([S:10][CH2:3][C:4]2[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=2)=[C:14]([CH:21]=[CH:22][CH:23]=1)[C:15]([O:17][CH:18]([CH3:20])[CH3:19])=[O:16]
Reactant: Cc1cccc(C(=O)OC(C)C)c1[N+](=O)[O-]
Reactant: SCc1ccccc1
Agent: [H-]
Agent: [K+]
Solvent: C1CCOC1
Product: Cc1cccc(C(=O)OC(C)C)c1SCc1ccccc1
Temperature: 25 °C
Reaction time: 0.25 h

Procedure:
To a stirred suspension of dry tetrahydrofuran (125mL) and 35% potassium hydride in oil (6.3 g) was slowly added benzyl mercaptan (6.1 mL) at 0° C. under an inert atmosphere. After 15 minutes, 3-methyl-2-nitrobenzoic acid, 1-methylethyl ester (11.23 g) was added and the resulting mixture was stirred at room temperature overnight. The reaction mixture was partitioned between 6N sodium hydroxide (25 mL) and ethyl acetate (150 mL). The organic phase was dried over magnesium sulfate, filtered, concentrated, and chromatographed on silica gel eluted with 5% ethyl acetate in hexanes to give 13.7 g of the title compound as a yellow oil, nD 1.5642.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([NH2:20])[CH:5]=[C:6]([Cl:19])[C:7]=1[CH2:8][C:9]1[N:10]=[CH:11][C:12]2[C:17]([CH:18]=1)=[CH:16][CH:15]=[CH:14][CH:13]=2.[Cl:21][C:22]1[CH:27]=[C:26]([Cl:28])[CH:25]=[CH:24][C:23]=1[S:29](Cl)(=[O:31])=[O:30]>N1C=CC=CC=1>[Cl:21][C:22]1[CH:27]=[C:26]([Cl:28])[CH:25]=[CH:24][C:23]=1[S:29]([NH:20][C:4]1[CH:5]=[C:6]([Cl:19])[C:7]([CH2:8][C:9]2[N:10]=[CH:11][C:12]3[C:17]([CH:18]=2)=[CH:16][CH:15]=[CH:14][CH:13]=3)=[C:2]([Cl:1])[CH:3]=1)(=[O:31])=[O:30]
Reactant: Nc1cc(Cl)c(Cc2cc3ccccc3cn2)c(Cl)c1
Reactant: O=S(=O)(Cl)c1ccc(Cl)cc1Cl
Solvent: c1ccncc1
Product: O=S(=O)(Nc1cc(Cl)c(Cc2cc3ccccc3cn2)c(Cl)c1)c1ccc(Cl)cc1Cl

Procedure:
2,4-Dichloro-N-(3,5-dichloro-4-isoquinolin-3-ylmethyl-phenyl)-benzenesulfonamide was synthesized (63%) from 3,5-dichloro-4-isoquinolin-3-ylmethyl-phenylamine (236), 2,4-dichlorobenzenesulfonyl chloride (Maybridge) and pyridine (EM) in a similar manner as described in Examples 70-91.
Reaction SMILES: [Br:1]Br.[C:3]([C:7]1[CH:13]=[CH:12][C:11]([C:14]([CH3:17])([CH3:16])[CH3:15])=[CH:10][C:8]=1[NH2:9])([CH3:6])([CH3:5])[CH3:4].C(Cl)(Cl)Cl.[OH-].[Na+]>CO>[Br:1][C:12]1[C:11]([C:14]([CH3:17])([CH3:16])[CH3:15])=[CH:10][C:8]([NH2:9])=[C:7]([C:3]([CH3:6])([CH3:5])[CH3:4])[CH:13]=1
Reactant: CC(C)(C)c1ccc(C(C)(C)C)c(N)c1
Reactant: BrBr
Agent: [Na+]
Agent: [OH-]
Solvent: ClC(Cl)Cl
Solvent: CO
Product: CC(C)(C)c1cc(Br)c(C(C)(C)C)cc1N
Temperature: 25 °C
Reaction time: 0.17 h

Procedure:
Bromine (271 μL, 5.29 mmol) was added dropwise via syringe to a solution of 2,5-di-tert-butylaniline (1.09 g, 5.29 mmol) in methanol (80 mL). The solution was stirred at room temperature for 10 min. Chloroform and 0.1 N NaOH were added and the organic layer was dried (Na2SO4), filtered and concentrated to a pale yellow solid (1.46 g, 97%): mp 89-90° C.; 1H NMR δ1.38 (s, 9H), 1.45 (s, 9H), 3.77 (brs, 2H), 6.68 (s, 1H), 7.35 (s, 1H); 13C NMR δ29.4, 29.7, 33.7, 35.8, 111.0, 117.4, 133.1, 133.8, 143.3, 145.9; FAB-MS obsd 283.0936; calcd 283.0937; Anal calcd for C14H22BrN: C, 59.16; H, 7.80; Br, 28.11; Found, C, 59.33; H, 7.78; Br, 27.86.
Reaction SMILES: CC1C=CC(S(O[CH2:12][C@H:13]2[O:18][C@@:17]3([C:26]4[C:21](=[CH:22][C:23]([Cl:36])=[C:24]([CH2:27][C:28]5[CH:33]=[CH:32][C:31]([CH2:34][CH3:35])=[CH:30][CH:29]=5)[CH:25]=4)[CH2:20][O:19]3)[C@H:16]([OH:37])[C@@H:15]([OH:38])[C@@H:14]2[OH:39])(=O)=O)=CC=1.[N-:40]=[N+:41]=[N-:42].[Na+].O>CN(C=O)C.CCCC[N+](CCCC)(CCCC)CCCC.[I-]>[N:40]([CH2:12][C@H:13]1[O:18][C@@:17]2([C:26]3[C:21](=[CH:22][C:23]([Cl:36])=[C:24]([CH2:27][C:28]4[CH:33]=[CH:32][C:31]([CH2:34][CH3:35])=[CH:30][CH:29]=4)[CH:25]=3)[CH2:20][O:19]2)[C@H:16]([OH:37])[C@@H:15]([OH:38])[C@@H:14]1[OH:39])=[N+:41]=[N-:42]
Reactant: [N-]=[N+]=[N-]
Reactant: CCc1ccc(Cc2cc3c(cc2Cl)CO[C@]32O[C@H](COS(=O)(=O)c3ccc(C)cc3)[C@@H](O)[C@H](O)[C@H]2O)cc1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [I-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: CCc1ccc(Cc2cc3c(cc2Cl)CO[C@]32O[C@H](CN=[N+]=[N-])[C@@H](O)[C@H](O)[C@H]2O)cc1
Temperature: 60 °C
Yield: 78.2 %

Procedure:
To a solution of ((1S,3′R,4′S,5′S,6′R)-5-chloro-6-(4-ethylbenzyl)-3′,4′,5′-trihydroxy-3′,4′,5′,6′-tetrahydro-3H-spiro[isobenzofuran-1,2′-pyran]-6′-yl)methyl 4-methylbenzenesulfonate (38 mg, 0.066 mmol) in 1 mL of DMF was added sodium azide (22 mg, 0.338 mmol) and a catalytic amount of TBAI. The solution was warmed to 60° C. and kept at the same temperature overnight. 5 mL of water was added and the solution was extracted with ethyl acetate. The combined organic layers were washed with brine prior to drying over sodium sulfate. Concentration under reduced pressure provided the crude product, which was purified by preparative TLC to give 23 mg of title compound. 1H NMR (CD3OD, 400 MHz) δ 7.36 (s, 1H), 7.22 (s, 1H), 7.08 (s, 4H), 5.14 (d, J=12.4 Hz, 1H), 5.09 (d, J=12.4 Hz, 1H), 4.08 (s, 2H), 3.96-3.91 (m, 1H), 3.77-3.70 (m, 2H), 3.52-3.45 (m, 2H), 3.35-3.31 (m, 1H), 2.59 (q, J=7.6 Hz, 2H), 1.20 (t, J=7.6 Hz, 3H); MS ESI (m/z) 446 (M+1)+, calc. 445.
Reaction SMILES: [CH2:1]([O:3][C:4]1[CH:9]=[CH:8][C:7]([S:10]([N:13]2[CH2:18][CH2:17][N:16]3[C:19](=[O:27])[C:20]4[CH:25]=[CH:24][C:23]([CH3:26])=[N:22][C:21]=4[CH:15]3[CH2:14]2)(=[O:12])=[O:11])=[CH:6][CH:5]=1)[CH3:2].[Li+].[CH3:29][Si]([N-][Si](C)(C)C)(C)C.CI>C1COCC1>[CH2:1]([O:3][C:4]1[CH:9]=[CH:8][C:7]([S:10]([N:13]2[CH2:18][CH2:17][N:16]3[C:19](=[O:27])[C:20]4[CH:25]=[CH:24][C:23]([CH3:26])=[N:22][C:21]=4[C:15]3([CH3:29])[CH2:14]2)(=[O:11])=[O:12])=[CH:6][CH:5]=1)[CH3:2]
Reactant: C[Si](C)(C)[N-][Si](C)(C)C
Reactant: CCOc1ccc(S(=O)(=O)N2CCN3C(=O)c4ccc(C)nc4C3C2)cc1
Agent: [Li+]
Solvent: CI
Solvent: C1CCOC1
Product: CCOc1ccc(S(=O)(=O)N2CCN3C(=O)c4ccc(C)nc4C3(C)C2)cc1
Temperature: -78 °C
Reaction time: 0.5 h

Procedure:
To a solution of 9-{[4-(ethyloxy)phenyl]sulfonyl}-2-methyl-8,9,10,10a-tetrahydropyrido[2′,3′:3,4]pyrrolo[1,2-a]pyrazin-5(7H)-one (31 mg) in dry THF (0.5 mL) under argon at −78° C. was added LiHMDS (0.104 mL, 1M, in THF) dropwise. The reaction was stirred at −78° C. for 30 minutes and then the temperature of the cool bath raised to −50° C. over 15 minutes. A solution of methyl iodide (75 μL) in dry THF (1 mL) was made and then 100 μL of this solution added to the reaction dropwise. The reaction was then allowed to warm to −10° C. naturally in the cool bath and then the cool bath removed and the reaction stirred for 20 minutes. LCMS showed good conversion to product. The reaction mixture was concentrated in vacuo and then the mixture taken up in 1:1 MeOH:DMSO and this mixture filtered before purification by MDAP to give the title compound (14 mg) as white solid.
Reaction SMILES: [CH:1](=[O:10])[CH:2]=[CH:3][C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1.[CH2:11]([O:18][C:19]1[CH:32]=[CH:31][C:22]([C:23]([C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=2)=[O:24])=[CH:21][CH:20]=1)[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1>>[C:25]1([C:23]([C:22]2[CH:31]=[CH:32][C:19]([O:18][CH2:11][C:12]3[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=3)=[CH:20][CH:21]=2)([OH:24])[CH:3]([C:4]2[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=2)[CH2:2][CH2:1][OH:10])[CH:26]=[CH:27][CH:28]=[CH:29][CH:30]=1
Reactant: O=CC=Cc1ccccc1
Reactant: O=C(c1ccccc1)c1ccc(OCc2ccccc2)cc1
Product: OCCC(c1ccccc1)C(O)(c1ccccc1)c1ccc(OCc2ccccc2)cc1

Procedure:
The (RR,SS; RS,SR)-isomer mixture is prepared from 13.2 g of cinnamaldehyde and 28.8 g of 4-benzyloxybenzophenone according to the procedure described in Example 9. Recrystallization is performed from toluene. The yield is 32.5 g (77%) of a product having m.p. 109°-15° C. The product contains both isomer pairs (RR,SS: RS,SR 1:1).
Reaction SMILES: [NH3:1].C[O:3][C:4]([C:6]1[C:15]2[C:10](=[CH:11][CH:12]=[C:13]([O:16][CH3:17])[CH:14]=2)[C:9]([CH2:18][C:19]2[C:24]([Cl:25])=[CH:23][N:22]=[CH:21][C:20]=2[Cl:26])=[N:8][N:7]=1)=O.N#N>CO>[Cl:25][C:24]1[CH:23]=[N:22][CH:21]=[C:20]([Cl:26])[C:19]=1[CH2:18][C:9]1[C:10]2[C:15](=[CH:14][C:13]([O:16][CH3:17])=[CH:12][CH:11]=2)[C:6]([C:4]([NH2:1])=[O:3])=[N:7][N:8]=1
Reactant: COC(=O)c1nnc(Cc2c(Cl)cncc2Cl)c2ccc(OC)cc12
Reactant: N
Agent: N#N
Solvent: CO
Product: COc1ccc2c(Cc3c(Cl)cncc3Cl)nnc(C(N)=O)c2c1
Reaction time: 48 h
Yield: 67.7 %

Procedure:
An excess of NH3 was bubbled into a suspension of 4-(3,5-dichloro-pyridin-4-ylmethyl)-7-methoxy-phthalazin-1-carboxylic acid methyl ester (1.6 g, 4.23 mmoles), prepared as described in example 102, in dry CH3OH, under stirring and dry N2 at 10° C., and the mixture was left for 3 hours at room temperature, then refluxed for 1.5 hours in environment saturated of NH3. After 2 days at room temperature, the mixture was dried to give 1.48 g of the title compound (yield: 67.7%).
Reaction SMILES: [F:1][C:2]([F:16])([F:15])[CH2:3][O:4][C:5]1[CH:10]=[C:9](F)[CH:8]=[CH:7][C:6]=1[N+:12]([O-:14])=[O:13].C([O-])([O-])=O.[K+].[K+].[OH:23][CH:24]1[CH2:29][CH2:28][NH:27][CH2:26][CH2:25]1>CS(C)=O>[N+:12]([C:6]1[CH:7]=[CH:8][C:9]([N:27]2[CH2:28][CH2:29][CH:24]([OH:23])[CH2:25][CH2:26]2)=[CH:10][C:5]=1[O:4][CH2:3][C:2]([F:16])([F:15])[F:1])([O-:14])=[O:13]
Reactant: O=[N+]([O-])c1ccc(F)cc1OCC(F)(F)F
Reactant: OC1CCNCC1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CS(C)=O
Product: O=[N+]([O-])c1ccc(N2CCC(O)CC2)cc1OCC(F)(F)F
Reaction time: 60 h
Yield: 92.3 %

Procedure:
5-Fluoro-2-nitrophenyl 2,2,2-trifluoroethyl ether (1.48 g, 6.19 mmol) was dissolved in 30 mL of DMSO with K2CO3 (1.11 g, 8.03 mmol) and 4-hydroxypiperidine (0.657 g, 6.50 mmol). The reaction was stirred for 2.5 days and quenched with H2O. The mixture was poured into EtOAc and H2O. The layers were separated, and the organic layer was washed with H2O (2×) and brine. The organic layer was dried over MgSO4, filtered, and concentrated in vacuo. The residue was purified by flash chromatography to afford 1.83 g (92%) of the title compound of step B. 1H NMR (400 MHz, DMSO-d6) δ 7.85 (d, J=9.5 Hz, 1H), 6.63 (dd, J=9.5, 2.4 Hz, 1H), 6.55 (d, J=2.4 Hz, 1H), 4.88 (q, J=8.8 Hz, 2H), 4.72 (d, J=4.2 Hz, 1H), 3.65-3.84 (m, 3H), 3.16 (ddd, J=13.3, 9.8, 2.9 Hz, 2H), 1.74 (br. s., 2H), 1.28-1.43 (m, 2H).
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([C@H:8]([N:10]2[C:18](=[O:19])[C:17]3[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=3)[C:11]2=[O:20])[CH3:9])=[CH:4][CH:3]=1.[Cl:21][C:22]1[C:27](B(O)O)=[CH:26][C:25]([F:31])=[CH:24][N:23]=1.C(=O)([O-])[O-].[Na+].[Na+]>COCCOC.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[Cl:21][C:22]1[C:27]([C:2]2[CH:7]=[CH:6][C:5]([C@H:8]([N:10]3[C:18](=[O:19])[C:17]4[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=4)[C:11]3=[O:20])[CH3:9])=[CH:4][CH:3]=2)=[CH:26][C:25]([F:31])=[CH:24][N:23]=1
Reactant: OB(O)c1cc(F)cnc1Cl
Reactant: C[C@H](c1ccc(Br)cc1)N1C(=O)c2ccccc2C1=O
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: COCCOC
Product: C[C@H](c1ccc(-c2cc(F)cnc2Cl)cc1)N1C(=O)c2ccccc2C1=O
Temperature: 150 °C
Yield: 44.4 %

Procedure:
To a solution of (R)-2-[1-(4-bromo-phenyl)-ethyl]-isoindole-1,3-dione (1.19 g, 3.6 mmol) (Example 26) in 1,2-dimethoxyethane (3 ml) was added 2-chloro-5-fluoropyridine-3-boronic acid (0.95 g, 5.4 mmol), tetrakis(triphenylphosphine)palladium (0) (0.21 g, 0.2 mmol) and 2M aqueous sodium carbonate (3.2 ml, 6.4 mmol). The reaction mixture was heated in a microwave oven at 150° C. for 10 min and the solvent evaporated. The residue was partitioned between ethyl acetate and water. The organic phase washed with brine, dried over anhydrous magnesium sulfate and the solvent evaporated. The residue was purified over silica gel eluting with heptane/ethyl acetate to give (R)-2-{1-[4-(2-chloro-5-fluoro-pyridin-3-yl)-phenyl]-ethyl}-isoindole-1,3-dione (0.62 g, 1.6 mmol, 44%) as a clear glass. To a solution of (R)-2-[1-(4-bromo-phenyl)-ethyl]-isoindole-1,3-dione (0.16 g, 0:4 mmol) in methanol (4 ml) was added hydrazine hydrate (0.43 g, 8.6 mmol). The reaction mixture was stirred at room temperature for 18 h and then concentrated under reduced pressure. Dichloromethane was added and the resultant white precipitate filtered off. The solvent was evaporated to give 1-[4-(2-chloro-5-fluoro-pyridin-3-yl)-phenyl]-ethylamine (0.11 g, 0.4 mmol, 100%) as a yellow gum. To a solution of (R)-1-[4-(2-chloro-5-fluoro-pyridin-3-yl)-phenyl]-ethylamine (26 mg, 0.1 mmol) in dichloromethane (1 ml) was added triethylamine (31.6 mg, 0.31 mmol) followed by 3,4-difluorobenzenesulfonyl chloride (28.7 mg, 0.14 mmol). The reaction mixture was agitated for 64 h at room temperature and the solvent evaporated. The crude product was taken up in dimethyl sulfoxide (1 ml) and purified by preparatory LCMS. The solvent was evaporated under reduced pressure to give the title compound (6.7 mg, 0.04 mmol, 38%). 1H NMR (400 MHz, DMSO-d6): δ 8.48 (m, 2H), 7.78 (dd, 1H), 7.45-7.60 (m, 3H), 7.27-7.34 (m, 4H), 4.50 (q, 1H), 1.33 (d, 3H) ppm; MS (ESI) m/z: 427 [M+H]+.
Reaction SMILES: Cl[C:2]1[CH:7]=[CH:6][N:5]2[N:8]=[CH:9][C:10]([C:11]([O:13][CH2:14][CH3:15])=[O:12])=[C:4]2[N:3]=1.Cl.Cl.[F:18][C:19]1[CH:20]=[N:21][CH:22]=[C:23]([C@H:25]2[CH2:29][CH2:28][CH2:27][NH:26]2)[CH:24]=1.C(N(C(C)C)CC)(C)C>C(O)(C)C>[F:18][C:19]1[CH:24]=[C:23]([CH:25]2[CH2:29][CH2:28][CH2:27][N:26]2[C:2]2[CH:7]=[CH:6][N:5]3[N:8]=[CH:9][C:10]([C:11]([O:13][CH2:14][CH3:15])=[O:12])=[C:4]3[N:3]=2)[CH:22]=[N:21][CH:20]=1
Reactant: CCOC(=O)c1cnn2ccc(Cl)nc12
Reactant: Fc1cncc([C@H]2CCCN2)c1
Agent: Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: CC(C)O
Product: CCOC(=O)c1cnn2ccc(N3CCCC3c3cncc(F)c3)nc12
Temperature: 95 °C
Yield: 68.4 %

Procedure:
Ethyl 5-chloropyrazolo[1,5-a]pyrimidine-3-carboxylate (Preparation B; 0.50 g, 2.22 mmol), (R)-3-fluoro-5-(pyrrolidin-2-yl)pyridine dihydrochloride (0.53 g, 2.22 mmol) and diisopropylethylamine (1.46 mL, 8.86 mmol) were combined in isopropanol (2 mL) and heated at 95° C. for 70 hours. The crude product was purified by reverse phase chromatography, eluting with 0-50% acetonitrile/water to yield the title compound (540 mg, 68.6% yield). MS (apci) m/z=356.0 (M+H).
Reaction SMILES: Cl[C:2]1[CH:11]=[CH:10][C:9]2[C:4](=[C:5]([C:12]3[NH:20][C:19]4[CH2:18][CH2:17][NH:16][C:15](=[O:21])[C:14]=4[CH:13]=3)[CH:6]=[CH:7][CH:8]=2)[N:3]=1.[CH3:22][C:23]1[CH:24]=[C:25]([CH:27]=[CH:28][CH:29]=1)[NH2:26].[Li+].C[Si]([N-][Si](C)(C)C)(C)C.C1COCC1>>[CH3:22][C:23]1[CH:24]=[C:25]([NH:26][C:2]2[CH:11]=[CH:10][C:9]3[C:4](=[C:5]([C:12]4[NH:20][C:19]5[CH2:18][CH2:17][NH:16][C:15](=[O:21])[C:14]=5[CH:13]=4)[CH:6]=[CH:7][CH:8]=3)[N:3]=2)[CH:27]=[CH:28][CH:29]=1
Reactant: O=C1NCCc2[nH]c(-c3cccc4ccc(Cl)nc34)cc21
Reactant: Cc1cccc(N)c1
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Li+]
Solvent: C1CCOC1
Product: Cc1cccc(Nc2ccc3cccc(-c4cc5c([nH]4)CCNC5=O)c3n2)c1
Yield: 4 %

Procedure:
Prepared according to Example 102, using 2-(2-chloroquinolin-8-yl)-6,7-dihydro-1H-pyrrolo[3,2-c]pyridin-4(5H)-one (Example 1; 50 mg, 0.168 mmol), 3-methylaniline (91 μl, 0.840 mmol, Sigma Aldrich), and 1.0 M LHMDS in THF (163 μl, 0.840 mmol, Sigma Aldrich) and stirring at 25° C. for 2.h. Purification by column chromatography (silica gel: 0 to 4% MeOH/DCM) provided 2-(2-((3-methylphenyl)amino)-8-quinolinyl)-1,5,6,7-tetrahydro-4H-pyrrolo[3,2-c]pyridin-4-one (2.5 mg, 4%). 1H NMR (400 MHz, MeOH-d4) δ ppm 7.84-7.90 (2H, m) 7.37-7.43 (1H, m) 7.27-7.32 (2H, m) 7.17 (3H, s) 6.88 (2H, m) 3.40 (2H, t, J=1.00 Hz) 2.50 (2H, t, J=1.00 Hz) 2.24 (3H, s). m/z (ESI, +ve) 369.2 (M+H)+.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5]([Cl:19])=[C:6]([CH:8]([C:10]2[CH:11]=[CH:12][C:13]3[O:17][CH2:16][CH2:15][C:14]=3[CH:18]=2)O)[CH:7]=1.C([SiH](CC)CC)C.B(F)(F)F.CCOCC>ClCCl>[Br:1][C:2]1[CH:3]=[CH:4][C:5]([Cl:19])=[C:6]([CH2:8][C:10]2[CH:11]=[CH:12][C:13]3[O:17][CH2:16][CH2:15][C:14]=3[CH:18]=2)[CH:7]=1
Reactant: OC(c1ccc2c(c1)CCO2)c1cc(Br)ccc1Cl
Agent: CC[SiH](CC)CC
Agent: FB(F)F
Solvent: ClCCl
Solvent: CCOCC
Product: Clc1ccc(Br)cc1Cc1ccc2c(c1)CCO2
Reaction time: 16 h
Yield: 100 %

Procedure:
(5-bromo-2-chloro-phenyl)-(2,3-dihydrobenzofuran-5-yl)methanol 5c (10.5 g, 30.9 mmol) was dissolved in 100 mL dichloromethane, followed by addition of triethylsilane (14.8 mL, 92.7 mmol) and dropwise addition of boron trifluoride etherate (7.8 mL, 61.8 mmol). The reaction mixture was stirred for 16 hours. Thereafter, the reaction mixture was concentrated under reduced pressure and the resulting residue was purified by silica gel chromatography with elution system D to obtain the title compound 5-[(5-bromo-2-chloro-phenyl)methyl]-2,3-dihydrobenzo-furan 5d (10.0 g, pale yellow grease), yield: 100%. 1H NMR (400 MHz, CDCl3): δ 7.29-7.21 (m, 3H), 7.00 (s, 1H), 6.93 (d, 1H), 6.73 (d, 1H), 4.56 (t, 2H), 3.98 (s, 2H), 3.18 (t, 2H).
Reaction SMILES: CC1C=CC(S(O[CH2:12][CH:13]2[CH2:17][C:16]3[CH:18]=[C:19]([C:36]([F:39])([F:38])[F:37])[CH:20]=[C:21]([C:22]4[CH:27]=[C:26]([C:28]([F:31])([F:30])[F:29])[CH:25]=[C:24]([C:32]([F:35])([F:34])[F:33])[CH:23]=4)[C:15]=3[O:14]2)(=O)=O)=CC=1.[CH3:40][NH2:41]>>[F:29][C:28]([F:30])([F:31])[C:26]1[CH:27]=[C:22]([C:21]2[C:15]3[O:14][CH:13]([CH2:12][NH:41][CH3:40])[CH2:17][C:16]=3[CH:18]=[C:19]([C:36]([F:39])([F:37])[F:38])[CH:20]=2)[CH:23]=[C:24]([C:32]([F:34])([F:33])[F:35])[CH:25]=1
Reactant: Cc1ccc(S(=O)(=O)OCC2Cc3cc(C(F)(F)F)cc(-c4cc(C(F)(F)F)cc(C(F)(F)F)c4)c3O2)cc1
Reactant: CN
Product: CNCC1Cc2cc(C(F)(F)F)cc(-c3cc(C(F)(F)F)cc(C(F)(F)F)c3)c2O1

Procedure:
The title compound was prepared (0.033 g, 58%) following the general procedure of Example 390 as a white solid, hydrochloride salt from [7-[3,5-bis(trifluoromethyl)phenyl]-5-(trifluoromethyl)-2,3-dihydro-1-benzofuran-2-yl]methyl 4-methylbenzenesulfonate (0.070 g, 0.12 mmol) and methylamine (0.12 g, 3.9 mmol). mp 205-207° C.
Reaction SMILES: [C:1]1([CH3:21])[CH:6]=[CH:5][CH:4]=[C:3]([S:7]([N:10]2[CH2:15][CH2:14][O:13][C:12]3[CH:16]=[CH:17][C:18]([NH2:20])=[N:19][C:11]2=3)(=[O:9])=[O:8])[CH:2]=1.[Cl:22][C:23]1[CH:31]=[CH:30][CH:29]=[C:28]([Cl:32])[C:24]=1[C:25](Cl)=[O:26].C([O-])(O)=O.[Na+]>O1CCOCC1.O>[Cl:22][C:23]1[CH:31]=[CH:30][CH:29]=[C:28]([Cl:32])[C:24]=1[C:25]([NH:20][C:18]1[CH:17]=[CH:16][C:12]2[O:13][CH2:14][CH2:15][N:10]([S:7]([C:3]3[CH:2]=[C:1]([CH3:21])[CH:6]=[CH:5][CH:4]=3)(=[O:9])=[O:8])[C:11]=2[N:19]=1)=[O:26]
Reactant: O=C(Cl)c1c(Cl)cccc1Cl
Reactant: Cc1cccc(S(=O)(=O)N2CCOc3ccc(N)nc32)c1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: C1COCCO1
Solvent: O
Product: Cc1cccc(S(=O)(=O)N2CCOc3ccc(NC(=O)c4c(Cl)cccc4Cl)nc32)c1
Temperature: 25 °C
Reaction time: 15 h

Procedure:
4-(Toluene-3-sulfonyl)-3,4-dihydro-2H-pyrido[3,2-b][1,4]oxazin-6-ylamine (20 mg, 0.065 mmol) was dissolved in p-dioxane (0.400 mL) and water (0.100 mL), followed by 2,6-dichlorobenzoyl chloride (21 μL, 0.098 mmol) and NaHCO3 (11 mg, 0.13 mmol). The resulting mixture was stirred at room temperature for 15 hours, concentrated under vacuum, and purified by HPLC to give 2,6-dichloro-N-[4-(toluene-3-sulfonyl)-3,4-dihydro-2H-pyrido[3,2-b][1,4]oxazin-6-yl]-benzamide. LCMS (ESI): calc. C21H17Cl2N3O4S=477; obs. M+H=478.
Reaction SMILES: [H-].[Na+].[C:3]1([NH:9][C:10]2[S:11][C:12]3[CH:18]=[CH:17][CH:16]=[CH:15][C:13]=3[N:14]=2)[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.Br[CH2:20][CH2:21][CH2:22][CH2:23][Cl:24]>O1CCCC1>[Cl:24][CH2:23][CH2:22][CH2:21][CH2:20][N:9]([C:3]1[CH:4]=[CH:5][CH:6]=[CH:7][CH:8]=1)[C:10]1[S:11][C:12]2[CH:18]=[CH:17][CH:16]=[CH:15][C:13]=2[N:14]=1
Reactant: c1ccc(Nc2nc3ccccc3s2)cc1
Reactant: ClCCCCBr
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: ClCCCCN(c1ccccc1)c1nc2ccccc2s1
Reaction time: 0.25 h
Yield: 66 %

Procedure:
Sodium hydride (0.05 mol) was added portionwise to a solution of N-phenyl-2-benzothiazolamine, prepared according to the procedure described in J. Chem. Soc, 1962, 230, (0.05 mol) in tetrahydrofuran (200 ml). The mixture was stirred for 15 minutes. A solution of 1-bromo-4-chlorobutane (0.05 mol) in tetrahydrofuran (50 ml) was added dropwise and the resulting reaction mixture was stirred and refluxed for 48 hours. The mixture was cooled, and the solvent was evaporated. The residue was partitioned between water and CH2Cl2. The organic layer was separated, dried, filtered and the solvent evaporated. The residue was purified by column chromatography over silica gel (eluent: CH2Cl2). The desired fractions were collected and the solvent was evaporated, yielding 10.4 g (66%) of N-(4-chlorobutyl)-N-phenyl-2-benzothiazolamine (interm. 10).