Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]1([N:7]2[CH:11]=[C:10]([CH2:12][N:13]([CH:26]3[C:35]4[N:34]=[CH:33][CH:32]=[CH:31][C:30]=4[CH2:29][CH2:28][CH2:27]3)[CH2:14][CH2:15][CH2:16][CH2:17][NH:18]C(=O)OC(C)(C)C)[N:9]=[N:8]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.S(Cl)([Cl:38])=O>CO>[ClH:38].[ClH:38].[ClH:38].[ClH:38].[NH2:18][CH2:17][CH2:16][CH2:15][CH2:14][N:13]([CH2:12][C:10]1[N:9]=[N:8][N:7]([C:1]2[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=2)[CH:11]=1)[CH:26]1[C:35]2[N:34]=[CH:33][CH:32]=[CH:31][C:30]=2[CH2:29][CH2:28][CH2:27]1
Reactant: O=S(Cl)Cl
Reactant: CC(C)(C)OC(=O)NCCCCN(Cc1cn(-c2ccccc2)nn1)C1CCCc2cccnc21
Solvent: CO
Product: Cl
Product: NCCCCN(Cc1cn(-c2ccccc2)nn1)C1CCCc2cccnc21
Reaction time: 2 h

Procedure:
To a solution of tert-butyl 4-(((1-phenyl-1H-1,2,3-triazol-4-yl)methyl)(5,6,7,8-tetrahydroquinolin-8-yl)-amino)butylcarbamate, 10 (0.85 g, 1.80 mmol) in methanol (20 mL) was added thionyl chloride (1.27 g, 10.7 mmol) at room temperature. The reaction mixture was stirred for 2 h. The reaction mixture was concentrated in vacuo yielding 790 mg (85%) of Z: 1H NMR (400 MHz, d6-DMSO) δ 10.78, (bs, 1H), 8.93, (s, 1H), 8.51 (d, J=4.4 Hz, 1H), 8.25-8.06 (m, 3H), 7.84, (d, J=7.6 Hz, 2H), 7.71, (d, J=7.2 Hz, 2H), 7.62-7.55 (m, 2H), 7.52-7.46, (m, 1H), 7.40-7.35, (m, 1H), 4.77, (m, 1H), 4.50-4.38, (m, 2H), 3.32-3.22, (m, 1H), 3.15-3.02 (m, 1H), 2.88-2.66 (m, 4H), 2.50-2.39 (m, 1H), 2.15-2.00, (m, 2H), 1.95-1.68, (m, 3H), 1.64-1.50, (m, 2H), ESI+ MS: m/z (rel intensity) 377 (100, M+H).
Reaction SMILES: [OH:1][NH:2][C:3]([CH2:5][N:6]([CH2:20][CH:21]([CH3:23])[CH3:22])[C:7](=[O:19])[CH2:8][CH:9]([CH2:15][CH:16]([CH3:18])[CH3:17])[C:10]([N:12]([CH3:14])[CH3:13])=[O:11])=[O:4].CN1CCOCC1.C(Cl)CCl.C1C=CC2N(O)N=NC=2C=1.[CH2:45](ON)[C:46]1[CH:51]=[CH:50][CH:49]=[CH:48][CH:47]=1>CN(C=O)C>[CH2:45]([O:1][NH:2][C:3]([CH2:5][N:6]([CH2:20][CH:21]([CH3:23])[CH3:22])[C:7](=[O:19])[CH2:8][CH:9]([CH2:15][CH:16]([CH3:17])[CH3:18])[C:10]([N:12]([CH3:14])[CH3:13])=[O:11])=[O:4])[C:46]1[CH:51]=[CH:50][CH:49]=[CH:48][CH:47]=1
Reactant: NOCc1ccccc1
Reactant: CC(C)CC(CC(=O)N(CC(=O)NO)CC(C)C)C(=O)N(C)C
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Solvent: CN1CCOCC1
Solvent: ClCCCl
Product: CC(C)CC(CC(=O)N(CC(=O)NOCc1ccccc1)CC(C)C)C(=O)N(C)C
Temperature: 0 °C
Reaction time: 0.33 h
Yield: 28.5 %

Procedure:
N4 -(Hydroxycarbamoyl-methyl)-2,N4 -diisobutyl-N1,N1 -dimethyl-succinamide (1.30 g, 0.0041 mol) was dissolved in DMF (10 ml) and treated at 0° C. with NMM (0.56 g, 0.0041 mol) followed by EDC (0.95 g, 0.005 mol) and HOBt (0.67 g, 0.005 mol). The reaction mixture was allowed to stir at 0° C. for 20 minutes and then at ambient temperature for 2 hours before O-benzylhydroxylamine (0.76 g, 0.0062 mol) was added. The reaction mixture was allowed to stir at room temperature for a further 1.5 hours. The solvent was removed under reduced pressure and the resulting crude oil was taken up in ethyl acetate (100 ml). The solution was washed consecutively with saturated aqueous NaHCO3, 1M HCl and brine, dried over anhydrous MgSO4, filtered and concentrated in vacuo to a crude oil. The crude oil was purified by flash chromatography (silica gel, gradient elution with 5% to 10% methanol in dichloromethane) to give the title compound as a white solid (0.49 g, 29%). 1H NMR: δ (CD3OD), 7.38-7.21 (5H, br m), 4.75 (2H, s), 4.11-3.65 (2H, br m), 3.25 (1H, br m), 3.17-2.97 (2H, br m), 3.07 (3H, s), 2.81 (3H, s), 2.79-2.24 (2H, br m), 1.75 (1H, br m), 1.55-1.25 (3H, br m) and 0.91-0.64 (12H, br m).
Reaction SMILES: [F:1][C:2]1[CH:27]=[CH:26][C:25]([F:28])=[CH:24][C:3]=1[CH2:4][N:5]1[CH2:10][CH2:9][NH:8][C:7]2[N:11]=[CH:12][C:13]([C:15]3[CH:23]=[CH:22][C:18]([C:19]([OH:21])=O)=[CH:17][CH:16]=3)=[CH:14][C:6]1=2.[NH:29]1[CH2:34][CH2:33][O:32][CH2:31][CH2:30]1>>[F:1][C:2]1[CH:27]=[CH:26][C:25]([F:28])=[CH:24][C:3]=1[CH2:4][N:5]1[CH2:10][CH2:9][NH:8][C:7]2[N:11]=[CH:12][C:13]([C:15]3[CH:16]=[CH:17][C:18]([C:19]([N:29]4[CH2:34][CH2:33][O:32][CH2:31][CH2:30]4)=[O:21])=[CH:22][CH:23]=3)=[CH:14][C:6]1=2
Reactant: O=C(O)c1ccc(-c2cnc3c(c2)N(Cc2cc(F)ccc2F)CCN3)cc1
Reactant: C1COCCN1
Product: O=C(c1ccc(-c2cnc3c(c2)N(Cc2cc(F)ccc2F)CCN3)cc1)N1CCOCC1
Yield: 59 %

Procedure:
4-[1-(2,5-Difluorobenzyl)-1,2,3,4-tetrahydropyrido[2,3-b]pyrazin-7-yl]benzoic acid (60 mg) was reacted with morpholine as in General Procedure 8 to give the title compound as a light yellow foam (59% yield). M.p. (foam), LCMS: m/z=451.21 (M+H+), 1H-NMR (CDCl3, 400 MHz) δ 3.444-3.48 (m, 2H), 3.62-3.66 (m, 2H), 3.64-3.76 (m, 8H), 4.50 (s, 2H), 5.00 (s, 1H), 6.75 (s, 1H), 6.84-7.15 (m, 3H) 7.43 (dd, J=8.3 Hz, 4H), 7.71 (d, J=1.8 Hz, 1H).
Reaction SMILES: Cl.[F:2][C:3]1[CH:8]=[CH:7][C:6]([CH:9]([OH:26])[CH2:10][CH2:11][CH2:12][N:13]2[CH2:18][CH2:17][N:16]([C:19]3[N:24]=[CH:23][C:22]([F:25])=[CH:21][N:20]=3)[CH2:15][CH2:14]2)=[CH:5][CH:4]=1.CCN(CC)CC.[F:34][C:35]1[CH:43]=[CH:42][C:38]([C:39]([Cl:41])=[O:40])=[CH:37][CH:36]=1.Cl.CCO>C(Cl)Cl>[ClH:41].[F:34][C:35]1[CH:43]=[CH:42][C:38]([C:39]([O:26][CH:9]([C:6]2[CH:7]=[CH:8][C:3]([F:2])=[CH:4][CH:5]=2)[CH2:10][CH2:11][CH2:12][N:13]2[CH2:18][CH2:17][N:16]([C:19]3[N:20]=[CH:21][C:22]([F:25])=[CH:23][N:24]=3)[CH2:15][CH2:14]2)=[O:40])=[CH:37][CH:36]=1
Reactant: OC(CCCN1CCN(c2ncc(F)cn2)CC1)c1ccc(F)cc1
Reactant: O=C(Cl)c1ccc(F)cc1
Agent: Cl
Solvent: CCO
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: O=C(OC(CCCN1CCN(c2ncc(F)cn2)CC1)c1ccc(F)cc1)c1ccc(F)cc1
Temperature: 23 °C
Reaction time: 20 h

Procedure:
A cold (5° C.) mixture of 1-(4-fluorophenyl)-4-(4-(5-fluoro-2-pyrimidinyl)-1-piperazinyl)-1-butanol monohydrochloride. (3.0 g, 7.8 mmol) and Et3N (2.40 mL, 17.2 mmol) in CH2Cl2 (55 mL) was treated dropwise (10 min) with 4-fluorobenzoyl chloride (1.11 mL, 9.4 mmol). The cooling bath was removed and the reaction mixture stirred at 23° C. for 20 h before being diluted with CH2Cl2 (250 mL). The organic solution was washed with water (30 mL), saturated Na2CO3 solution to bring pH to 9, water (30 mL) and brine, dried (MgSO4) and concentrated in vacuo to a crude mixture which was purified on silica gel column using a mixture of 20-30% AcOEt in CH2Cl2. The appropriate fractions were concentrated in vacuo to a thick syrup, 3.4 g, 93%. The free base was solubilized in EtOH and treated with HCl in EtOH (one equivalent). The solvent was removed under reduced pressure leaving a gum which was crystallized from AcOEt affording analytical sample mp 94°-8° C.
Reaction SMILES: O.[NH2:2][NH2:3].F[C:5]1[CH:12]=[CH:11][CH:10]=[C:9]([I:13])[C:6]=1[C:7]#[N:8].O>C(O)C>[I:13][C:9]1[CH:10]=[CH:11][CH:12]=[C:5]2[C:6]=1[C:7]([NH2:8])=[N:2][NH:3]2
Reactant: N#Cc1c(F)cccc1I
Reactant: NN
Solvent: CCO
Solvent: O
Product: Nc1n[nH]c2cccc(I)c12
Temperature: 78 °C

Procedure:
1.2 cm3 of hydrazine monohydrate are added to 2 g of 2-fluoro-6-iodobenzonitrile in 25 cm3 of ethanol. The reaction medium is then refluxed at about 78° C. for 12 hours. The medium is allowed to return to about 20° C. and 20 cm 3 of distilled water are then added in order to precipitate the product. The insoluble material is filtered on a sinter funnel, rinsed with 20 cm3 of distilled water and then taken up in 20 cm3 of dichloromethane. The organic phase is then dried over magnesium sulphate and evaporated under reduced pressure (2 kPa; 45° C.). After drying (90 Pa; 50° C.), 1.65 g of 4-iodo-1H-indazole-3-amine are obtained in the form of a yellow solid melting at 157° C.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([S:8]([C:11]2[CH:12]=[N:13][C:14]3[C:19]([CH:20]=2)=[CH:18][CH:17]=[CH:16][C:15]=3I)(=[O:10])=[O:9])[CH:5]=[CH:6][CH:7]=1.[Cl-].[CH2:23]([NH+:30]1[CH2:35][CH2:34][CH:33]2[CH2:36][NH2+:37][CH2:38][CH:32]2[CH2:31]1)[C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1.[Cl-]>>[CH2:23]([N:30]1[CH2:35][CH2:34][CH:33]2[CH2:36][N:37]([C:15]3[CH:16]=[CH:17][CH:18]=[C:19]4[C:14]=3[N:13]=[CH:12][C:11]([S:8]([C:4]3[CH:5]=[CH:6][CH:7]=[C:2]([F:1])[CH:3]=3)(=[O:10])=[O:9])=[CH:20]4)[CH2:38][CH:32]2[CH2:31]1)[C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1
Reactant: c1ccc(C[NH+]2CCC3C[NH2+]CC3C2)cc1
Reactant: O=S(=O)(c1cccc(F)c1)c1cnc2c(I)cccc2c1
Agent: [Cl-]
Product: O=S(=O)(c1cccc(F)c1)c1cnc2c(N3CC4CCN(Cc5ccccc5)CC4C3)cccc2c1

Procedure:
0.367 g of 8-(5-benzyl-1H-pyrrolo[3,4-c]pyridin-2(3H,3aH,4H,5H,6H,7H,7aH)-yl)-3-(3-fluorophenylsulfonyl)quinoline were prepared by analogy to the method of Example 27 by coupling of 3-(3-fluorophenylsulfonyl)-8-iodoquinoline with 5-benzyloctahydro-1H-pyrrolo[3,4-c]pyridine-2,5-diium chloride
Reaction SMILES: [Cl-].[CH3:2][O:3][CH2:4][P+](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.[Li]CCCC.[CH2:29]([O:36][C:37]1[CH:38]=[C:39]([CH:44]=[C:45]([CH:47]=O)[CH:46]=1)[C:40]([O:42][CH3:43])=[O:41])[C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1>C1COCC1>[CH2:29]([O:36][C:37]1[CH:38]=[C:39]([CH:44]=[C:45]([CH:47]=[CH:2][O:3][CH3:4])[CH:46]=1)[C:40]([O:42][CH3:43])=[O:41])[C:30]1[CH:31]=[CH:32][CH:33]=[CH:34][CH:35]=1
Reactant: COC[P+](c1ccccc1)(c1ccccc1)c1ccccc1
Reactant: COC(=O)c1cc(C=O)cc(OCc2ccccc2)c1
Agent: [Cl-]
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: COC=Cc1cc(OCc2ccccc2)cc(C(=O)OC)c1
Temperature: -78 °C
Reaction time: 0.5 h

Procedure:
To a solution of (methoxymethyl)(triphenyl)phosphonium chloride (1.5 eq.) in THF (0.1 M) at −78° C. was added n-BuLi (1.5 eq.) dropwise. The reaction was stirred at −78° C. for 30 min and then added a solution of methyl 3-(benzyloxy)-5-formylbenzoate (1 eq.) from the previous step in THF. After stirring at rt for 40 min, the reaction was quenched with saturated aqueous NH4Cl solution. The aqueous layer was extracted with ether. The combined organic extracts were washed with brine, dried over MgSO4, and concentrated in vacuo. The crude product was purified by flash column chromatography (SiO2, 15% EtOAc in Hex) to afford a mixture of E- and Z-methyl 3-(benzyloxy)-5-[2-methoxyvinyl]benzoate.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([F:8])[C:3]=1[C:9]([N:11]1[CH2:16][CH2:15][NH:14][CH2:13][CH2:12]1)=[O:10].CO.C(N(CC)CC)C.Cl[C:27]1[N:32]=[C:31]([CH3:33])[C:30]([N+:34]([O-:36])=[O:35])=[CH:29][CH:28]=1>O>[F:8][C:4]1[CH:5]=[CH:6][CH:7]=[C:2]([F:1])[C:3]=1[C:9]([N:11]1[CH2:12][CH2:13][N:14]([C:27]2[CH:28]=[CH:29][C:30]([N+:34]([O-:36])=[O:35])=[C:31]([CH3:33])[N:32]=2)[CH2:15][CH2:16]1)=[O:10]
Reactant: O=C(c1c(F)cccc1F)N1CCNCC1
Reactant: Cc1nc(Cl)ccc1[N+](=O)[O-]
Solvent: O
Solvent: CO
Solvent: CCN(CC)CC
Product: Cc1nc(N2CCN(C(=O)c3c(F)cccc3F)CC2)ccc1[N+](=O)[O-]
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 101.8 %

Procedure:
Charge (2,6-difluoro-phenyl)-piperazin-1-yl-methanone (1.07 equiv, 1.55 moles, 350.00 g), methanol (37.06 moles, 1.50 L, 1.19 kg), triethylamine (1.79 moles, 250.00 mL, 181.50 g), 6-chloro-2-methyl-3-nitro-pyridine (1.00 equiv, 1.45 moles, 250.00 g) to a 5 L flask with over head stirrer. Stir the reaction mixture at room temperature for 0.5 hours. Slowly heat to 60° C., and continue to stir at 60° C. overnight. Add water (750 mL) drop wise while maintaining the temperature at 60° C. Allow mixture to cool to room temperature. Filter and wash cake with 2:1 methanol/water 150 mL, then twice with MTBE. Dry under reduced pressure at 45° C. to obtain (2,6-difluoro-phenyl)-[4-(6-methyl-5-nitro-pyridin-2-yl)-piperazin-1-yl]-methanone as a yellow solid (535 g).
Reaction SMILES: [C:1]([CH2:3][CH2:4][CH2:5][C:6]([OH:8])=O)#[N:2].C[O-].[Na+].C(Cl)(=O)C(C)(C)C.[Cl:19][C:20]1[CH:21]=[C:22]([CH:35]=[CH:36][CH:37]=1)[C:23]([C:25]1[C:26]([NH:32][CH2:33][CH3:34])=[N:27][C:28]([CH3:31])=[CH:29][CH:30]=1)=O>CO.C1COCC1.C(O)C>[Cl:19][C:20]1[CH:21]=[C:22]([C:23]2[C:25]3[C:26](=[N:27][C:28]([CH3:31])=[CH:29][CH:30]=3)[N:32]([CH2:33][CH3:34])[C:6](=[O:8])[C:5]=2[CH2:4][CH2:3][C:1]#[N:2])[CH:35]=[CH:36][CH:37]=1
Reactant: N#CCCCC(=O)O
Reactant: CCNc1nc(C)ccc1C(=O)c1cccc(Cl)c1
Agent: CC(C)(C)C(=O)Cl
Agent: C[O-]
Agent: [Na+]
Solvent: CCO
Solvent: C1CCOC1
Solvent: CO
Product: CCn1c(=O)c(CCC#N)c(-c2cccc(Cl)c2)c2ccc(C)nc21

Procedure:
After the treatment of 4-cyanobutanoic acid with sodium methoxide in methanol, the treated compound was reacted with pivaloyl chloride in THF. Thus obtained compound was reacted with 3-(3-chlorobenzoyl)-2-ethylamino-6-methylpyridine under heating. Then, the compound obtained by usual work-up was reacted in ethanol in the presence of sodium methoxide under heating. Thereafter, the reaction mixture was worked up and purified in a usual manner to obtain 4-(3-chlorophenyl)-3-(2-cyanoethyl)-1-ethyl-7-methyl-1,8-naphthyridin-2(1H)-one as a pale yellow solid. MS: 352.
Reaction SMILES: O[CH2:2][CH2:3][N:4]1[C:9]2[N:10]=[C:11]([N:14]3[CH2:19][CH2:18][N:17]([CH3:20])[CH2:16][CH2:15]3)[N:12]=[CH:13][C:8]=2[C:7](=[O:21])[C:6]([C:22]([O:24][CH2:25][CH3:26])=[O:23])=[CH:5]1.S(Cl)([Cl:29])=O>C(Cl)(Cl)Cl>[Cl:29][CH2:2][CH2:3][N:4]1[C:9]2[N:10]=[C:11]([N:14]3[CH2:19][CH2:18][N:17]([CH3:20])[CH2:16][CH2:15]3)[N:12]=[CH:13][C:8]=2[C:7](=[O:21])[C:6]([C:22]([O:24][CH2:25][CH3:26])=[O:23])=[CH:5]1
Reactant: CCOC(=O)c1cn(CCO)c2nc(N3CCN(C)CC3)ncc2c1=O
Reactant: O=S(Cl)Cl
Solvent: ClC(Cl)Cl
Product: CCOC(=O)c1cn(CCCl)c2nc(N3CCN(C)CC3)ncc2c1=O
Reaction time: 2 h

Procedure:
To a solution of 8.0 g of ethyl 5,8-dihydro-8-(2-hydroxyethyl)-2-(4-methyl-1-piperazinyl)-5-oxopyrido[2,3-d]pyrimidine-6-carboxylate in 80 ml of chloroform was added with stirring 6 ml of thionyl chloride, the resulting mixture was allowed to react at room temperature for 30 minutes and then heated to refux for 2 hours. After removal of the solvent and an excess of the reagent, the residue was taken up in chloroform. The chloroform solution was washed with water, dried and the solvent distilled off. The solid obtained was recrystallized from ethyl acetate to give 6.9 g of the product, m.p. 154° - 155°C.
Reaction SMILES: [CH3:1][N:2]1[C:6]([CH3:7])=[CH:5][C:4]([NH:8][C:9](=[O:23])[C:10]2[CH:15]=[C:14]([OH:16])[CH:13]=[C:12]([O:17][CH:18]([CH2:21][F:22])[CH2:19][F:20])[CH:11]=2)=[N:3]1.C(=O)([O-])[O-].[K+].[K+].[N:30]1([C:34]([C:36]2[CH:37]=[C:38]([Cl:43])[C:39](Cl)=[N:40][CH:41]=2)=[O:35])[CH2:33][CH2:32][CH2:31]1>C(#N)C>[N:30]1([C:34]([C:36]2[CH:37]=[C:38]([Cl:43])[C:39]([O:16][C:14]3[CH:15]=[C:10]([CH:11]=[C:12]([O:17][CH:18]([CH2:19][F:20])[CH2:21][F:22])[CH:13]=3)[C:9]([NH:8][C:4]3[CH:5]=[C:6]([CH3:7])[N:2]([CH3:1])[N:3]=3)=[O:23])=[N:40][CH:41]=2)=[O:35])[CH2:33][CH2:32][CH2:31]1
Reactant: O=C(c1cnc(Cl)c(Cl)c1)N1CCC1
Reactant: Cc1cc(NC(=O)c2cc(O)cc(OC(CF)CF)c2)nn1C
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: Cc1cc(NC(=O)c2cc(Oc3ncc(C(=O)N4CCC4)cc3Cl)cc(OC(CF)CF)c2)nn1C
Temperature: 120 °C
Yield: 55.2 %

Procedure:
A solution of N-(1,5-dimethyl-1H-pyrazol-3-yl)-3-{[2-fluoro-1-(fluoromethyl)ethyl]oxy}-5-hydroxybenzamide (0.61 mmol) in acetonitrile (5 mL), was treated with the potassium carbonate (1.23 mmol) and 5-(azetidin-1-ylcarbonyl)-2,3-dichloropyridine (0.68 mmol), before being heated to 120° C. in a microwave reactor for 4 hours. The mixture was filtered and evaporated in vacuo before being chromatographed on silica, eluting with 0-5% methanol in ethyl acetate, to give the desired compound as a white foam (175 mg).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([NH:9][C:10]2[CH:11]=[C:12]3[C:16](=[CH:17][CH:18]=2)[CH2:15][CH:14]([NH:19][C:20]2[CH:29]=[CH:28][C:27]([N+:30]([O-:32])=[O:31])=[CH:26][C:21]=2[C:22]([O:24]C)=[O:23])[CH2:13]3)[CH:5]=[CH:6][C:7]=1[Cl:8].[OH-].[Na+]>C1COCC1.CO>[Cl:1][C:2]1[CH:3]=[C:4]([NH:9][C:10]2[CH:11]=[C:12]3[C:16](=[CH:17][CH:18]=2)[CH2:15][CH:14]([NH:19][C:20]2[CH:29]=[CH:28][C:27]([N+:30]([O-:32])=[O:31])=[CH:26][C:21]=2[C:22]([OH:24])=[O:23])[CH2:13]3)[CH:5]=[CH:6][C:7]=1[Cl:8]
Reactant: COC(=O)c1cc([N+](=O)[O-])ccc1NC1Cc2ccc(Nc3ccc(Cl)c(Cl)c3)cc2C1
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CO
Product: O=C(O)c1cc([N+](=O)[O-])ccc1NC1Cc2ccc(Nc3ccc(Cl)c(Cl)c3)cc2C1
Yield: 18 %

Procedure:
By following the procedure of Example 4, methyl 2-[5-(3,4-dichlorophenylamino)-indan-2-ylamino]-5-nitro-benzoate was reacted with sodium hydroxide in THF/MeOH to give 2-[5-(3,4-dichlorophenylamino)-indan-2-ylamino]-5-nitro-benzoic acid (0.017 g, 18% yield). MS (APCI) m/z 457.9 (M++1).
Reaction SMILES: [CH2:1]([NH:8][C:9]([N:11]1[CH2:16][CH2:15][C:14](=[O:17])[N:13]2[C@@H:18]([CH2:34][C:35]3[CH:40]=[CH:39][C:38]([OH:41])=[CH:37][CH:36]=3)[C:19](=[O:33])[N:20]([CH2:22][C:23]3[C:32]4[C:27](=[CH:28][CH:29]=[CH:30][CH:31]=4)[CH:26]=[CH:25][CH:24]=3)[CH2:21][CH:12]12)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:42](OC(=O)C)(=[O:44])[CH3:43]>N1C=CC=CC=1.C(OCC)(=O)C>[C:42]([O:41][C:38]1[CH:37]=[CH:36][C:35]([CH2:34][C@@H:18]2[N:13]3[C:14](=[O:17])[CH2:15][CH2:16][N:11]([C:9](=[O:10])[NH:8][CH2:1][C:2]4[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=4)[CH:12]3[CH2:21][N:20]([CH2:22][C:23]3[C:32]4[C:27](=[CH:28][CH:29]=[CH:30][CH:31]=4)[CH:26]=[CH:25][CH:24]=3)[C:19]2=[O:33])=[CH:40][CH:39]=1)(=[O:44])[CH3:43]
Reactant: CC(=O)OC(C)=O
Reactant: O=C1[C@H](Cc2ccc(O)cc2)N2C(=O)CCN(C(=O)NCc3ccccc3)C2CN1Cc1cccc2ccccc12
Solvent: CCOC(C)=O
Solvent: c1ccncc1
Product: CC(=O)Oc1ccc(C[C@H]2C(=O)N(Cc3cccc4ccccc34)CC3N(C(=O)NCc4ccccc4)CCC(=O)N32)cc1
Temperature: 25 °C
Reaction time: 24 h

Procedure:
To a solution of (6S)—N-benzyl-6-(4-hydroxybenzyl)-8-(naphthalen-1-ylmethyl)-4,7-dioxooctahydro-1H-pyrazino[1,2-a]pyrimidine-1-carboxamide 60 mg (0.106 mmol) in pyridine (1 ml), acetic anhydride 1 ml (10.579 mmol) was added and the mixture was stirred at room temperature for 24 hr. The reaction mixture was diluted with ethyl acetate (10 ml) and washed with 10% citric acid (10 ml) 3 times and brine (10 ml). The organic layer was dried with sodium sulfate and filtered. The filtrate was concentrated in vacuo and the residue was purified by Büchi silica gel column chromatography (chloroform:methanol=99:1 to 98:2) to obtain title compound.
Reaction SMILES: [Br:1][C:2]1[CH:11]=[C:10]2[C:5]([CH2:6][CH2:7][C:8](=[O:12])[CH2:9]2)=[CH:4][CH:3]=1.[CH2:13](O)[CH2:14][OH:15].C1(C)C=CC(S(O)(=O)=O)=CC=1>C1C=CC=CC=1.C(OCC)C>[Br:1][C:2]1[CH:11]=[C:10]2[C:5]([CH2:6][CH2:7][C:8]3([O:15][CH2:14][CH2:13][O:12]3)[CH2:9]2)=[CH:4][CH:3]=1
Reactant: OCCO
Reactant: O=C1CCc2ccc(Br)cc2C1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: c1ccccc1
Solvent: CCOCC
Product: Brc1ccc2c(c1)CC1(CC2)OCCO1
Yield: 91 %

Procedure:
A solution of 7-bromo-2-tetralone (1.1 g, 4.9 mmol), ethylene glycol (0.62 g, 10 mmol), and p-toluensulfonic acid (80 mg, 0.42 mmol) in benzene (20 ml) was stirred under N2 at reflux utilizing a Dean-Stark trap for 45 minutes. The cooled solution was diluted with diethyl ether (60 ml), washed with saturated NaHCO3 solution (2×10 ml), dried (MgSO4) and concentrated in vacuo to give 7'-bromo-3',4'-dihydrospiro[1,3-dioxolane-2,2'(1'H)-naphthalene] as an oil (1.2 g). 1H NMR (CDCl3, 200 MHz) δ: 1.95 (t, J=7 Hz, 2H, CH2), 2.91 (t, J=7 Hz, 2H, CH2), 2.95 (s, 2H, CH2), 4.01 (s, 4H, OCH2CH2O), 6.97 (d, J=8 Hz, 1H, Ar), 7.15-7.27 (m, 2H, Ar).
Reaction SMILES: [Br:1][C:2]1[CH:7]=[C:6]([CH:8]([CH3:10])[CH3:9])[CH:5]=[CH:4][C:3]=1[N:11]1[C:20]2[N:19]=[C:18]([CH3:21])[N:17]=[C:16]([N:22]([CH2:27][CH3:28])[CH2:23][CH2:24][CH2:25][CH3:26])[C:15]=2[NH:14][C:13](=[NH:29])[CH2:12]1.[CH2:30](OC(OCC)CBr)[CH3:31]>C(O)C>[Br:1][C:2]1[CH:7]=[C:6]([CH:8]([CH3:9])[CH3:10])[CH:5]=[CH:4][C:3]=1[N:11]1[C:20]2[C:15](=[C:16]([N:22]([CH2:23][CH2:24][CH2:25][CH3:26])[CH2:27][CH3:28])[N:17]=[C:18]([CH3:21])[N:19]=2)[N:14]2[CH:30]=[CH:31][N:29]=[C:13]2[CH2:12]1
Reactant: CCOC(CBr)OCC
Reactant: CCCCN(CC)c1nc(C)nc2c1NC(=N)CN2c1ccc(C(C)C)cc1Br
Solvent: CCO
Product: CCCCN(CC)c1nc(C)nc2c1-n1ccnc1CN2c1ccc(C(C)C)cc1Br

Procedure:
A solution of the compound of Example 248 and a slight excess of bromoacetaldehyde diethyl acetal in ethanol is heated to reflux until the starting material is consumed. The reaction mixture is evaporated, and the residual material is purified by chromatography or recrystallization to afford the title product.
Reaction SMILES: C(O)(C(F)(F)F)=O.C(OC([N:15](C(OC(C)(C)C)=O)[C:16]1[C:17]([C:36]2[O:40][N:39]=[C:38]([C:41]3[CH:46]=[CH:45][C:44]([CH2:47][N:48](C)[C:49](=O)OC(C)(C)C)=[CH:43][C:42]=3[F:57])[CH:37]=2)=[N:18][C:19]([C:22]2[CH:27]=[CH:26][C:25]([S:28]([CH:31]3[CH2:35][CH2:34][O:33][CH2:32]3)(=[O:30])=[O:29])=[CH:24][CH:23]=2)=[CH:20][N:21]=1)=O)(C)(C)C>ClCCl>[F:57][C:42]1[CH:43]=[C:44]([CH2:47][NH:48][CH3:49])[CH:45]=[CH:46][C:41]=1[C:38]1[CH:37]=[C:36]([C:17]2[C:16]([NH2:15])=[N:21][CH:20]=[C:19]([C:22]3[CH:27]=[CH:26][C:25]([S:28]([CH:31]4[CH2:35][CH2:34][O:33][CH2:32]4)(=[O:29])=[O:30])=[CH:24][CH:23]=3)[N:18]=2)[O:40][N:39]=1
Reactant: CN(Cc1ccc(-c2cc(-c3nc(-c4ccc(S(=O)(=O)C5CCOC5)cc4)cnc3N(C(=O)OC(C)(C)C)C(=O)OC(C)(C)C)on2)c(F)c1)C(=O)OC(C)(C)C
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CNCc1ccc(-c2cc(-c3nc(-c4ccc(S(=O)(=O)C5CCOC5)cc4)cnc3N)on2)c(F)c1
Reaction time: 2 h
Yield: 54 %

Procedure:
TFA (281.6 mg, 190.3 μL, 2.470 mmol) was added to a solution of tert-butyl N-[[4-[5-[3-[bis(tert-butoxycarbonyl)amino]-6-(4-tetrahydrofuran-3-ylsulfonylphenyl)pyrazin-2-yl]isoxazol-3-yl]-3-fluoro-phenyl]methyl]-N-methyl-carbamate (100 mg, 0.1235 mmol) in dichloromethane (2.069 mL) at room temperature and the resulting solution stirred for 2 h. The reaction mixture was concentrated in vacuo and purified by reverse phase preparative HPLC [Waters Sunfire C18, 10 μM, 100 Å column, gradient 10%-95% B (solvent A: 0.05% TFA in water; solvent B: CH3 CN) over 16 minutes at 25 mL/min]. The product fractions were collected and lypholised to give the product as a yellow solid (34.0 mg, 44% yield); 1H NMR (400.0 MHz, DMSO) d 2.13-2.19 (m, 2H), 2.63 (m, 3H), 3.66 (m, 1H), 3.76 (m, 1H), 3.85 (m, 1H), 4.04 (m, 1H), 4.21-4.28 (m, 3H), 7.27 (m, 2H), 7.52 (m, 1H), 7.60-7.65 (m, 2H), 8.00 (m, 2H), 8.12 (t, 1H), 8.36 (m, 2H) and 8.94 (m, 3H) ppm; MS (ES+) 510.2
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]([O:38][CH:39]([F:41])[F:40])=[C:6]([C:8]2[C:12]([NH:13][C:14]([C:16]3[CH:17]=[N:18][N:19]4[CH:24]=[CH:23][CH:22]=[N:21][C:20]=34)=[O:15])=[CH:11][N:10]([CH2:25][CH:26]=[C:27]3[CH2:32][CH2:31][CH:30]([NH:33][CH2:34][CH2:35][C:36]#[N:37])[CH2:29][CH2:28]3)[N:9]=2)[CH:7]=1.C=O.[BH3-][C:45]#N.[Na+]>CO>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([O:38][CH:39]([F:41])[F:40])=[C:6]([C:8]2[C:12]([NH:13][C:14]([C:16]3[CH:17]=[N:18][N:19]4[CH:24]=[CH:23][CH:22]=[N:21][C:20]=34)=[O:15])=[CH:11][N:10]([CH2:25][CH:26]=[C:27]3[CH2:32][CH2:31][CH:30]([N:33]([CH2:34][CH2:35][C:36]#[N:37])[CH3:45])[CH2:29][CH2:28]3)[N:9]=2)[CH:7]=1
Reactant: [BH3-]C#N
Reactant: N#CCCNC1CCC(=CCn2cc(NC(=O)c3cnn4cccnc34)c(-c3cc(Cl)ccc3OC(F)F)n2)CC1
Agent: C=O
Agent: [Na+]
Solvent: CO
Product: CN(CCC#N)C1CCC(=CCn2cc(NC(=O)c3cnn4cccnc34)c(-c3cc(Cl)ccc3OC(F)F)n2)CC1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of N-[3-[5-chloro-2-(difluoromethoxy)phenyl]-1-(2-[4-[(2-cyanoethyl)amino]cyclohexylidene]ethyl)-1H-pyrazol-4-yl]pyrazolo[1,5-a]pyrimidine-3-carboxamide (140.0 mg, 0.241 mmol) in methanol (20 mL) was added 40% HCHO aqueous solution (75 mg, 0.96 mmol). The resulting solution was stirred at room temperature overnight. Then NaBH3CN (15.14 mg, 0.241 mmol) was added. The resulting solution was stirred at room temperature for 4 h and concentrated under vacuum. The residue was purified by flash chromatography on silica gel eluting with dichloromethane/MeOH (10/1). This resulted in 34.7 mg (24%) of N-[3-[5-chloro-2-(difluoromethoxy)phenyl]-1-(2-[4-[(2-cyano ethyl)(methyl)amino]cyclohexylidene]ethyl)-1H-pyrazol-4-yl]pyrazolo[1,5-a]pyrimidine-3-carboxamide as a light yellow solid. LCMS (Method 33) [M+H]+=595.4, RT=1.43 min. 1H NMR (300 MHz, DMSO-d6) δ: (ppm) 9.73 (s, 1H), 9.33 (dd, 1H, J=1.5, 6.9 Hz), 8.69-8.66 (m, 2H), 8.28 (s, 1H), 7.64-7.60 (m, 2H), 7.43 (d, 1H, J=8.4 Hz), 7.27 (dd, 1H, J=4.5, 7.5 Hz), 7.00 (t, 1H, J=73.5 Hz), 5.43 (t, 1H, J=7.2 Hz), 4.81 (d, 2H, J=6.9 Hz), 2.88-2.82 (m, 1H), 2.66-2.59 (m, 5H), 2.33-2.29 (m, 1H), 2.22 (s, 3H), 2.10-2.05 (m, 1H), 1.93-1.80 (m, 3H), 1.37-1.25 (m, 2H).