Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C:2]1[N:7]=[C:6]([N:8]2[CH2:22][CH2:21][C:11]3([CH2:15][NH:14][C@H:13]([C:16]([O:18]CC)=[O:17])[CH2:12]3)[CH2:10][CH2:9]2)[CH:5]=[C:4]([O:23][CH:24]([C:29]2[CH:34]=[CH:33][C:32]([C:35](=[O:37])[NH2:36])=[CH:31][C:30]=2[N:38]2[CH:42]=[CH:41][C:40]([CH3:43])=[N:39]2)[C:25]([F:28])([F:27])[F:26])[N:3]=1.[Li+].[OH-]>>[NH2:1][C:2]1[N:7]=[C:6]([N:8]2[CH2:22][CH2:21][C:11]3([CH2:15][NH:14][C@H:13]([C:16]([OH:18])=[O:17])[CH2:12]3)[CH2:10][CH2:9]2)[CH:5]=[C:4]([O:23][C@H:24]([C:29]2[CH:34]=[CH:33][C:32]([C:35](=[O:37])[NH2:36])=[CH:31][C:30]=2[N:38]2[CH:42]=[CH:41][C:40]([CH3:43])=[N:39]2)[C:25]([F:28])([F:27])[F:26])[N:3]=1
Reactant: CCOC(=O)[C@@H]1CC2(CCN(c3cc(OC(c4ccc(C(N)=O)cc4-n4ccc(C)n4)C(F)(F)F)nc(N)n3)CC2)CN1
Agent: [Li+]
Agent: [OH-]
Product: Cc1ccn(-c2cc(C(N)=O)ccc2[C@@H](Oc2cc(N3CCC4(CC3)CN[C@H](C(=O)O)C4)nc(N)n2)C(F)(F)F)n1

Procedure:
Hydrolysis of (3S)-ethyl 8-(2-amino-6-(1-(4-carbamoyl-2-(3-methyl-1H-pyrazol-1-yl)phenyl)-2,2,2-trifluoroethoxy)pyrimidin-4-yl)-2,8-diazaspiro[4.5]decane-3-carboxylate using the LiOH general method provides the title compound as a white solid.
Reaction SMILES: I.CS[C:4](=[NH:18])[NH:5][C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][C:7]=1[N:12]1[CH2:17][CH2:16][O:15][CH2:14][CH2:13]1.[CH3:19][CH:20]([NH2:23])[CH2:21]N>C(O)C>[CH3:19][CH:20]1[CH2:21][NH:18][C:4](=[N:5][C:6]2[CH:11]=[CH:10][CH:9]=[CH:8][C:7]=2[N:12]2[CH2:17][CH2:16][O:15][CH2:14][CH2:13]2)[NH:23]1
Reactant: CSC(=N)Nc1ccccc1N1CCOCC1
Reactant: CC(N)CN
Agent: I
Solvent: CCO
Product: CC1CNC(=Nc2ccccc2N2CCOCC2)N1

Procedure:
A mixture of 2-methyl-1-(2-morpholinophenyl)-2-thiopseudourea hydroiodide (3.8 g prepared as described in Example 166), 2-methylethylenediamine (2.2 g) and ethanol (45 ml) was heated under reflux for 8 hours to give a solid which was recrystallised from ethyl acetate to give 4-[2-(4-methyl-2-imidazolidinylideneamino)phenyl]morpholine (m.p. 173°-174° C.).
Reaction SMILES: [NH2:1][C:2]1[C:7]([F:8])=[C:6]([C:9]([CH3:12])([CH3:11])[CH3:10])[N:5]=[C:4]([CH:13]=[O:14])[CH:3]=1.[Cl:15]N1C(C)(C)C(=O)N(Cl)C1=O>>[NH2:1][C:2]1[C:7]([F:8])=[C:6]([C:9]([CH3:11])([CH3:10])[CH3:12])[N:5]=[C:4]([CH:13]=[O:14])[C:3]=1[Cl:15]
Reactant: CC(C)(C)c1nc(C=O)cc(N)c1F
Reactant: CC1(C)C(=O)N(Cl)C(=O)N1Cl
Product: CC(C)(C)c1nc(C=O)c(Cl)c(N)c1F
Yield: 0.1 %

Procedure:
Using the procedure for Example 15, 4-amino-6-(tert-butyl)-5-fluoropicolinaldehyde (0.5 g, 2.55 mol), 1,3-dichloro-5,5-dimethylimidazolidine-2,4-dione (0.276 g, 1.401 mol) CH3CN (26 mL) gave 4-amino-6-(tert-butyl)-3-chloro-5-fluoropicolinaldehyde (423 mg, 70.5%) as a yellow oil: 1H NMR (400 MHz, CDCl3) δ 10.01 (s, 1H), 4.76 (d, J=7.2 Hz, 3H), 1.42 (d, J=1.6 Hz, 9H); 19F NMR (376 MHz, CDCl3) δ −132.69; 13C NMR (101 MHz, CDCl3) δ 191.27, 152.89, 149.20, 146.51, 141.75, 139.93, 36.97, 28.39; EIMS m/z 230.
Reaction SMILES: [C:1]1([CH2:7][O:8][C:9]2[CH:23]=[CH:22][C:21]([O:24][CH2:25][C@H:26]3[CH2:30][CH2:29][CH2:28][NH:27]3)=[CH:20][C:10]=2[C:11]([NH:13][C:14]2[CH:15]=[N:16][CH:17]=[CH:18][CH:19]=2)=[O:12])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C=O.[C:33](=O)=O.C([O-])(O)=O.[Na+]>C(O)=O>[CH3:33][N:27]1[CH2:28][CH2:29][CH2:30][C@@H:26]1[CH2:25][O:24][C:21]1[CH:22]=[CH:23][C:9]([O:8][CH2:7][C:1]2[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=2)=[C:10]([CH:20]=1)[C:11]([NH:13][C:14]1[CH:15]=[N:16][CH:17]=[CH:18][CH:19]=1)=[O:12]
Reactant: O=C(Nc1cccnc1)c1cc(OC[C@H]2CCCN2)ccc1OCc1ccccc1
Reactant: O=C=O
Agent: C=O
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O=CO
Product: CN1CCC[C@@H]1COc1ccc(OCc2ccccc2)c(C(=O)Nc2cccnc2)c1

Procedure:
2-[(Phenylmethyl)oxy]-N-3-pyridinyl-5-{[(2R)-2-pyrrolidinylmethyl]oxy}benzamide (may be prepared as described in Example 44; 250 mg, 0.62 mmol) was added to formic acid (4.5 ml) at 5° C., followed by 40% aqueous formaldehyde (2.4 ml). When the initial evolution of carbon dioxide had subsided, the mixture was refluxed for 2 h. After the solution was cooled, the pH of the solution was adjusted to 7-8 by adding aqueous NaHCO3 solution. The mixture was extracted with dichloromethane. The organic layer was dried over Na2SO4, and concentrated to obtain a crude product, which was purified by prep-HPLC to yield the title compound as a white solid. 47 mg.
Reaction SMILES: [OH-].[NH4+:2].[Cl:3][C:4]1[C:9]([N+:10]([O-:12])=[O:11])=[C:8](Cl)[N:7]=[CH:6][N:5]=1>C(OCC)C.CO>[Cl:3][C:4]1[N:5]=[CH:6][N:7]=[C:8]([NH2:2])[C:9]=1[N+:10]([O-:12])=[O:11]
Reactant: O=[N+]([O-])c1c(Cl)ncnc1Cl
Reactant: [NH4+]
Agent: [OH-]
Solvent: CCOCC
Solvent: CO
Product: Nc1ncnc(Cl)c1[N+](=O)[O-]
Reaction time: 2 h
Yield: 74.9 %

Procedure:
A solution of 28% aqueous ammonium hydroxide (670 mL, 5.35 mol, 1.04 equiv) was added in a drop-wise fashion to a rapidly stirred solution of the 4,6-dichloro-5-nitropyrimidine solid (1000 g, 5.16 mol, 1.00 equiv) in diethyl ether (4000 mL) and methanol (670 mL). The addition was carried out over a period of 2 hours. Upon completion of addition, the resulting yellow solid was filtered off, washed with water and hexane, and dried under reduced pressure to give the title compound as a yellow solid (yield: 675 g). This crude solid was used in the next step without any further purification. 1H NMR (400 MHz, DMSO-d6): δ 8.97 (s, 1H), 7.91 (broad s, 2H). MS (EI) for C4H3ClN4O2: 175 (MH+).
Reaction SMILES: [NH2:1][C:2]1[N:3]=[CH:4][C:5]2[CH:11]=[C:10]([C:12]3[C:17]([Cl:18])=[CH:16][CH:15]=[CH:14][C:13]=3[Cl:19])[C:9](=O)[N:8]([CH3:21])[C:6]=2[N:7]=1.COC1C=CC(P2(SP(C3C=CC(OC)=CC=3)(=S)S2)=[S:31])=CC=1>N1C=CC=CC=1>[NH2:1][C:2]1[N:3]=[CH:4][C:5]2[CH:11]=[C:10]([C:12]3[C:17]([Cl:18])=[CH:16][CH:15]=[CH:14][C:13]=3[Cl:19])[C:9](=[S:31])[N:8]([CH3:21])[C:6]=2[N:7]=1
Reactant: Cn1c(=O)c(-c2c(Cl)cccc2Cl)cc2cnc(N)nc21
Reactant: COc1ccc(P2(=S)SP(=S)(c3ccc(OC)cc3)S2)cc1
Solvent: c1ccncc1
Product: Cn1c(=S)c(-c2c(Cl)cccc2Cl)cc2cnc(N)nc21
Reaction time: 24 h

Procedure:
A mixture of 0.321 g (1.0 mmol) of 2-amino-6-(2,6-dichlorophenyl)-8-methyl-pyrido[2,3-d]pyrimidin-7-(8H)-one from Example 12 and 0.404 g (1.0 mmol) of Lawesson's Reagent in 10 mL of pyridine was heated at reflux with stirring for 24 hours. The solvent was evaporated under reduced pressure, and the residue was triturated with 20 mL of water, filtered, and the cake washed well with water. Purification was by silica gel chromatography to afford the desired compound identified as 2-amino-6-(2,6-dichlorophenyl)-8-methyl-pyrido[2,3-d]-pyrimidin-7(8H)-thione.
Reaction SMILES: [Cl:1][C:2]1[C:3]2[N:4]([CH:27]=[N:28][CH:29]=2)[C:5]([N:20]2[CH2:24][CH2:23][C@H:22]([O:25]C)[CH2:21]2)=[C:6]([CH:8]([NH:10][C:11]2[N:19]=[CH:18][N:17]=[C:16]3[C:12]=2[N:13]=[CH:14][NH:15]3)[CH3:9])[CH:7]=1.C(Cl)Cl.B(Br)(Br)Br>>[Cl:1][C:2]1[C:3]2[N:4]([CH:27]=[N:28][CH:29]=2)[C:5]([N:20]2[CH2:24][CH2:23][C@H:22]([OH:25])[CH2:21]2)=[C:6]([CH:8]([NH:10][C:11]2[N:19]=[CH:18][N:17]=[C:16]3[C:12]=2[N:13]=[CH:14][NH:15]3)[CH3:9])[CH:7]=1
Reactant: CO[C@H]1CCN(c2c(C(C)Nc3ncnc4[nH]cnc34)cc(Cl)c3cncn23)C1
Agent: BrB(Br)Br
Solvent: ClCCl
Product: CC(Nc1ncnc2[nH]cnc12)c1cc(Cl)c2cncn2c1N1CC[C@H](O)C1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 11.5 %

Procedure:
To a cooled solution of N-(1-{8-chloro-5-[(3S)-3-methoxypyrrolidin-1-yl]imidazo[1,5-a]pyridin-6-yl}ethyl)-9H-purin-6-amine (18.0 mg, 0.0436 mmol) in methylene chloride (1.0 mL, 16 mmol) at −78° C. under an atmosphere of nitrogen was added slowly 1.0 M boron tribromide in methylene chloride (0.47 mL, 0.47 mmol). The mixture was allowed to warm up to room temperature and stirred for 30 minutes. The resultant mixture was quenched with Na2CO3 (aq). The cloudy suspension was filtered and washed with water. The filtrate was extracted with ethyl acetate and the organic layer was washed with brine and evaporated. Purification by preparative LCMS (pH 10) gave the desired compound (2.0 mg, 12%). LCMS calculated for C18H20ClN8O (M+H)+: m/z=399.1. found: 399.0.
Reaction SMILES: [Cl:1][S:2]([C:5]1[CH:13]=[CH:12][C:8]([C:9](Cl)=[O:10])=[CH:7][CH:6]=1)(=[O:4])=[O:3].[F:14][C:15]1[CH:23]=[CH:22][C:18]([CH2:19][CH2:20][NH2:21])=[CH:17][CH:16]=1>C(Cl)Cl>[F:14][C:15]1[CH:23]=[CH:22][C:18]([CH2:19][CH2:20][NH:21][C:9]([C:8]2[CH:12]=[CH:13][C:5]([S:2]([Cl:1])(=[O:4])=[O:3])=[CH:6][CH:7]=2)=[O:10])=[CH:17][CH:16]=1
Reactant: NCCc1ccc(F)cc1
Reactant: O=C(Cl)c1ccc(S(=O)(=O)Cl)cc1
Solvent: ClCCl
Product: O=C(NCCc1ccc(F)cc1)c1ccc(S(=O)(=O)Cl)cc1
Temperature: 0 °C
Reaction time: 0.17 h

Procedure:
TEA (474 μL, 3.4 mmol), is added dropwise to a suspension of the title A compound, 4-chlorosulfonyl-benzoyl chloride in DCM (10 mL) at −78° C. To this mixture is added p-fluorophenethylamine over 5 min. After another 10 min at −78° C., the solution is allowed to warm to 0° C. and stirring is continued at this temperature for 1 h. The reaction is quenched by adding it to ice-water (30 mL), and the mixture is extracted with DCM (3×10 mL). The combined organic phases are dried over anhydrous magnesium sulfate, filtered, and concentrated under vacuum to obtain the crude product which is chromatographed on silica gel using EtOAc as the eluent to give 4-[2-(4-fluoro-phenyl)-ethylcarbamoyl]-benzenesulfonyl chloride.
Reaction SMILES: [C:1]([C:3]1[N:7]([C:8]([N:10]([C:14]2[CH:15]=[C:16]([CH:27]=[CH:28][CH:29]=2)[C:17]([O:19]CC2C=CC=CC=2)=[O:18])[CH:11]([CH3:13])[CH3:12])=[O:9])[N:6]=[N:5][C:4]=1[C:30]1[C:35]([F:36])=[CH:34][CH:33]=[CH:32][C:31]=1[F:37])#[N:2].[H][H]>CO.[Pd]>[C:1]([C:3]1[N:7]([C:8]([N:10]([C:14]2[CH:15]=[C:16]([CH:27]=[CH:28][CH:29]=2)[C:17]([OH:19])=[O:18])[CH:11]([CH3:13])[CH3:12])=[O:9])[N:6]=[N:5][C:4]=1[C:30]1[C:31]([F:37])=[CH:32][CH:33]=[CH:34][C:35]=1[F:36])#[N:2]
Reactant: [H][H]
Reactant: CC(C)N(C(=O)n1nnc(-c2c(F)cccc2F)c1C#N)c1cccc(C(=O)OCc2ccccc2)c1
Agent: [Pd]
Solvent: CO
Product: CC(C)N(C(=O)n1nnc(-c2c(F)cccc2F)c1C#N)c1cccc(C(=O)O)c1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
To a solution of benzyl ester (6) (1.0 equiv) in methanol (0.1 M) under argon was added 5% Pd/C (0.1 equiv) and the inert atmosphere was replaced with hydrogen. The resulting mixture was stirred at rt for 30 min, filtered through a pad of Celite with aid of methanol and the resulting filtrate concentrated in vacuo. The residue was purified by preparative HPLC (0.1% formic acid in acetonitrile/water) to afford 3-(5-cyano-4-(2,6-difluorophenyl)-N-isopropyl-1H-1,2,3-triazole-1-carboxamido)benzoic acid (7) as a lyophilized powder.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][N:9]2[C:18](=[O:19])[C:17]3[C:12](=[CH:13][CH:14]=[C:15]([C:20]([OH:23])([CH3:22])[CH3:21])[CH:16]=3)[N:11]=[C:10]2[CH2:24][CH2:25][CH2:26][CH3:27])=[CH:4][CH:3]=1.[Si:28](Cl)([C:31]([CH3:34])([CH3:33])[CH3:32])([CH3:30])[CH3:29].N1C=CN=C1>CN(C=O)C.O>[Br:1][C:2]1[CH:3]=[CH:4][C:5]([CH2:8][N:9]2[C:18](=[O:19])[C:17]3[C:12](=[CH:13][CH:14]=[C:15]([C:20]([O:23][Si:28]([C:31]([CH3:34])([CH3:33])[CH3:32])([CH3:30])[CH3:29])([CH3:21])[CH3:22])[CH:16]=3)[N:11]=[C:10]2[CH2:24][CH2:25][CH2:26][CH3:27])=[CH:6][CH:7]=1
Reactant: CCCCc1nc2ccc(C(C)(C)O)cc2c(=O)n1Cc1ccc(Br)cc1
Reactant: CC(C)(C)[Si](C)(C)Cl
Agent: c1c[nH]cn1
Solvent: CN(C)C=O
Solvent: O
Product: CCCCc1nc2ccc(C(C)(C)O[Si](C)(C)C(C)(C)C)cc2c(=O)n1Cc1ccc(Br)cc1
Temperature: 25 °C
Reaction time: 18 h

Procedure:
To a solution of 1.00 g of 3-[(4-bromophenyl) methyl]-2-butyl-6-(1-hydroxy-1-methylethyl)-4(3H)-quinazolinone in 2.0 ml of DMF is added 0.438 g of t-butyldimethylsilyl chloride followed by 0.4 g of imidazole. The reaction mixture is stirred at room temperature for 18 hours and then diluted with water and extracted with ether. The combined ether extracts are dried over MgSO4, filtered and concentrated in vacuo. The residue was purified by flash chromatography eluting with ethyl acetate/hexanes (1:5) to provide the desired product as a white solid.
Reaction SMILES: [NH2:1][C:2]1[N:3]=[C:4]([C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)[C:5]([C:9]2[CH:10]=[CH:11][C:12](=[O:18])[N:13]([CH:15]([CH3:17])[CH3:16])[N:14]=2)=[N:6][C:7]=1Br.[CH2:25]([NH2:29])[CH2:26][CH2:27][CH3:28].O>CN1CCN(C)C1=O.CC(C)=O>[NH2:1][C:2]1[N:3]=[C:4]([C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)[C:5]([C:9]2[CH:10]=[CH:11][C:12](=[O:18])[N:13]([CH:15]([CH3:17])[CH3:16])[N:14]=2)=[N:6][C:7]=1[NH:29][CH2:25][CH2:26][CH2:27][CH3:28]
Reactant: CCCCN
Reactant: CC(C)n1nc(-c2nc(Br)c(N)nc2-c2ccccc2)ccc1=O
Solvent: O
Solvent: CC(C)=O
Solvent: CN1CCN(C)C1=O
Product: CCCCNc1nc(-c2ccc(=O)n(C(C)C)n2)c(-c2ccccc2)nc1N
Temperature: 122.5 °C

Procedure:
In a sealed tube, a mixture of 6-(5-amino-6-bromo-3-phenyl-2-pyrazinyl)-2-isopropyl-3(2H)-pyridazinone (150 mg) and butylamine (0.116 ml) in 1,3-dimethyl-2-imidazolidinone (0.3 ml) was heated at 120-125° C. for 50 hours. After addition of water (3 ml), a precipitate was collected by filtration and purified by column chromatography on silica gel eluting with a mixture of n-hexane and EtOAc (50:50 v/v) to give a solid. The solid was suspended in acetone to give 6-[5-amino-6-(butylamino)-3-phenyl-2-pyrazinyl]-2-isopropyl-3(2H)-pyridazinone (71 mg).
Reaction SMILES: [CH3:1][N:2]1[C:6]([CH:7]=C)=[CH:5][N:4]=[C:3]1[N+:9]([O-:11])=[O:10].C[O:13]CCOC>O=[Os](=O)(=O)=O.O>[CH3:1][N:2]1[C:6]([CH:7]=[O:13])=[CH:5][N:4]=[C:3]1[N+:9]([O-:11])=[O:10]
Reactant: C=Cc1cnc([N+](=O)[O-])n1C
Reactant: COCCOC
Agent: O=[Os](=O)(=O)=O
Solvent: O
Product: Cn1c(C=O)cnc1[N+](=O)[O-]
Temperature: 25 °C
Reaction time: 8 h
Yield: 63 %

Procedure:
To a solution of 0.67 g. of 1-methyl-2-nitro-5-vinylimidazole in 20 ml. of 1,2-dimethoxyethane, a solution of 2 g. of NaIO4 in 5 ml. of water, followed by 0.025 g. of OsO4 is added with stirring at room temperature. After stirring for four hours, the mixture is allowed to stand overnight. The residue which is obtained by evaporation of the reaction medium to dryness under vacuum is extracted with ethyl acetate. The resulting solution after filtering is concentrated, yielding 0.43 g. of a product which, after crystallization from ethyl acetate, melts at 114°-115° C. Yield 63%.
Reaction SMILES: [F:1][C:2]1[CH:10]=[C:9]2[C:5]([C:6]([CH2:11][N:12]3[CH2:17][CH2:16][N:15]([C:18](=O)[CH2:19][C:20]4[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=4)[CH2:14][CH2:13]3)=[N:7][NH:8]2)=[CH:4][CH:3]=1.[H-].[H-].[H-].[H-].[Li+].[Al+3]>C1COCC1.CCOC(C)=O.[OH-].[Na+]>[F:1][C:2]1[CH:10]=[C:9]2[C:5]([C:6]([CH2:11][N:12]3[CH2:13][CH2:14][N:15]([CH2:18][CH2:19][C:20]4[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=4)[CH2:16][CH2:17]3)=[N:7][NH:8]2)=[CH:4][CH:3]=1
Reactant: O=C(Cc1ccccc1)N1CCN(Cc2n[nH]c3cc(F)ccc23)CC1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: Fc1ccc2c(CN3CCN(CCc4ccccc4)CC3)n[nH]c2c1
Temperature: 40 °C
Reaction time: 1 h
Yield: 87.3 %

Procedure:
A solution of 6-fluoro-3-[4-(2-phenylacetyl)piperazin-1-ylmethyl]-1H-indazole (156 mg, 0.44 mmol) in THF (5 mL) was treated with LiAlH4 (0.44 mL of a 1.0M solution in THF, 0.44 mmol) and heated at 40° C. for 16 h. The solution was cooled, diluted with EtOAc (50 mL), 2M aqueous NaOH was added (200 mL) and the resulting suspension was stirred for 1 h at 20° C., filtered, concentrated and the residue purified by flash chromatography (EtOAc→10% MeOH in EtOAc) to give the title compound (130 mg, 87%) as a white solid; mp 148°-149° C. (from Et2O/hexane); 1H NMR (360 MHz, d6 -DMSO) δ12.85 (bs, 1H, NH), 7.89 (dd, J=8.9, 5.5 Hz, 1H, indazole), 7.28-7.14 (m, 6H, aromatic), 6.96 (dt, J=9.3, 2.2 Hz, 1H, indazole), 3.79 (s, 2H, Ar--CH2N), 2.70 (t, J=7.2 Hz, 2H, CH2 --Ph), 2.51-2.40 (m, 10H, piperazine, CH2); MS (CI+) m/e 339 (M+H+); Anal. calcd for C20H23FN4 : C, 70.98; H, 6.85, N, 16.56. Found: C, 71.35; H, 6.88; N, 16.56.
Reaction SMILES: Cl[C:2]1[C:7]2[CH2:8][C:9](=[O:17])[C:10]3[CH:16]=[CH:15][CH:14]=[CH:13][C:11]=3[S:12][C:6]=2[CH:5]=[CH:4][CH:3]=1.[Cu](C#N)[C:19]#[N:20].CN1CCCC1=O.N>S([O-])([O-])(=O)=O.[Cu+2].O>[C:19]([C:2]1[C:7]2[CH2:8][C:9](=[O:17])[C:10]3[CH:16]=[CH:15][CH:14]=[CH:13][C:11]=3[S:12][C:6]=2[CH:5]=[CH:4][CH:3]=1)#[N:20]
Reactant: O=C1Cc2c(Cl)cccc2Sc2ccccc21
Reactant: N#C[Cu]C#N
Agent: [Cu+2]
Agent: N
Agent: O=S(=O)([O-])[O-]
Solvent: O
Solvent: CN1CCCC1=O
Product: N#Cc1cccc2c1CC(=O)c1ccccc1S2
Temperature: 200 °C
Reaction time: 8 h

Procedure:
The mixture of 2.6 g of 9-chloro-10,11-dihydro-11-oxo-dibenzo[b,f]thiepin, 2.0 g. of copper cyanide, 0.1 g of anhydrous copper sulfate and 50 ml of N-methyl pyrrolidone was heated with stirring at 200° C. overnight in a flask equipped with a tube packed with silica gel. After cooling, to the reaction mixture were added 100 ml of conc. aqueous ammonia and 200 ml of water, and the resulting mixture was extracted with benzene. The extract was washed with water, diluted hydrochloric acid and then water, which was dried over potassium sulfate and the solvent was evaporated therefrom. The residue thus obtained was chromatographed on 200 g of silica gel, and eluted with chloroform/methanol (50/1). 0.6 g of the starting material was recovered from a first eluate. Recrystallization of the residue of a second eluate from benzene gave 0.7 g of 9-cyano-10,11-dihydro-11-oxo-dibenzo[b,f]thiepin as pale yellow prismatic crystals having a melting point of 165°-167° C.
Reaction SMILES: C([O-])([O-])=O.[Cs+].[Cs+].[CH3:7][O:8][C:9]1[CH:14]=[C:13]([CH3:15])[CH:12]=[CH:11][C:10]=1B(O)O.Cl[C:20]1[C:29]2[C:24](=[CH:25][C:26]([S:30]([N:33](CC3C=CC(OC)=CC=3)[C:34]3[S:35][CH:36]=[CH:37][N:38]=3)(=[O:32])=[O:31])=[CH:27][CH:28]=2)[CH:23]=[CH:22][N:21]=1>COCCOC.O.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>[CH3:7][O:8][C:9]1[CH:14]=[C:13]([CH3:15])[CH:12]=[CH:11][C:10]=1[C:20]1[C:29]2[C:24](=[CH:25][C:26]([S:30]([NH:33][C:34]3[S:35][CH:36]=[CH:37][N:38]=3)(=[O:32])=[O:31])=[CH:27][CH:28]=2)[CH:23]=[CH:22][N:21]=1
Reactant: COc1cc(C)ccc1B(O)O
Reactant: COc1ccc(CN(c2nccs2)S(=O)(=O)c2ccc3c(Cl)nccc3c2)cc1
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: [Cs+]
Solvent: COCCOC
Solvent: O
Product: COc1cc(C)ccc1-c1nccc2cc(S(=O)(=O)Nc3nccs3)ccc12
Reaction time: 2 h
Yield: 50.4 %

Procedure:
A microwave vial containing Cs2CO3 (0.175 g, 0.538 mmol), (2-methoxy 4-methyl phenyl)boronic acid (27 mg, 0.175 mmol) and 1-chloro-N-(4-methoxybenzyl)-N-(thiazol-2-yl)isoquinoline-6-sulfonamide (Intermediate JJJ; 0.06 g, 0.135 mmol) in DME (1.500 ml) and water (0.225 ml) was purged with nitrogen and Pd(PPh3)4(0.016 g, 0.013 mmol) was added and the reaction was irradiated under microwave irradiation at 125° C. for 1.5 h. The aqueous layer was discarded and the organic layer was concentrated. To this was then added DCM (1 mL) and TFA (0.5 mL) and the reaction was shaken for 2 h. The reaction mixture was purified by reverse-phase chromatography with 0.1% NH4OH in ACN and water as mobile phase to obtain 1-(2-methoxy-4-methylphenyl)-N-(thiazol-2-yl)isoquinoline-6-sulfonamide (28 mg, 51%) as a light yellow solid. 1H NMR (500 MHz, DMSO-d6) δ ppm 12.87 (br. s., 1H) 8.65 (d, J=5.61 Hz, 1H) 8.51 (s, 1H) 8.05 (d, J=5.73 Hz, 1H) 7.85 (dd, J=8.88, 1.66 Hz, 1H) 7.71 (d, J=8.94 Hz, 1H) 7.27 (d, J=4.58 Hz, 1H) 7.20 (d, J=7.56 Hz, 1H) 7.04 (s, 1H) 6.93 (d, J=7.45 Hz, 1H) 6.87 (d, J=4.58 Hz, 1H) 3.63 (s, 3H) 2.43 (s, 3H); m/z (ESI) 416.0 (M+H)+.
Reaction SMILES: Br[C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[CH:5]=[N:4][CH:3]=1.[C:12](=[NH:25])([C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1)[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1.C1C=CC(P(C2C(C3C(P(C4C=CC=CC=4)C4C=CC=CC=4)=CC=C4C=3C=CC=C4)=C3C(C=CC=C3)=CC=2)C2C=CC=CC=2)=CC=1.C(N(CC)CC)C.C([O-])([O-])=O.[Cs+].[Cs+]>C1(C)C=CC=CC=1.CC([O-])=O.CC([O-])=O.[Pd+2].C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.[Fe+2]>[C:19]1([C:12]([C:13]2[CH:14]=[CH:15][CH:16]=[CH:17][CH:18]=2)=[N:25][C:2]2[C:11]3[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=3)[CH:5]=[N:4][CH:3]=2)[CH:20]=[CH:21][CH:22]=[CH:23][CH:24]=1
Reactant: Brc1cncc2ccccc12
Reactant: N=C(c1ccccc1)c1ccccc1
Agent: [Fe+2]
Agent: [Pd+2]
Agent: CC(=O)[O-]
Solvent: Cc1ccccc1
Solvent: CCN(CC)CC
Product: c1ccc(C(=Nc2cncc3ccccc23)c2ccccc2)cc1
Temperature: 110 °C
Yield: 58 %

Procedure:
In a 250 mL round flask 4-bromoisoquinoline (1 g, 4.81 mmol), benzophenone imine (2.41 mL, 14.42 mL), Pd(OAc)2 (33 mg, 0.14 mmol), BINAP (299 mg, 0.05 mmol), DPPF (266 g, 0.05 mmol) and triethylamine (0.17 mL, 1.20 mmol) were concentrated in vacuum for 15 min and then dissolved in 50 mL anhydrous toluene at room temperature for 20 min. Cs2CO3 (2.35 g, 7.21 mmol) was added to the reaction mixture. The reaction mixture was heated at 110° C. for 18 h. The reaction mixture was cooled to room temperature and filtered. The filtrate was concentrated under reduced pressure to afford the crude which was purified by column chromatography to give N-(diphenylmethylene)-isoquinolin-4-amine (853 mg, 58%).
Reaction SMILES: [CH2:1]([O:4][C:5]1[CH:6]=[CH:7][C:8]([N+:13]([O-:15])=[O:14])=[C:9]([CH:12]=1)[CH2:10][OH:11])[CH:2]=[CH2:3].ClC1C=C(C=CC=1)C(OO)=[O:21]>ClCCl>[CH2:1]([O:4][C:5]1[CH:6]=[CH:7][C:8]([N+:13]([O-:15])=[O:14])=[C:9]([CH:12]=1)[CH2:10][OH:11])[CH:2]1[O:21][CH2:3]1
Reactant: C=CCOc1ccc([N+](=O)[O-])c(CO)c1
Reactant: O=C(OO)c1cccc(Cl)c1
Solvent: ClCCl
Product: O=[N+]([O-])c1ccc(OCC2CO2)cc1CO

Procedure:
5-allyloxy-2-nitrobenzyl alcohol (7.3 g, 35 mmol) and m-chloroperoxybenzoic acid (77 wt. %, 9.4 g, 42 mmol) were dissolved in dichloromethane and refluxed until the allyl peaks disappeared from the 1H-NMR spectrum (approximately 48 hours). The reaction was then washed with aqueous sodium carbonate twice, water three times and then dried over sodium sulfate. The solvent was partially removed by rotary evaporation and then poured into hexanes to precipitate the product. The resulting solid was collected by suction filtration and was used in the next step without further purification.
Reaction SMILES: [C:1]([O:5][C@@H:6]([C:12]1[C:13]([CH3:34])=[N:14][C:15]2[N:16]([N:26]=[C:27]([C:29]([O:31]CC)=[O:30])[CH:28]=2)[C:17]=1[C:18]1[CH2:23][CH2:22][C:21]([CH3:25])([CH3:24])[CH2:20][CH:19]=1)[C:7]([O:9][CH2:10][CH3:11])=[O:8])([CH3:4])([CH3:3])[CH3:2].[OH-].[Na+]>CCO>[C:1]([O:5][C@@H:6]([C:12]1[C:13]([CH3:34])=[N:14][C:15]2[N:16]([N:26]=[C:27]([C:29]([OH:31])=[O:30])[CH:28]=2)[C:17]=1[C:18]1[CH2:23][CH2:22][C:21]([CH3:25])([CH3:24])[CH2:20][CH:19]=1)[C:7]([O:9][CH2:10][CH3:11])=[O:8])([CH3:2])([CH3:3])[CH3:4]
Reactant: CCOC(=O)c1cc2nc(C)c([C@H](OC(C)(C)C)C(=O)OCC)c(C3=CCC(C)(C)CC3)n2n1
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: CCOC(=O)[C@@H](OC(C)(C)C)c1c(C)nc2cc(C(=O)O)nn2c1C1=CCC(C)(C)CC1
Temperature: 25 °C
Reaction time: 4 h
Yield: 86.2 %

Procedure:
To a solution of (S)-ethyl 6-(1-(tert-butoxy)-2-ethoxy-2-oxoethyl)-7-(4,4-dimethylcyclohex-1-en-1-yl)-5-methylpyrazolo[1,5-a]pyrimidine-2-carboxylate (185 mg, 0.392 mmol) in EtOH (4 mL) was added 1N NaOH (0.392 mL, 0.392 mmol) and the resulting mixture was stirred at room temp for 4 h. A this point LCMS indicated completion of reaction. Solvents were then removed under reduced pressure and the mixture was diluted with water (3 mL), acidified with 1N HCl, extracted with ethyl acetate (25 mL), washed with brine (10 mL), dried (Na2SO4), filtered and concentrated to afford (S)-6-(1-(tert-butoxy)-2-ethoxy-2-oxoethyl)-7-(4,4-dimethylcyclohex-1-en-1-yl)-5-methylpyrazolo[1,5-a]pyrimidine-2-carboxylic acid (150 mg, 0.338 mmol, 86% yield) as light yellow solid. 1H NMR (500 MHz, CDCl3) δ 7.15 (s, 1H), 6.26 (br. s., 0.6H), 5.93 (br. s., 0.4H), 5.53 (s, 0.6H), 5.46 (s, 0.4H), 4.29-4.19 (m, 2H), 2.79 (s, 1H), 2.72 (s, 2H), 2.19-2.14 (m, 2H), 1.77-1.54 (m, 4H), 1.29-1.16 (m, 18H). LCMS (M+H)=444.4.