Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:10]=[C:11]([CH:16]=[C:17]([O:19][CH3:20])[CH:18]=1)[C:12]([O:14]C)=[O:13])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[OH-].[Na+]>C(O)C.O>[CH2:1]([O:8][C:9]1[CH:10]=[C:11]([CH:16]=[C:17]([O:19][CH3:20])[CH:18]=1)[C:12]([OH:14])=[O:13])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: COC(=O)c1cc(OC)cc(OCc2ccccc2)c1
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CCO
Product: COc1cc(OCc2ccccc2)cc(C(=O)O)c1
Yield: 90 %

Procedure:
4.45 g (0.0174 mmol) of methyl 3-(benzyloxy)-5-methoxybenzoate (161) was suspended in 120 mL of 95% ethanol and 5 mL water. An amount of 2.00 g (0.05 mmol) of sodium hydroxide was added. The mixture was heated at reflux for 1 h. After the mixture was evaporated, the residue was quenched with 150 mL of water. The solution was neutralized with dil aq HCl and then the precipitate was collected and washed with water and acetone to give 162.
Reaction SMILES: [CH3:1][O:2][CH2:3][CH2:4][C:5]1[N:6]([CH2:32][CH2:33][CH3:34])[C:7]2[C:16]3[CH:15]=[CH:14][C:13]([O:17][CH:18]4[CH2:23][CH2:22][N:21]([C:24]([O:26][C:27]([CH3:30])([CH3:29])[CH3:28])=[O:25])[CH2:20][CH2:19]4)=[CH:12][C:11]=3[N:10]=[CH:9][C:8]=2[N:31]=1.C1C=C(Cl)C=C(C(OO)=O)C=1.[OH-].[NH4+:47].C1(C)C=CC(S(Cl)(=O)=O)=CC=1>C(Cl)(Cl)Cl>[NH2:47][C:9]1[C:8]2[N:31]=[C:5]([CH2:4][CH2:3][O:2][CH3:1])[N:6]([CH2:32][CH2:33][CH3:34])[C:7]=2[C:16]2[CH:15]=[CH:14][C:13]([O:17][CH:18]3[CH2:23][CH2:22][N:21]([C:24]([O:26][C:27]([CH3:28])([CH3:29])[CH3:30])=[O:25])[CH2:20][CH2:19]3)=[CH:12][C:11]=2[N:10]=1
Reactant: CCCn1c(CCOC)nc2cnc3cc(OC4CCN(C(=O)OC(C)(C)C)CC4)ccc3c21
Reactant: [NH4+]
Agent: Cc1ccc(S(=O)(=O)Cl)cc1
Agent: O=C(OO)c1cccc(Cl)c1
Agent: [OH-]
Solvent: ClC(Cl)Cl
Product: CCCn1c(CCOC)nc2c(N)nc3cc(OC4CCN(C(=O)OC(C)(C)C)CC4)ccc3c21
Reaction time: 0.75 h

Procedure:
A stirred solution of tert-butyl 4-{[2-(2-methoxyethyl)-1-propyl-1H-imidazo[4,5-c]quinolin-7-yl]oxy}piperidine-1-carboxylate (9.77 g, 20.8 mmol) in chloroform (175 mL) at room temperature was treated with mCPBA (55% pure, 6.54 g, 20.8 mmol). After 45 minutes, concentrated ammonium hydroxide (175 mL) was added, followed by p-toluenesulfonyl chloride (3.97 g, 20.8 mmol). The mixture was stirred for 62 hours, then the layers were separated and the aqueous layer was extracted with chloroform. The combined organic layers were washed with water and saturated aqueous sodium chloride, dried over anhydrous sodium sulfate, filtered and evaporated under reduced pressure. The crude product was purified by flash chromatography (silica gel, gradient elution with 1.5-12.5% CMA in chloroform) followed by recrystallization from acetonitrile to afford 6.3 g of tert-butyl 4-{[4-amino-2-(2-methoxyethyl)-1-propyl-1H-imidazo[4,5-c]quinolin-7-yl]oxy}piperidine-1-carboxylate as tan crystals, mp 173-175° C.
Reaction SMILES: C(OC(=O)[NH:7][C:8]1[S:9][C:10]([C:19]2[O:23][N:22]=[C:21]([CH3:24])[N:20]=2)=[C:11]([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)[N:12]=1)(C)(C)C.C(O)(C(F)(F)F)=O.N>C(O)(=O)C.[Cl-].[Na+].O>[CH3:24][C:21]1[N:20]=[C:19]([C:10]2[S:9][C:8]([NH2:7])=[N:12][C:11]=2[C:13]2[CH:14]=[CH:15][CH:16]=[CH:17][CH:18]=2)[O:23][N:22]=1
Reactant: Cc1noc(-c2sc(NC(=O)OC(C)(C)C)nc2-c2ccccc2)n1
Agent: N
Agent: [Cl-]
Agent: [Na+]
Solvent: O
Solvent: CC(=O)O
Solvent: O=C(O)C(F)(F)F
Product: Cc1noc(-c2sc(N)nc2-c2ccccc2)n1
Temperature: 25 °C
Reaction time: 8 h
Yield: 98 %

Procedure:
[5-(3-Methyl-[1,2,4]oxadiazol-5-yl)-4-phenyl-thiazol-2-yl]-carbamic acid tert-butyl ester was suspended in glacial acetic acid (20 mL). TFA (20 mL) was added. The reaction mixture was stirred at room temperature overnight. The reaction mixture was added to brine (100 mL) and pH was adjusted to pH 10 with ammonia. The mixture was extracted with EtOAc (2×75 mL). The combined organic phases was washed with brine (50 mL), dried with MgSO4 and solvents were removed in vacuo to give a white solid. Yield 98%.
Reaction SMILES: [F:1][C:2]1([F:11])[CH2:7][CH2:6][CH:5]([C:8]([OH:10])=O)[CH2:4][CH2:3]1.O=C1N(P(Cl)(N2CCOC2=O)=O)CCO1.CN(C=O)C.[Cl:32][C:33]1[C:42]2[C:37](=[CH:38][CH:39]=[CH:40][CH:41]=2)[C:36]([N:43]2[CH2:48][CH2:47][NH:46][CH2:45][C@H:44]2[CH3:49])=[N:35][N:34]=1>C(OCC)(=O)C.C(N(CC)CC)C>[Cl:32][C:33]1[C:42]2[C:37](=[CH:38][CH:39]=[CH:40][CH:41]=2)[C:36]([N:43]2[CH2:48][CH2:47][N:46]([C:8]([CH:5]3[CH2:4][CH2:3][C:2]([F:1])([F:11])[CH2:7][CH2:6]3)=[O:10])[CH2:45][C@H:44]2[CH3:49])=[N:35][N:34]=1
Reactant: O=C(O)C1CCC(F)(F)CC1
Reactant: C[C@@H]1CNCCN1c1nnc(Cl)c2ccccc12
Agent: O=C1OCCN1P(=O)(Cl)N1CCOC1=O
Solvent: CCN(CC)CC
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: C[C@@H]1CN(C(=O)C2CCC(F)(F)CC2)CCN1c1nnc(Cl)c2ccccc12
Temperature: 25 °C
Reaction time: 24 h

Procedure:
4,4-difluorocyclohexanecarboxylic acid (386 mg, 2.35 mmol) and bis(2-oxo-3-oxazolidinyl)phosphinic chloride (624 mg, 2.45 mmol), DMF (4 mL), and triethylamine (0.57 mL) were stirred at RT for 2 minutes. (R)-1-chloro-4-(2-methylpiperazin-1-yl)phthalazine (JK-2) (537 mg, 2.04 mmol) was added and the reaction stirred at rt for 24 hours. The reaction was then taken up in ethyl acetate (80 mL), washed with aqueous K2CO3 (10%), water, and then saturated sodium chloride. The organics were dried (MgSO4) and evaporated to give a brown oil. Chromatography over silica gel with a gradient of hexanes/0-70% ethyl acetate gave an off-white solid, JK-27. MS (M+H)+=409.1
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH3:29])[C:5]2[N:10]=[C:9]([C:11]3[N:15]([C:16]4[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=4[Cl:22])[N:14]=[C:13]([C:23]([F:26])([F:25])[F:24])[CH:12]=3)[O:8][C:7](=[O:27])[C:6]=2[CH:28]=1.O.[NH2:31][NH2:32].O1CCCC1>O>[Cl:1][C:2]1[CH:3]=[C:4]([CH3:29])[C:5]([NH:10][C:9]([C:11]2[N:15]([C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=3[Cl:22])[N:14]=[C:13]([C:23]([F:26])([F:24])[F:25])[CH:12]=2)=[O:8])=[C:6]([C:7]([NH:31][NH2:32])=[O:27])[CH:28]=1
Reactant: NN
Reactant: Cc1cc(Cl)cc2c(=O)oc(-c3cc(C(F)(F)F)nn3-c3ccccc3Cl)nc12
Solvent: C1CCOC1
Solvent: O
Product: Cc1cc(Cl)cc(C(=O)NN)c1NC(=O)c1cc(C(F)(F)F)nn1-c1ccccc1Cl
Temperature: 25 °C
Reaction time: 2 h

Procedure:
A mixture of 0.88 g of 6-chloro-2-[1-(2-chlorophenyl)-3-trifluoromethyl-1H-pyrazol-5-yl]-8-methyl-4H-3,1-benzoxazine-4-one, 0.19 ml of hydrazine monohydrate and 3 ml of tetrahydrofuran was stirred at room temperature for 2 hours. Water was poured into the reaction mixture, and the mixture was extracted with ethyl acetate three times. The organic layers were combined, washed with an aqueous saturated sodium chloride solution, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure to obtain 0.94 g of N-[4-chloro-2-(hydrazinocarbonyl)-6-methylphenyl]-1-(2-chlorophenyl)-3-trifluoromethyl-1H-pyrazole-5-carboxamide of the formula:
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([Br:8])=[CH:4][N:3]=1.[NH:9]1[CH2:14][CH2:13][NH:12][CH2:11][CH2:10]1>>[Br:8][C:5]1[CH:6]=[CH:7][C:2]([N:9]2[CH2:14][CH2:13][NH:12][CH2:11][CH2:10]2)=[N:3][CH:4]=1
Reactant: Brc1ccc(Br)nc1
Reactant: C1CNCCN1
Product: Brc1ccc(N2CCNCC2)nc1
Temperature: 25 °C

Procedure:
The 5-bromo-2-(piperazin-1-yl)pyridine was prepared by heating a mixture of 2,5-dibromopyridine (10.0 g, 42.4 mmol) and piperazine (7.98 g, 92.8 mmol) as a melt at 125° for 3 h. On cooling to room temperature the mixture was triturated with methanol-dichloromethane to afford the desired product (7.0 g) as a beige solid. δH (CDCl3) 8.18 (1H, d, J 2.1 Hz), 7.25 (1H, dd, J 9.1, 2.1 Hz), 6.52 (1H, d, J 9.1 Hz), 3.47 (4H, m), 2.97 (4H, m) and 1.75 (1H br s).
Reaction SMILES: Br[C:2]1[C:3]([C:11]2[CH:16]=[CH:15][CH:14]=[C:13]([CH3:17])[N:12]=2)=[N:4][N:5]2[CH:10]=[CH:9][CH:8]=[CH:7][C:6]=12.C([Li])(C)(C)C.B(OC(C)C)(OC(C)C)OC(C)C.FC(F)(F)C([NH:40][C:41]1[N:42]=[C:43]2[CH:48]=[CH:47][C:46](I)=[CH:45][N:44]2[CH:50]=1)=O>C1COCC1.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>[CH3:17][C:13]1[N:12]=[C:11]([C:3]2[C:2]([C:46]3[CH:47]=[CH:48][C:43]4[N:44]([CH:50]=[C:41]([NH2:40])[N:42]=4)[CH:45]=3)=[C:6]3[CH:7]=[CH:8][CH:9]=[CH:10][N:5]3[N:4]=2)[CH:16]=[CH:15][CH:14]=1
Reactant: Cc1cccc(-c2nn3ccccc3c2Br)n1
Reactant: O=C(Nc1cn2cc(I)ccc2n1)C(F)(F)F
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: CC(C)OB(OC(C)C)OC(C)C
Agent: [Li]C(C)(C)C
Solvent: C1CCOC1
Product: Cc1cccc(-c2nn3ccccc3c2-c2ccc3nc(N)cn3c2)n1
Temperature: 90 °C
Reaction time: 1 h

Procedure:
Stir 3-bromo-2-(6-methyl-pyridin-2-yl)-pyrazolo[1,5-a]pyridine (500 mg, 1.74 mmol) in THF (20 ml) at −60° C. and add t-butyl lithium (4 ml, 6.94 mmol, 1.7M in pentane). Stir for 1 hour, then add tri-isopropyl borate (1.2 ml, 5.2 mmol) and warm to 0° C. for 1 hour. Quench with 1M HCl (5 ml). Concentrate in vacuo and redissolve in a 2:1 toluene/methanol mixture (30 ml). Adjust to pH 8 with aqueous 2M Na2CO3. Add 100 mg Pd(PPh3)4 and 2,2,2-trifluoro-N-(6-iodo-imidazo[1,2-a]pyridin-2-yl)-acetamide (200 mg, 563 mmol) and heat to 90° C. for 18 hours. Acidify with 1M HCl and extract with ethyl acetate (3×100 ml). Neutralize aqueous layer with 5N NaOH and extract with ethyl acetate (3×100 ml). Concentrate organic layer in vacuo and purify on Silica gel (eluting with 70/30 Hexane/EtOAc). MS ES+ m/e 341.1 (M+1).
Reaction SMILES: C([O:3][C:4]([C:6]1[C:14]2[CH2:13][CH2:12][N:11]([C:15]3[CH:20]=[CH:19][C:18]([N:21]4[CH:26]=[CH:25][CH:24]=[CH:23][C:22]4=[O:27])=[CH:17][CH:16]=3)[C:10](=[O:28])[C:9]=2[N:8]([C:29]2[CH:34]=[CH:33][C:32]([O:35][CH3:36])=[CH:31][CH:30]=2)[N:7]=1)=O)C.[Li+].[BH4-]>C1COCC1>[OH:3][CH2:4][C:6]1[C:14]2[CH2:13][CH2:12][N:11]([C:15]3[CH:20]=[CH:19][C:18]([N:21]4[CH:26]=[CH:25][CH:24]=[CH:23][C:22]4=[O:27])=[CH:17][CH:16]=3)[C:10](=[O:28])[C:9]=2[N:8]([C:29]2[CH:30]=[CH:31][C:32]([O:35][CH3:36])=[CH:33][CH:34]=2)[N:7]=1
Reactant: CCOC(=O)c1nn(-c2ccc(OC)cc2)c2c1CCN(c1ccc(-n3ccccc3=O)cc1)C2=O
Agent: [BH4-]
Agent: [Li+]
Solvent: C1CCOC1
Product: COc1ccc(-n2nc(CO)c3c2C(=O)N(c2ccc(-n4ccccc4=O)cc2)CC3)cc1

Procedure:
To 1-(4-methoxy-phenyl)-7-oxo-6-[4-(2-oxo-2H-pyridin-1-yl)-phenyl]-4,5,6,7-tetrahydro-1H-pyrazolo[3,4-c]pyridine-3-carboxylic acid ethyl ester (0.2 g, 0.4 mmol) in THF (25 mL) was added 2M LiBH4 in THF (0.31 mL, 0.66 mmol) and the reaction was heated to reflux for 3 h. After extraction into EtOAc and washing with water and brine, the product crystallized out upon standing; High Resolution Mass Spec (M+H)+ for C25H23N4O4 443.1730.
Reaction SMILES: C(=O)([O-])[O-].[K+].[K+].[O:7]1[CH:11]=[CH:10][CH:9]=[C:8]1B(O)O.[CH2:15]([O:19][C:20]1[C:25]([C:26]2[NH:27][C:28](=[O:41])[C:29]3[C:30](=[C:32]([CH2:39][CH3:40])[N:33]([CH2:35][CH2:36][O:37][CH3:38])[N:34]=3)[N:31]=2)=[CH:24][C:23](I)=[CH:22][N:21]=1)[CH2:16][CH2:17][CH3:18]>O1CCOCC1.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>[CH2:15]([O:19][C:20]1[C:25]([C:26]2[NH:27][C:28](=[O:41])[C:29]3[C:30](=[C:32]([CH2:39][CH3:40])[N:33]([CH2:35][CH2:36][O:37][CH3:38])[N:34]=3)[N:31]=2)=[CH:24][C:23]([C:8]2[O:7][CH:11]=[CH:10][CH:9]=2)=[CH:22][N:21]=1)[CH2:16][CH2:17][CH3:18]
Reactant: OB(O)c1ccco1
Reactant: CCCCOc1ncc(I)cc1-c1nc2c(CC)n(CCOC)nc2c(=O)[nH]1
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: [K+]
Solvent: C1COCCO1
Solvent: O
Product: CCCCOc1ncc(-c2ccco2)cc1-c1nc2c(CC)n(CCOC)nc2c(=O)[nH]1
Yield: 69.1 %

Procedure:
Pd(PPh3)4 (46.5 mg, 0.04 mmol) was added to a stirred mixture of potassium carbonate (55 mg, 0.40 mmol), 2-furylboronic acid (54 mg, 0.48 mmol) and the title compound of Example 1 (200 mg, 0.40 mmol) in degassed dioxan/water (10 mL of 4:1 mixture). The mixture was heated at reflux for 2 h and cooled. The solvent was removed in vacuo and the residue triturated with ethyl acetate to give an orange solid. Purification by flash column chromatography (elution with 50:1 dichloromethane/methanol) gave the title compound as a cream solid (121 mg, 58%).
Reaction SMILES: Br[C:2]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[N:4]2[CH2:11][N:12]([CH3:15])[CH2:13][CH2:14][C:3]=12.[Li]C(C)(C)C.[CH:21]([C:23]1[CH:32]=[CH:31][C:26]([C:27]([O:29][CH3:30])=[O:28])=[CH:25][CH:24]=1)=[O:22]>CCOCC>[OH:22][CH:21]([C:2]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[N:4]2[CH2:11][N:12]([CH3:15])[CH2:13][CH2:14][C:3]=12)[C:23]1[CH:24]=[CH:25][C:26]([C:27]([O:29][CH3:30])=[O:28])=[CH:31][CH:32]=1
Reactant: CN1CCc2c(Br)c3ccccc3n2C1
Reactant: COC(=O)c1ccc(C=O)cc1
Agent: [Li]C(C)(C)C
Solvent: CCOCC
Product: COC(=O)c1ccc(C(O)c2c3n(c4ccccc24)CN(C)CC3)cc1
Reaction time: 0.25 h
Yield: 59.6 %

Procedure:
To a solution of 5-bromo-2-methyl-1,2,3,4-tetrahydropyrimido[1,6-a]indole (0.254 g) in 8 mL of ether cooled at −78° C. was added t-BuLi (1.4 mL, 1.7 M in pentane) dropwise. After attiring at −78° C. for 15 min, a solution of methyl 4-formylbenzoate (0.200 g in 2 mL of ether) was added quickly by a syringe. The reaction mixture was wormed to r.t. over 10 min, and quenched with 10 mL of saturated aqueous solution of NH4Cl, and 20 mL of EtOAc was added. The solid was collected by filtration to give 0.2 g of the title compound as a white solid.
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8](=[N:13][O:14][CH3:15])[C:9](OC)=[O:10].OC1C=CC=CC=1/[C:23](=[N:28]/OC)/C(OC)=O.CN.CO>O1CCCC1>[CH3:23][NH:28][C:9](=[O:10])[C:8]([C:3]1[CH:4]=[CH:5][CH:6]=[CH:7][C:2]=1[OH:1])=[N:13][O:14][CH3:15]
Reactant: CO/N=C(\C(=O)OC)c1ccccc1O
Reactant: CON=C(C(=O)OC)c1ccccc1O
Agent: CN
Solvent: CO
Solvent: C1CCOC1
Product: CNC(=O)C(=NOC)c1ccccc1O
Temperature: 10 °C
Reaction time: 0.5 h

Procedure:
0.5 g (0.0013 mol) of methyl 2-(2-hydroxyphenyl)-2-methoxyimino-acetate (in particular Example II-Id from process step 4; HPLC: 54.4% methyl Z-2-(2-hydroxyphenyl)-2-methoxyimino-acetate of log p=2.39 is disolved in 6 ml of tetrahydrofuran and cooled to 10° C. With cooling, methylamine is introduced. After about 30 minutes, 2 ml of methanol are added, the solution is saturated with methylamine and the mixture is allowed to stand at 10° C. overnight. The solvents are distilled off under reduced pressure and the residue is mixed with a mixture of 5 ml of 2 N hydrochloric acid and 5 ml of saturated sodium chloride solution and extracted three times with 10 ml of ethyl acetate each time. The organic phase is dried over sodium sulphate and the solvent is distilled off under reduced pressure, giving 0.6 g of crude product. This crude product is chromatographed with a mixture of 7 parts of n-hexane and 3 parts of acetone on silica gel. This gives 0.4 g of product which, according to HPLC, contains 99.2% N-methyl-Z-2-(2-hydroxyphenyl)-2-methoxyiminoacetamide of log p=1.29.
Reaction SMILES: [N-:1]=[N+:2]=[N-:3].[Na+].Br[CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][OH:13]>CN(C=O)C>[N:1]([CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][OH:13])=[N+:2]=[N-:3]
Reactant: [N-]=[N+]=[N-]
Reactant: OCCCCCCCBr
Agent: [Na+]
Solvent: CN(C)C=O
Product: [N-]=[N+]=NCCCCCCCO
Temperature: 80 °C
Reaction time: 3 h
Yield: 79.2 %

Procedure:
NaN3 (390 mg, 6.0 mmol) was added to a solution of 7-bromoheptanol (880 μL, 5.7 mmol) in DMF (5 mL). The mixture was stirred for 24 at r.t. and additional 3 h at 80° C. to complete the reaction. The mixture was concentrated under reduced pressure, the residue was dissolved in water/Et2O (10/20 mL), the organic layer was separated, dried over Na2SO4 and filtered. Concentration under reduced pressure yielded 7-azidoheptanol (710 mg, 78%) as an colourless oil which was pure enough for further reactions.
Reaction SMILES: [Cl:1][C:2]1[CH:23]=[CH:22][C:5]2[C:6]3[N:21]=[CH:20][N:19]=[CH:18][C:7]=3[CH2:8][N:9]=[C:10]([C:11]3[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=3[Cl:17])[C:4]=2[CH:3]=1.C(O)(=O)C>C(Cl)Cl.[Zn]>[Cl:1][C:2]1[CH:23]=[CH:22][C:5]2[C:6]3[N:21]=[CH:20][N:19]=[CH:18][C:7]=3[CH2:8][NH:9][CH:10]([C:11]3[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=3[Cl:17])[C:4]=2[CH:3]=1
Reactant: Clc1ccc2c(c1)C(c1ccccc1Cl)=NCc1cncnc1-2
Agent: [Zn]
Solvent: ClCCl
Solvent: CC(=O)O
Product: Clc1ccc2c(c1)C(c1ccccc1Cl)NCc1cncnc1-2
Temperature: -30 °C
Reaction time: 2 h

Procedure:
A mixture of 68 g (0.2 mol) of 9-chloro-7-(2-chlorophenyl)-5H-pyrimido[5,4-d][2]benzazepine, 27 g of zinc dust and 250 ml of acetic acid in 600 ml of methylene chloride was stirred at -30° C. for 2 hr. The mixture was filtered over hyflo into a stirred mixture of 600 ml of concentrated ammonium hydroxide and 500 ml of ice. The methylene chloride solution was separated, dried over anhydrous sodium sulfate and concentrated at reduced pressure. The residue crystallized from a mixture of methylene chloride and ether to give the product as a colorless solid. Recrystallization from a mixture of ether and methylene chloride gave the product as colorless needles, mp 169°-170° C.
Reaction SMILES: C([O:3][C:4](=O)[CH2:5][C:6]([CH:9]1[CH2:11][CH2:10]1)([CH3:8])[CH3:7])C.[H-].[H-].[H-].[H-].[Li+].[Al+3]>O1CCCC1>[CH:9]1([C:6]([CH3:8])([CH3:7])[CH2:5][CH2:4][OH:3])[CH2:11][CH2:10]1
Reactant: CCOC(=O)CC(C)(C)C1CC1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: C1CCOC1
Product: CC(C)(CCO)C1CC1
Temperature: 0 °C
Reaction time: 1 h
Yield: 46.5 %

Procedure:
Step C To a solution of 3-cyclopropyl-3-methyl-butyric acid ethyl ester (2 g, 11.75 mmol) in anhydrous tetrahydrofuran (40 mL) at 0° C. was added a tetrhydrofuran solution (1 M) of LiAlH4 (23.5 mL, 23.5 mmol) under nitrogen. The reaction mixture was stirred at 0° C. for 1 h, then poured into a ice-water. The mixture was extracted with ethyl acetate. The organic layer were separated, washed with water, aqueous HCl solution, brine, dried over MgSO4, and concentrated. The residue was purified by chromatography (EtOAc:hexanes=1:10, 1:5) to give 3-cyclopropyl-3-methyl-butan-1-ol as a colorless oil (0.7 g, 46%).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:19]=[CH:20][C:21]=1[N+:22]([O-])=O)[CH:5]=[C:6]1[CH2:11][CH2:10][N:9]([C:12]([O:14][C:15]([CH3:18])([CH3:17])[CH3:16])=[O:13])[CH2:8][CH2:7]1>C(O)C.[Pt](=O)=O>[NH2:22][C:21]1[CH:20]=[CH:19][C:4]([CH2:5][CH:6]2[CH2:7][CH2:8][N:9]([C:12]([O:14][C:15]([CH3:18])([CH3:16])[CH3:17])=[O:13])[CH2:10][CH2:11]2)=[CH:3][C:2]=1[Cl:1]
Reactant: CC(C)(C)OC(=O)N1CCC(=Cc2ccc([N+](=O)[O-])c(Cl)c2)CC1
Agent: O=[Pt]=O
Solvent: CCO
Product: CC(C)(C)OC(=O)N1CCC(Cc2ccc(N)c(Cl)c2)CC1
Reaction time: 0.75 h
Yield: 83.5 %

Procedure:
A slurry of platinum (IV) oxide (0.037 mmol, 8.37 mg) in ethanol was added to a solution of tert-butyl 4-(3-chloro-4-nitrobenzylidene)piperidine-1-carboxylate (0.737 mmol, 260 mg) in ethanol and the resulting suspension was hydrogenated at 3 bar for 45 minutes. The reaction mixture was filtered through celite, washing with ethanol. The filtrate was concentrated under vacuum to afford the intermediate tert-butyl 4-(4-amino-3-chlorobenzyl)piperidine-1-carboxylate (200 mg).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[NH:13][C:12](=O)[CH:11]=[CH:10][C:9]=2[C:15]2[CH:20]=[CH:19][C:18]([S:21]([CH3:24])(=[O:23])=[O:22])=[CH:17][CH:16]=2)=[CH:4][CH:3]=1.P(Cl)(Cl)([Cl:27])=O>>[Cl:27][C:12]1[CH:11]=[CH:10][C:9]([C:15]2[CH:20]=[CH:19][C:18]([S:21]([CH3:24])(=[O:23])=[O:22])=[CH:17][CH:16]=2)=[C:8]([C:5]2[CH:6]=[CH:7][C:2]([F:1])=[CH:3][CH:4]=2)[N:13]=1
Reactant: O=P(Cl)(Cl)Cl
Reactant: CS(=O)(=O)c1ccc(-c2ccc(=O)[nH]c2-c2ccc(F)cc2)cc1
Product: CS(=O)(=O)c1ccc(-c2ccc(Cl)nc2-c2ccc(F)cc2)cc1
Temperature: 200 °C

Procedure:
A mixture of 1.00 g (2.92 mMol) of 6-(4-fluorophenyl)-1,2-dihydro-5-[4-(methylsulfonyl)phenyl]-2-oxopyridine from Step 8 and 25 ml of phosphorous oxychloride was heated in a bomb to 200° C. and maintained for 3 hours. After cooling, the mixture was evaporated to dryness. Chromatography of the residue over silica gel using 50% ethyl acetate/hexane as eluent gave 2-chloro-6-(4-fluorophenyl)-5-[4-(methylsulfonyl)phenyl]pyridine (211 mg) as a pure white crystalline solid: m.p. 192° C. (DSC). Anal. Calc'd for C18H13ClFNO2S·1/4 H2O (MW 366.33): C, 59.02; H, 3.58; N, 3.82. Found: C, 58.68; H, 3.65; N, 3.86.
Reaction SMILES: C([NH:5][S:6]([C:9]1[CH:14]=[CH:13][CH:12]=[C:11]([C:15]2[CH:20]=[C:19]([C:21]3[N:26]=[C:25]([C:27]4[CH:32]=[CH:31][C:30]([F:33])=[C:29]([F:34])[CH:28]=4)[CH:24]=[C:23]([C:35]([F:38])([F:37])[F:36])[N:22]=3)[CH:18]=[CH:17][N:16]=2)[CH:10]=1)(=[O:8])=[O:7])(C)(C)C.C(O)(C(F)(F)F)=O>ClCCl>[F:34][C:29]1[CH:28]=[C:27]([C:25]2[CH:24]=[C:23]([C:35]([F:36])([F:38])[F:37])[N:22]=[C:21]([C:19]3[CH:18]=[CH:17][N:16]=[C:15]([C:11]4[CH:10]=[C:9]([S:6]([NH2:5])(=[O:7])=[O:8])[CH:14]=[CH:13][CH:12]=4)[CH:20]=3)[N:26]=2)[CH:32]=[CH:31][C:30]=1[F:33]
Reactant: CC(C)(C)NS(=O)(=O)c1cccc(-c2cc(-c3nc(-c4ccc(F)c(F)c4)cc(C(F)(F)F)n3)ccn2)c1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: NS(=O)(=O)c1cccc(-c2cc(-c3nc(-c4ccc(F)c(F)c4)cc(C(F)(F)F)n3)ccn2)c1
Temperature: 25 °C
Reaction time: 15 h
Yield: 71.3 %

Procedure:
To a cooled and stirred solution of 3-{4-[4-(3,4-difluoro-phenyl)-6-trifluoromethyl-pyrimidin-2-yl]-pyridin-2-yl}-benzenesulfonic acid tert-butylamide (0.25 g) in dichloromethane (4 ml) was added TFA (4 ml) and the reaction mixture was allowed to stir at room temperature for 15 h. The mixture was evaporated to dryness, poured into 2N NaHCO3 solution (20 ml) and extracted with ethyl acetate (3×50 ml). The combined organic layers were washed with brine (50 ml), dried (MgSO4) and evaporated. Further purification by crystallization (ethyl acetate/heptane) yielded the title compound as a white solid (0.16 g, 48%). MS (ISP) 492.9 [(M+H)+]; mp 233.5° C.
Reaction SMILES: Cl[C:2]1[N:7]=[CH:6][N:5]=[C:4]([C:8]2[CH:17]=[CH:16][CH:15]=[CH:14][C:9]=2[C:10]([O:12][CH3:13])=[O:11])[CH:3]=1.C(N(CC)CC)C>CO.[C].[Pd]>[N:7]1[CH:2]=[CH:3][C:4]([C:8]2[CH:17]=[CH:16][CH:15]=[CH:14][C:9]=2[C:10]([O:12][CH3:13])=[O:11])=[N:5][CH:6]=1
Reactant: COC(=O)c1ccccc1-c1cc(Cl)ncn1
Agent: [Pd]
Solvent: CCN(CC)CC
Solvent: CO
Product: COC(=O)c1ccccc1-c1ccncn1
Temperature: 25 °C
Reaction time: 1 h
Yield: 94.8 %

Procedure:
A suspension of methyl 2-(6-chloropyrimidin-4-yl)benzoate (0.60 g), triethylamine (1.7 mL) and 10% palladium carbon (containing water (50%), 0.26 g) in methanol (20 mL) was stirred at room temperature for 1 hr under a hydrogen atmosphere. The reaction mixture was filtered, and the filtrate was concentrated under reduced pressure. To the residue was added ethyl acetate, and the mixture was washed with saturated brine. The extract was dried over anhydrous sodium sulfate, and the solvent was evaporated under reduced pressure to give the title compound (0.49 g).