Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([O:5][CH2:6][CH3:7])(=[O:4])[CH:2]=O.[F:8][C:9]1[CH:15]=[CH:14][C:12]([NH2:13])=[CH:11][CH:10]=1.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].C(O)(=O)C>ClCCCl>[CH2:6]([O:5][C:1](=[O:4])[CH2:2][NH:13][C:12]1[CH:14]=[CH:15][C:9]([F:8])=[CH:10][CH:11]=1)[CH3:7]
Reactant: CCOC(=O)C=O
Reactant: Nc1ccc(F)cc1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: ClCCCl
Solvent: CC(=O)O
Product: CCOC(=O)CNc1ccc(F)cc1
Reaction time: 2 h
Yield: 65.6 %

Procedure:
A solution of ethyl glyoxylate (2.47 g, 0.024 mol) in 1,2-dichloroethane (30 mL) under argon at room temperature was treated succesively with 4-fluoroaniline (1.80 g, 0.016 mol), sodium triacetoxyborohydride (5.12 g, 0.024 mol) and acetic acid (1 mL). After stirring for two hours, the mixture was concentrated, dissolved in ethyl acetate and washed 5% sodium bicarbonate, water and brine. The dried (anhydrous magnesium sulfate) organic solution was concentrated and crystallized from ether/hexanes to give the title product (2.07 g, 65%) as a colorless solid, mp 72°-73° C. Analysis calculated for C10H12 FNO2 ·0.07 H2O: C, 60.54; H, 6.16; N, 7.06; F, 9.58. Found: C, 60.75; H, 6.15; N, 6.96; F, 9.13.
Reaction SMILES: [CH:1]1[C:13]2[CH2:12][C:11]3[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=3)[C:5]=2[CH:4]=[CH:3][CH:2]=1.C([Li])CCC.Cl[Si:20]([CH3:23])([CH3:22])[CH3:21].[NH4+].[Cl-]>O1CCCC1.O>[CH3:21][Si:20]([CH3:23])([CH3:22])[CH:12]1[C:11]2[CH:10]=[CH:9][CH:8]=[CH:7][C:6]=2[C:5]2[C:13]1=[CH:1][CH:2]=[CH:3][CH:4]=2
Reactant: c1ccc2c(c1)Cc1ccccc1-2
Reactant: C[Si](C)(C)Cl
Agent: [Cl-]
Agent: [Li]CCCC
Agent: [NH4+]
Solvent: O
Solvent: C1CCOC1
Product: C[Si](C)(C)C1c2ccccc2-c2ccccc21
Reaction time: 1 h

Procedure:
First, 8.3 g (0.05 m) of fluorene was dissolved in 150 ml of tetrahydrofuran. Then 31.8 ml (0.05 m) of butyl lithium (1.6 molar in hexane) was added dropwise to this solution. After a stirring period of one hour, 6.3 ml (0.05 mol) of chlorotrimethylsilane, dissolved in 25 ml of tetrahydrofuran was added to this solution over 3 hours. The reaction mixture was stirred for an additional 3 hours. Then, 50 ml of an aqueous NH4Cl solution was added to the dark yellow solution. The solution was treated with 50 ml of water. The organic phase was dried over Na2SO4. Then the solvent was removed in vacuo. The yellow residue was dissolved in pentane. The product 9-(trimethylsilyl)fluorene was crystallized at 4° C. A yield of 8.33 g was obtained.
Reaction SMILES: [CH3:1][C:2]([O:41][CH2:42][C@H:43]1[CH2:45][O:44]1)([CH3:40])[CH2:3][N:4]1[CH:8]=[CH:7][C:6]([NH:9][C:10]([CH:12]2[CH:16]([C:17]3[CH:22]=[CH:21][CH:20]=[C:19]([Cl:23])[C:18]=3[F:24])[C:15]([C:27]3[CH:32]=[CH:31][C:30]([Cl:33])=[CH:29][C:28]=3[F:34])([C:25]#[N:26])[CH:14]([CH2:35][C:36]([CH3:39])([CH3:38])[CH3:37])[NH:13]2)=[O:11])=[N:5]1.C(O)(C)C.[OH-].[NH4+:51]>C(Cl)Cl>[NH2:51][CH2:45][C@@H:43]([OH:44])[CH2:42][O:41][C:2]([CH3:1])([CH3:40])[CH2:3][N:4]1[CH:8]=[CH:7][C:6]([NH:9][C:10]([CH:12]2[CH:16]([C:17]3[CH:22]=[CH:21][CH:20]=[C:19]([Cl:23])[C:18]=3[F:24])[C:15]([C:27]3[CH:32]=[CH:31][C:30]([Cl:33])=[CH:29][C:28]=3[F:34])([C:25]#[N:26])[CH:14]([CH2:35][C:36]([CH3:38])([CH3:39])[CH3:37])[NH:13]2)=[O:11])=[N:5]1
Reactant: [NH4+]
Reactant: CC(C)(C)CC1NC(C(=O)Nc2ccn(CC(C)(C)OC[C@H]3CO3)n2)C(c2cccc(Cl)c2F)C1(C#N)c1ccc(Cl)cc1F
Agent: [OH-]
Solvent: CC(C)O
Solvent: ClCCl
Product: CC(C)(C)CC1NC(C(=O)Nc2ccn(CC(C)(C)OC[C@H](O)CN)n2)C(c2cccc(Cl)c2F)C1(C#N)c1ccc(Cl)cc1F
Yield: 26 %

Procedure:
A mixture of rac-(2R,3S,4R,5S)-3-(3-chloro-2-fluoro-phenyl)-4-(4-chloro-2-fluoro-phenyl)-4-cyano-5-(2,2-dimethylpropyl)-pyrrolidine-2-carboxylic acid {1-[2-methyl-2-((R)-1-oxiranylmethoxy)-propyl]-1H-pyrazol-3-yl}-amide (43.6 mg, 0.066 mmol), isopropyl alcohol (2 mL), and ammonium hydroxide (1 mL) was microwaved at 130° C. for 15 min. The mixture was then diluted with CH2Cl2 and washed with water, brine. The organic phase was separated, filtered and dried over Na2SO4. The mixture was then concentrated and purified by reverse phase chromatography (20-95% of ACN/water) to give rac-(2R,3S,4R,5S)-3-(3-chloro-2-fluoro-phenyl)-4-(4-chloro-2-fluoro-phenyl)-4-cyano-5-(2,2-dimethyl-propyl)-pyrrolidine-2-carboxylic acid {1-[2-((R)-3-amino-2-hydroxy-propoxy)-2-methyl-propyl]-1H-pyrazol-3-yl}-amide (11.4 mg, 26%) as an off-white solid. HRMS (ES+) m/z Calcd for C33H40Cl2F2N6O3+H [(M+H)+]: 677.2580. found: 677.2576.
Reaction SMILES: CC(OC([N:8]1[CH2:13][CH2:12][CH:11]([CH2:14][C:15]2[CH:16]=[C:17]([C:21]([NH:23][CH2:24][C:25]3[CH:26]=[CH:27][C:28]([F:52])=[C:29]([C:31]4[CH:36]=[CH:35][CH:34]=[C:33]([CH2:37][N:38]5[CH2:43][CH2:42][N:41](C(OC(C)(C)C)=O)[C@@H:40]([CH3:51])[CH2:39]5)[CH:32]=4)[CH:30]=3)=[O:22])[CH:18]=[CH:19][CH:20]=2)[CH2:10][CH2:9]1)=O)(C)C.[H-].[Na+].[C:55]1([O:61][CH2:62][CH2:63][CH2:64]Br)[CH:60]=[CH:59][CH:58]=[CH:57][CH:56]=1>CN(C=O)C>[F:52][C:28]1[C:29]([C:31]2[CH:36]=[CH:35][CH:34]=[C:33]([CH2:37][N:38]3[CH2:43][CH2:42][NH:41][C@@H:40]([CH3:51])[CH2:39]3)[CH:32]=2)=[CH:30][C:25]([CH2:24][N:23]([CH2:64][CH2:63][CH2:62][O:61][C:55]2[CH:60]=[CH:59][CH:58]=[CH:57][CH:56]=2)[C:21](=[O:22])[C:17]2[CH:18]=[CH:19][CH:20]=[C:15]([CH2:14][CH:11]3[CH2:10][CH2:9][NH:8][CH2:13][CH2:12]3)[CH:16]=2)=[CH:26][CH:27]=1
Reactant: C[C@H]1CN(Cc2cccc(-c3cc(CNC(=O)c4cccc(CC5CCN(C(=O)OC(C)(C)C)CC5)c4)ccc3F)c2)CCN1C(=O)OC(C)(C)C
Reactant: BrCCCOc1ccccc1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: C[C@H]1CN(Cc2cccc(-c3cc(CN(CCCOc4ccccc4)C(=O)c4cccc(CC5CCNCC5)c4)ccc3F)c2)CCN1
Yield: 24.1 %

Procedure:
Following the general procedure outlined in Example 66, 1,1-dimethylethyl (2S)-4-[(5′-{[({3-[(1-{[(1,1-dimethylethyl)oxy]carbonyl}-4-piperidinyl)methyl]phenyl}carbonyl)amino]methyl)-2′-fluoro-3-biphenylyl)methyl]-2-methyl-1-piperazinecarboxylate (75.4 mg, 0.105 mmol), NaH (5.37 mg, 0.243 mmol) and 3-bromopropyl phenyl ether (0.020 mL, 0.127 mmol) in DMF (0.5 mL) were reacted to give the desired product (16.4 mg, 24.0%). EI-MS m/z 649(M−H)+.
Reaction SMILES: [C:1]([N:4]1[C:12]2[C:7](=[CH:8][CH:9]=[C:10]([C:13]([F:16])([F:15])[F:14])[CH:11]=2)[CH2:6][C:5]1=[O:17])(=[O:3])[CH3:2].[C:18](O)(=[O:25])[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1>>[C:1]([N:4]1[C:12]2[C:7](=[CH:8][CH:9]=[C:10]([C:13]([F:15])([F:14])[F:16])[CH:11]=2)[C:6](=[C:18]([OH:25])[C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)[C:5]1=[O:17])(=[O:3])[CH3:2]
Reactant: O=C(O)c1ccccc1
Reactant: CC(=O)N1C(=O)Cc2ccc(C(F)(F)F)cc21
Product: CC(=O)N1C(=O)C(=C(O)c2ccccc2)c2ccc(C(F)(F)F)cc21

Procedure:
Prepared from 1-acetyl-6-trifluoromethyl-2-indolinone and benzoic acid
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[C@@:9]([OH:40])([CH2:32][Si](OC(C)C)(C)C)[C@H:10]([N:12]1[C:16](=[O:17])[N:15]([C:18]2[CH:23]=[CH:22][C:21]([O:24][CH2:25][C:26]([F:31])([F:30])[CH:27]([F:29])[F:28])=[CH:20][CH:19]=2)[CH:14]=[N:13]1)[CH3:11].C(=O)([O-])[OH:42].[Na+]>CO.O1CCCC1.OO>[F:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[C@@:9]([OH:40])([CH2:32][OH:42])[C@H:10]([N:12]1[C:16](=[O:17])[N:15]([C:18]2[CH:23]=[CH:22][C:21]([O:24][CH2:25][C:26]([F:31])([F:30])[CH:27]([F:29])[F:28])=[CH:20][CH:19]=2)[CH:14]=[N:13]1)[CH3:11]
Reactant: CC(C)O[Si](C)(C)C[C@](O)(c1ccc(F)cc1F)[C@@H](C)n1ncn(-c2ccc(OCC(F)(F)C(F)F)cc2)c1=O
Reactant: O=C([O-])O
Agent: OO
Agent: [Na+]
Solvent: CO
Solvent: C1CCOC1
Product: C[C@@H](n1ncn(-c2ccc(OCC(F)(F)C(F)F)cc2)c1=O)[C@](O)(CO)c1ccc(F)cc1F
Yield: 90.5 %

Procedure:
2-[(1R,2S)-2-(2,4-Difluorophenyl)-2-hydroxy-3-(isopropoxydimethylsilyl)-1-methylpropyl]-4-[4-(2,2,3,3-tetrafluoropropoxy)phenyl]-3(2H,4H)-1,2,4-triazolone (11 g) was dissolved in a mixture of methanol and tetrahydrofuran (1:1, 90 ml), to which 19.2 ml of 30% aqueous hydrogen peroxide and 1.57 g of sodium hydrogencarbonate were added. Then, the mixture was heated at 70° to 80° C. for 90 minutes. The reaction solution was cooled and extracted with a mixture of 500 ml of ethyl acetate and 100 ml of diisopropyl ether. The extract was washed with 100 ml of water, an aqueous solution of Na2S2O3 (50 ml×2) and 50 ml of an aqueous solution of sodium chloride successively, and dried over magnesium sulfate. After the solvent was distilled off under reduced pressure, the residue was recrystallized from 50 ml of diisopropyl ether to give 8.27 g of 2-[(1R,2S)-2-(2,4-difluorophenyl)-2,3-dihydroxy-1-methylpropyl]-4-[4-(2,2,3,3-tetrafluoropropoxy)phenyl]-3(2H,4H)-1,2,4-triazolone as colorless prisms. The mother liquor of recrystallization was submitted to silica gel chromatography (silica gel: 40 g, eluent; hexane:ethyl acetate=1:1). The resultant was recrystallized from diisopropyl ether to give 0.33 g of the above compound (total yield: 93.7%).
Reaction SMILES: Cl.[NH2:2][CH:3]([C:5]1[N:6]=[C:7]2[S:22][CH:21]=[C:20]([CH3:23])[N:8]2[C:9](=[O:19])[C:10]=1[C:11]1[CH:16]=[C:15]([F:17])[CH:14]=[C:13]([F:18])[CH:12]=1)[CH3:4].[F:24][C:25]1[N:33]=[C:32]2[C:28]([NH:29][CH:30]=[N:31]2)=[C:27](Cl)[N:26]=1.C(N(CC)C(C)C)(C)C>C(O)(C)C>[F:18][C:13]1[CH:12]=[C:11]([C:10]2[C:9](=[O:19])[N:8]3[C:20]([CH3:23])=[CH:21][S:22][C:7]3=[N:6][C:5]=2[CH:3]([NH:2][C:27]2[N:26]=[C:25]([F:24])[N:33]=[C:32]3[C:28]=2[N:29]=[CH:30][NH:31]3)[CH3:4])[CH:16]=[C:15]([F:17])[CH:14]=1
Reactant: Cc1csc2nc(C(C)N)c(-c3cc(F)cc(F)c3)c(=O)n12
Reactant: Fc1nc(Cl)c2[nH]cnc2n1
Agent: Cl
Solvent: CC(C)O
Solvent: CCN(C(C)C)C(C)C
Product: Cc1csc2nc(C(C)Nc3nc(F)nc4[nH]cnc34)c(-c3cc(F)cc(F)c3)c(=O)n12
Temperature: 100 °C

Procedure:
A mixture of 7-(1-aminoethyl)-6-(3,5-difluorophenyl)-3-methyl-5H-[1,3]thiazolo[3,2-a]pyrimidin-5-one hydrochloride (0.030 g, 0.084 mmol), 2-fluoro-6-chloropurine (0.015 g, 0.084 mmol), and N,N-diisopropylethylamine (0.044 mL, 0.25 mmol) in isopropyl alcohol (0.2 mL) was heated at 100° C. for three days, in a sealed tube. The resultant mixture was purified on RP-HPLC (XBridge C18 Column, eluting with a gradient of acetonitrile/water containing 0.15% NH4OH) to give the desired product. LCMS calculated for C20H15F3N7OS (M+H)+: m/z=458.1. Found: 458.0.
Reaction SMILES: [C:1]([O:4][C:5]1[CH:10]=[CH:9][C:8]([CH:11]2[C:16](=[O:17])[N:15]([CH2:18][C:19](O)=[O:20])[C:14]3[CH:22]=[CH:23][CH:24]=[CH:25][C:13]=3[S:12]2)=[CH:7][CH:6]=1)(=[O:3])[CH3:2].C([N:28](CC)CC)C.O.N>C(Cl)Cl.C(OC(Cl)=O)C(C)C>[C:1]([O:4][C:5]1[CH:10]=[CH:9][C:8]([CH:11]2[C:16](=[O:17])[N:15]([CH2:18][C:19]([NH2:28])=[O:20])[C:14]3[CH:22]=[CH:23][CH:24]=[CH:25][C:13]=3[S:12]2)=[CH:7][CH:6]=1)(=[O:3])[CH3:2]
Reactant: CC(=O)Oc1ccc(C2Sc3ccccc3N(CC(=O)O)C2=O)cc1
Reactant: CCN(CC)CC
Agent: CC(C)COC(=O)Cl
Agent: N
Solvent: ClCCl
Solvent: O
Product: CC(=O)Oc1ccc(C2Sc3ccccc3N(CC(N)=O)C2=O)cc1
Reaction time: 0.17 h
Yield: 76 %

Procedure:
To a stirred solution of [2-(4-acetoxyphenyl)-3,4-dihydro-3-oxo-2H-1,4-benzothiazin-4-yl]acetic acid (compound No. 26, 4.6 g) and triethylamine (1.8 ml) in CH2Cl2 (45 ml), isobutylchloroformate (1.7 ml) is added dropwise at -12° C. After the addition, the reaction mixture is stirred for 10 minutes at the same temperature. Conc. ammonia water (7.2 ml) is added to the mixture. The mixture is stirred for 30 minutes at room temperature, and washed with saturated sodium hydrogen carbonate solution and N HCl. The organic layer is dried over anhydrous sodium sulfate and concentrated in vacuo to give 3.5 g (76%) of the titled compound.
Reaction SMILES: [F:1][C:2]1[CH:16]=[CH:15][C:5]([O:6][C:7]2[CH:14]=[CH:13][C:10]([CH:11]=[O:12])=[CH:9][CH:8]=2)=[CH:4][CH:3]=1.[BH4-].[Na+]>CO>[F:1][C:2]1[CH:16]=[CH:15][C:5]([O:6][C:7]2[CH:14]=[CH:13][C:10]([CH2:11][OH:12])=[CH:9][CH:8]=2)=[CH:4][CH:3]=1
Reactant: O=Cc1ccc(Oc2ccc(F)cc2)cc1
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Product: OCc1ccc(Oc2ccc(F)cc2)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 65.9 %

Procedure:
To a solution of 4-(4-fluorophenoxyl)benzaldehyde (10 g, 46.3 mmol) in methanol (50 mL) was added NaBH4 (1.750 g, 46.3 mmol) portionwise, after addition the mixture was stirred at room temperature overnight. After removing the solvent, the residue was diluted with DCM (50 mL), the suspension was filtered though a pad of Celite, the filtrate was concentrated to afford the title compound (7 g, 30.5 mmol, 65.9% yield) as a gray solid. LCMS: rt=1.49 min, [M+H+]=219
Reaction SMILES: [CH3:1][C:2]1[C:11]([N+:12]([O-:14])=[O:13])=[CH:10][C:9]([CH3:15])=[C:8]2[C:3]=1[C:4](=O)[CH2:5][CH:6]=[N:7]2.P(Br)(Br)([Br:19])=O.N1C=CC=CC=1>C1(C)C=CC=CC=1>[Br:19][C:4]1[C:3]2[C:8](=[C:9]([CH3:15])[CH:10]=[C:11]([N+:12]([O-:14])=[O:13])[C:2]=2[CH3:1])[N:7]=[CH:6][CH:5]=1
Reactant: Cc1cc([N+](=O)[O-])c(C)c2c1N=CCC2=O
Reactant: O=P(Br)(Br)Br
Solvent: c1ccncc1
Solvent: Cc1ccccc1
Product: Cc1cc([N+](=O)[O-])c(C)c2c(Br)ccnc12
Temperature: 90 °C

Procedure:
A mixture of 5,8-dimethyl-6-nitro-4-quinolone (7.12 g, 32.7 mmol), phosphorus oxybromide (7.47 g, 26.12 mmol), pyridine (5.3 mL), and toluene (90 mL) is heated at 90° C. for 6 hours. The mixture is filtered hot, and the solid is washed with water and methylene chloride. The filtrate is extracted with methylene chloride (3×100 mL), and the combined organic layers are dried (sodium sulfate) and evaporated to afford 4-bromo-5,8-dimethyl-6-nitroquinoline.
Reaction SMILES: [C:1]([C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1)(=O)[CH3:2].[NH2:10][NH2:11]>C(O)C>[C:1](=[N:10][NH2:11])([C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1)[CH3:2]
Reactant: CC(=O)c1ccccc1
Reactant: NN
Solvent: CCO
Product: CC(=NN)c1ccccc1
Reaction time: 2 h
Yield: 68.8 %

Procedure:
acetophenone (2.0 g, 16 mmol) is diluted in 16 ml of absolute ethanol and then hydrazine (2.3 ml, 48 mmol) is added. The mixture is heated to reflux temperature. After 2 h, the solvent is evaporated and the residue is taken up in ether (150 ml). The medium is washed with water (100 ml). After drying over Na2SO4, the ether is evaporated off. A pale yellow oil (1.5 g, 11 mmol, 69%) is obtained.
Reaction SMILES: O.O.[C:3]([O:7][C:8]([NH:10][C@H:11]([C:19]([OH:21])=O)[CH2:12][CH:13]1[CH2:18][CH2:17][CH2:16][CH2:15][CH2:14]1)=[O:9])([CH3:6])([CH3:5])[CH3:4].[NH2:22][CH2:23][CH2:24][N:25]1[CH2:30][CH2:29][CH2:28][CH2:27][CH2:26]1.O.ON1C2C=CC=CC=2N=N1.C1(N=C=NC2CCCCC2)CCCCC1>O1CCCC1>[N:25]1([CH2:24][CH2:23][NH:22][C:19](=[O:21])[C@H:11]([CH2:12][CH:13]2[CH2:14][CH2:15][CH2:16][CH2:17][CH2:18]2)[NH:10][C:8]([O:7][C:3]([CH3:4])([CH3:5])[CH3:6])=[O:9])[CH2:30][CH2:29][CH2:28][CH2:27][CH2:26]1
Reactant: NCCN1CCCCC1
Reactant: CC(C)(C)OC(=O)N[C@@H](CC1CCCCC1)C(=O)O
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: On1nnc2ccccc21
Solvent: C1CCOC1
Solvent: O
Product: CC(C)(C)OC(=O)N[C@@H](CC1CCCCC1)C(=O)NCCN1CCCCC1
Yield: 96.5 %

Procedure:
To a solution of 200.5 mg of N-t-butoxycarbonyl-β-cyclohexyl-L-alanine dihydrate (0.652 mmol) in tetrahydrofuran (1.5 mL), 101.7 mg of 1-(aminoethyl)piperidine (0.793 mmol), 89.7 mg of 1-hydroxybenzotriazole hydrate (0.664 mmol), and 146.1 mg of N,N′-dicyclohexylcarbodiimide (0.708 mmol) were added with stirring under ice cooling. The reaction mixture was stirred for 1 hour under ice cooling and for 1 hour at room temperature, and then concentrated under reduced pressure. Ethyl acetate (1 mL) was added to the residue. Insoluble materials were removed by filtration, and then the filtrate was concentrated under reduced pressure. The residue (438 mg) was purified by column chromatography on alumina (alumina 2 g, chloroform), whereby 267 mg of the crude product was obtained. The crude product was purified by silica gel column chromatography [silica gel 10 g, about 15% ammonia/methanol-chloroform (1:100)], whereby 240.0 mg of N-t-butoxycarbonyl-β-cyclohexyl-L-alanine 2-(1-piperidinyl)ethyl amide was obtained as a colorless oil (yield 96%)
Reaction SMILES: [Br:1][C:2]1[N:10]=[CH:9][CH:8]=[CH:7][C:3]=1[C:4]([OH:6])=[O:5].CO.N(C(OCC)=O)=N[C:15](OCC)=O.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>CCOCC>[Br:1][C:2]1[N:10]=[CH:9][CH:8]=[CH:7][C:3]=1[C:4]([O:6][CH3:15])=[O:5]
Reactant: O=C(O)c1cccnc1Br
Reactant: CCOC(=O)N=NC(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CO
Solvent: CCOCC
Product: COC(=O)c1cccnc1Br
Reaction time: 2 h
Yield: 111 %

Procedure:
2-Bromonicotinic acid (7.33 g, 36 mmol) was suspended in dry Et2O (40 mL), and MeOH (2.3 mL) and diethyl azodicarboxylate (5.8 mL, 37 mmol) were added. Triphenylphosphine (9.61 g in 40 mL Et2O, 37 mmol) was added dropwise over 2.5 hours. After stirring an additional two hours, the reaction was filtered and evaporated. The resulting clear liquid was chromatographed on silica gel (10-40% EtOAc/hexanes) to yield a clear oil (8.63 g, 100%). 1H NMR (CDCl13): δ8.49 (dd, 1H, J=4.8, J′=2.2), 8.09 (dd, 1H, J=7.7, J′=1.8), 7.36 (m, 1H), 3.97 (s, 3H).
Reaction SMILES: FC(F)(F)C([NH:5][C:6]1[CH:11]=[CH:10][C:9]([CH2:12][CH:13]2[CH2:18][CH2:17][N:16]([S:19]([N:22]3[CH2:27][CH2:26][CH2:25][CH2:24][CH2:23]3)(=[O:21])=[O:20])[CH2:15][CH2:14]2)=[CH:8][CH:7]=1)=O.[OH-].[Li+]>CO.O>[N:22]1([S:19]([N:16]2[CH2:15][CH2:14][CH:13]([CH2:12][C:9]3[CH:10]=[CH:11][C:6]([NH2:5])=[CH:7][CH:8]=3)[CH2:18][CH2:17]2)(=[O:21])=[O:20])[CH2:23][CH2:24][CH2:25][CH2:26][CH2:27]1
Reactant: O=C(Nc1ccc(CC2CCN(S(=O)(=O)N3CCCCC3)CC2)cc1)C(F)(F)F
Agent: [Li+]
Agent: [OH-]
Solvent: CO
Solvent: O
Product: Nc1ccc(CC2CCN(S(=O)(=O)N3CCCCC3)CC2)cc1
Temperature: 60 °C
Yield: 80.1 %

Procedure:
A mixture of 2,2,2-trifluoro-N-[4-(1-piperidinesulfonylpiperidin-4-ylmethyl)-phenyl]acetamide (0.48 g, 1.11 mmol) and lithium hydroxide (0.23 g, 5.54 mmol) in methanol (10 mL) and water (1 mL) was heated at 60° C. for about 2 hours. The reaction mixture was concentrated in vacuo, diluted with water, and extracted with dichloromethane. The organic extracts were washed with water and brine, and dried (Na2SO4). The residue was crystallized from ethyl acetate/hexanes, to give 4-(1-piperidinesulfonylpiperidin-4-ylmethyl)-phenylamine (0.30 g) as a white solid, m.p. 144-145° C.; Analysis for C17H27N3O2S: Calc.: C, 60.50; H, 8.06; N, 12.45; Found: C, 60.76; H, 8.07; N, 12.56.
Reaction SMILES: C1C(=O)N([Br:8])C(=O)C1.[CH3:9][N:10]1[C:16]2[CH:17]=[CH:18][CH:19]=[CH:20][C:15]=2[C:14](=[O:21])[CH2:13][C:12]2[CH:22]=[CH:23][CH:24]=[CH:25][C:11]1=2>CN(C)C=O>[Br:8][C:19]1[CH:18]=[CH:17][C:16]2[N:10]([CH3:9])[C:11]3[CH:25]=[CH:24][CH:23]=[CH:22][C:12]=3[CH2:13][C:14](=[O:21])[C:15]=2[CH:20]=1
Reactant: CN1c2ccccc2CC(=O)c2ccccc21
Reactant: O=C1CCC(=O)N1Br
Solvent: CN(C)C=O
Product: CN1c2ccccc2CC(=O)c2cc(Br)ccc21
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 100.5 %

Procedure:
22.81 g of N-bromosuccimide were added over 15 minutes at room temperature to a solution of 25 g of 5-methyl-10,11-dihydro [5H] dibenzo (b,f) azepine-10-one in 250 ml of dimethylformamide under a nitrogen atmosphere and the mixture was stirred for 30 minutes at room temperature. The reaction mixture was poured into 2 liters of ice water and was extracted with ether. The ether extracts were washed with water, dried over magnesium sulfate and evaporated to dryness to obtain 34 g of 2-bromo-5-methyl-10,11-dihydro [5H] dibenzo (b,f) azepine-11-one. The product was dissolved in 100 ml of refluxing ethyl acetate and the solution was filtered hot and concentrated to the start of crystallization. The mixture was iced for 30 minutes and vacuum filtered. The recovered precipitate was washed with ethyl acetate and dried under reduced pressure to obtain 29.5 g of the said product in the form of pale yellow crystals melting at 128°-129°C.
Reaction SMILES: [CH2:1]([O:8][C:9](=[O:22])[NH:10][C:11]1[CH:16]=[CH:15][CH:14]=[C:13]([C:17]2O[CH:19]=[N:20][N:21]=2)[CH:12]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH:23]1([NH2:26])[CH2:25][CH2:24]1.FC(F)(F)C(O)=O>C(O)CCC>[CH2:1]([O:8][C:9](=[O:22])[NH:10][C:11]1[CH:16]=[CH:15][CH:14]=[C:13]([C:17]2[N:26]([CH:23]3[CH2:25][CH2:24]3)[CH:19]=[N:20][N:21]=2)[CH:12]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=C(Nc1cccc(-c2nnco2)c1)OCc1ccccc1
Reactant: NC1CC1
Solvent: CCCCO
Solvent: O=C(O)C(F)(F)F
Product: O=C(Nc1cccc(-c2nncn2C2CC2)c1)OCc1ccccc1
Temperature: 110 °C
Yield: 30.8 %

Procedure:
A mixture of (3-[1,3,4]Oxadiazol-2-yl-phenyl)-carbamic acid benzyl ester (200 mg, 0.68 mmol), cyclopropylamine (0.5 mL, 7.2 mmol), trifluoroacetic acid (0.05 mL, 0.65 mmol) in anhydrous 1-butanol mL) was heated at 110° C. overnight in a sealed tube. The reaction mixture was cooled to room temperature and the solvent was removed. The residue was partitioned between ethyl acetate and saturated sodium bicarbonate solution, and the aqueous phase was extracted with ethyl acetate. Solvent was removed after drying with sodium sulfate and purified by silica gel chromatography (rf=0.26 in 20:1 ethyl acetate/methanol) to obtain [3-(4-Cyclopropyl-4H-[1,2,4]triazol-3-yl)-phenyl]-carbamic acid benzyl ester as a white powder (70 mg, 31%). M+1=335.1
Reaction SMILES: F[C:2]1[C:7]([C:8]2[CH:13]=[CH:12][N:11]=[C:10]([CH3:14])[CH:9]=2)=[CH:6][CH:5]=[CH:4][N:3]=1.[NH2:15][C:16]1[CH:21]=[CH:20][C:19]([OH:22])=[CH:18][CH:17]=1.C(=O)([O-])[O-].[Cs+].[Cs+]>CS(C)=O.O>[CH3:14][C:10]1[CH:9]=[C:8]([C:7]2[C:2]([O:22][C:19]3[CH:20]=[CH:21][C:16]([NH2:15])=[CH:17][CH:18]=3)=[N:3][CH:4]=[CH:5][CH:6]=2)[CH:13]=[CH:12][N:11]=1
Reactant: Nc1ccc(O)cc1
Reactant: Cc1cc(-c2cccnc2F)ccn1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: O
Solvent: CS(C)=O
Product: Cc1cc(-c2cccnc2Oc2ccc(N)cc2)ccn1

Procedure:
To a 25 mL round bottomed flask was added 2-fluoro-3-(2-methylpyridin-4-yl)pyridine (0.7204 g, 3.828 mmol), 4-aminophenol (0.4254 g, 3.832 mmol), and cesium carbonate (1.6144 g, 4.593 mmol) in dimethyl sulfoxide at 90° C. Upon completion, the reaction was filtered through Celite™ and the filtrate was condensed. The reaction mixture was diluted with water (50 mL) and extracted with DCM (3×20 mL). The organic extract was washed with water (3×15 mL), brine (3×15 mL), dried with magnesium sulfate, filtered, and concentrated. The crude product was adsorbed onto a plug of silica gel and chromatographed through a Biotage™ pre-packed silica gel column (40M), eluting with a gradient of 1% to 5% methanol in DCM, to provide 4-(3-(2-methylpyridin-4-yl)pyridin-2-yloxy)benzenamine.
Reaction SMILES: [O:1]1[CH2:6][CH2:5][CH:4]([OH:7])[CH2:3][CH2:2]1.[H-].[Na+].[Cl:10][C:11]1[S:15][C:14]([C:16]2[CH:17]=[C:18]([C:23](=[O:25])[CH3:24])[CH:19]=[CH:20][C:21]=2F)=[CH:13][CH:12]=1>CS(C)=O>[Cl:10][C:11]1[S:15][C:14]([C:16]2[CH:17]=[C:18]([C:23](=[O:25])[CH3:24])[CH:19]=[CH:20][C:21]=2[O:7][CH:4]2[CH2:5][CH2:6][O:1][CH2:2][CH2:3]2)=[CH:13][CH:12]=1
Reactant: OC1CCOCC1
Reactant: CC(=O)c1ccc(F)c(-c2ccc(Cl)s2)c1
Agent: [H-]
Agent: [Na+]
Solvent: CS(C)=O
Product: CC(=O)c1ccc(OC2CCOCC2)c(-c2ccc(Cl)s2)c1
Temperature: 10 °C
Reaction time: 0.5 h

Procedure:
Tetrahydro-pyran-4-ol (1.01 g, 5.01 mmol) was added dropwise at 0° C. to a suspension of sodium hydride (200 mg, 5.01 mmol) in DMSO (10 ml). After stirring for 30 min at 10° C., a solution of the product obtained from step 1 (850 mg, 3.34 mmol) in DMSO (2 ml) was added dropwise and stirring was continued for 1 h at RT. The reaction was quenched with ice/water (50 ml). Ethyl acetate (50 ml) was added and the aqueous phase was extrated with ethyl acetate (2×30 ml). The combined organic phases were washed with brine (2×50 ml), dried over sodium sulphate, filtered, and evaporated. The product was obtained in quantitative yield and used in the next step without further purification.
Reaction SMILES: [CH2:1]([O:3][C:4]([N:6]1[CH2:16][CH2:15][C:9]2[N:10]=[N:11][C:12](S)=[CH:13][C:8]=2[CH2:7]1)=[O:5])[CH3:2].[CH3:17][NH:18][NH2:19]>>[CH2:1]([O:3][C:4]([N:6]1[CH2:16][CH2:15][C:9]2[N:10]=[N:11][C:12]([N:18]([CH3:17])[NH2:19])=[CH:13][C:8]=2[CH2:7]1)=[O:5])[CH3:2]
Reactant: CNN
Reactant: CCOC(=O)N1CCc2nnc(S)cc2C1
Product: CCOC(=O)N1CCc2nnc(N(C)N)cc2C1

Procedure:
A solution of 4.8 g of 5,6,7,8-tetrahydro-3-mercapto-6-pyrido[4,3-c]pyridazinecarboxylic acid ethyl ester in 20 cc of methylhydrazine is stirred at a bath temperature of 100° for 1 hour. The reaction solution is cooled with ice, and the precipitated reaction product is filtered off. The title compound has a M.P. of 121°-123° (decomp., from dimethoxyethane).