Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([O:4][C@H:5]1[CH2:22][CH2:21][C@@:20]2([CH3:23])[C:7](=[CH:8][C:9](=[N:28][O:29][CH2:30][CH2:31][CH2:32]Cl)[C@@H:10]3[C@@H:19]2[CH2:18][CH2:17][C@@:15]2([CH3:16])[C@H:11]3[CH2:12][CH2:13][C@@H:14]2[O:24][C:25](=[O:27])[CH3:26])[CH2:6]1)(=[O:3])[CH3:2].[NH:34]1[CH:38]=[CH:37][N:36]=[CH:35]1>>[C:1]([O:4][C@H:5]1[CH2:22][CH2:21][C@@:20]2([CH3:23])[C:7](=[CH:8][C:9](=[N:28][O:29][CH2:30][CH2:31][CH2:32][N:34]3[CH:38]=[CH:37][N:36]=[CH:35]3)[C@@H:10]3[C@@H:19]2[CH2:18][CH2:17][C@@:15]2([CH3:16])[C@H:11]3[CH2:12][CH2:13][C@@H:14]2[O:24][C:25](=[O:27])[CH3:26])[CH2:6]1)(=[O:3])[CH3:2]
Reactant: c1c[nH]cn1
Reactant: CC(=O)O[C@H]1CC[C@@]2(C)C(=CC(=NOCCCCl)[C@H]3[C@@H]4CC[C@H](OC(C)=O)[C@@]4(C)CC[C@@H]32)C1
Product: CC(=O)O[C@H]1CC[C@@]2(C)C(=CC(=NOCCCn3ccnc3)[C@H]3[C@@H]4CC[C@H](OC(C)=O)[C@@]4(C)CC[C@@H]32)C1
Reaction time: 5 h

Procedure:
A mixture of 7-[O-(3-chloropropyl)oximino]-5-androstene-3β,17β-diol diacetate (23) (1 g, 2.08 mmol) and powdered imidazole (1.5 g) was fused at 110-120° C. for 5 h. The completion of reaction was monitored by TLC. The reaction was quenched with iced water to afford a the product 7-[O-{3-(imidazol-1-yl)propyl}oximino]-5-androstene-3β,17β-diol diacetate (24)
Reaction SMILES: [C:1]1([C:7]2[N:8]=[CH:9]O[C:11]=2[CH2:12][CH2:13][CH2:14][CH3:15])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C(O)(=O)/[CH:17]=[CH:18]\[C:19]([OH:21])=[O:20]>>[C:1]1([C:7]2[C:11]([CH2:12][CH2:13][CH2:14][CH3:15])=[C:18]([CH:17]=[CH:9][N:8]=2)[C:19]([OH:21])=[O:20])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: CCCCc1ocnc1-c1ccccc1
Reactant: O=C(O)/C=C\C(=O)O
Product: CCCCc1c(C(=O)O)ccnc1-c1ccccc1
Temperature: 100 °C

Procedure:
A mixture of 4-phenyl-5-butyloxazole (12,5 g, 25 mmol) and maleic acid (3.5 g, 30 mmol) is heated at 100° C. for 30 min. After cooling, the semisolid mass is triturated with ether and the solid collected by filtration. 1H NMR (δ, CDCl3, 400 MHz) 11.68 (brs, 1H), 8.72 (d, J=6.0 Hz, 1H), 7.73 (d, J=5.6 Hz, 1H), 7.48-7.51 (m, 2H), 7.42-7.44 (m, 2H), 6.25 (s, 1H), 2.86 (d, J=7.6 Hz, 2H), 1.36 (m, 2H), 1.11 (dt, J=7.6, 7.2 Hz, 2H), 0.68 (t, J=7.6 Hz, 3H). MS (M+1): 256, (M−1) 254.
Reaction SMILES: [S:1]([CH2:5][CH2:6][OH:7])[CH2:2][CH2:3][OH:4].N1C=CN=C1.[C:13]([Si:17](Cl)([C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1)[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1)([CH3:16])([CH3:15])[CH3:14].C(OCC)(=O)C>ClCCl>[Si:17]([O:4][CH2:3][CH2:2][S:1][CH2:5][CH2:6][OH:7])([C:13]([CH3:16])([CH3:15])[CH3:14])([C:24]1[CH:25]=[CH:26][CH:27]=[CH:28][CH:29]=1)[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1
Reactant: OCCSCCO
Reactant: CC(C)(C)[Si](Cl)(c1ccccc1)c1ccccc1
Agent: c1c[nH]cn1
Solvent: ClCCl
Solvent: CCOC(C)=O
Product: CC(C)(C)[Si](OCCSCCO)(c1ccccc1)c1ccccc1
Temperature: 25 °C
Reaction time: 14 h
Yield: 54.2 %

Procedure:
In dichloromethane (200 ml) were dissolved 2,2′-thiodiethanol (10.0 g, 81.8 mmol) and imidazole (4.70 g, 69.0 mmol), followed by the dropwise addition of t-butylchlorodiphenylsilane (15.0 ml, 57.7 mmol) at room temperature. After completion of the dropwise addition, the reaction mixture was stirred at room temperature for 14 hours. After concentration under reduced pressure, diethyl ether was added to the residue. Then, the insoluble matter was filtered off. The residue obtained by concentrating the filtrate under reduced pressure was subjected to flash silica gel chromatography, and the fraction obtained from the hexane:ethyl acetate=3:1 eluate was concentrated under reduced pressure, whereby the title compound (11.3 g, 31.3 mmol, 54%) was obtained as a colorless oil.
Reaction SMILES: COC1C=C(C=CC=1OC)C[NH:7][C:8]1[N:9]=[C:10]([C:25]2[O:26][CH:27]=[CH:28][CH:29]=2)[C:11]2[CH:16]=[CH:15][N:14]([CH2:17][C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=3[F:24])[C:12]=2[N:13]=1>C(O)(C(F)(F)F)=O>[F:24][C:19]1[CH:20]=[CH:21][CH:22]=[CH:23][C:18]=1[CH2:17][N:14]1[C:12]2[N:13]=[C:8]([NH2:7])[N:9]=[C:10]([C:25]3[O:26][CH:27]=[CH:28][CH:29]=3)[C:11]=2[CH:16]=[CH:15]1
Reactant: COc1ccc(CNc2nc(-c3ccco3)c3ccn(Cc4ccccc4F)c3n2)cc1OC
Solvent: O=C(O)C(F)(F)F
Product: Nc1nc(-c2ccco2)c2ccn(Cc3ccccc3F)c2n1
Yield: 51.4 %

Procedure:
A solution of N-(3,4-dimethoxybenzyl)-7-(2-fluorobenzyl)-4-(2-furyl)-7H-pyrrolo[2,3-d]pyrimidine-2-amine (110 mg, 0.24 mmol) in TFA (1 mL) was heated to 50° C. for 3 h, concentrated in vacuo, treated with saturated NaHCO3, extracted with EtOAc, dried (MgSO4), concentrated in vacuo, purified by chromatography (EtOAc:Heptane, 1:4) and recrystallised (EtOAc) to give the title compound (38 mg, 51%) as a cream solid.
Reaction SMILES: [Cl:1][C:2]1[C:3]([NH:11][NH2:12])=[N:4][N:5]2[CH2:10][CH2:9][CH2:8][CH2:7][C:6]=12.C(O[CH:16]=[C:17]([C:20]#[N:21])[C:18]#[N:19])C>C(O)C>[NH2:21][C:20]1[N:11]([C:3]2[C:2]([Cl:1])=[C:6]3[CH2:7][CH2:8][CH2:9][CH2:10][N:5]3[N:4]=2)[N:12]=[CH:16][C:17]=1[C:18]#[N:19]
Reactant: CCOC=C(C#N)C#N
Reactant: NNc1nn2c(c1Cl)CCCC2
Solvent: CCO
Product: N#Cc1cnn(-c2nn3c(c2Cl)CCCC3)c1N

Procedure:
1.1 g (5.92 mmole) 3-Chloro-2-hydrazino-4,5,6,7-tetrahydropyrazolo[1,5-a]pyridine and 0.72 g (5.92 mmole) ethoxymethylenemalononitrile in 10 ml ethanol was heated at reflux for 2 hours. The resulting precipitate was suction filtered, washed with ethanol, dried and purified by silica gel column chromatography (hexane/ethyl acetate).
Reaction SMILES: Cl.Cl.[Cl:3][C:4]1[CH:9]=[C:8]([Cl:10])[CH:7]=[CH:6][C:5]=1[C:11]([OH:24])([CH2:18][N:19]1[CH:23]=[N:22][CH:21]=[N:20]1)[CH2:12][C:13](=[NH:17])[O:14]CC>ClC1C=CC=CC=1Cl>[C:13]([CH2:12][C:11]([C:5]1[CH:6]=[CH:7][C:8]([Cl:10])=[CH:9][C:4]=1[Cl:3])([OH:24])[CH2:18][N:19]1[CH:23]=[N:22][CH:21]=[N:20]1)(=[O:14])[NH2:17]
Reactant: CCOC(=N)CC(O)(Cn1cncn1)c1ccc(Cl)cc1Cl
Agent: Cl
Solvent: Clc1ccccc1Cl
Product: NC(=O)CC(O)(Cn1cncn1)c1ccc(Cl)cc1Cl
Temperature: 178 °C
Reaction time: 0.17 h

Procedure:
3-(2,4-Dichlorophenyl)-3-hydroxy-4-(1H-1,2,4-triazol-1-yl)butyrimidic acid, ethyl ester dihydrochloride (3.42 g) was suspended in 1,2-dichlorobenzene (35 ml) and the mixture was heated to the reflux temperature of the solvent (178° C.). After refluxing for five minutes, a solution was obtained. Refluxing was then continued for an additional 10 minutes. The reaction mixture was cooled, evaporated, and the resulting gum was triturated with hexane and heated with acetone. On cooling a cream colored granular solid was formed which was filtered to yield the title compound as a solvate (1.26 g). On standing overnight in a refrigerator some further solvated product precipitated (0.62 g). After drying at 80° C. for 6 hours to remove the solvent the pure (unsolvated) title compound was obtained, yield 1.5 g, m.p. 144°-145° C.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[CH2:13][CH2:12][NH:11][CH2:10][CH2:9]2)=[CH:4][CH:3]=1.[CH3:14][N:15]1[C:19]2[CH:20]=[CH:21][C:22]([CH2:24][CH2:25]Br)=[CH:23][C:18]=2[O:17][C:16]1=[O:27]>O1CCOCC1>[CH3:14][N:15]1[C:19]2[CH:20]=[CH:21][C:22]([CH2:24][CH2:25][N:11]3[CH2:12][CH2:13][N:8]([C:5]4[CH:4]=[CH:3][C:2]([F:1])=[CH:7][CH:6]=4)[CH2:9][CH2:10]3)=[CH:23][C:18]=2[O:17][C:16]1=[O:27]
Reactant: Cn1c(=O)oc2cc(CCBr)ccc21
Reactant: Fc1ccc(N2CCNCC2)cc1
Solvent: C1COCCO1
Product: Cn1c(=O)oc2cc(CCN3CCN(c4ccc(F)cc4)CC3)ccc21
Yield: 64.7 %

Procedure:
0.025 mol (4.5 g) of 1-(4-fluorophenyl)-piperazine and 0.02 mol (5.12 g) of 3-methyl-6-(2-bromoethyl)-benzoxazolinone, dissolved beforehand in 50 cm3 of dioxane, were introduced into a 100 cm3 flask with a ground glass neck, fitted with a reflux condenser, and the mixture was then heated under reflux for 72 hours, with stirring. After cooling, filtration and drying, 100 cm3 of a 3% strength aqueous solution of sodium hydroxide were added to the precipitate obtained, and the mixture was stirred for 30 minutes. Filtration, drying and recrystallisation from toluene gave 4.6 g of the title product having a melting point of 161°-164° C.
Reaction SMILES: [Cl:1][CH:2]([CH2:7][C:8]1[CH:13]=[CH:12][C:11]([N:14]2[C:19](=[O:20])[CH:18]=[C:17]([C:21]([F:24])([F:23])[F:22])[N:16]([CH3:25])[C:15]2=[O:26])=[C:10]([F:27])[CH:9]=1)[C:3]([O:5][CH3:6])=[O:4].[N+:28]([O-])([OH:30])=[O:29]>S(=O)(=O)(O)O>[Cl:1][CH:2]([CH2:7][C:8]1[CH:9]=[C:10]([F:27])[C:11]([N:14]2[C:19](=[O:20])[CH:18]=[C:17]([C:21]([F:23])([F:24])[F:22])[N:16]([CH3:25])[C:15]2=[O:26])=[CH:12][C:13]=1[N+:28]([O-:30])=[O:29])[C:3]([O:5][CH3:6])=[O:4]
Reactant: O=[N+]([O-])O
Reactant: COC(=O)C(Cl)Cc1ccc(-n2c(=O)cc(C(F)(F)F)n(C)c2=O)c(F)c1
Agent: O=S(=O)(O)O
Product: COC(=O)C(Cl)Cc1cc(F)c(-n2c(=O)cc(C(F)(F)F)n(C)c2=O)cc1[N+](=O)[O-]
Temperature: 10 °C
Reaction time: 1 h
Yield: 28.2 %

Procedure:
A mixture of 10.4 grams (0.025 mole) of methyl 2-chloro-3-[3-fluoro-4-(1-methyl-6-trifluoromethyl-2,4(1H,3H)-pyrimidinedion-3-yl)phenyl]propanoate in 100 mL of concentrated sulfuric acid was stirred for two hours until the methyl propanoate was completely dissolved. The mixture was then cooled to 10° C., and 2.7 grams (0.030 mole) of 70% nitric acid was added dropwise while the temperature of the reaction mixture was held at 10° C. Upon completion of addition, the reaction mixture was allowed to warm to ambient temperature, where it was stirred for one hour. The reaction mixture was then poured into ice-water and stirred until the ice melted. The mixture was extracted with diethyl ether. The extract was washed with water and dried with magnesium sulfate. The mixture was filtered, and the filtrate was concentrated under reduced pressure to a residue. The residue was subjected to column chromatography on silica gel. Elution was accomplished using methylene chloride. The product-containing fractions were combined and concentrated under reduced pressure, yielding 3.2 grams of methyl 2-chloro-3-[5-fluoro-2-nitro-4-(1-methyl-6-trifluoromethyl-2,4(1H,3H)-pyrimidinedion-3-yl)phenyl]propanoate, mp 60°-65° C. The NMR spectrum was consistent with the proposed structure.
Reaction SMILES: C(OC([N:8]([CH:34]([CH3:36])[CH3:35])[C:9]1[S:10][C:11]([C:14]2[CH:15]=[C:16]([C:28]3[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=3)[C:17]3[N:18]([CH:20]=[C:21]([C:23]([O:25][CH2:26][CH3:27])=[O:24])[N:22]=3)[CH:19]=2)=[CH:12][N:13]=1)=O)(C)(C)C>C(O)(C(F)(F)F)=O>[CH:34]([NH:8][C:9]1[S:10][C:11]([C:14]2[CH:15]=[C:16]([C:28]3[CH:29]=[CH:30][CH:31]=[CH:32][CH:33]=3)[C:17]3[N:18]([CH:20]=[C:21]([C:23]([O:25][CH2:26][CH3:27])=[O:24])[N:22]=3)[CH:19]=2)=[CH:12][N:13]=1)([CH3:35])[CH3:36]
Reactant: CCOC(=O)c1cn2cc(-c3cnc(N(C(=O)OC(C)(C)C)C(C)C)s3)cc(-c3ccccc3)c2n1
Solvent: O=C(O)C(F)(F)F
Product: CCOC(=O)c1cn2cc(-c3cnc(NC(C)C)s3)cc(-c3ccccc3)c2n1
Yield: 83.1 %

Procedure:
A solution of ethyl 6-(2-(tert-butoxycarbonyl-(isopropyl)amino)thiazol-5-yl)-8-phenylimidazo[1,2-a]pyridine-2-carboxylate (75 mg) in 4 ml of TFA was stirred at room temperature for 2 hours. The solvent was evaporated and the residue was purified by column chromatography on silica gel using ethyl acetate/hexane (50-100%) as eluent to give 50 mg of Ethyl 6-(2-(isopropylamino)thiazol-5-yl)-8-phenylimidazo[1,2-a]pyridine-2-carboxylate as a light yellow solid. LCMS (Conditions C): 2.90 min (RT); (M+H)+=407.33 (100%). 1H NMR, 400 MHz, CDCl3: δ 8.25 (s, 1 H), 8.16 (m, 1 H), 8.02 (m, 2 H), 7.52-7.43 (m, 3 H), 7.37 (d, 1H), 7.29 (s, 1H), 4.44 (q, J=7.1 Hz, 2 H), 3.60 (m, 1 H), 1.42 (m, 9 H).
Reaction SMILES: Br[CH2:2][CH2:3][CH2:4][C:5]([O:7][CH2:8][CH3:9])=[O:6].[CH3:10][N:11]1[CH2:16][CH2:15][NH:14][CH2:13][CH2:12]1.C([O-])([O-])=O.[K+].[K+]>C(#N)C>[CH3:10][N:11]1[CH2:16][CH2:15][N:14]([CH2:2][CH2:3][CH2:4][C:5]([O:7][CH2:8][CH3:9])=[O:6])[CH2:13][CH2:12]1
Reactant: CCOC(=O)CCCBr
Reactant: CN1CCNCC1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: CCOC(=O)CCCN1CCN(C)CC1
Yield: 95.1 %

Procedure:
A mixture of ethyl 4-bromobutanoate (5.75 g, 29.5 mmol; Aldrich No. 167118) and 1-methylpiperazine (3.55 mL, 32.0 mmol; Aldrich No. 130001) and anhydrous K2CO3 (4.5 g, 32.5 mmol; Fisher No. P208) in acetonitrile (MeCN, 150 mL) was refluxed for 18 h before concentrated in vacuo. The organic layer was then separated and the aqueous layer was extracted with dichloromethane (DCM, 3×150 mL). The combined organic extracts were washed with water (150 mL), dried (Na2SO4), and concentrated in vacuo to give ethyl 4-(4-methylpiperzin-1-yl)butanoate (6.01 g, 96%) as a yellow oil.
Reaction SMILES: Br[C:2]1[C:7]([Br:8])=[CH:6][C:5]([F:9])=[CH:4][N:3]=1.[CH3:10]B(O)O.C([O-])([O-])=O.[K+].[K+].O>O1CCOCC1.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>[Br:8][C:7]1[C:2]([CH3:10])=[N:3][CH:4]=[C:5]([F:9])[CH:6]=1
Reactant: Fc1cnc(Br)c(Br)c1
Reactant: CB(O)O
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: C1COCCO1
Product: Cc1ncc(F)cc1Br
Temperature: 110 °C
Yield: 32.2 %

Procedure:
2,3-Dibromo-5-fluoropyridine (5.0 g, 19.6 mmol), Pd(PPh3)4 (1.13 g, 0.98 mmol) and methyl boronic acid (3.52 g, 58.9 mmol) were combined in dioxane (50 mL) then treated with K2CO3 (8.13, 58.9 mmol) and water (10 mL). The mixture was purged with N2 then heated to 110° C. in a sealed vessel for 16 hours. The cooled mixture was partitioned between water (100 mL) and EtOAc (50 mL) and the layers separated. The aqueous layer was extracted with EtOAc (2×50 mL) and the combined organic phases were washed with brine (50 mL), dried over Na2SO4, filtered and concentrated. The residue was purified by silica gel column chromatography eluting with 1-3% EtOAc/hexanes to afford the product as a white solid (1.20 g, 32% yield). MS (apci) m/z=190.2 (M+).
Reaction SMILES: [N:1]1([C:6]2[CH:11]=[C:10]([S:12]([C:15]3[CH:20]=[CH:19][C:18]([NH2:21])=[CH:17][CH:16]=3)(=[O:14])=[O:13])[CH:9]=[C:8]([CH:22]=[CH2:23])[N:7]=2)[CH2:5][CH2:4][CH2:3][CH2:2]1.[N+](=[CH2:26])=[N-]>C(OCC)C.C(O)(=O)C.CC([O-])=O.CC([O-])=O.[Pd+2]>[CH:22]1([C:8]2[CH:9]=[C:10]([S:12]([C:15]3[CH:20]=[CH:19][C:18]([NH2:21])=[CH:17][CH:16]=3)(=[O:14])=[O:13])[CH:11]=[C:6]([N:1]3[CH2:5][CH2:4][CH2:3][CH2:2]3)[N:7]=2)[CH2:26][CH2:23]1
Reactant: C=[N+]=[N-]
Reactant: C=Cc1cc(S(=O)(=O)c2ccc(N)cc2)cc(N2CCCC2)n1
Agent: [Pd+2]
Agent: CC(=O)[O-]
Solvent: CC(=O)O
Solvent: CCOCC
Product: Nc1ccc(S(=O)(=O)c2cc(C3CC3)nc(N3CCCC3)c2)cc1
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 87 %

Procedure:
0.165 g (0.0005 Mol) 4-(2-Pyrrolidin-1-yl-6-vinyl-pyridine-4-sulfonyl)-phenylamine were dissolved in ethyl ether (100 ml) and cooled to 0° C. A solution of diazomethane in ethyl ether (30 ml) was carefully added. Upon addition of a catalytic amount of Pd(OAc)2 gas evolution started. The reaction mixture was allowed to warm to ambient temperature and stirred for 30 min. After addition of a few drops of acetic acid the solvent was evaporated and the residue chromatographed on SiO2 with ethyl acetate hexane 1:2. It was obtained 0.149 g (87%) of 4-(2-cyclopropyl-6-pyrrolidin-1-yl-pyridine-4-sulfonyl)-phenylamine as bright yellow cristals; mp.: 216-218° C.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([C:8](=[O:11])[NH:9][CH3:10])[CH:5]=[CH:4][C:3]=1[N:12]([CH3:31])[C:13]([C:15]1[S:30][C:18]2[C:19]3[CH:27]=[C:26]([C:28]#[N:29])[CH:25]=[CH:24][C:20]=3[O:21][CH2:22][CH2:23][C:17]=2[CH:16]=1)=[O:14].C(=O)([O-])[O-:33].[K+].[K+].OO>CS(C)=O.O>[Cl:1][C:2]1[CH:7]=[C:6]([C:8](=[O:11])[NH:9][CH3:10])[CH:5]=[CH:4][C:3]=1[N:12]([CH3:31])[C:13]([C:15]1[S:30][C:18]2[C:19]3[CH:27]=[C:26]([C:28]([NH2:29])=[O:33])[CH:25]=[CH:24][C:20]=3[O:21][CH2:22][CH2:23][C:17]=2[CH:16]=1)=[O:14]
Reactant: O=C([O-])[O-]
Reactant: CNC(=O)c1ccc(N(C)C(=O)c2cc3c(s2)-c2cc(C#N)ccc2OCC3)c(Cl)c1
Agent: OO
Agent: [K+]
Solvent: O
Solvent: CS(C)=O
Product: CNC(=O)c1ccc(N(C)C(=O)c2cc3c(s2)-c2cc(C(N)=O)ccc2OCC3)c(Cl)c1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
To a solution of N-(2-chloro-4-(methylcarbamoyl)phenyl)-9-cyano-N-methyl-4,5-dihydrobenzo[b]thieno[2,3-d]oxepine-2-carboxamide 298 (100 mg) and potassium carbonate (37 mg) in DMSO (3 mL) at 0° C. was added hydrogen peroxide (30 μL of a 33% solution in water). The reaction was stirred at room temperature for 16 h. Water was then added and the resulting solid collected by filtration and air-dried to give 306. NMR: (DMSO): 2.81 (3H, d, J 4.5, Me), 2.91-2.93 (2H, m), 3.68 (3H, s, Me), 4.19-4.22 (2H, m), 6.41 (1H, s, NH), 7.03 (1H, d, J 8.4, Ar), 7.35 (1H, s), 7.71-7.77 (2H, m, Ar), 7.92 (1H, dd, J 8.3 and 2.0, Ar), 8.03-8.05 (3H, m) and 8.65-8.67 (1H, m). MS: (ESI+) MH+ 469.35
Reaction SMILES: [CH:1]([C:4]1[CH:9]=[CH:8][C:7]([NH:10][C:11]([C:13]2[CH:14]=[N:15][C:16]([O:19][CH3:20])=[CH:17][CH:18]=2)=O)=[CH:6][CH:5]=1)([CH3:3])[CH3:2].Cl.C(=O)([O-])O.[Na+]>C1COCC1>[CH:1]([C:4]1[CH:5]=[CH:6][C:7]([NH:10][CH2:11][C:13]2[CH:14]=[N:15][C:16]([O:19][CH3:20])=[CH:17][CH:18]=2)=[CH:8][CH:9]=1)([CH3:3])[CH3:2]
Reactant: COc1ccc(C(=O)Nc2ccc(C(C)C)cc2)cn1
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: C1CCOC1
Product: COc1ccc(CNc2ccc(C(C)C)cc2)cn1
Temperature: 25 °C
Reaction time: 24 h
Yield: 86 %

Procedure:
A BH3-THF complex/1M THF solution (6.3 mL) was added to N-(4-isopropylphenyl)-6-methoxypyridine-3-carboxamide (0.76 g), and the mixture was heated under reflux for 4 hr. After cooling the reaction mixture, 1 mol/L hydrochloric acid (15 mL) was added and the mixture was stirred at room temperature for one day. The reaction mixture was poured into saturated aqueous sodium hydrogencarbonate and extracted with chloroform. The organic layer was washed with saturated brine and dried over anhydrous sodium sulfate. The solvent was evaporated and the residue was purified by silica gel column chromatography to give (4-isopropylphenyl)[(6-methoxypyridin-3-yl)methyl]amine (0.62 g).
Reaction SMILES: [C:1]([OH:7])([C:3]([F:6])([F:5])[F:4])=[O:2].C(OC([N:15]1[C@@H:20]([C:21]2[NH:22][CH:23]=[C:24]([C:26]3[CH:27]=[C:28]4[C:33](=[CH:34][CH:35]=3)[CH:32]=[C:31]([C:36]3[CH:37]=[C:38]([C:42]5[N:43]=[C:44]([C@@H:47]6[CH2:52][C@@H:51]7[C@@H:49]([CH2:50]7)[N:48]6C(OC(C)(C)C)=O)[NH:45][CH:46]=5)[CH:39]=[CH:40][CH:41]=3)[CH:30]=[CH:29]4)[N:25]=2)[CH2:19][C@H:18]2[C@@H:16]1[CH2:17]2)=O)(C)(C)C>C(Cl)Cl>[C:1]([OH:7])([C:3]([F:6])([F:5])[F:4])=[O:2].[C@H:16]12[CH2:17][C@H:18]1[CH2:19][C@H:20]([C:21]1[NH:22][CH:23]=[C:24]([C:26]3[CH:27]=[C:28]4[C:33](=[CH:34][CH:35]=3)[CH:32]=[C:31]([C:36]3[CH:37]=[C:38]([C:42]5[N:43]=[C:44]([C@@H:47]6[CH2:52][C@@H:51]7[C@@H:49]([CH2:50]7)[NH:48]6)[NH:45][CH:46]=5)[CH:39]=[CH:40][CH:41]=3)[CH:30]=[CH:29]4)[N:25]=1)[NH:15]2
Reactant: CC(C)(C)OC(=O)N1[C@@H]2C[C@@H]2C[C@H]1c1nc(-c2cccc(-c3ccc4cc(-c5c[nH]c([C@H]6C[C@@H]7C[C@@H]7N6C(=O)OC(C)(C)C)n5)ccc4c3)c2)c[nH]1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: c1cc(-c2ccc3cc(-c4c[nH]c([C@H]5C[C@@H]6C[C@@H]6N5)n4)ccc3c2)cc(-c2c[nH]c([C@@H]3C[C@H]4C[C@H]4N3)n2)c1
Temperature: 25 °C
Reaction time: 2 h
Yield: 103.3 %

Procedure:
TFA (2 mL, 26.0 mmol) was added to a solution of tert-butyl (1R,3S,5R)-3-(4-(3-(6-(2-((1S,3R,5S)-2-(tert-butoxycarbonyl)-2-azabicyclo[3.1.0]hex-3-yl)-1H-imidazol-4-yl)-2-naphthyl)phenyl)-1H-imidazol-2-yl)-2-azabicyclo[3.1.0]hexane-2-carboxylate (130 mg, 0.20 mmol) in DCM (2 mL) and the mixture was stirred for 2 h at RT. The volatiles were removed under vacuum and the crude product was purified by prep HPLC (methanol/water, 0.1% TFA) to yield a TFA salt of (1R,3S,5R)-3-(4-(3-(6-(2-((1S,3R,5S)-2-azabicyclo[3.1.0]hex-3-yl)-1H-imidazol-4-yl)-2-naphthyl)phenyl)-1H-imidazol-2-yl)-2-azabicyclo[3.1.0]hexane (103 mg) as a tan solid. LC-MS retention time 1.303 min; m/z 499.13 (MH+). LC data was recorded on a Shimadzu LC-10AS liquid chromatograph equipped with a Waters Sunfire C18 4.6×30 mm 5 μM column using a SPD-10AV UV-Vis detector at a detector wave length of 220 nM. The elution conditions employed a flow rate of 4 mL/min, a gradient of 100% Solvent A/0% Solvent B to 0% Solvent A/100% Solvent B, a gradient time of 2 min, a hold time of 1 min, and an analysis time of 3 min where Solvent A was 10% methanol/90% water/0.1% TFA and Solvent B was 10% water/90% methanol/0.1% TFA. MS data was determined using a MICROMASS® Platform for LC in electrospray mode. 1H NMR (500 MHz, MeOD) δ ppm 8.33 (s, 1H), 8.22 (d, J=12.5 Hz, 2H), 8.02 (dd, J=8.6, 5.8 Hz, 2H), 7.90-7.97 (m, 2H), 7.75-7.82 (m, 4H), 7.58 (t, J=7.8 Hz, 1H), 4.74-4.78 (m, 2H), 3.46-3.53 (m, 2H), 2.64-2.74 (m, 4H), 2.04-2.12 (m, 2H), 1.19-1.26 (m, 2H), 1.02 (ddd, J=14.2, 7.3, 7.2 Hz, 2H).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([F:8])[C:3]=1[N:9]1[C:14]2[N:15]=[C:16]([NH:27][CH2:28][C:29]#[N:30])[N:17]=[C:18]([C:19]3[CH:24]=[CH:23][C:22]([F:25])=[CH:21][C:20]=3[CH3:26])[C:13]=2[CH:12]=[CH:11][C:10]1=[O:31].Cl.C(N(CC)CC)C.[N-:40]=[N+:41]=[N-:42].[Na+]>>[F:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([F:8])[C:3]=1[N:9]1[C:14]2[N:15]=[C:16]([NH:27][CH2:28][C:29]3[NH:42][N:41]=[N:40][N:30]=3)[N:17]=[C:18]([C:19]3[CH:24]=[CH:23][C:22]([F:25])=[CH:21][C:20]=3[CH3:26])[C:13]=2[CH:12]=[CH:11][C:10]1=[O:31]
Reactant: [N-]=[N+]=[N-]
Reactant: Cc1cc(F)ccc1-c1nc(NCC#N)nc2c1ccc(=O)n2-c1c(F)cccc1F
Agent: Cl
Agent: [Na+]
Solvent: CCN(CC)CC
Product: Cc1cc(F)ccc1-c1nc(NCc2nnn[nH]2)nc2c1ccc(=O)n2-c1c(F)cccc1F
Yield: 9.9 %

Procedure:
Following the procedure outlined in Example 210, the crude product of Example 212(a), [8-(2,6-difluoro-phenyl)-4-(4-fluoro-2-methyl-phenyl)-7-oxo-7,8-dihydro-pyrido[2,3-d]pyrimidin-2-ylamino]-acetonitrile (460 mg), triethylaminehydrochloride (1.54 g, 11.2 mmol) and NaN3 (728 mg, 11.2 mmol) were reacted to give the desired product 50 mg (9.6%). LC-MS: 465.2 (MH+, m/z), 1.79 (Rt, min).
Reaction SMILES: [H-].[Na+].Cl[CH2:4][CH2:5][S:6](Cl)(=[O:8])=[O:7].[F:10][C:11]1[CH:30]=[CH:29][C:14]([O:15][C:16]2[CH:21]=[CH:20][C:19]([C:22]3[C:23]([NH2:28])=[N:24][CH:25]=[CH:26][CH:27]=3)=[CH:18][CH:17]=2)=[C:13]([CH3:31])[CH:12]=1>C1COCC1>[F:10][C:11]1[CH:30]=[CH:29][C:14]([O:15][C:16]2[CH:17]=[CH:18][C:19]([C:22]3[C:23]4=[N:28][S:6](=[O:8])(=[O:7])[CH2:5][CH2:4][N:24]4[CH:25]=[CH:26][CH:27]=3)=[CH:20][CH:21]=2)=[C:13]([CH3:31])[CH:12]=1
Reactant: Cc1cc(F)ccc1Oc1ccc(-c2cccnc2N)cc1
Reactant: O=S(=O)(Cl)CCCl
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: Cc1cc(F)ccc1Oc1ccc(C2=CC=CN3CCS(=O)(=O)N=C23)cc1
Reaction time: 0.08 h

Procedure:
To a suspension of NaH (60%, 241 mg) in THF (dry) (25 mL) was added 2-chloroethanesulfonyl chloride (0.380 ml) at 0° C. and the mixture was stirred for 5 min at the same temperature. A solution of 3-(4-(4-fluoro-2-methylphenoxy)phenyl)pyridin-2-amine (354 mg) in THF (dry) (40 mL) was added at 0° C. and the mixture was stirred at room temperature overnight. The mixture was quenched with water at 0° C. Water, EtOAc and THF were added and the extracted organic layer was washed with brine, dried over anhydrous magnesium sulfate and concentrated in vacuo. The residue was washed with IPE/EtOAc, dried in vacuo to give the title compound (375 mg) as a slightly yellow solid. A part of this was recrystallized from MeCN/IPE.
Reaction SMILES: [C:1]([O:4][C:5](=O)[CH3:6])(=[O:3])[CH3:2].[C:8]([O:12][C:13](=[O:23])[NH:14][C@H:15]1[CH2:20]C[CH2:18][C@H:17](CO)[CH2:16]1)([CH3:11])([CH3:10])[CH3:9].N1C=CC=CC=1>C(Cl)Cl>[C:8]([O:12][C:13]([NH:14][C@H:15]1[CH2:16][CH2:17][CH2:18][C@H:6]([CH2:5][O:4][C:1](=[O:3])[CH3:2])[CH2:20]1)=[O:23])([CH3:11])([CH3:10])[CH3:9]
Reactant: CC(C)(C)OC(=O)N[C@H]1CCC[C@H](CO)C1
Reactant: CC(=O)OC(C)=O
Solvent: ClCCl
Solvent: c1ccncc1
Product: CC(=O)OC[C@H]1CCC[C@H](NC(=O)OC(C)(C)C)C1
Temperature: 50 °C
Reaction time: 8 h
Yield: 100 %

Procedure:
Acetic anhydride (0.85 mL, 9.012 mmol) was added at 0° C. to a mixture of racemic trans 3-hydroxymethyl-cyclohexyl-carbamic acid tert-butyl ester (1.69 g, 7.37 mmol) and pyridine (0.78 mL, 9.646 mmol) in 20 mL of DCM. The resulting mixture was stirred at 0° C. to RT overnight and then at 50° C. for 4 hours before being cooled to RT and partitioned between DCM and aqueous 1M HCl. The aqueous layer was back extracted twice with DCM. The combined organic layers were dried (Na2SO4), filtered, and evaporated to give 2 g of racemic trans acetic acid 3-tert-butoxycarbonylamino-cyclohexylmethyl ester (>95% yield).