Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [OH:1][CH2:2][CH:3]([NH:8][S:9]([C:12]1[CH:17]=[CH:16][C:15]([O:18][CH3:19])=[CH:14][CH:13]=1)(=[O:11])=[O:10])[C:4]([O:6][CH3:7])=[O:5].[H-].[Na+].[CH3:22][C:23]1[CH:24]=[CH:25][C:26]([N+:31]([O-:33])=[O:32])=[C:27]([CH:30]=1)[CH2:28]Cl.[I-].[Na+]>CN(C)C=O.CCCCCC.C(OCC)(=O)C>[OH:1][CH2:2][CH:3]([N:8]([S:9]([C:12]1[CH:13]=[CH:14][C:15]([O:18][CH3:19])=[CH:16][CH:17]=1)(=[O:11])=[O:10])[CH2:28][C:27]1[CH:30]=[C:23]([CH3:22])[CH:24]=[CH:25][C:26]=1[N+:31]([O-:33])=[O:32])[C:4]([O:6][CH3:7])=[O:5]
Reactant: COC(=O)C(CO)NS(=O)(=O)c1ccc(OC)cc1
Reactant: Cc1ccc([N+](=O)[O-])c(CCl)c1
Agent: [H-]
Agent: [I-]
Agent: [Na+]
Solvent: CCCCCC
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: COC(=O)C(CO)N(Cc1cc(C)ccc1[N+](=O)[O-])S(=O)(=O)c1ccc(OC)cc1
Temperature: 25 °C
Reaction time: 0.33 h
Yield: 0.3 %

Procedure:
A solution of 23.14 g (0.08 mol) of methyl 3-hydroxy-2-(4-methoxybenzenesulfonylamino)propionate in 120 ml of dry N,N-dimethylformamide was added dropwise to a stirred suspension of 3.2 g (0.08 mol) of sodium hydride (57% in oil) in 120 ml of N,N-dimethylformide. When gas evolution ceased, the mixture was chilled in an ice bath and a solution of 16.4 g (0.084 mol) of 5-methyl-2-nitrobenzyl chloride in 100 ml of N N-dimethylformamide was added. To the mixture was added 12.6 g (0.084 mol) of anhydrous sodium iodide and the mixture was chilled in an ice bath and stirred for 20 minutes. The mixture was allowed to warm to room temperature and was stirred overnight. The solvent was removed under vacuum and the residue diluted with 200 ml of H2O and extracted with 500 ml of ethyl acetate. The aqueous layer was extracted with an additional 200 ml of ethyl acetate. The combined extract was washed with H2O, brine and dried with Na2SO4. The solvent was removed to give 41.18 g of crude product. The product was chromatographed on silica gel with hexane-ethyl acetate (1:1) as solvent to give 8.14 g (RF 0.38) of product as a yellow semi-solid. From a small scale run (1 mmol) the product was chromatographed twice on thick silica gel plates with hexane-ethyl acetate (1:1) to give 0.12 g of a yellow semi-solid. Anal. for C19H22N2SO8 : Calc'd: C,52.0; H,5.1; N,6.4: Found: C,51.7; H,5.1; N,6.0.
Reaction SMILES: [CH2:1]([O:5][C:6]1[CH:11]=[CH:10][C:9]([S:12]([NH:15][CH:16]([CH2:21]O)[C:17]([O:19][CH3:20])=[O:18])(=[O:14])=[O:13])=[CH:8][CH:7]=1)[C:2]#[C:3][CH3:4].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.CCOC(/N=N/C(OCC)=O)=O>C1COCC1>[CH2:1]([O:5][C:6]1[CH:11]=[CH:10][C:9]([S:12]([N:15]2[CH2:21][CH:16]2[C:17]([O:19][CH3:20])=[O:18])(=[O:14])=[O:13])=[CH:8][CH:7]=1)[C:2]#[C:3][CH3:4]
Reactant: CC#CCOc1ccc(S(=O)(=O)NC(CO)C(=O)OC)cc1
Agent: CCOC(=O)/N=N/C(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: CC#CCOc1ccc(S(=O)(=O)N2CC2C(=O)OC)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 58 %

Procedure:
To a THF solution (10 mL) of methyl 2-({[4-(2-butynyloxy)phenyl]sulfonyl}amino)-3-hydroxypropanoate (0.33 g, 1 mmol) and triphenylphosphine (0.32 g, 1.2 mmol), diethylazodicarboxylate (0.19 mL, 1.2 mmol) was added dropwise. The mixture was stirred at room temperature overnight. After removing the solvent, the residue was extracted with ether. The organic layer was washed with 1N NaHCO3, water and brine, dried over sodium sulfate, filtered and concentrated. The residue was purified by column chromatography on silica gel eluting with hexane:ethyl acetate (1:1) to provide 0.18 g of 1-({[4-(2-butynyloxy)phenyl]sulfonyl}-2-aziridinecarboxylic acid, methyl ester. Yield 58.0%. Electrospray Mass Spec 310.2(M+H)+.
Reaction SMILES: [CH3:1][S:2][CH:3]([C:7]1[CH:12]=[C:11]([CH:13]=[O:14])[CH:10]=[CH:9][C:8]=1[O:15][CH3:16])[C:4]([OH:6])=[O:5].C(=O)([O-])[O-].[K+].[K+].[CH2:23](Br)[C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1>CN(C)C=O>[CH3:1][S:2][CH:3]([C:7]1[CH:12]=[C:11]([CH:13]=[O:14])[CH:10]=[CH:9][C:8]=1[O:15][CH3:16])[C:4]([O:6][CH2:23][C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1)=[O:5]
Reactant: COc1ccc(C=O)cc1C(SC)C(=O)O
Reactant: BrCc1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: COc1ccc(C=O)cc1C(SC)C(=O)OCc1ccccc1
Temperature: 0 °C
Yield: 83 %

Procedure:
Ethyl 2-methylthio-2-(5-formyl-2-methoxyphenyl)acetate (4.80 g, 17.9 mmol), ethanol (30 mL) and 10% aqueous solution of sodium hydroxide (20 mL) were mixed and the mixture was stirred for 3 hours at room temperature. The reaction mixture was poured in ice water and made acidic with concentrated hydrochloric acid, which was then extracted with ethyl acetate. The extracte was washed with water, dried over anhydrous sodium sulfate, and then concentrated to afford 4.00 g of crude 2-methylthio-2-(5-formyl-2-methoxyphenyl)acetic acid as yellow crystals (this compound was used for next reaction without further purification). Next, 2-methylthio-2-(5-formyl-2-methoxyphenyl)acetic acid (4.00 g, 16.4 mmol) and N,N-dimethylformamide (50 mL) were mixed and, after anhydrous potassium carbonate (3.71 g, 26.8 mmol) and benzyl bromide (3.06 g, 17.9 mmol) were added at room temperature under stirring, the mixture was stirred for 5 hours. The reaction mixture was poured in ice water and extracted with ether. The extracted solution was washed with water and brine, and then dried over anhydrous sodium sulfate. The reaction mixture was concentrated and the residue was purified by silica gel column chromatography (eluate n-hexane:ethyl acetate=6:1 v/v) to afford 4.50 g (76%) of the title compound as a light brown oil.
Reaction SMILES: [OH:1][C:2]1[C:7]([O:8][CH3:9])=[CH:6][C:5]([C:10]2([C:14]#[N:15])[CH2:13][CH2:12][CH2:11]2)=[C:4]([N+:16]([O-:18])=[O:17])[CH:3]=1.C(=O)([O-])[O-].[K+].[K+].[Cl:25][CH2:26][CH2:27][CH2:28]I>CC#N>[Cl:25][CH2:26][CH2:27][CH2:28][O:1][C:2]1[C:7]([O:8][CH3:9])=[CH:6][C:5]([C:10]2([C:14]#[N:15])[CH2:11][CH2:12][CH2:13]2)=[C:4]([N+:16]([O-:18])=[O:17])[CH:3]=1
Reactant: ClCCCI
Reactant: COc1cc(C2(C#N)CCC2)c([N+](=O)[O-])cc1O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: COc1cc(C2(C#N)CCC2)c([N+](=O)[O-])cc1OCCCCl
Temperature: 80 °C
Reaction time: 3 h
Yield: 97 %

Procedure:
1-(4-(Hydroxyl)-5-methoxy-2-nitrophenyl)cyclobutanecarbonitrile (0.5 g, 2 mmol) in MeCN (10 mL) was treated with potassium carbonate (0.306 g, 2.2 mmol) and 1-chloro-3-iodopropane (0.425 mL, 4 mmol) and stirred at 80° C. for 3 hours. The reaction mixture was concentrated, extracted with dichloromethane and washed with brine. The organic layer was dried (MgSO4), filtered and concentrated. Purification by flash chromatography (silica gel, 5-24% EtOAc/hexane) afforded 0.63 g (96%) of 1-(4-(3-chloropropoxy)-5-methoxy-2-nitrophenyl)cyclobutanecarbonitrile. MS (ESI) m/z 325 (M+H)+.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][C:4]([N:7]2[CH2:12][CH2:11][N:10]([C:13]([CH:15]3[CH2:20][CH2:19][NH:18][CH2:17][CH2:16]3)=[O:14])[CH2:9][CH2:8]2)=[N:3][CH:2]=1.[Cl:21][C:22]1[CH:27]=[CH:26][C:25]([S:28](Cl)(=[O:30])=[O:29])=[CH:24][CH:23]=1.CCN(CC)CC.C([O-])(O)=O.[Na+]>C(Cl)Cl>[Cl:21][C:22]1[CH:27]=[CH:26][C:25]([S:28]([N:18]2[CH2:19][CH2:20][CH:15]([C:13]([N:10]3[CH2:9][CH2:8][N:7]([C:4]4[CH:5]=[CH:6][N:1]=[CH:2][N:3]=4)[CH2:12][CH2:11]3)=[O:14])[CH2:16][CH2:17]2)(=[O:30])=[O:29])=[CH:24][CH:23]=1
Reactant: O=S(=O)(Cl)c1ccc(Cl)cc1
Reactant: O=C(C1CCNCC1)N1CCN(c2ccncn2)CC1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: O=C(C1CCN(S(=O)(=O)c2ccc(Cl)cc2)CC1)N1CCN(c2ccncn2)CC1
Yield: 26 %

Procedure:
4-(1-(4-Pyrimidinyl)piperazin-4ylcarbonyl)piperidine (412 mg; 1.5 mmol) was dissolved in CH2Cl2 (16 ml), cooled in an ice bath, stirred and treated dropwise with a mixture of 4-Chlorobenzenesulfonyl chloride (338 mg; 1.6 mmol) and Et3N (0.3 ml; 2 mmol) in CH2Cl2 (16 ml). The reaction mixture was allowed to reach room temperature and stirred thus for 18 h before treating with saturated NaHCO3 (aq) This mixture was then extacted twice with CH2Cl2. The combined organic extracts were washed twice each with water and brine, dried over MgSO4, filtered and evaporated under reduced pressure to a yellow solid. The solid thus obtained was chromatographed through a 10 g silica "bond elut" prepacked column, eluting with 1% methanol, 1% ammonimum hydroxide and 98% CH2Cl2 to obtain 1-(4-chlorophenylsulphonyl)-4-(1-(4-pyrimidinyl)piperazin-4-ylcarbonyl)piperidine (178 mg; 26% yield based on the amine ), a white solid, m.p. 125-128° C.;
Reaction SMILES: [CH:1]([N:4]1[CH2:9][CH2:8][CH:7]([C:10]2[CH:15]=[CH:14][C:13]([N+:16]([O-])=O)=[CH:12][CH:11]=2)[CH2:6][CH2:5]1)([CH3:3])[CH3:2].O.NN>C(O)C.[Pd]>[CH:1]([N:4]1[CH2:5][CH2:6][CH:7]([C:10]2[CH:11]=[CH:12][C:13]([NH2:16])=[CH:14][CH:15]=2)[CH2:8][CH2:9]1)([CH3:3])[CH3:2]
Reactant: CC(C)N1CCC(c2ccc([N+](=O)[O-])cc2)CC1
Agent: [Pd]
Agent: NN
Solvent: CCO
Solvent: O
Product: CC(C)N1CCC(c2ccc(N)cc2)CC1

Procedure:
To a solution of 1-isopropyl-4-(4-nitro-phenyl)-piperidine (2.405 g, 9.698 mmol), prepared according to Example 5, in ethanol (100 mL) under nitrogen is added Pd/C 10% (515.9 mg, 0.485 mmol), followed by dropwise addition of hydrazine hydrate (2.427 g, 48.49 mmol). The mixture is refluxed overnight until completion of the reaction. After filtration through a celite plug, the solvent is removed under reduced pressure to yield the title compound, which is used as such for the next step.
Reaction SMILES: C([O:3][C:4]([C:6](=[N:10][NH:11][C:12]1[C:13]([O:27][CH3:28])=[C:14]([C:18]2[CH:23]=[CH:22][CH:21]=[C:20]([C:24]([OH:26])=[O:25])[CH:19]=2)[CH:15]=[CH:16][CH:17]=1)[C:7](=O)[CH3:8])=O)C.Cl.[CH3:30][C:31]1[CH:32]=[C:33]([NH:38][NH2:39])[CH:34]=[CH:35][C:36]=1[CH3:37].C([O-])(=O)C.[Na+]>C(O)(=O)C>[CH3:30][C:31]1[CH:32]=[C:33]([N:38]2[C:4](=[O:3])[C:6](=[N:10][NH:11][C:12]3[C:13]([O:27][CH3:28])=[C:14]([C:18]4[CH:23]=[CH:22][CH:21]=[C:20]([C:24]([OH:26])=[O:25])[CH:19]=4)[CH:15]=[CH:16][CH:17]=3)[C:7]([CH3:8])=[N:39]2)[CH:34]=[CH:35][C:36]=1[CH3:37]
Reactant: CCOC(=O)C(=NNc1cccc(-c2cccc(C(=O)O)c2)c1OC)C(C)=O
Reactant: Cc1ccc(NN)cc1C
Agent: CC(=O)[O-]
Agent: Cl
Agent: [Na+]
Solvent: CC(=O)O
Product: COc1c(NN=C2C(=O)N(c3ccc(C)c(C)c3)N=C2C)cccc1-c1cccc(C(=O)O)c1

Procedure:
A solution of 3′-{-2-[1-(ethoxycarbonyl)-2-oxopropylidene]hydrazino}-2′-methoxybiphenyl-3-carboxylic acid (3.5 g) prepared as in Example 7, and 3,4-dimethylphenylhydrazine hydrochloride (1.72 g) and sodium acetate(0.9 g) in glacial acetic acid (120 mL) was stirred and heated to about reflux temperature for about 4 hours. The mixture was cooled to about room temperature and stirred for about 1 hour. It was filtered, washed with water (25 mL) and dried in an oven at about 55° C. to about 60° C. for about 12 hours to an orange solid.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:11]2[O:15][C:14](=[O:16])[NH:13][CH2:12]2)[CH:6]=[CH:7][C:8]=1[O:9][CH3:10].[H-].[Na+].[CH3:19]I>CN(C)C=O>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:11]2[O:15][C:14](=[O:16])[N:13]([CH3:19])[CH2:12]2)[CH:6]=[CH:7][C:8]=1[O:9][CH3:10]
Reactant: COc1ccc(C2CNC(=O)O2)cc1OC
Reactant: CI
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: COc1ccc(C2CN(C)C(=O)O2)cc1OC
Reaction time: 0.67 h
Yield: 60 %

Procedure:
10 mmol of 5-(3,4-dimethoxyphenyl)-2oxazolidinone is dissolved in 20 ml. of absolute dimethylformamide and combined with 11 mmol of sodium hydride. The mixture is then stirred for 40 minutes at 40°. After cooling, 20 mmol of methyl iodide in 5 ml. of dimethylformamide is added dropwise and thereafter the reaction mixture is agitated for 6 hours at 50°. After the dimethylformamide has been removed by evaporation, the mixture is taken up in chloroform and then washed first with a small amount of water and then with saturated sodium chloride solution, dried, filtered, and concentrated. The residue is chromatographed over 60 g. of silica gel with chloroform/methanol (96:4) as the eluent. Recrystallization from ethanol produces a 60% yield of 5-(3,4-dimethoxyphenyl)-3-methyl-2-oxazolidinone, m.p. 132°-133°.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([Cl:8])=[CH:4][C:3]=1[C:9](=O)[CH3:10].[O:12]1[CH2:17][CH2:16][N:15]([S:18]([C:21]2[CH:22]=[C:23]([CH:28]=[CH:29][CH:30]=2)[C:24]([NH:26][NH2:27])=[O:25])(=[O:20])=[O:19])[CH2:14][CH2:13]1>CO.C(O)(=O)C>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([Cl:8])=[CH:4][C:3]=1/[C:9](=[N:27]/[NH:26][C:24](=[O:25])[C:23]1[CH:28]=[CH:29][CH:30]=[C:21]([S:18]([N:15]2[CH2:16][CH2:17][O:12][CH2:13][CH2:14]2)(=[O:19])=[O:20])[CH:22]=1)/[CH3:10]
Reactant: CC(=O)c1cc(Cl)ccc1Cl
Reactant: NNC(=O)c1cccc(S(=O)(=O)N2CCOCC2)c1
Solvent: CC(=O)O
Solvent: CO
Product: C/C(=N\NC(=O)c1cccc(S(=O)(=O)N2CCOCC2)c1)c1cc(Cl)ccc1Cl
Temperature: 120 °C

Procedure:
1-(2,5-Dichlorophenyl)ethanone (20 mg, 0.106 mmol) and 3-(morpholinosulfonyl)benzohydrazide (30.2 mg, 0.106 mmol) were dissolved in methanol (4 mL) in the presence of acetic acid as a catalyst, and the reaction mixture was heated via microwave irradiation to 120° C. for 30 min. Following cooling, the solvent was removed by vacuum and the resulting crude material was purified by flash column chromatography affording the title compound in a 10 mg yield. 1H NMR (400 MHz, CDCl3): δ 8.29 (m, 1H), 8.09 (m, 1H), 7.81 (m, 1H), 7.57 (m, 1H), 7.40 (m, 1H), 7.26 (m, 2H), 3.52 (m, 4H), 2.91 (m, 4H), 2.28 (s, 3H). ESI-MS: 456.1 [M+H]+.
Reaction SMILES: [F:1][CH:2]([F:16])[C@@:3]12[CH2:15][CH2:14][CH2:13][N:4]1[C@@H](C(Cl)(Cl)Cl)[O:6][C:7]2=O.[NH3:17]>CO>[F:1][CH:2]([F:16])[C@@:3]1([C:7]([NH2:17])=[O:6])[CH2:15][CH2:14][CH2:13][NH:4]1
Reactant: N
Reactant: O=C1O[C@H](C(Cl)(Cl)Cl)N2CCC[C@@]12C(F)F
Solvent: CO
Product: NC(=O)[C@]1(C(F)F)CCCN1
Reaction time: 72 h

Procedure:
A mixture of (3R,7aS)-7a-difluoromethyl-3-trichloromethyl-tetrahydro-pyrrolo[1,2-c]oxazol-1-one (0.19 g) and 7M ammonia in methanol (4 ml) is stood at room temperature for 3 days in a sealed vessel. The reaction mixture is then filtered and evaporated to give the title compound as a pale brown oil which is used without further purification. MS (Method D) M+H 165.
Reaction SMILES: [Cl:1][C:2]1[CH:30]=[CH:29][C:5]2[N:6]([CH2:20][C:21]3[CH:26]=[CH:25][C:24]([O:27][CH3:28])=[CH:23][CH:22]=3)[C:7](=[O:19])[CH2:8][N:9]=[C:10]([C:11]3[CH:16]=[CH:15][C:14]([O:17][CH3:18])=[CH:13][CH:12]=3)[C:4]=2[CH:3]=1.CC(C)([O-])C.[K+].[Cl:37][C:38]1[CH:45]=[CH:44][CH:43]=[CH:42][C:39]=1[CH2:40]Br>C1COCC1>[Cl:1][C:2]1[CH:30]=[CH:29][C:5]2[N:6]([CH2:20][C:21]3[CH:26]=[CH:25][C:24]([O:27][CH3:28])=[CH:23][CH:22]=3)[C:7](=[O:19])[CH:8]([CH2:40][C:39]3[CH:42]=[CH:43][CH:44]=[CH:45][C:38]=3[Cl:37])[N:9]=[C:10]([C:11]3[CH:16]=[CH:15][C:14]([O:17][CH3:18])=[CH:13][CH:12]=3)[C:4]=2[CH:3]=1
Reactant: COc1ccc(CN2C(=O)CN=C(c3ccc(OC)cc3)c3cc(Cl)ccc32)cc1
Reactant: Clc1ccccc1CBr
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: C1CCOC1
Product: COc1ccc(CN2C(=O)C(Cc3ccccc3Cl)N=C(c3ccc(OC)cc3)c3cc(Cl)ccc32)cc1
Temperature: -78 °C
Reaction time: 0.08 h
Yield: 28.7 %

Procedure:
(Z)-7-Chloro-1-(4-methoxybenzyl)-5-(4-methoxyphenyl)-1H-benzo[e][1,4]diazepin-2(3H)-one (0.344 g, 0.817 mmol) was dissolved in dry THF (8 mL) and cooled to −78° C. under nitrogen. Potassium tert-butoxide (0.119 g, 1.063 mmol) was added in one portion. The reaction mixture was stirred for 5 min. turning deep red. 2-chlorobenzylbromide (0.128 mL, 0.981 mmol) was added by syringe. The mixture was stirred at −78° C. for 1.5 h then the cold bath was removed. After 1 h, the reaction was quenched with methanol and diluted with ethyl acetate. The organic layer was washed with water (2×) then brine and dried (MgSO4). Chromatography on silica gel eluting with 25-30% ethyl acetate in hexanes gave (Z)-7-chloro-3-(2-chlorobenzyl)-1-(4-methoxybenzyl)-5-(4-methoxyphenyl)-1H-benzo[e][1,4]diazepin-2(3H)-one (128 mg, 29%). 1H NMR (300 MHz, CDCl3) δ 3.6-3.8 (m, 2H), 3.7 (s, 3H), 3.8 (s, 3H), 3.9-4.0 (m, 1H), 4.55 (d, 1H), 5.7 (d, 1H), 6.6 (d, 2H), 6.8-6.9 (m, 4H), 7.1-7.4 (m, 8H), 7.6 (dd, 1H); ESI m/z.
Reaction SMILES: [OH-:1].[Na+].Cl[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=1[CH2:10][C:11]([OH:13])=[O:12]>O.O.O.O.O.S([O-])([O-])(=O)=O.[Cu+2]>[OH:1][C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=1[CH2:10][C:11]([OH:13])=[O:12]
Reactant: O=C(O)Cc1ccccc1Cl
Reactant: [OH-]
Agent: [Cu+2]
Agent: O=S(=O)([O-])[O-]
Agent: [Na+]
Solvent: O
Product: O=C(O)Cc1ccccc1O
Temperature: 180 °C
Reaction time: 15 h
Yield: 17.8 %

Procedure:
Solid pearl sodium hydroxide (as discrete spheres) (24 g) was suspended in `SOLVESSO` 200 (100 ml) at 25° C. (2-Chlorophenyl)acetic acid (17.0 g) was added to this in one portion and the mixture was stirred for 20 minutes at room temperature after which time copper sulphate pentahydrate (1.0 g) was added. The reaction mixture was then heated and stirred at 180° C. After 15 hours gas/liquid chromatography indicated that all the (2-chlorophenyl)acetic acid had been consumed. The reaction mixture was cooled to room temperature and during this process it thickened. (The pearl sodium hydroxide was still in discrete spheres). The reaction mixture was filtered and the residue washed twice with hexane. After briefly air drying the residue, it was dissolved in water. The water solution was filtered to remove some brown solid before being washed with ethyl acetate. Charcoal was then added to the water solution and the resulting mixture was filtered through `Hyflo` (`Hyflo` is a Trade Name of Trade Mark). The filtrate was acidified to pH 3.5 and a few oily specs were formed. These were filtered off. The resulting filtrate was extracted with ethyl acetate. The extracts were combined, dried and evaporated to give a crude product (10.5 g). The crude product was recrystallised from water and then recrystallised from acetic acid to give 2.7 g of (2-hydroxyphenyl)acetic acid as a crystalline solid (melting point 141.4°-142° C.) (theoretical m.pt. 147°-149° C.).
Reaction SMILES: C[O:2][C:3]([C:5]1[CH:10]=[CH:9][C:8]([O:11][CH2:12][CH2:13][O:14][CH3:15])=[CH:7][N:6]=1)=[O:4].[OH-].[Na+]>C1COCC1>[CH3:15][O:14][CH2:13][CH2:12][O:11][C:8]1[CH:9]=[CH:10][C:5]([C:3]([OH:4])=[O:2])=[N:6][CH:7]=1
Reactant: COCCOc1ccc(C(=O)OC)nc1
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Product: COCCOc1ccc(C(=O)O)nc1
Temperature: 25 °C
Reaction time: 2.5 h

Procedure:
To a solution of 5-(2-methoxy-ethoxy)-pyridine-2-carboxylic acid methyl ester (390 mg, 0.489 mmol) in THF (3 ml) was added 1M aqueous NaOH (0.538 ml). The reaction mixture was stirred at room temperature for 2.5 h, concentrated, the residue was dissolved in EtOAc and washed twice with water. The aqueous layers were acidified with 1M aqueous HCl (0.538 ml) and the title compound was isolated by lyophilisation.
Reaction SMILES: [F:1][C:2]([F:32])([CH2:7][CH2:8][C@H:9]([C@@H:11]1[C@:28]2([CH3:29])[C@H:14]([C@H:15]3[C@H:25]([CH2:26][CH2:27]2)[C@:23]2([CH3:24])[C:18]([CH2:19][C@@H:20]([OH:31])[CH2:21][C@@H:22]2[OH:30])=[CH:17][CH2:16]3)[CH2:13][CH2:12]1)[CH3:10])[C:3]([OH:6])([CH3:5])[CH3:4].C(O[C:37](=[O:39])[CH3:38])(=O)C>N1C=CC=CC=1.CN(C)C1C=CN=CC=1>[C:3]([O:30][C@@H:22]1[C@@:23]2([CH3:24])[C:18](=[CH:17][CH2:16][C@@H:15]3[C@@H:25]2[CH2:26][CH2:27][C@@:28]2([CH3:29])[C@H:14]3[CH2:13][CH2:12][C@@H:11]2[C@H:9]([CH3:10])[CH2:8][CH2:7][C:2]([F:32])([F:1])[C:3]([O:6][C:22](=[O:30])[CH3:21])([CH3:4])[CH3:5])[CH2:19][C@@H:20]([O:31][C:37](=[O:39])[CH3:38])[CH2:21]1)(=[O:6])[CH3:2]
Reactant: C[C@H](CCC(F)(F)C(C)(C)O)[C@H]1CC[C@H]2[C@@H]3CC=C4C[C@@H](O)C[C@H](O)[C@]4(C)[C@H]3CC[C@]12C
Reactant: CC(=O)OC(C)=O
Agent: CN(C)c1ccncc1
Solvent: c1ccncc1
Product: CC(=O)O[C@@H]1CC2=CC[C@H]3[C@@H]4CC[C@H]([C@H](C)CCC(F)(F)C(C)(C)OC(C)=O)[C@@]4(C)CC[C@@H]3[C@@]2(C)[C@@H](OC(C)=O)C1

Procedure:
When a mixture of [1α,3β]-24,24-difluorocholest-5-en-1,3,25-triol in pyridine is reacted with acetic anhydride and a catalytic amount of 4-dimethylaminopyridine, [1α,3β]-24,24-difluorocholest-5-en-1,3,25-triol 1,3,25-triacetate can be obtained.
Reaction SMILES: C([O:5][C:6]([N:8]1[C:12]([CH3:13])=[C:11]([Cl:14])[C:10]([C:15]([F:18])([F:17])[F:16])=[N:9]1)=[O:7])(C)(C)C.Cl.O1CCOCC1.CCOCC>ClCCl>[Cl:14][C:11]1[C:10]([C:15]([F:17])([F:16])[F:18])=[N:9][N:8]([C:6]([OH:7])=[O:5])[C:12]=1[CH3:13]
Reactant: Cc1c(Cl)c(C(F)(F)F)nn1C(=O)OC(C)(C)C
Agent: Cl
Solvent: ClCCl
Solvent: C1COCCO1
Solvent: CCOCC
Product: Cc1c(Cl)c(C(F)(F)F)nn1C(=O)O
Reaction time: 2 h

Procedure:
To a stirred solution of 43.62 mmol of 4-chloro-5-methyl -3-trifluoromethyl pyrazole-1-carboxylic acid tertbutyl ester in 20 mL of dichloromethane, carefully add 40 mL of 4M HCl/dioxane. The reaction mixture was allowed to stir for 2 hours. Add fresh ether and filter the white solid obtained. Vaccum dry to give the title compound 4-chloro-5-methyl -3-trifluoromethyl pyrazole-1-carboxylic acid in 96% yield. LC-MS ink=242 (M+)
Reaction SMILES: [F:1][C:2]1[C:35]([F:36])=[CH:34][CH:33]=[CH:32][C:3]=1[CH2:4][S:5][C:6]1[N:11]=[C:10]([O:12][C@H:13]([CH3:19])[C:14](OCC)=[O:15])[CH:9]=[C:8]([NH:20][S:21]([N:24]2[CH2:29][CH2:28][N:27]([CH2:30][CH3:31])[CH2:26][CH2:25]2)(=[O:23])=[O:22])[N:7]=1.[Li+].[BH4-].[NH4+].[Cl-]>C1COCC1>[F:1][C:2]1[C:35]([F:36])=[CH:34][CH:33]=[CH:32][C:3]=1[CH2:4][S:5][C:6]1[N:7]=[C:8]([NH:20][S:21]([N:24]2[CH2:25][CH2:26][N:27]([CH2:30][CH3:31])[CH2:28][CH2:29]2)(=[O:22])=[O:23])[CH:9]=[C:10]([O:12][C@H:13]([CH3:19])[CH2:14][OH:15])[N:11]=1
Reactant: CCOC(=O)[C@@H](C)Oc1cc(NS(=O)(=O)N2CCN(CC)CC2)nc(SCc2cccc(F)c2F)n1
Agent: [BH4-]
Agent: [Cl-]
Agent: [Li+]
Solvent: C1CCOC1
Product: CCN1CCN(S(=O)(=O)Nc2cc(O[C@H](C)CO)nc(SCc3cccc(F)c3F)n2)CC1
Temperature: 25 °C
Reaction time: 18 h

Procedure:
To a solution of ethyl(2R)-2-[(2-[(2,3-Difluorobenzyl)thio]-6-{[(4-ethylpiperazin-1-yl)sulfonyl]amino}pyrimidin-4-yl)oxy]propanoate (the product from step i) (0.72 g) in THF (10 ml) was added 2M LiBH4 in TI-IF (1.3 ml). The reaction was then stirred for 18 h at RT. Saturated NH4Cl (150 ml) was then added to the reaction mixture which was extracted with DCM (3×150 ml). Organics were combined, dried (MgSO4) and reduced in vacuo and the resulting residue was purified by prep HPLC to give the title compound as a white solid.
Reaction SMILES: [NH2:1][C:2]1[C:3]([NH:10][C:11]2[CH:16]=[CH:15][C:14]([I:17])=[CH:13][C:12]=2[F:18])=[CH:4][C:5](=[O:9])[N:6]([CH3:8])[CH:7]=1.[CH2:19]([C:22]1([S:25](Cl)(=[O:27])=[O:26])[CH2:24][CH2:23]1)[CH:20]=[CH2:21].Cl>N1C=CC=CC=1>[CH2:19]([C:22]1([S:25]([NH:1][C:2]2[C:3]([NH:10][C:11]3[CH:16]=[CH:15][C:14]([I:17])=[CH:13][C:12]=3[F:18])=[CH:4][C:5](=[O:9])[N:6]([CH3:8])[CH:7]=2)(=[O:27])=[O:26])[CH2:24][CH2:23]1)[CH:20]=[CH2:21]
Reactant: Cn1cc(N)c(Nc2ccc(I)cc2F)cc1=O
Reactant: C=CCC1(S(=O)(=O)Cl)CC1
Agent: Cl
Solvent: c1ccncc1
Product: C=CCC1(S(=O)(=O)Nc2cn(C)c(=O)cc2Nc2ccc(I)cc2F)CC1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
5-Amino-4-(2-fluoro-4-iodophenylamino)-1-methylpyridin-2(1H)-one (prepared as described in steps a-e in example 1 above) was dissolved in dry pyridine at 0° C. under an ice-salt bath, and 1-allylcyclopropane-1-sulfonyl chloride was added. The resultant reaction mixture was allowed to warm to room temperature. After stirring for 16 hours at room temperature, aqueous HCl (1N) was added and the mixture was stirred for 15 minutes. The formed precipitate was filtered and dried under vacuum, and purified by preparative TLC (SiO2, EtOAc:MeOH=9:1 (v:v), Rf˜0.4).
Reaction SMILES: [CH:1]1([CH2:5][N:6]2[CH:14]=[C:13]3[C:8]([CH:9]=[C:10]([C:15]4[CH:16]=[C:17]([CH:25]5[CH2:30][CH2:29][NH:28][CH2:27][CH2:26]5)[N:18]5[C:23]=4[C:22]([NH2:24])=[N:21][CH:20]=[N:19]5)[CH:11]=[CH:12]3)=[N:7]2)[CH2:4][CH2:3][CH2:2]1.ClC[C:33]([N:35]([CH3:37])[CH3:36])=[O:34]>>[NH2:24][C:22]1[C:23]2=[C:15]([C:10]3[CH:11]=[CH:12][C:13]4[C:8]([CH:9]=3)=[N:7][N:6]([CH2:5][CH:1]3[CH2:2][CH2:3][CH2:4]3)[CH:14]=4)[CH:16]=[C:17]([CH:25]3[CH2:30][CH2:29][N:28]([C:33]([N:35]([CH3:37])[CH3:36])=[O:34])[CH2:27][CH2:26]3)[N:18]2[N:19]=[CH:20][N:21]=1
Reactant: Nc1ncnn2c(C3CCNCC3)cc(-c3ccc4cn(CC5CCC5)nc4c3)c12
Reactant: CN(C)C(=O)CCl
Product: CN(C)C(=O)N1CCC(c2cc(-c3ccc4cn(CC5CCC5)nc4c3)c3c(N)ncnn23)CC1
Yield: 85 %

Procedure:
In a manner similar to the procedure described for Example 369 and using 5-[2-(cyclobutylmethyl)-2H-indazol-6-yl]-7-piperidin-4-ylpyrrolo[2,1-f][1,2,4]triazin-4-amine and substituting dimethylcarbamyl chloride for 2-chloro-N,N-dimethylacetamide as starting materials, 60 mg, (85%) of the desired product was isolated. LC-MS [M+H]+=473.3, RT=2.55 min.