Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([C:5]1[CH:13]=[CH:12][C:8]([C:9]([OH:11])=[O:10])=[C:7]([O:14]COC)[CH:6]=1)([CH3:4])([CH3:3])[CH3:2].[CH3:18]O>>[C:1]([C:5]1[CH:13]=[CH:12][C:8]([C:9]([O:11][CH3:18])=[O:10])=[C:7]([OH:14])[CH:6]=1)([CH3:4])([CH3:3])[CH3:2]
Reactant: COCOc1cc(C(C)(C)C)ccc1C(=O)O
Reactant: CO
Product: COC(=O)c1ccc(C(C)(C)C)cc1O
Temperature: 25 °C

Procedure:
A solution of 4-tert-butyl-2-(methoxymethoxy)benzoic acid (61.80 g, 259 mmol) and MeOH (865 mL) was cooled in an ice bath. Gaseous HCl was sparged through the cold fluid for 30 min to saturate it, and the solution was then heated to reflux. A Soxhlet extractor containing 3 Å molecular sieves was used to absorb the water produced in the reaction. After 16 h the heating mantle was removed, and the solution was allowed to cool to ambient temperature. The filtrate was concentrated to a thick semisolid which was taken up in 1:1 water/CH2Cl2 (800 mL). The aqueous layer was extracted once with CH2Cl2 (100 mL), and the combined organic layers were washed with water (250 mL) and 5% (w/w) NaHCO3 (200 mL). The organic layer was dried (MgSO4), filtered and concentrated to 49.54 g (92%) of yellow oil:
Reaction SMILES: Cl.[CH2:2]([O:4][C:5]([C:7]1[CH:12]([C:13]2[CH:18]=[CH:17][CH:16]=[C:15]([N+:19]([O-:21])=[O:20])[CH:14]=2)[N:11]2[CH:22]=[CH:23][N:24]=[C:10]2[NH:9][C:8]=1[CH:25]=O)=[O:6])[CH3:3].Cl.[NH2:28][OH:29].C(=O)([O-])[O-].[Na+].[Na+]>C(O)C.CN(C)C=O>[CH2:2]([O:4][C:5]([C:7]1[CH:12]([C:13]2[CH:18]=[CH:17][CH:16]=[C:15]([N+:19]([O-:21])=[O:20])[CH:14]=2)[N:11]2[CH:22]=[CH:23][N:24]=[C:10]2[NH:9][C:8]=1[CH:25]=[N:28][OH:29])=[O:6])[CH3:3]
Reactant: CCOC(=O)C1=C(C=O)Nc2nccn2C1c1cccc([N+](=O)[O-])c1
Reactant: NO
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CCO
Solvent: CN(C)C=O
Product: CCOC(=O)C1=C(C=NO)Nc2nccn2C1c1cccc([N+](=O)[O-])c1
Temperature: 50 °C
Reaction time: 1.5 h

Procedure:
To a solution of 6-ethoxycarbonyl-7-formyl-5-(3-nitrophenyl)-5,8-dihydroimidazo[1,2-a]pyrimidine hydrochloride in a mixture of 20 ml of ethanol and 20 ml of dimethylformamide are added 0.88 g of hydroxylamine hydrochloride and 1.22 g of sodium carbonate and the mixture is stirred at 50° C. for 1.5 hours. The solvent is distilled off under reduced pressure and water is added to the residue, then precipitated crystals are collected by filtration. The crystals are recrystallized from a mixture of chloroform and methanol to give 2.0 g of 6-ethoxycarbonyl-7-hydroxyiminomethyl-5-(3-nitrophenyl)-5,8-dihydroimidazo[1,2-a]pyrimidine, melting at 229°-230° C. with decomposition.
Reaction SMILES: [C:1]([O:4][CH:5](SC)[C:6](=[O:19])[C@@H:7]([NH:11][C:12]([O:14][C:15]([CH3:18])([CH3:17])[CH3:16])=[O:13])[CH:8]([CH3:10])[CH3:9])(=[O:3])[CH3:2].CCO.[BH4-].[Na+].Cl>O.CCOC(C)=O>[C:1]([O:4][CH2:5][CH:6]([OH:19])[C@@H:7]([NH:11][C:12]([O:14][C:15]([CH3:16])([CH3:18])[CH3:17])=[O:13])[CH:8]([CH3:10])[CH3:9])(=[O:3])[CH3:2]
Reactant: CSC(OC(C)=O)C(=O)[C@@H](NC(=O)OC(C)(C)C)C(C)C
Agent: Cl
Agent: [BH4-]
Agent: [Na+]
Solvent: O
Solvent: CCO
Solvent: CCOC(C)=O
Product: CC(=O)OCC(O)[C@@H](NC(=O)OC(C)(C)C)C(C)C
Temperature: -20 °C
Reaction time: 1 h

Procedure:
To a suitable reactor was added 3e (1.32 g, 1.0 equiv) and EtOH (26 mL) at 20-30° C. under N2. The mixture was cooled to −25 to −15° C., and NaBH4 (117.4 mg, 0.8 equiv) in H2O (2.6 mL) was added at below −15° C. The reaction mixture was warmed to −5-5° C. and stirred for 1 hr. The reaction was deemed completed as determined by TLC. 1N HCl aqueous solution (13 mL) was added at below 10° C., and the mixture was warmed to 20-30° C. EtOAc (160 mL) was added at 20-30° C., and the mixture was stirred at this temperature for 30 min. The separated organic portion was concentrated at 40-50° C. under reduced pressure to afford crude 4e. The diastereomeric ratio of crude 4e was determined to be 78/22 by HPLC analysis. The residue was purified by flash column chromatography (EtOAc/n-heptane=1/2) to give a diastereomeric mixture of 4e (0.92 g, 81% yield) as a yellow oil.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]2[C:12](=[CH:13][CH:14]=1)[NH:11][C:10]1[CH2:9][CH2:8][C@H:7]([NH2:15])[CH2:6][C:5]2=1.FC1C=C2C(=CC=1)NC1CC[C@@H](N[C@H](C3C=CC=CC=3)C)CC2=1>>[F:1][C:2]1[CH:3]=[C:4]2[C:12](=[CH:13][CH:14]=1)[NH:11][C:10]1[CH2:9][CH2:8][C@@H:7]([NH2:15])[CH2:6][C:5]2=1
Reactant: N[C@H]1CCc2[nH]c3ccc(F)cc3c2C1
Agent: C[C@H](N[C@@H]1CCc2[nH]c3ccc(F)cc3c2C1)c1ccccc1
Product: N[C@@H]1CCc2[nH]c3ccc(F)cc3c2C1

Procedure:
Following the same procedure as (S)-6-fluoro-2,3,4,9-tetrahydro-1H-carbazol-3-amine, hydrogenation of (R)-6-fluoro-N—((S)-1-phenylethyl)-2,3,4,9-tetrahydro-1H-carbazol-3-amine (8.7 g, 0.028 mol) gave the title compound as a white solid.
Reaction SMILES: [NH2:1][CH:2]1[CH:9]2[CH2:10][CH:5]3[CH2:6][CH:7]([CH2:11][CH:3]1[CH2:4]3)[CH2:8]2.[N+]([O-])(O)=[O:13].[OH-].[Na+]>OS(O)(=O)=O>[NH2:1][CH:2]1[CH:3]2[CH2:11][C:7]3([OH:13])[CH2:6][CH:5]([CH2:10][CH:9]1[CH2:8]3)[CH2:4]2
Reactant: NC1C2CC3CC(C2)CC1C3
Reactant: O=[N+]([O-])O
Agent: O=S(=O)(O)O
Agent: [Na+]
Agent: [OH-]
Product: NC1C2CC3CC1CC(O)(C3)C2
Reaction time: 8 h
Yield: 14 %

Procedure:
To 2-aminoadamantane (10 g, 54 mmol) was added H2SO4 (150 mL) and HNO3 (15 ml) at 0° C. and the mixture was stirred overnight. The mixture was poured onto ice and adjusted to pH=10-11 using 40% aq NaOH under ice bath. The mixture was extracted with CH2Cl2. The organic layer was dried, filtered and concentrated to give 4-aminoadamantan-1-ol (3.0 g, 14%).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:9]2([CH2:30][CH2:31]OS(C)(=O)=O)[O:13][C:12](=[O:14])[N:11]([CH2:15][C:16]3[CH:21]=[C:20]([C:22]([F:25])([F:24])[F:23])[CH:19]=[C:18]([C:26]([F:29])([F:28])[F:27])[CH:17]=3)[CH2:10]2)[CH:5]=[CH:6][C:7]=1[Cl:8].[C:37]1([CH:43]2[CH2:48][CH2:47][NH:46][CH2:45][CH2:44]2)[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=1.O.Cl>CN(C=O)C.C(Cl)Cl.CCOCC>[ClH:1].[Cl:1][C:2]1[CH:3]=[C:4]([C:9]2([CH2:30][CH2:31][N:46]3[CH2:47][CH2:48][CH:43]([C:37]4[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=4)[CH2:44][CH2:45]3)[O:13][C:12](=[O:14])[N:11]([CH2:15][C:16]3[CH:21]=[C:20]([C:22]([F:23])([F:24])[F:25])[CH:19]=[C:18]([C:26]([F:28])([F:27])[F:29])[CH:17]=3)[CH2:10]2)[CH:5]=[CH:6][C:7]=1[Cl:8]
Reactant: c1ccc(C2CCNCC2)cc1
Reactant: CS(=O)(=O)OCCC1(c2ccc(Cl)c(Cl)c2)CN(Cc2cc(C(F)(F)F)cc(C(F)(F)F)c2)C(=O)O1
Agent: Cl
Solvent: ClCCl
Solvent: CCOCC
Solvent: O
Product: O=C1OC(CCN2CCC(c3ccccc3)CC2)(c2ccc(Cl)c(Cl)c2)CN1Cc1cc(C(F)(F)F)cc(C(F)(F)F)c1
Temperature: 80 °C
Yield: 79.4 %

Procedure:
A mixture of 1.5 g of the compound obtained in step B of EXAMPLE 21 and 1.03 g of 4-phenylpiperidine in 3 ml of DMF is heated at 80° C. for 3 hours. After cooling, the reaction mixture is poured into water and extracted with AcOEt, the organic phase is washed with water and dried over MgSO4 and the solvent is evaporated off under vacuum. The residue is chromatographed on silica H using a DCM/MeOH mixture (100/1; v/v) as the eluent. The product obtained is dissolved in DCM, a saturated solution of gaseous HCl in ether is added until the pH is 1, and the solvent is evaporated off under vacuum to give 0.7 g of the expected product after crystallization from a DCM/pentane mixture. M.p.=112-114° C.
Reaction SMILES: [H-].[Na+].[OH:3][CH2:4][C@H:5]1[C@H:14]2[CH2:15][CH2:16][N:17]([C:18]([C@H:20]3[CH2:25][CH2:24][CH2:23][CH2:22][C@H:21]3[NH:26][C:27](=[O:34])[C:28]3[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=3)=[O:19])[C@H:13]2[C:12]2[CH:11]=[CH:10][CH:9]=[CH:8][C:7]=2[NH:6]1.CI.[C:37](=O)([O-])O.[Na+]>O1CCCC1>[CH3:37][O:3][CH2:4][C@H:5]1[C@H:14]2[CH2:15][CH2:16][N:17]([C:18]([C@H:20]3[CH2:25][CH2:24][CH2:23][CH2:22][C@H:21]3[NH:26][C:27](=[O:34])[C:28]3[CH:29]=[CH:30][CH:31]=[CH:32][CH:33]=3)=[O:19])[C@H:13]2[C:12]2[CH:11]=[CH:10][CH:9]=[CH:8][C:7]=2[NH:6]1
Reactant: O=C(N[C@@H]1CCCC[C@@H]1C(=O)N1CC[C@@H]2[C@H](CO)Nc3ccccc3[C@@H]21)c1ccccc1
Reactant: O=C([O-])O
Agent: [H-]
Agent: [Na+]
Solvent: CI
Solvent: C1CCOC1
Product: COC[C@@H]1Nc2ccccc2[C@H]2[C@@H]1CCN2C(=O)[C@H]1CCCC[C@H]1NC(=O)c1ccccc1
Reaction time: 1 h
Yield: 84 %

Procedure:
Sodium hydride (60% in oil, 14 mg, 0.1 mmol) was suspended in tetrahydrofuran (1 ml), the compound (35 mg, 0.08 mmol) synthesized in Example 50 was added under ice-cooling, and the suspension was stirred for 1 hr. Methyl iodide (14 mg, 0.1 mmol) was added thereto, and the mixture was stirred under ice-cooling for 30 min., and then at room temperature for 2 hrs. Saturated aqueous sodium hydrogen carbonate solution was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The extract was dried (over anhydrous Na2SO4), and the solvent was evaporated under reduced pressure. The residue was subjected to column chromatography using silica gel (10 g) and eluted with hexane-ethyl acetate (4:1, v/v) to give the title compound (30 mg, 84%) as an amorphous form.
Reaction SMILES: [C:1]1([C:7]2[N:8]=[N:9][C:10](=[S:12])[N:11]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C[O-].[Na+].Br[C:17]1[S:18][C:19]([N+:22]([O-:24])=[O:23])=[CH:20][N:21]=1>CO>[N+:22]([C:19]1[S:18][C:17]([S:12][C:10]2[N:11]=[C:7]([C:1]3[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=3)[NH:8][N:9]=2)=[N:21][CH:20]=1)([O-:24])=[O:23]
Reactant: O=[N+]([O-])c1cnc(Br)s1
Reactant: S=C1N=NC(c2ccccc2)=N1
Agent: C[O-]
Agent: [Na+]
Solvent: CO
Product: O=[N+]([O-])c1cnc(Sc2n[nH]c(-c3ccccc3)n2)s1
Temperature: 25 °C
Reaction time: 2 h
Yield: 49.1 %

Procedure:
The key starting material 2-bromo-5-nitrothiazole was prepared by treating 2-amino-5-nitrothiazole (Aldrich) with sodium nitrite and hydrogen bromide (Fr. Demande 2,015,434, 1970). 3-Phenyl-1,2,4-triazole-5-thione (E. Hogarth, J. Chem. Soc. (1949) 1163) was prepared by first reacting benzoyl chloride with thiosemicarbazide in pyridine at 0° C. to give benzoyl thiosemicarbazide. Benzoyl thiosemicarbazide was treated with potassium hydroxide in ethanol to give 3-phenyl-1,2,4-triazole-5-thione. 3-Phenyl-1,2,4-triazole-5-thione (1.77 g) was then dissolved in 50 mL of methanol and treated with 0.57 g of 95% sodium methoxide, and then with 2-bromo-5-nitrothiazole (2.09 g). The mixture was stirred at room temperature for 2 hours and the precipitated sodium bromide was removed by filtration. The methanol was evaporated and the product crystallized from ethanol and water to give 1.5 g of 3-[(5-nitrothiazol-2-yl)mercapto]-5-phenyl-1,2,4-triazole, an orange solid.
Reaction SMILES: [NH2:1][C:2]1[S:3][CH:4]=[C:5]([CH3:7])[N:6]=1.[CH3:8][N:9]([CH3:13])[C:10](Cl)=[O:11].[Cl-].[Al+3].[Cl-].[Cl-]>C1(C)C(C)=CC=CC=1>[CH3:8][N:9]([CH3:13])[C:10]([NH:1][C:2]1[S:3][CH:4]=[C:5]([CH3:7])[N:6]=1)=[O:11]
Reactant: CN(C)C(=O)Cl
Reactant: Cc1csc(N)n1
Agent: [Al+3]
Agent: [Cl-]
Solvent: Cc1ccccc1C
Product: Cc1csc(NC(=O)N(C)C)n1
Yield: 93.5 %

Procedure:
A mixture of 2-amino-4-methylthiazole (1.14 g), N,N-dimethylcarbamoyl chloride (1.29 g), aluminum chloride (1.60 g), and xylene (40 ml) is refluxed for 20 hours. The reaction mixture is worked up as in Example 1, whereby 1,1-dimethyl-3-(4-methyl-2-thiazolyl)urea (1.73 g) is obtained. Yield is 93.5%. Melting point is 97° to 98° C. (Pure product is recrystallized from ether/petroleum ether).
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][C:5]([O:8][CH3:9])=[CH:4][C:3]=1[OH:10].[CH3:11][C:12](=O)[CH2:13][CH2:14][CH3:15].C1(C)C=CC(S(O)(=O)=O)=CC=1.C1C=CC=CC=1>C(OCC)C>[CH3:9][O:8][C:5]1[CH:6]=[CH:7][C:2]2[O:1][C:12]([CH3:11])([CH2:13][CH2:14][CH3:15])[O:10][C:3]=2[CH:4]=1
Reactant: COc1ccc(O)c(O)c1
Reactant: CCCC(C)=O
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: CCOCC
Solvent: c1ccccc1
Product: CCCC1(C)Oc2ccc(OC)cc2O1

Procedure:
0.35 mole (48.5 g) of 1,2-dihydroxy-4-methoxybenzene, 0.38 mole (32.7 g) of 2-pentanone and 1 g of p-toluenesulphonic acid are added to 350 ml of benzene. The mixture is heated under benzene reflux in order to remove the water formed. After 50 hours' heating, the reaction mixture is cooled and is then filtered through paper. After evaporation under reduced pressure, a brown oil is obtained and is dissolved in 500 ml of ethyl ether. After extraction with a solution of sodium carbonate in water in order to remove the unreacted 1,2-dihydroxy-4-methoxybenzene, the ethereal phase is dried with sodium sulphate. After evaporation of the ethyl ether under reduced pressure, the expected product is obtained and is employed as such in the following stage.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:12][C@:11]([CH2:14][N:15]=[N+]=[N-])([F:13])[CH2:10][C@H:9]1[C:18]([O:20][CH2:21][C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1)=[O:19])=[O:7])([CH3:4])([CH3:3])[CH3:2].CP(C)C.O>C1COCC1>[C:1]([O:5][C:6]([N:8]1[CH2:12][C@:11]([CH2:14][NH2:15])([F:13])[CH2:10][C@H:9]1[C:18]([O:20][CH2:21][C:22]1[CH:23]=[CH:24][CH:25]=[CH:26][CH:27]=1)=[O:19])=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)N1C[C@@](F)(CN=[N+]=[N-])C[C@H]1C(=O)OCc1ccccc1
Agent: CP(C)C
Solvent: C1CCOC1
Solvent: O
Product: CC(C)(C)OC(=O)N1C[C@@](F)(CN)C[C@H]1C(=O)OCc1ccccc1

Procedure:
A solution of (2S,4R)-4-azidomethyl-4-fluoro-pyrrolidine-1,2-dicarboxylic acid 2-benzyl ester 1-tert-butyl ester (prepared as described in Scheme B16) (1 g, 2.64 mmol), trimethylphosphine in THF (3.17 mL, 3.17 mmol) and water (0.10 mL, 5.29 mmol) in THF (40 mL) was stirred for 16 h at RT. The reaction mixture was quenched with water, extracted with EtOAc, washed with brine, dried over Na2SO4, filtered and concentrated. Purification by flash column chromatography on silica gel (CH2Cl2/MeOH 9:1). MS (UPLC/MS): 353 [M+H]+, 411 [M+HCOO]−; tR (HPLC conditions f): 1.62 min.
Reaction SMILES: Cl.[NH2:2][C@H:3]([CH2:7][OH:8])[CH2:4][CH2:5][CH3:6].CO[CH:11](O)[C:12]([F:15])([F:14])[F:13].C(N(CC)CC)C.O>C1C=CC=CC=1.CCOCC>[CH2:4]([C@H:3]1[CH2:7][O:8][CH:11]([C:12]([F:15])([F:14])[F:13])[NH:2]1)[CH2:5][CH3:6]
Reactant: CCC[C@H](N)CO
Reactant: COC(O)C(F)(F)F
Agent: Cl
Solvent: O
Solvent: CCN(CC)CC
Solvent: CCOCC
Product: CCC[C@H]1COC(C(F)(F)F)N1
Reaction time: 3 h

Procedure:
(L)-Norvalinol hydrochloride (5.25 g, 37.60 mmol) and trifluoroacetaldehyde methyl hemiacetal (5 mL, 37.6 mmol) were heated in benzene (100 mL) in the presence of triethylamine (5.26 mL, 37.6 mmol) at reflux, using a Dean-Stark apparatus to trap water. After 3 hours, the reaction mixture was cooled, diluted with ether (100 mL), filtered, and evaporated to dryness, giving (4S)-4-propyl-2-trifluoromethyloxazolidine, which was used without further purification.
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[CH:14]=[C:13]([OH:15])[C:12]2[C:7](=[CH:8][C:9]([CH3:16])=[CH:10][CH:11]=2)[N:6]=1)=[O:4].C(=O)([O-])[O-].[Cs+].[Cs+].[CH2:23]([O:30][C:31](=[O:34])[CH2:32]Br)[C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1>CN(C=O)C.O>[CH3:1][O:2][C:3]([C:5]1[CH:14]=[C:13]([O:15][CH2:32][C:31]([O:30][CH2:23][C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)=[O:34])[C:12]2[C:7](=[CH:8][C:9]([CH3:16])=[CH:10][CH:11]=2)[N:6]=1)=[O:4]
Reactant: COC(=O)c1cc(O)c2ccc(C)cc2n1
Reactant: O=C(CBr)OCc1ccccc1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: O
Solvent: CN(C)C=O
Product: COC(=O)c1cc(OCC(=O)OCc2ccccc2)c2ccc(C)cc2n1
Temperature: 25 °C
Reaction time: 12 h

Procedure:
To a solution of 5.00 g 4-Hydroxy-7-methyl-quinoline-2-carboxylic acid methyl ester in 35 ml of DMF, 8.25 g of cesium carbonate and 5.80 g of Bromo-acetic acid benzyl ester were added and the reaction mixture was stirred for 12 h at RT. Then, the reaction mixture was diluted with water and extracted with ethyl acetate. The organic phase was dried over MgSO4 and the solvents were removed under reduced pressure. The isolated crude product was pure enough for the next reaction step. Yield: 10.00 g.
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([C:8]2[CH:9]=[N:10][N:11]([CH:13]([CH:17]3[CH2:19][CH2:18]3)[CH2:14][C:15]#[N:16])[CH:12]=2)[C:5]([O:20][CH3:21])=[CH:4][N:3]=1.[NH2:22][C:23]1[CH:24]=[C:25]([CH:29]=[CH:30][CH:31]=1)[C:26]([OH:28])=[O:27].C1(C)C=CC(S(O)(=O)=O)=CC=1.O1CCOCC1>>[C:15]([CH2:14][CH:13]([N:11]1[CH:12]=[C:8]([C:6]2[C:5]([O:20][CH3:21])=[CH:4][N:3]=[C:2]([NH:22][C:23]3[CH:24]=[C:25]([CH:29]=[CH:30][CH:31]=3)[C:26]([OH:28])=[O:27])[N:7]=2)[CH:9]=[N:10]1)[CH:17]1[CH2:19][CH2:18]1)#[N:16]
Reactant: Nc1cccc(C(=O)O)c1
Reactant: COc1cnc(Cl)nc1-c1cnn(C(CC#N)C2CC2)c1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: C1COCCO1
Product: COc1cnc(Nc2cccc(C(=O)O)c2)nc1-c1cnn(C(CC#N)C2CC2)c1
Temperature: 25 °C
Yield: 99.5 %

Procedure:
A mixture of 3-[4-(2-chloro-5-methoxypyrimidin-4-yl)-1H-pyrazol-1-yl]-3-cyclopropylpropanenitrile (from example 320 step 1, 250 mg, 0.00082 mol), 3-aminobenzoic acid (169 mg, 0.00123 mol), and p-toluenesulfonic acid (120 mg, 0.00070 mol) in dry 1,4-dioxane (5 mL, 0.07 mol) was refluxed overnight, then cooled to room temperature. The insoluble material was filtered off. The filtration was evaporated to dryness to give the crude product (330 mg, 99.14%). LCMS (M+H) 405.3.
Reaction SMILES: [NH2:1][C:2]([CH3:6])([CH3:5])[CH2:3][OH:4].[Cl:7][C:8]1[S:12][C:11]([S:13](Cl)(=[O:15])=[O:14])=[CH:10][C:9]=1[N+:17]([O-:19])=[O:18].C(N(CC)CC)C.O>O1CCOCC1>[OH:4][CH2:3][C:2]([NH:1][S:13]([C:11]1[S:12][C:8]([Cl:7])=[C:9]([N+:17]([O-:19])=[O:18])[CH:10]=1)(=[O:15])=[O:14])([CH3:6])[CH3:5]
Reactant: O=[N+]([O-])c1cc(S(=O)(=O)Cl)sc1Cl
Reactant: CC(C)(N)CO
Solvent: O
Solvent: CCN(CC)CC
Solvent: C1COCCO1
Product: CC(C)(CO)NS(=O)(=O)c1cc([N+](=O)[O-])c(Cl)s1
Temperature: 25 °C
Reaction time: 17 h
Yield: 30.4 %

Procedure:
To a stirred solution of 2-amino-2-methyl-1-propanol (0.75 g, 8.39 mmol) in dioxane (21 ml) was added at room temperature 5-chloro-4-nitrothiophene-2-sulfonyl chloride (2.0 g, 7.63 mmol) and triethylamine (1.17 ml, 8.39 mmol). The light yellow suspension was stirred at room temperature for 17 h, poured into water (100 ml) and extracted with dichloromethane (3×75 ml). The combined organic layers were washed with water (100 ml) and brine (70 ml), dried (MgSO4) and evaporated. The crude product was further purified by column chromatography on silica gel (heptane/ethyl acetate 1:1) and subsequent crystallization from ethyl acetate/hexane to yield 5-chloro-4-nitro-thiophene-2-sulfonic acid (2-hydroxy-1,1-dimethyl-ethyl)-amide (0.73 g, 30%) as a light brown solid. MS (ISP) 313.1 [(M−H)−], mp 136° C.
Reaction SMILES: Br[C:2]1[N:15]([CH2:16][C:17](OCC)=[O:18])[C:5]2=[N:6][C:7]([C:10]([O:12][CH2:13][CH3:14])=[O:11])=[CH:8][CH:9]=[C:4]2[C:3]=1[CH:22]1[CH2:27][CH2:26][CH2:25][CH2:24][CH2:23]1.CC1(C)C(C)(C)OB([C:36]2[CH:41]=[CH:40][CH:39]=[CH:38][C:37]=2[NH2:42])O1.O.C(=O)([O-])O.[Na+]>COCCOC.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>[CH:22]1([C:3]2[C:4]3[CH:9]=[CH:8][C:7]([C:10]([O:12][CH2:13][CH3:14])=[O:11])=[N:6][C:5]=3[N:15]3[C:2]=2[C:36]2[CH:41]=[CH:40][CH:39]=[CH:38][C:37]=2[NH:42][C:17](=[O:18])[CH2:16]3)[CH2:23][CH2:24][CH2:25][CH2:26][CH2:27]1
Reactant: CCOC(=O)Cn1c(Br)c(C2CCCCC2)c2ccc(C(=O)OCC)nc21
Reactant: CC1(C)OB(c2ccccc2N)OC1(C)C
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: [Na+]
Solvent: COCCOC
Solvent: O
Product: CCOC(=O)c1ccc2c(C3CCCCC3)c3n(c2n1)CC(=O)Nc1ccccc1-3
Temperature: 110 °C
Yield: 26.2 %

Procedure:
To a suspension of ethyl 2-bromo-3-cyclohexyl-1-ethoxycarbonylmethyl-1H-pyrrolo[2,3-b]pyridine-6-carboxylate (457 mg, 1.05 mmol) and 2-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenylamine (275 mg, 1.25 mmol) obtained in the same manner as in the method described in Example 1-1, Step 1 in 1,2-dimethoxyethane (7.5 ml) and water (3.5 ml) were added sodium hydrogen carbonate (260 mg, 3.14 mmol) and tetrakis(triphenylphosphine)palladium (60 mg, 0.05 mmol) and the mixture was stirred with heating at 110° C. for 3.5 hr. The mixture was allowed to cool to room temperature and the reaction mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine and dried over anhydrous magnesium sulfate. After filtration, the solvent was evaporated under reduced pressure and the obtained residue was purified by silica gel chromatography (hexane:ethyl acetate=1:1) to give ethyl 12-cyclohexyl-6-oxo-6,7-dihydro-5H-5,7a,8-triazadibenzo[a,e]azulene-9-carboxylate (111 mg, yield 26%).
Reaction SMILES: [CH2:1]([O:8][CH2:9][C:10]1[NH:11][C:12]([S:18][C:19]2[CH:24]=[CH:23][CH:22]=[C:21]([O:25][CH3:26])[CH:20]=2)=[C:13]([CH:15]([CH3:17])[CH3:16])[N:14]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[N:27]1[CH:32]=[CH:31][C:30]([CH2:33]Cl)=[CH:29][CH:28]=1.[OH-].[Na+].[I-].[Li+]>C1COCC1.[Br-].C([N+](CCCC)(CCCC)CCCC)CCC>[CH2:1]([O:8][CH2:9][C:10]1[N:11]([CH2:33][C:30]2[CH:31]=[CH:32][N:27]=[CH:28][CH:29]=2)[C:12]([S:18][C:19]2[CH:24]=[CH:23][CH:22]=[C:21]([O:25][CH3:26])[CH:20]=2)=[C:13]([CH:15]([CH3:17])[CH3:16])[N:14]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: ClCc1ccncc1
Reactant: COc1cccc(Sc2[nH]c(COCc3ccccc3)nc2C(C)C)c1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [Br-]
Agent: [I-]
Solvent: C1CCOC1
Product: COc1cccc(Sc2c(C(C)C)nc(COCc3ccccc3)n2Cc2ccncc2)c1
Temperature: 25 °C
Reaction time: 48 h
Yield: 65.3 %

Procedure:
To a solution of sulfide 36 (247 mg, 0.67 mmol) in THF (10 mL) was added 4-picolylchloride (220 mg, 1.34 mmol), powder NaOH (59 mg, 1.47 mmol), lithium iodide (44 mg, 0.33 mmol), and tetrabutylammonium bromide (22 mg, 0.067 mmol). See Scheme 22. After the reaction mixture was stirred for 2 d at room temperature, the mixture was partitioned between EtOAc and sat. NH4Cl. The organic phase was dried over Na2SO4, filtered, and evaporated under reduced pressure. The crude product was chromatographed on silica gel (eluting 60-100% EtOAc/hexane) to give 4-[2-benzyloxymethyl-4-isopropyl-5-(3-methoxy-phenylsulfanyl)-imidazol-1-ylmethyl]-pyridine 37 (201 mg, 65%) as a yellow oil.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[CH:4][CH:5]=[C:6]2[C:11]=1[N:10]=[CH:9][CH:8]=[CH:7]2.C(=O)([O-])[O-].[K+].[K+].Br[CH2:19][C:20]1[CH:29]=[CH:28][C:23]([C:24]([O:26][CH3:27])=[O:25])=[CH:22][CH:21]=1>CN(C=O)C>[N:10]1[C:11]2[C:6](=[CH:5][CH:4]=[CH:3][C:2]=2[NH:1][CH2:19][C:20]2[CH:29]=[CH:28][C:23]([C:24]([O:26][CH3:27])=[O:25])=[CH:22][CH:21]=2)[CH:7]=[CH:8][CH:9]=1
Reactant: COC(=O)c1ccc(CBr)cc1
Reactant: Nc1cccc2cccnc12
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: COC(=O)c1ccc(CNc2cccc3cccnc23)cc1
Reaction time: 20 h
Yield: 172.4 %

Procedure:
8-Aminoquinoline (1.26 g) was dissolved in DMF (20 ml), and potassium carbonate (1.2 g) and methyl 4-bromomethylbenzoate (1.0 g) were added. After stirring for 20 hours, the reaction solution was concentrated. The resulting residue was diluted with chloroform and water was added. The mixture was extracted with chloroform. The organic layer was washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated to obtain the title compound (2.20 g) as a yellow syrup.
Reaction SMILES: ClC1C=C(C=CC=1)C(OO)=[O:6].[Si:12]([O:19][C@@H:20]([C@@H:22]1[C@@H:25]([S:26][C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=2)[NH:24][C:23]1=[O:33])[CH3:21])([C:15]([CH3:18])([CH3:17])[CH3:16])([CH3:14])[CH3:13]>C(Cl)Cl>[Si:12]([O:19][C@@H:20]([C@@H:22]1[C@@H:25]([S:26]([C:27]2[CH:28]=[CH:29][CH:30]=[CH:31][CH:32]=2)=[O:6])[NH:24][C:23]1=[O:33])[CH3:21])([C:15]([CH3:18])([CH3:16])[CH3:17])([CH3:14])[CH3:13]
Reactant: O=C(OO)c1cccc(Cl)c1
Reactant: C[C@@H](O[Si](C)(C)C(C)(C)C)[C@H]1C(=O)N[C@@H]1Sc1ccccc1
Solvent: ClCCl
Product: C[C@@H](O[Si](C)(C)C(C)(C)C)[C@H]1C(=O)N[C@@H]1S(=O)c1ccccc1
Temperature: 25 °C
Reaction time: 6 h
Yield: 90.7 %

Procedure:
1.5 g of 3-chloroperoxybenzoic acid was added, whilst ice-cooling, to a solution of 2 g of (3S,4R)-3-[(1R)-1-t-butyldimethylsilyloxyethyl]-4-phenylthio-2-azetidinone [prepared as described in step (i) above] in 30 ml of methylene chloride, and the resulting mixture was stirred at room temperature for 6 hours. At the end of this time, the reaction mixture was mixed with 30 ml of methylene chloride, end the organic layer was separated and washed with water, with a saturated aqueous solution of sodium hydrogencarbonate and again with water, in that order. It was then dried over anhydrous magnesium sulfate, and the solvent was removed by distillation under reduced pressure. The resulting residue was purified by flash chromatography, using a 1:1 by volume mixture of cyclohexane and ethyl acetate as the eluent, to give 1.9 g of the title compound consisting of two diastereomers, differing in the configuration of the sulfoxide group, as colorless crystals, melting at 65°-70° C.