Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[OH:9])[CH3:2].C(C1C=C(O)C=CC=1)C.C(C1C=CC(O)=CC=1)C>C1(C)C=CC=CC=1>[CH:1]([C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[OH:9])=[CH2:2]
Reactant: CCc1ccccc1O
Agent: CCc1ccc(O)cc1
Agent: CCc1cccc(O)c1
Solvent: Cc1ccccc1
Product: C=Cc1ccccc1O

Procedure:
As a result, 3.5 liters of a toluene solution containing 1.5 mols of a vinylphenol mixture of 37.0 mol% o-vinylphenol, 24.7 mol% m-vinylphenol, 36.9 mol% p-vinylphenol and 1.4 mol% ethylphenol was obtained as the extract. As the raffinate, 10.4 liters of a toluene solution containing 2.6 mols of an ethylphenol mixture of 9.9 mol% o-ethylphenol, 4.0 mol% m-ethylphenol, 85.1 mol% p-ethylphenol and 1.0 mol% vinylphenol was obtained.
Reaction SMILES: [Zn:1].[Br:2]CCBr.Cl[Si](C)(C)C.Br[CH:12]([C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)[CH3:13]>C1COCC1>[Br-:2].[C:14]1([CH:12]([Zn+:1])[CH3:13])[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1
Reactant: [Zn]
Reactant: BrCCBr
Reactant: CC(Br)c1ccccc1
Agent: C[Si](C)(C)Cl
Solvent: C1CCOC1
Product: CC([Zn+])c1ccccc1
Product: [Br-]
Temperature: 25 °C

Procedure:
To a suspension mixture of zinc powder (active, 5.1 g, 80.0 mmol) in dry THF (20 mL) was added dropwise 1,2-dibromoethane (0.28 mL, 5.7 mmol) at 70° C. under nitrogen atmosphere, followed by the addition of chlorotrimethylsilane (1.2 mL, 10.6 mmol). Subsequently, (1-bromoethyl)benzene (3.7 g, 20 mmol) was added dropwise. The resultant suspension was stirred at 70° C. for another 1 h. The reaction mixture was cooled to RT and directly used for the next step.
Reaction SMILES: [Br:1][C:2]1[CH:15]=[CH:14][C:5]2[C:6](=[O:13])[C:7]([CH3:12])([CH3:11])[S:8](=[O:10])(=[O:9])[C:4]=2[CH:3]=1.[BH4-].[Na+]>CO.C(Cl)Cl>[Br:1][C:2]1[CH:15]=[CH:14][C:5]2[CH:6]([OH:13])[C:7]([CH3:11])([CH3:12])[S:8](=[O:9])(=[O:10])[C:4]=2[CH:3]=1
Reactant: CC1(C)C(=O)c2ccc(Br)cc2S1(=O)=O
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Solvent: ClCCl
Product: CC1(C)C(O)c2ccc(Br)cc2S1(=O)=O
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 97.2 %

Procedure:
A cooled (0° C.) solution of 6-bromo-2,2-dimethyl-1-benzothiophen-3(2H)-one 1,1-dioxide (Intermediate 241; 652 mg; 2.25 mmol) in MeOH (15 ml) and DCM (7 ml) was treated with NaBH4 (43 mg; 1.13 mmol) portionwise. The resulting solution was stirred at RT for 1.5 h, before being cooled to 0° C. and carefully quenched with water. The mixture was concentrated under reduced pressure, water was added to the residue and the aqueous phase was extracted three times with DCM. The combined organic phases were washed with brine, dried with MgSO4, filtered and concentrated to dryness to give the title compound as a white solid (637 mg, 97%).
Reaction SMILES: C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.N1C=CN=C1.[I:25]I.[Cl:27][C:28]1[C:33]([C:34]2[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=2)=[N:32][N:31]=[C:30]2[N:40]([CH2:49][CH2:50]O)[N:41]=[C:42]([C:43]3[CH:48]=[CH:47][CH:46]=[CH:45][CH:44]=3)[C:29]=12>C(Cl)Cl>[Cl:27][C:28]1[C:33]([C:34]2[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=2)=[N:32][N:31]=[C:30]2[N:40]([CH2:49][CH2:50][I:25])[N:41]=[C:42]([C:43]3[CH:48]=[CH:47][CH:46]=[CH:45][CH:44]=3)[C:29]=12
Reactant: OCCn1nc(-c2ccccc2)c2c(Cl)c(-c3ccccc3)nnc21
Reactant: II
Agent: c1c[nH]cn1
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: ClCCl
Product: Clc1c(-c2ccccc2)nnc2c1c(-c1ccccc1)nn2CCI
Temperature: 25 °C
Reaction time: 1 h
Yield: 84.3 %

Procedure:
Triphenylphosphine (160 mg, 0.62 mmol), imidazole (42 mg, 0.62 mmol) and iodine (160 mg, 0.62 mmol) were added to a solution of 2-(4-chloro-3,5-diphenyl-1H pyrazolo[3,4-c]pyridazin-1-yl)ethanol (181 mg, 0.52 mmol) in CH2Cl2 (6 mL). After stirring at ambient temperature for 1 h the reaction was filtered and solvent removed in vacuo. Purification using chromatography (silica gel, gradient 10 to 60% ethyl acetate/isohexane) gave 4-chloro-1-(2-iodoethyl)-3,5-diphenyl-1H-pyrazolo[3,4-c]pyridazine as a clear oil (202 mg) which was used as such in the subsequent step.
Reaction SMILES: Cl[C:2]1[N:10]=[C:9]([S:11][CH2:12][C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)[N:8]=[C:7]2[C:3]=1[NH:4][C:5](=[O:19])[NH:6]2.CN1CCCC1=O.O.Cl.[NH2:29][C@H:30]([CH2:32][OH:33])[CH3:31]>>[OH:33][CH2:32][C@H:30]([NH:29][C:2]1[N:10]=[C:9]([S:11][CH2:12][C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)[N:8]=[C:7]2[C:3]=1[NH:4][C:5](=[O:19])[NH:6]2)[CH3:31]
Reactant: C[C@H](N)CO
Reactant: O=c1[nH]c2nc(SCc3ccccc3)nc(Cl)c2[nH]1
Agent: Cl
Solvent: CN1CCCC1=O
Solvent: O
Product: C[C@H](CO)Nc1nc(SCc2ccccc2)nc2[nH]c(=O)[nH]c12
Temperature: 100 °C
Reaction time: 48 h
Yield: 19.4 %

Procedure:
A solution of the product from example 2, step (f) (0.1 g) in a mixture of alaninol (0.128 g), disopropylethylamine (0.35 ml) and N-methylpyrrolidinone (3 ml) was stirred at 100° C. for 48 h before pouring into H2O (75 ml). 2M HCl solution was then added to pH=2 and the light brown solid formed filtered and recrystallised from EtOH to afford the subtitle compound (22 mg, 19%)
Reaction SMILES: Cl[C:2]1[CH:17]=[C:6]2[C:7]3[C:12]([CH2:13][CH2:14][N:5]2[C:4](=[O:18])[N:3]=1)=[CH:11][C:10]([O:15][CH3:16])=[CH:9][CH:8]=3.[CH3:19][O:20][C:21]1[CH:28]=[CH:27][C:24]([CH2:25][NH2:26])=[CH:23][CH:22]=1>>[CH3:16][O:15][C:10]1[CH:11]=[C:12]2[C:7](=[CH:8][CH:9]=1)[C:6]1=[CH:17][C:2]([NH:26][CH2:25][C:24]3[CH:27]=[CH:28][C:21]([O:20][CH3:19])=[CH:22][CH:23]=3)=[N:3][C:4](=[O:18])[N:5]1[CH2:14][CH2:13]2
Reactant: COc1ccc2c(c1)CCn1c-2cc(Cl)nc1=O
Reactant: COc1ccc(CN)cc1
Product: COc1ccc(CNc2cc3n(c(=O)n2)CCc2cc(OC)ccc2-3)cc1

Procedure:
The title compound was prepared from 2-chloro-9-methoxy-6,7-dihydro-pyrimido[6,1-a]isoquinolin-4-one (4) and 4-methoxy-benzylamine as in Example 1 d. 1H-NMR (400 MHz, d6-DMSO) δ 7.89 (t, 1H), 7.63 (d, 1H), 7.25 (d, 2H), 7.0-6.93 (2H), 6.90 (d, 2H), 6.16 (s, 1H), 4.45 (d, 2H), 3.92 (t, 2H), 3.82 (s, 3H), 3.73 (s, 3H) and 2.92 (t, 2H); MS (ESI) (M+H)+ 364.
Reaction SMILES: [Br:1][C:2]1[CH:6]=[CH:5][S:4][C:3]=1[C:7]([NH2:9])=O.COC(OC)[N:13]([CH3:15])C.C1(C)C=CC=CC=1.C(O)(=O)C.[NH2:29]N>>[Br:1][C:2]1[CH:6]=[CH:5][S:4][C:3]=1[C:7]1[NH:9][CH:15]=[N:13][N:29]=1
Reactant: NC(=O)c1sccc1Br
Reactant: NN
Reactant: COC(OC)N(C)C
Solvent: CC(=O)O
Solvent: Cc1ccccc1
Product: Brc1ccsc1-c1nnc[nH]1
Temperature: 90 °C
Reaction time: 0.67 h
Yield: 85.6 %

Procedure:
3-Bromothiophene-2-carboxamide (33.2 g, 161 mmol) in 1,1-dimethoxy-N,N-dimethylmethanamine (100 mL, 800 mmol) and toluene (100 mL, 900 mmol) was heated at 90° C. for 2 h. The solvent was evaporated off and the residue was dissolved in acetic acid (183 mL, 3220 mmol). Hydrazine (20 mL, 600 mmol) was added and the mixture was heated at 90° C. again. After 40 min, LCMS showed complete reaction. The reaction mixture was evaporated to remove most of the acetic acid. Water was added and the precipitate was collected and dried in air overnight to afford 3-(3-bromothiophen-2-yl)-4H-1,2,4-triazole as a white powder (31.7 g, 85.6%). LCMS: (FA) ES+ 230.0, 232.0
Reaction SMILES: [NH2:1][CH2:2][CH:3]1[O:8][CH2:7][CH2:6][N:5]([C:9]([O:11][C:12]([CH3:15])([CH3:14])[CH3:13])=[O:10])[CH2:4]1.[C:16]([C:18]1[CH:19]=[C:20]([CH:36]([CH3:38])[CH3:37])[C:21]2[O:25][C:24]([C:26]3[CH:34]=[CH:33][C:29]([C:30](O)=[O:31])=[CH:28][CH:27]=3)=[N:23][C:22]=2[CH:35]=1)#[N:17]>>[C:16]([C:18]1[CH:19]=[C:20]([CH:36]([CH3:38])[CH3:37])[C:21]2[O:25][C:24]([C:26]3[CH:34]=[CH:33][C:29]([C:30]([NH:1][CH2:2][CH:3]4[O:8][CH2:7][CH2:6][N:5]([C:9]([O:11][C:12]([CH3:15])([CH3:14])[CH3:13])=[O:10])[CH2:4]4)=[O:31])=[CH:28][CH:27]=3)=[N:23][C:22]=2[CH:35]=1)#[N:17]
Reactant: CC(C)(C)OC(=O)N1CCOC(CN)C1
Reactant: CC(C)c1cc(C#N)cc2nc(-c3ccc(C(=O)O)cc3)oc12
Product: CC(C)c1cc(C#N)cc2nc(-c3ccc(C(=O)NCC4CN(C(=O)OC(C)(C)C)CCO4)cc3)oc12

Procedure:
The title compound was then prepared from tert-butyl 2-(aminomethyl)morpholine-4-carboxylate (48 mg) and 4-(5-cyano-7-isopropyl-1,3-benzoxazol-2-yl)benzoic acid, INTERMEDIATE 2) as described in EXAMPLE 35. Mass spectrum (ESI) 505.3 (M+1).
Reaction SMILES: [CH2:1](N1CC(C)(C)NCC21CCCC2)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH3:20][CH:21]([CH3:26])[CH:22]([NH2:25])[CH2:23][NH2:24].[CH3:27][C:28]([CH3:32])(O)[C:29]#N>>[CH2:1]([N:24]1[CH2:23][CH:22]([CH:21]([CH3:26])[CH3:20])[NH:25][CH2:27][C:28]1([CH3:32])[CH3:29])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CC1(C)CN(Cc2ccccc2)C2(CCCC2)CN1
Reactant: CC(C)C(N)CN
Reactant: CC(C)(O)C#N
Product: CC(C)C1CN(Cc2ccccc2)C(C)(C)CN1

Procedure:
1-Benzyl-5-isopropyl-2,2-dimethyl-piperazine was synthesized in analogy to 6-benzyl-8,8-dimethyl-6,9-diaza-spiro[4.5]decane starting from 3-methyl-butane-1,2-diamine and acetone cyanohydrin.
Reaction SMILES: P(Cl)(Cl)(Cl)=O.[C:6]([C:10]1[N:11]=[C:12]([NH:15][C:16]([C:18]2[CH:34]=[CH:33][N:21]3[C:22](=[O:32])[CH:23]=[C:24]([N:26]4[CH2:31][CH2:30][O:29][CH2:28][CH2:27]4)[N:25]=[C:20]3[CH:19]=2)=[O:17])[S:13][CH:14]=1)([CH3:9])([CH3:8])[CH3:7].[C:35](=O)([O-])[OH:36].[Na+]>CN(C)C=O>[C:6]([C:10]1[N:11]=[C:12]([NH:15][C:16]([C:18]2[CH:34]=[CH:33][N:21]3[C:22](=[O:32])[C:23]([CH:35]=[O:36])=[C:24]([N:26]4[CH2:27][CH2:28][O:29][CH2:30][CH2:31]4)[N:25]=[C:20]3[CH:19]=2)=[O:17])[S:13][CH:14]=1)([CH3:9])([CH3:7])[CH3:8]
Reactant: O=C([O-])O
Reactant: CC(C)(C)c1csc(NC(=O)c2ccn3c(=O)cc(N4CCOCC4)nc3c2)n1
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O=P(Cl)(Cl)Cl
Product: CC(C)(C)c1csc(NC(=O)c2ccn3c(=O)c(C=O)c(N4CCOCC4)nc3c2)n1
Temperature: 25 °C
Reaction time: 0.25 h

Procedure:
Dimethylformamide (1 ml) was added dropwise with phosphorus oxychloride (66 μl, 0.712 mmol) under ice cooling, then warmed to room temperature, and stirred for 15 minutes. The reaction solution was cooled to 0° C. with ice, added with N8-[4-(tert-butyl)-1,3-thiazol-2-yl]-2-morpholino-4-oxo-4H-pyrido[1,2-a]pyrimidine-8-carboxamide (147 mg, 0.356 mmol) dissolved in dimethylformamide (4 ml) under ice cooling, and stirred at 0° C. for 2 hours and 30 minutes. The reaction solution was neutralized with saturated aqueous sodium hydrogencarbonate and concentrated under reduced pressure. The resulting residue was added with chloroform for extraction, and the organic layer was dried over magnesium sulfate and concentrated under reduced pressure. The resulting residue was purified by thin layer silica gel chromatography (chloroform:methanol=40:1) to obtain 98.2 mg of the title compound as yellow crystals in a mixture with dimethylformamide.
Reaction SMILES: [C:1]([NH:11][C@@H:12]([CH2:32][C:33]1[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=1)[C@H:13]([OH:31])[CH2:14][N:15]([CH2:24][C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1)[C:16](=[O:23])[C:17](=[N+:21]=[N-:22])C(=O)C)([O:3][CH2:4][C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1)=[O:2].[Li+].[OH-]>C1COCC1.O.O.ClCCl>[C:1]([NH:11][C@@H:12]([CH2:32][C:33]1[CH:34]=[CH:35][CH:36]=[CH:37][CH:38]=1)[C@H:13]([OH:31])[CH2:14][N:15]([CH2:24][C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1)[C:16](=[O:23])[CH:17]=[N+:21]=[N-:22])([O:3][CH2:4][C:5]1[CH:6]=[CH:7][CH:8]=[CH:9][CH:10]=1)=[O:2]
Reactant: CC(=O)C(=[N+]=[N-])C(=O)N(Cc1ccccc1)C[C@@H](O)[C@H](Cc1ccccc1)NC(=O)OCc1ccccc1
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: ClCCl
Solvent: O
Product: [N-]=[N+]=CC(=O)N(Cc1ccccc1)C[C@@H](O)[C@H](Cc1ccccc1)NC(=O)OCc1ccccc1
Reaction time: 5 h
Yield: 81 %

Procedure:
The diazo ketamide (XII) (0.020 g, 0.038 mmol) was dissolved in 0.5 ml of 1:1 THF/H2O and to this LiOH (5 mg, 0.19 mmol) dissolved in 0.2 ml of water was added. The reaction mixture was stirred for 5 hrs and diluted with 2 ml of dichloromethane. The organic layer was separated, dried (Na2SO4), and concentrated. The product (XIII) was then isolated by passing through a plug of silica as an oil. 0.015 g. (81% yield). 1H NMR (500 MHz, CDCl3) δ 7.13-7.49 (m, 15H), 5.02-5.37 (m, 3H), 4.46-4.87 (m, 2H), 3.75-4.04 (m, 2H), 3.28-3.47 (m, 1H), 2.75-2.94 (m, 2H). 13CNMR (125 MHz, CDCl3) 163.4, 155.85, 140.91, 140.36, 139.22, 129.14, 128.68, 128.26, 128.17, 128.10, 127.72, 127.41, 127.64, 126.75, 78.33, 60.18, 52.04, 50.15, 46.89, 44.7, 36.43.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([NH2:9])=[CH:5][CH:4]=1.C(N(CC)CC)C.[N:17]1([C:28]2[CH:36]=[CH:35][C:31]([C:32](Cl)=[O:33])=[CH:30][CH:29]=2)[C:27]2[C:22](=[CH:23][CH:24]=[CH:25][CH:26]=2)[CH2:21][CH2:20][C:18]1=[O:19].O>C(Cl)(Cl)Cl>[CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([NH:9][C:32]([C:31]2[CH:30]=[CH:29][C:28]([N:17]3[C:27]4[C:22](=[CH:23][CH:24]=[CH:25][CH:26]=4)[CH2:21][CH2:20][C:18]3=[O:19])=[CH:36][CH:35]=2)=[O:33])=[CH:5][CH:4]=1
Reactant: O=C(Cl)c1ccc(N2C(=O)CCc3ccccc32)cc1
Reactant: COc1ccc(N)cc1
Solvent: CCN(CC)CC
Solvent: ClC(Cl)Cl
Solvent: O
Product: COc1ccc(NC(=O)c2ccc(N3C(=O)CCc4ccccc43)cc2)cc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of p-anisidine (0.11 g) in chloroform (5 ml) is added triethylamine (0.15 g) and thereto is added with stirring a solution of 4-(3,4-dihydrocarbostyril-1-yl)benzoic acid chloride obtained above in chloroform (2 ml) under ice cooling. The mixture is stirred at room temperature overnight. Water is added to the reaction mixture and the mixture is extracted with dichloromethane, washed with water and dried with magnesium sulfate. The solvent is distilled off under reduced pressure and the resulting residue is crystallized from diethyl ether and further recrystallized from ethanol/diethyl ether/n-hexane to give 1-[4-(4-methoxyanilinocarbonyl)phenyl]-3,4-dihydrocarbostyril (240 mg) as white powder, m.p.: 254°-255° C.
Reaction SMILES: [Li]CCCC.Br[C:7]1[CH:8]=[C:9]2[C:14](=[C:15]([CH3:17])[CH:16]=1)[N:13]=[C:12]([Cl:18])[C:11]([C:19]1[CH:24]=[CH:23][CH:22]=[C:21]([F:25])[CH:20]=1)=[C:10]2[Cl:26].[CH3:27][N:28]1[C:32]([C:33]([C:35]2[CH:36]=[N:37][C:38]([C:41]([F:44])([F:43])[F:42])=[CH:39][CH:40]=2)=[O:34])=[CH:31][N:30]=[CH:29]1>C1COCC1>[Cl:18][C:12]1[C:11]([C:19]2[CH:24]=[CH:23][CH:22]=[C:21]([F:25])[CH:20]=2)=[C:10]([Cl:26])[C:9]2[C:14](=[C:15]([CH3:17])[CH:16]=[C:7]([C:33]([C:32]3[N:28]([CH3:27])[CH:29]=[N:30][CH:31]=3)([C:35]3[CH:36]=[N:37][C:38]([C:41]([F:43])([F:42])[F:44])=[CH:39][CH:40]=3)[OH:34])[CH:8]=2)[N:13]=1
Reactant: Cn1cncc1C(=O)c1ccc(C(F)(F)F)nc1
Reactant: Cc1cc(Br)cc2c(Cl)c(-c3cccc(F)c3)c(Cl)nc12
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: Cc1cc(C(O)(c2ccc(C(F)(F)F)nc2)c2cncn2C)cc2c(Cl)c(-c3cccc(F)c3)c(Cl)nc12
Temperature: -78 °C
Reaction time: 0.02 h

Procedure:
n-BuLi (1.6 M in hexane, 1.91 mL, 3.05 mmol) was added over approximately 1 minute to a solution of 6-bromo-2,4-dichloro-3-(3-fluorophenyl)-8-methylquinoline (1.23 g, 3.20 mmol, Intermediate 50, step c) in THF (10 mL) under argon at −78° C. After 1 minute, a solution of (1-methyl-1H-imidazol-5-yl)(6-(trifluoromethyl)pyridin-3-yl)methanone (817 mg, 3.20 mmol, Intermediate 15, step c) in 10 mL THF under argon was added via cannula. The resulting mixture was stirred at −78° C. for 10 minutes, then transferred to an ice water bath and stirred 1 hour. The reaction was quenched by addition of saturated aqueous NH4Cl, diluted with water and extracted with EtOAc (3×). The organic phase was dried (Na2SO4), filtered, and concentrated. The residue was purified by flash column chromatography (silica gel, 45-60% CH3CN in [2% conc. aqueous NH4OH in DCM, aqueous phase removed]) to afford the title compound as a cream colored solid. 1H NMR (400 MHz, CHLOROFORM-d) δ 8.83 (s, 1H), 8.14 (dd, J=1.83, 7.46 Hz, 1H), 7.92 (d, J=8.31 Hz, 1H), 7.65 (d, J=8.31 Hz, 1H), 7.57-7.62 (m, 1H), 7.44-7.53 (m, 1H), 7.20 (td, J=2.20, 8.31 Hz, 1H), 7.09 (t, J=6.60 Hz, 1H), 7.01-7.07 (m, 1H), 6.29 (d, J=0.98 Hz, 1H), 6.02 (br. s., 1H), 3.37 (s, 3H), 2.74 (s, 3H). MS m/e 561.2 [M+H]+.
Reaction SMILES: [F:1][C:2]([CH:4]([OH:16])[CH2:5][C:6]([C:9]1[CH:14]=[CH:13][C:12]([F:15])=[CH:11][CH:10]=1)([CH3:8])[CH3:7])=[CH2:3].[CH2:17]([Zn]CC)C.ICI.O>C(OCC)(=O)C>[F:1][C:2]1([CH:4]([OH:16])[CH2:5][C:6]([C:9]2[CH:10]=[CH:11][C:12]([F:15])=[CH:13][CH:14]=2)([CH3:8])[CH3:7])[CH2:17][CH2:3]1
Reactant: C=C(F)C(O)CC(C)(C)c1ccc(F)cc1
Reactant: CC[Zn]CC
Solvent: O
Solvent: ICI
Solvent: CCOC(C)=O
Product: CC(C)(CC(O)C1(F)CC1)c1ccc(F)cc1
Reaction time: 0.08 h

Procedure:
To the above crude 2-fluoro-5-(4-fluorophenyl)-5-methylhex-1-en-3-ol (1.73 g, 7.65 mmol) stirred under nitrogen gas and cooled on ice, was added diethyl zinc (1.1 M in toluene, 8.0 mL). After 5 minutes, 1.0 mL of diiodomethane was added dropwise over 20 minutes and the mixture was stirred and allowed to come to room temperature and then stirred at room temperature for 4 days. 0.5 mL of water was then added to the reaction mixture, followed by ethyl acetate. The resulting mixture was then filtered through diatomaceous earth and the solvent was removed in vacuo and the residue was fractionated over silica gel (hexanes-dichloromethane (1:1) to dichloromethane gradient) to give 1-(1-fluorocyclopropyl)-3-(4-fluorophenyl)-3-methylbutan-1-ol as an oil.
Reaction SMILES: [CH3:1][S:2]([CH2:5][CH2:6][CH2:7][OH:8])(=[O:4])=[O:3].C(N(CC)CC)C.[CH3:16][S:17](Cl)(=[O:19])=[O:18].O>ClCCl>[CH3:1][S:2]([CH2:5][CH2:6][CH2:7][O:8][S:17]([CH3:16])(=[O:19])=[O:18])(=[O:4])=[O:3]
Reactant: CS(=O)(=O)CCCO
Reactant: CS(=O)(=O)Cl
Solvent: ClCCl
Solvent: O
Solvent: CCN(CC)CC
Product: CS(=O)(=O)CCCOS(C)(=O)=O
Temperature: 0 °C
Reaction time: 2 h
Yield: 89.9 %

Procedure:
Step A To a solution of 3-methanesulfonyl-propan-1-ol (Cambridge) (0.5 g, 3.6 mmol) in dichloromethane (3 mL) at 0° C. was added triethylamine (0.5 g, 5 mmol), and methanesulfonyl chloride (0.3 mL, 4 mmol, Aldrich). The reaction mixture was stirred at 0° C. for 2 h. The mixture was poured into water, extracted with dichloromethane. The organic layer was separated, washed with water, brine, dried over MgSO4, and concentrated to give crude methanesulfonic acid 3-methanesulfonyl-propyl ester as a yellow oil (Yield 0.7 g, 90%).
Reaction SMILES: [C:1](=[N:14][NH2:15])([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1>CCOCC.O.OO.[Ni]>[C:2]1([C:1]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)=[N+:14]=[N-:15])[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: NN=C(c1ccccc1)c1ccccc1
Agent: [Ni]
Agent: OO
Solvent: CCOCC
Solvent: O
Product: [N-]=[N+]=C(c1ccccc1)c1ccccc1
Reaction time: 1 h
Yield: 100 %

Procedure:
A solution of 0.59 g (3 mmol) of benzophenone hydrazone in 12 ml of ether is added dropwise at room temperature to a suspension of 2.95 g of nickel peroxide hydrate in 12 ml of ether, the mixture is stirred for one hour and the violet solution is filtered with suction through Celite and concentrated. The 3 mmol of diphenyldiazomethane obtained in this way are dissolved in 32 ml of absolute acetone and, while cooling in ice, added dropwise to a solution of 1.31 g (2.5 mmol) of 2-[N-(1S -menthyloxycarbonyl-3-phenylpropyl)-S-alanyl]-(1S,3S,5S)2-azabicyclo[3.3.0]octane-3-carboxylic acid (see Example 45) in 32 ml of absolute acetone. The mixture is then stirred at room temperature for 38 hours and concentrated, and the crude product is purified by column chromatography on silica gel (mobile phase toluene/ethanol 99.5:0.5 and cyclohexane/ethyl acetate 8:2).
Reaction SMILES: C[O:2][C:3](=O)[CH:4]([C:9]1[CH:14]=[CH:13][C:12]([Cl:15])=[CH:11][CH:10]=1)[C:5](OC)=[O:6].C[O-].[Na+].Cl.[CH:21]([NH2:23])=[NH:22]>CO>[Cl:15][C:12]1[CH:13]=[CH:14][C:9]([C:4]2[C:5]([OH:6])=[N:22][CH:21]=[N:23][C:3]=2[OH:2])=[CH:10][CH:11]=1
Reactant: COC(=O)C(C(=O)OC)c1ccc(Cl)cc1
Reactant: N=CN
Agent: C[O-]
Agent: Cl
Agent: [Na+]
Solvent: CO
Product: Oc1ncnc(O)c1-c1ccc(Cl)cc1
Temperature: 25 °C
Reaction time: 20 h
Yield: 94.8 %

Procedure:
A solution of 18.90 g of 2-(4-chloro-phenyl)-malonic acid dimethyl ester in 200 ml of methanol was added dropwise at 0° C. to a solution of 14.60 g sodium methylate in 150 ml of methanol. The mixture was stirred for 1 h at 0° C. before 7.66 g of formamidine hydrochloride was added. The suspension was stirred at rt for 20 h. The solvent was removed and the residue was suspended in 200 ml 2 N aq. HCl. The pH of the suspension was carfully adjusted to 4-5 by adding 20 ml of 10 M NaOH, stirring was continued for 30 min. The white precipitate was collected, washed with water and diethyl ether and dried to give 16.44 g of 5-(4-chlorophenyl)-pyrimidine-4,6-diol as a white powder. LC-MS: tR=2.75 min, [M+H]+=222.96 (ES+), [M−H]−=220.92 (ES−).
Reaction SMILES: C(O)(=O)CC(O)=[O:4].[CH2:8]1[CH2:13][CH2:12][CH:11]([N:14]=[C:15]=[N:16][CH:17]2[CH2:22][CH2:21][CH2:20][CH2:19][CH2:18]2)[CH2:10][CH2:9]1>C(Cl)Cl.CN(C1C=CN=CC=1)C>[CH:17]1([NH:16][C:15]([NH:14][CH:11]2[CH2:10][CH2:9][CH2:8][CH2:13][CH2:12]2)=[O:4])[CH2:22][CH2:21][CH2:20][CH2:19][CH2:18]1
Reactant: C(=NC1CCCCC1)=NC1CCCCC1
Reactant: O=C(O)CC(=O)O
Agent: CN(C)c1ccncc1
Solvent: ClCCl
Product: O=C(NC1CCCCC1)NC1CCCCC1
Temperature: 0 °C
Reaction time: 0.25 h
Yield: 60 %

Procedure:
104 mg (1 mmol) of malonic acid and 1.23 g (2.2 mmol) of alcohol 7 were dissolved in dry CH2Cl2 under N2 protection and the solution cooled in an ice bath. 41.0 mg (0.20 mmol) DMAP (10 mol %) and 454 mg (2.20 mmol) DCC were added subsequently. After stirring under N2-protection for 15 min at 0° C. and 2 h at RT, TLC control showed complete conversion of the starting material. Dicyclohexyl urea formed during the reaction precipitated and was filtered off. Traces of urea were subsequently removed by repeated precipitation from ethyl acetate. After evaporation of the solvent and purification by FC on silica (CH2Cl2:EtOH=94:6) 714 mg of a white solid was obtained (yield 60%).—1H NMR (400 MHz, RT, CDCl3): δ=6.22, 4.97 (2br, 4H), 4.11 (t, 3J=6.8 Hz, 4H), 3.66-3.48 (3m, 12H), 3.34 (s, 2H), 3.33 (dt, 4H), 3.20 (dt, 4H), 2.11 (t, 3J=7.6 Hz, 4H), 1.74 (m, 4H), 1.60 (m, 4H), 1.41 (s, 18H), 1.35-1.19 (m, 40H).—13C NMR (100.5 MHz, RT, CDCl3): δ=172.9 (2C), 166.4 (2C), 155.8 (2C), 78.9 (2C), 70.5, 70.5, 70.2, 70.1, 70.1, 69.5 (12C), 65.6 (2C), 41.7 (1C), 38.6, 37.9 (4C), 36.9 (2C), 29.7, 29.7, 29.6, 29.6, 29.5, 29.4, 29.3, 29.1 (20C), 28.5 (6C), 25.9, 25.8 (4C).—IR (Film/KBr): ν=3312, 3082, 2919, 2851, 1747, 1719, 1685, 1640, 1543, 1468, 1390, 1366, 1347, 1251, 1182, 1127, 1021, 997, 867, 720, 694, 603 cm−1.—MS (FAB): m/z=1322 [M+Cs]+, 1212 [M+Na]+, 1190 [M]+, 1190, 990, 443.
Reaction SMILES: [Cr:1]([O-:5])([O-:4])(=[O:3])=[O:2].[Na+:6].[Na+].[S:8](=[O:12])(=[O:11])([OH:10])[OH:9]>>[O-:2][Cr:1]([O:5][Cr:1]([O-:4])(=[O:3])=[O:2])(=[O:4])=[O:3].[Na+:6].[Na+:6].[S:8]([O-:12])([O-:11])(=[O:10])=[O:9].[Na+:6].[Na+:6]
Reactant: O=[Cr](=O)([O-])[O-]
Reactant: O=S(=O)(O)O
Agent: [Na+]
Product: O=S(=O)([O-])[O-]
Product: O=[Cr](=O)([O-])O[Cr](=O)(=O)[O-]

Procedure:
In a process wherein sodium chromate is reacted with aqueous sulfuric acid to produce an aqueous solution of sodium bichromate and solid sodium sulfate contaminated with hexavalent chromium, and said solid sodium sulfate is separated from said solution, the improvement comprising
Reaction SMILES: BrC1C=C(C(Cl)=O)C=CC=1.[Cl:11][C:12]1[CH:18]=[C:17]([O:19][C:20]2[C:29]3[C:24](=[CH:25][C:26]([O:32][CH3:33])=[C:27]([O:30][CH3:31])[CH:28]=3)[N:23]=[CH:22][CH:21]=2)[CH:16]=[CH:15][C:13]=1[NH2:14].[Br:34][C:35]1[CH:36]=[C:37]([C:41]([N:43]=[C:44]=[S:45])=[O:42])[CH:38]=[CH:39][CH:40]=1>C1(C)C=CC=CC=1.C(O)C>[Br:34][C:35]1[CH:36]=[C:37]([C:41]([N:43]=[C:44]=[S:45])=[O:42])[CH:38]=[CH:39][CH:40]=1.[Br:34][C:35]1[CH:36]=[C:37]([CH:38]=[CH:39][CH:40]=1)[C:41]([NH:43][C:44]([NH:14][C:13]1[CH:15]=[CH:16][C:17]([O:19][C:20]2[C:29]3[C:24](=[CH:25][C:26]([O:32][CH3:33])=[C:27]([O:30][CH3:31])[CH:28]=3)[N:23]=[CH:22][CH:21]=2)=[CH:18][C:12]=1[Cl:11])=[S:45])=[O:42]
Reactant: COc1cc2nccc(Oc3ccc(N)c(Cl)c3)c2cc1OC
Agent: O=C(Cl)c1cccc(Br)c1
Agent: O=C(N=C=S)c1cccc(Br)c1
Solvent: CCO
Solvent: Cc1ccccc1
Product: COc1cc2nccc(Oc3ccc(NC(=S)NC(=O)c4cccc(Br)c4)c(Cl)c3)c2cc1OC
Temperature: 25 °C
Reaction time: 2 h
Yield: 58 %

Procedure:
3-Bromo-1-benzenecarbonyl isothiocyanate was prepared using commercially available 3-bromo-1-benzenecarbonyl chloride (80 mg) as a starting compound according to the description of the literature. 2-Chloro-4-[(6,7-dimethoxy-4-quinolyl)oxy]aniline (50 mg) was dissolved in toluene (5 ml) and ethanol (1 ml) to prepare a solution. A solution of 3-bromo-1-benzenecarbonyl isothiocyanate in ethanol (1 ml) was then added to the solution, and the mixture was stirred at room temperature for 2 hr. The reaction solution was concentrated, and the residue was purified by chromatography on silica gel using chloroform/acetone for development to give the title compound (56 mg, yield 58%).