Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]1[CH:3]=[CH:4][C:5]([O:32][CH3:33])=[C:6]([C:8]([CH3:31])([CH3:30])[CH2:9][C:10]([C:26]([F:29])([F:28])[F:27])([OH:25])[C:11](=[N:13][C:14]2[CH:23]=[CH:22][CH:21]=[C:20]3[C:15]=2[CH:16]=[CH:17][C:18]([CH3:24])=[N:19]3)[CH3:12])[CH:7]=1.C(O)C.[BH4-].[Na+].[Na+].[Cl-]>O1CCCC1.[Ti]>[F:1][C:2]1[CH:3]=[CH:4][C:5]([O:32][CH3:33])=[C:6]([C:8]([CH3:30])([CH3:31])[CH2:9][C:10]([C:26]([F:27])([F:28])[F:29])([OH:25])[CH:11]([NH:13][C:14]2[CH:23]=[CH:22][CH:21]=[C:20]3[C:15]=2[CH:16]=[CH:17][C:18]([CH3:24])=[N:19]3)[CH3:12])[CH:7]=1
Reactant: COc1ccc(F)cc1C(C)(C)CC(O)(C(C)=Nc1cccc2nc(C)ccc12)C(F)(F)F
Agent: [Ti]
Agent: [BH4-]
Agent: [Cl-]
Solvent: C1CCOC1
Solvent: CCO
Product: COc1ccc(F)cc1C(C)(C)CC(O)(C(C)Nc1cccc2nc(C)ccc12)C(F)(F)F
Temperature: 25 °C
Reaction time: 1 h
Yield: 29.3 %

Procedure:
231 mg (0.5 mmol) of 5-(5-fluoro-2-methoxyphenyl)-5-methyl-2-(2-methylquinolin-5-ylimino)-3-(trifluoromethyl)hexan-3-ol is mixed in 10 ml of tetrahydrofuran and 4 ml of ethanol with 0.21 ml (1 mmol) of titanium tetraethylate. Then, 875 mg (23.1 mmol) of sodium borohydride is added in portions within 4 days at a reaction temperature of 65° C. The reaction mixture is mixed with 20 ml of saturated NaCl solution after cooling to room temperature, stirred for 1 hour at room temperature, filtered on Celite, and rewashed with ethyl acetate and tetrahydrofuran. The organic phase is separated, washed with saturated NaCl solution, dried and concentrated by evaporation. Column chromatography on silica gel with hexane-ethyl acetate yields 68 mg of the product as a mixture of the two possible diastereomers.
Reaction SMILES: C([O:3][C:4]([CH:6]1[CH:8]([CH:9]=[C:10]([Cl:12])[Cl:11])[C:7]1([CH3:14])[CH3:13])=[O:5])C.[OH-].[Na+].C(OS(C1C=CC=CC=1)(=O)=O)CCCCCCCCCCC.[Na].Cl>CCCCCC.O>[CH3:13][C:7]1([CH3:14])[CH:8]([CH:9]=[C:10]([Cl:12])[Cl:11])[CH:6]1[C:4]([OH:5])=[O:3]
Reactant: CCOC(=O)C1C(C=C(Cl)Cl)C1(C)C
Agent: CCCCCCCCCCCCOS(=O)(=O)c1ccccc1
Agent: Cl
Agent: [Na+]
Solvent: O
Solvent: CCCCCC
Product: CC1(C)C(C=C(Cl)Cl)C1C(=O)O
Yield: 85 %

Procedure:
27.9 g. of 2,2-dimethyl-3-(2,2-dichlorovinyl)cyclopropane-1-carboxylic acid ethyl ester (purity: 85%, cis) trans ratio: 40:60/, 6 g. of a 25% aqueous sodium hydroxide solution and 0.01 g. of sodium dodecylbenzene sulfonate are stirred at a temperature of 80° C. for 30 minutes. Hydrolysis is then continued with a further 5 g. portion of sodium hydroxide solution for 60 minutes and subsequently with an additional 5 g. portion of a sodium hydroxide solution for 150 minutes. The mixture is diluted with 30 ml. of water, cooled to 20° C. and the unreacted compounds are dissolved in 10 ml. of hexane. To the aqueous phase 80 ml. of hexane are added and the organic acid is set free by adding 12 g. of a 36% aqueous hydrochloric acid solution with stirring. The hexane solution is separated, decolored with 0.5 g. of activated carbon, filtered, 35 ml. of the solvent are distilled off and the residue is crystallized at -5° C. for 48 hours. The crystals are filtered off and dried. 17.8 g. (85%) of 2,2-dimethyl-3-(2,2-dichlorovinyl)-cyclopropane-1-carboxylic acid are obtained. Cis/trans ratio: 40:60.
Reaction SMILES: [C:1]1([CH:7]([O:14][C:15]([C:17]2[N:22]3[C:23](=[O:56])[C@@H:24]([NH:25][C:26](=[O:55])[C@H:27]([C:41]4[CH:46]=[CH:45][C:44](C(OC(C)(C)C)=O)=[CH:43][C:42]=4N)[NH:28][C:29]([N:31]4[CH2:36][CH2:35][N:34]([CH2:37][CH3:38])[C:33](=[O:39])[C:32]4=[O:40])=[O:30])[C@H:21]3[S:20][CH2:19][C:18]=2[CH2:57][O:58][C:59](=[O:61])[NH2:60])=[O:16])[C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.O.[C:63]1([CH3:73])[CH:68]=[CH:67][C:66]([S:69]([OH:72])(=[O:71])=[O:70])=[CH:65][CH:64]=1.C(#[N:76])C>>[C:63]1([CH3:73])[CH:64]=[CH:65][C:66]([S:69]([OH:72])(=[O:70])=[O:71])=[CH:67][CH:68]=1.[C:1]1([CH:7]([O:14][C:15]([C:17]2[N:22]3[C:23](=[O:56])[C@@H:24]([NH:25][C:26](=[O:55])[C@H:27]([C:41]4[CH:42]=[CH:43][C:44]([NH2:76])=[CH:45][CH:46]=4)[NH:28][C:29]([N:31]4[CH2:36][CH2:35][N:34]([CH2:37][CH3:38])[C:33](=[O:39])[C:32]4=[O:40])=[O:30])[C@H:21]3[S:20][CH2:19][C:18]=2[CH2:57][O:58][C:59](=[O:61])[NH2:60])=[O:16])[C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: CCN1CCN(C(=O)N[C@H](C(=O)N[C@@H]2C(=O)N3C(C(=O)OC(c4ccccc4)c4ccccc4)=C(COC(N)=O)CS[C@H]23)c2ccc(C(=O)OC(C)(C)C)cc2N)C(=O)C1=O
Reactant: CC#N
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: O
Product: CCN1CCN(C(=O)N[C@H](C(=O)N[C@@H]2C(=O)N3C(C(=O)OC(c4ccccc4)c4ccccc4)=C(COC(N)=O)CS[C@H]23)c2ccc(N)cc2)C(=O)C1=O

Procedure:
3.3 g of 7β-[(2S)-2-(4-BOC-aminophenyl)-2-(4-ethyl-2,3-dioxopiperazine-1-carboxamido)-acetamido]-3-carbamoyloxymethyl-3-cephem-4-carboxylic acid diphenylmethyl ester are reacted in 100 ml of acetonitrile with 1.46 g of p-toluenesulphonic acid monohydrate in the manner described in Example 22. 7β-[(2S)-2-(4-Aminophenyl)-2-(4-ethyl-2,3-dioxopiperazine-1-carboxamido)-acetamido]-3-carbamoyloxymethyl-3-cephem-4-carboxylic acid diphenylmethyl ester p-toluenesulphonate is obtained. [α]D20 =+27°±1° (0.954% in CH3OH);
Reaction SMILES: [Cl:1][C:2]1[CH:12]=[CH:11][C:5]2[NH:6][C:7](=O)[CH2:8][O:9][C:4]=2[CH:3]=1.B.C1COCC1>C1COCC1>[Cl:1][C:2]1[CH:12]=[CH:11][C:5]2[NH:6][CH2:7][CH2:8][O:9][C:4]=2[CH:3]=1
Reactant: O=C1COc2cc(Cl)ccc2N1
Agent: B
Solvent: C1CCOC1
Product: Clc1ccc2c(c1)OCCN2
Yield: 96.1 %

Procedure:
Using 7-chloro-4H-benzo[1,4]oxazin-3-one (2.3 g, 13.5 mmol) and borane-THF (40 mL of a 1M solution in THF, 40 mmol) in THF (40 mL) to yield the title compound as a cream solid (2.2 g, 96%). δH (CDCl3) 3.34-3.40 (2H, m), 4.16-4.28 (2H, m), 6.51-6.55 (1H, m), 6.59 (1H, d, J 2.4 Hz), 6.68 (1H, dd, J 8.1, 0.4 Hz). LCMS (ES+) 170 (M+H)+.
Reaction SMILES: [Br:1][C:2]1[CH:6]=[C:5]([C:7]([O:9]CC)=[O:8])[O:4][N:3]=1.[OH-].[Na+].Cl>CO.O>[Br:1][C:2]1[CH:6]=[C:5]([C:7]([OH:9])=[O:8])[O:4][N:3]=1
Reactant: CCOC(=O)c1cc(Br)no1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CO
Product: O=C(O)c1cc(Br)no1
Yield: 80.7 %

Procedure:
A solution of 442 mg (2.0 mmol) of ethyl 3-bromoisoxazole-5-carboxylate (Intermediate 119) and 5.0 ml of 1 N sodium hydroxide in 10 ml of MeOH was stirred at ambient temperature for 5 h, then acidified with 6.0 ml of 1 N hydrochloric acid, diluted with 25 ml of water and extracted with EtOAc (3×25 ml). The combined organic extract was dried over magnesium sulfate and concentrated in vacuo to give the title compound as a white solid (310 mg).
Reaction SMILES: [C:1]1([NH:7][C:8]([N:10]2[CH2:15][CH2:14][NH:13][CH2:12][CH2:11]2)=[O:9])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[I:16][C:17]1[CH:18]=[C:19]([CH:22]=[CH:23][CH:24]=1)[CH:20]=O>>[C:1]1([NH:7][C:8]([N:10]2[CH2:15][CH2:14][N:13]([CH2:20][C:19]3[CH:22]=[CH:23][CH:24]=[C:17]([I:16])[CH:18]=3)[CH2:12][CH2:11]2)=[O:9])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: O=C(Nc1ccccc1)N1CCNCC1
Reactant: O=Cc1cccc(I)c1
Product: O=C(Nc1ccccc1)N1CCN(Cc2cccc(I)c2)CC1

Procedure:
The title compound was prepared from piperazine-1-carboxylic acid phenylamide and 3-iodobenzaldehyde. 1H NMR (400 MHz, CDCl3): 7.71 (s, 1H), 7.62-7.60 (m, 1H), 7.36-7.26 (m, 5H), 7.09-7.01 (m, 2H), 6.33 (s, 1H), 3.52-3.48 (m, 6H), 2.49-2.46 (m, 4H).
Reaction SMILES: [CH:1]1[C:6]([OH:7])=[CH:5][CH:4]=[C:3]([CH3:8])[CH:2]=1.[C:9](=O)([O-])[O-].[K+].[K+].CN(C=O)C.IC>O>[CH3:9][O:7][C:6]1[CH:5]=[CH:4][C:3]([CH3:8])=[CH:2][CH:1]=1
Reactant: Cc1ccc(O)cc1
Reactant: O=C([O-])[O-]
Agent: [K+]
Solvent: CI
Solvent: CN(C)C=O
Solvent: O
Product: COc1ccc(C)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 86.2 %

Procedure:
p-cresol (20 g, 0.19 mol) and anhydrous potassium carbonate (75 g, 0.54 mol) were added into DMF (500 mL) and then iodomethane (27 g, 0.19 mol) was dropped under an ice bath. The system was stirred overnight at room temperature. At the end of reaction, the reaction system was added with water and then extracted with ethyl acetate, and the organic phase was washed with saturated brine, then dried and evaporated in vacuum to obtain 20 g of the product (86%) by column chromatography.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[N:11]([CH3:12])[C:10](=[O:13])[CH2:9][N:8]3[C:14]([C:17]([F:20])([F:19])[F:18])=[N:15][N:16]=[C:7]3[C:6]=2[CH:21]=1.[NH:22]1[CH2:27][CH2:26][O:25][CH2:24][CH2:23]1>>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([NH:11][CH3:12])=[C:6]([C:7]2[N:8]([CH2:9][C:10](=[O:13])[N:22]3[CH2:27][CH2:26][O:25][CH2:24][CH2:23]3)[C:14]([C:17]([F:20])([F:18])[F:19])=[N:15][N:16]=2)[CH:21]=1
Reactant: CN1C(=O)Cn2c(nnc2C(F)(F)F)-c2cc(Cl)ccc21
Reactant: C1COCCN1
Product: CNc1ccc(Cl)cc1-c1nnc(C(F)(F)F)n1CC(=O)N1CCOCC1

Procedure:
4.8 g. (0.0152 mole) of 10-chloro-7-methyl-3-(trifluoromethyl)-5H-s-triazolo[4,3-d] [1,4] benzodiazepin- 6(7H)-one from example 1a are dissolved in 40 ml. of morpholine and the resulting solution is refluxed for 3 days. The morpholine is removed under vacuum, 3N aqueous NaOH is added, and the mixture is extracted with benzene. The benzene solution is dried over Na2SO4, decanted from drying agent, and the solvent removed under vacuum to yield a gum. This gum is chromatographed on silica gel plates with chloroform/ethyl acetate, 6:4. The largest band is isolated, extracted with chloroform, the chloroform is evaporated, and the residue is recrystallized from ethanol to yield 3-[5-chloro-2-(methylamino)phenyl]-4-[2-oxo-2-(4-morpholinyl)ethyl]-5-(trifluoromethyl)-1,2,4-triazole; m.p. 152°-153°.
Reaction SMILES: Cl[C:2]1[CH:7]=[N:6][CH:5]=[C:4]([Cl:8])[N:3]=1.[CH:9]1[CH:14]=[N:13][CH:12]=[C:11]([CH2:15][OH:16])[CH:10]=1.[H-].[Na+]>O1CCOCC1>[Cl:8][C:4]1[CH:5]=[N:6][CH:7]=[C:2]([O:16][CH2:15][C:11]2[CH:12]=[N:13][CH:14]=[CH:9][CH:10]=2)[N:3]=1
Reactant: OCc1cccnc1
Reactant: Clc1cncc(Cl)n1
Agent: [H-]
Agent: [Na+]
Solvent: C1COCCO1
Product: Clc1cncc(OCc2cccnc2)n1

Procedure:
The title compound was prepared according to the procedure of example 4, step 1 starting from 2,6-dichloropyrazine (444 mg, 3.00 mmol), nicotinic alcohol (360 mg, 3.30 mmol) in dioxane (5 mL) and NaH (55% in oil, 144 mg, 3.30 mmol). The crude product, obtained as an oil (0.72 g), was used directly in the next step. MS m/z 221 (M)+.
Reaction SMILES: [CH3:1][O:2][C:3]1[N:8]=[CH:7][C:6]([NH:9][C:10](=[O:16])[O:11][C:12]([CH3:15])([CH3:14])[CH3:13])=[CH:5][CH:4]=1.[Li]CCCC.[CH3:22][C@:23]1([CH2:31][N:32]2[C:36]3[CH:37]=[C:38]([C:41]#[N:42])[CH:39]=[CH:40][C:35]=3[N:34]=[CH:33]2)CCC[C@:25]2(OC2)[CH2:24]1.CN1CCCC1=O>O1CCCC1.CCOC(C)=O.O>[CH3:1][O:2][C:3]1[N:8]=[CH:7][C:6]([N:9]2[CH2:14][C@@:12]3([CH2:13][CH2:25][CH2:24][C@@:23]([CH2:31][N:32]4[C:36]5[CH:37]=[C:38]([C:41]#[N:42])[CH:39]=[CH:40][C:35]=5[N:34]=[CH:33]4)([CH3:22])[CH2:15]3)[O:11][C:10]2=[O:16])=[CH:5][CH:4]=1
Reactant: COc1ccc(NC(=O)OC(C)(C)C)cn1
Reactant: C[C@]1(Cn2cnc3ccc(C#N)cc32)CCC[C@@]2(CO2)C1
Agent: [Li]CCCC
Solvent: CCOC(C)=O
Solvent: CN1CCCC1=O
Solvent: O
Product: COc1ccc(N2C[C@@]3(CCC[C@](C)(Cn4cnc5ccc(C#N)cc54)C3)OC2=O)cn1
Temperature: 25 °C
Reaction time: 0.33 h
Yield: 80.7 %

Procedure:
To a solution of tert-butyl (6-methoxypyridin-3-yl)carbamate (5.98 g, 26.7 mmol) in tetrahydrofuran (THF) (20 mL) at −78° C. under N2 was added n-BuLi (2.5M in hexanes) (10.66 mL, 26.7 mmol). The mixture was allowed to warm up to RT and stirred for 20 min, to the mixture was added 1-{[(3S,5S)-5-methyl-1-oxaspiro[2.5]oct-5-yl]methyl}-1H-benzimidazole-6-carbonitrile (6.0 g, 21.33 mmol) followed by N-methyl-2-pyrrolidone (NMP) (20.00 mL). The mixture was heated at 75° C. for 2 days and then cooled to RT. The reaction mixture was diluted with EtOAc/H2O and extracted with 3×EtOAc. The organic layers were washed with 2× brine, dried over Na2SO4, filtered and concentrated. To the residue was added 250 mL of i-PrOH, heated to reflux for 2 hours, and then cooled to RT for 2 days. The solid was filtered and air dried to afford 1-(((5S,7S)-3-(6-methoxypyridin-3-yl)-7-methyl-2-oxo-1-oxa-3-azaspiro[4.5]decan-7-yl)methyl)-1H-benzo[d]imidazole-6-carbonitrile as a white solid (7.43 g, 79% yield).
Reaction SMILES: [CH2:1]([N:8]([CH2:20][C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1)[CH:9]1[CH2:13][CH:12]([C:14]([O:16]CC)=[O:15])[CH:11]([CH3:19])[CH2:10]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1>O1CCOCC1>[CH2:20]([N:8]([CH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1)[CH:9]1[CH2:13][CH:12]([C:14]([OH:16])=[O:15])[CH:11]([CH3:19])[CH2:10]1)[C:21]1[CH:22]=[CH:23][CH:24]=[CH:25][CH:26]=1
Reactant: CCOC(=O)C1CC(N(Cc2ccccc2)Cc2ccccc2)CC1C
Solvent: C1COCCO1
Product: CC1CC(N(Cc2ccccc2)Cc2ccccc2)CC1C(=O)O
Yield: 98.3 %

Procedure:
Ethyl 4-(dibenzylamino)-2-methylcyclopentanecarboxylate (3.65 g, 10.38 mmol) was dissolved in a mixture of HC; (6 N aqueous, 20 mL) and 1,4-dioxane (50 mL) and the resulting mixture was heated at about 60° C. for about 72 h. The organic solvent was removed under reduced pressure. The aqueous phase was neutralized by the addition of saturated aqueous NaHCO3 (40 mL) and extracted with EtOAc (50 mL). The organic phase was washed with brine (40 mL), dried over anhydrous MgSO4 and coned under reduced pressure to yield 4-(dibenzylamino)-2-methylcyclopentanecarboxylic acid (3.3 g, 98%) as a white amorphous solid: LC/MS (Table 1, Method a) Rt=1.66 min.; MS m/z 324 (M+H)+. The procedure in Step A, Preparation #33 was utilized to provide (1S,2R,4S)-4-(dibenzylamino)-2-methylcyclopentanecarboxylic acid.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C:25]#[N:26])=[C:6]([C:8]2[C:13]([O:14][CH3:15])=[CH:12][N:11]([CH:16]([CH2:20][CH2:21][O:22][CH3:23])[C:17]([OH:19])=O)[C:10](=[O:24])[CH:9]=2)[CH:7]=1.[NH2:27][C:28]1[CH:29]=[C:30]2[C:34](=[CH:35][CH:36]=1)[NH:33][N:32]=[CH:31]2>>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C:25]#[N:26])=[C:6]([C:8]2[C:13]([O:14][CH3:15])=[CH:12][N:11]([CH:16]([CH2:20][CH2:21][O:22][CH3:23])[C:17]([NH:27][C:28]3[CH:29]=[C:30]4[C:34](=[CH:35][CH:36]=3)[NH:33][N:32]=[CH:31]4)=[O:19])[C:10](=[O:24])[CH:9]=2)[CH:7]=1
Reactant: Nc1ccc2[nH]ncc2c1
Reactant: COCCC(C(=O)O)n1cc(OC)c(-c2cc(Cl)ccc2C#N)cc1=O
Product: COCCC(C(=O)Nc1ccc2[nH]ncc2c1)n1cc(OC)c(-c2cc(Cl)ccc2C#N)cc1=O

Procedure:
150 mg (398 μmol) of 2-[4-(5-chloro-2-cyanophenyl)-5-methoxy-2-oxopyridin-1(2H)-yl]-4-methoxybutanoic acid (racemate) and 58.3 mg (438 μmol, 1.1 eq.) of 5-aminoindazole were reacted according to General Method 1. The crude product was purified by preparative HPLC (column: Chromatorex 125 mm×30 mm, 10 μm, mobile phase: water and acetonitrile, gradient 10% acetonitrile to 90% acetonitrile). Yield: 88 mg (42% of theory)
Reaction SMILES: [O:1]=[S:2]1(=[O:17])[N:7]=[CH:6][C:5]2[CH:8]=[C:9]([C:13]([CH3:16])([CH3:15])[CH3:14])[CH:10]=[C:11]([Cl:12])[C:4]=2[O:3]1>C(O)(=O)C.[Pt](=O)=O>[O:17]=[S:2]1(=[O:1])[NH:7][CH2:6][C:5]2[CH:8]=[C:9]([C:13]([CH3:15])([CH3:14])[CH3:16])[CH:10]=[C:11]([Cl:12])[C:4]=2[O:3]1
Reactant: CC(C)(C)c1cc(Cl)c2c(c1)C=NS(=O)(=O)O2
Agent: O=[Pt]=O
Solvent: CC(=O)O
Product: CC(C)(C)c1cc(Cl)c2c(c1)CNS(=O)(=O)O2
Reaction time: 0.08 h
Yield: 92.6 %

Procedure:
A solution of 2,2-dioxo-6-(1,1-dimethylethyl)-8-chloro-1,2,3-benzoxathiazine (2.5 g., 9.2 millimole) in acetic acid (200 ml.) contained in a Parr apparatus is hydrogenated in the presence of platinum (IV) oxide at 20° C. and a pressure (initial) of 50 p.s.i. for five minutes. The catalyst is removed by filtration and the filtrate is evaporated in vocuo to provide the title compound as a residual solid (2.35 g., 93%), m.p. 158°-160° C. Crystallization from 50% ethanol gives analytically pure 2,2-dioxo-3,4-dihydro-6-(1,1-dimethylethyl)-8-chloro-1,2,3-benzoxathiazine as colorless crystals, m.p. 162°-163° C.
Reaction SMILES: [CH3:1][CH2:2][O-].[Na+].[CH2:5]1[C:13]2[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=2)[CH:7]=[CH:6]1.C=O>CN(C=O)C>[CH2:5]1[C:13]2[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=2)[C:7]([CH2:8][C:9]2[C:1]3[C:2](=[CH:13][CH:5]=[CH:6][CH:7]=3)[CH2:11][CH:10]=2)=[CH:6]1
Reactant: CC[O-]
Reactant: C1=Cc2ccccc2C1
Agent: C=O
Agent: [Na+]
Solvent: CN(C)C=O
Product: C1=C(CC2=CCc3ccccc32)c2ccccc2C1
Yield: 254.1 %

Procedure:
1.05 g of EtONa (15.4 mmol) dissolved in 200 mL of DMF and 10.0 ml of indene (90%, 77.5 mmol) were introduced, at room temperature, in this order in a three-neck, 500 mL flask with stirring bar. 3.15 mL of aqueous formalin (37% solution, 38.8 mmol) dissolved in 10 mL of DMF were added dropwise, in 15 minutes: a mildly exothermic reaction was observed and the solution turned dark brown, with shades of violet. At the end of the addition, the reaction mixture was maintained under stirring for 20 hours, at room temperature. The reaction was quenched by pouring the mixture on ice and NH4Cl. The organic product was extracted with Et2O and the water layer was washed with Et2O; the organic layers were combined, dried over MgSO4, filtered and finally concentrated, thus obtaining an orange-brown oil. Said oil was further concentrated to eliminate the remaining indene, thus yielding 9.56 g of bis-(3-indenyl)methane, as an orange-brown oil (53.2% yield by GC).
Reaction SMILES: [F:1][C:2]([F:22])([F:21])[C:3]([C:9]1[CH:14]=[CH:13][C:12]([N:15]2[CH2:20][CH2:19][NH:18][CH2:17][CH2:16]2)=[CH:11][CH:10]=1)([OH:8])[C:4]([F:7])([F:6])[F:5].C(Cl)Cl.C(N(CC)CC)C.[S:33]1[CH:37]=[CH:36][CH:35]=[C:34]1[S:38](Cl)(=[O:40])=[O:39]>O>[F:22][C:2]([F:1])([F:21])[C:3]([C:9]1[CH:10]=[CH:11][C:12]([N:15]2[CH2:20][CH2:19][N:18]([S:38]([C:34]3[S:33][CH:37]=[CH:36][CH:35]=3)(=[O:40])=[O:39])[CH2:17][CH2:16]2)=[CH:13][CH:14]=1)([OH:8])[C:4]([F:7])([F:6])[F:5]
Reactant: O=S(=O)(Cl)c1cccs1
Reactant: OC(c1ccc(N2CCNCC2)cc1)(C(F)(F)F)C(F)(F)F
Solvent: CCN(CC)CC
Solvent: O
Solvent: ClCCl
Product: O=S(=O)(c1cccs1)N1CCN(c2ccc(C(O)(C(F)(F)F)C(F)(F)F)cc2)CC1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
A 100 mL round-bottomed flask was charged with 1,1,1,3,3,3-hexafluoro-2-(4-(1-piperazinyl)phenyl)-2-propanol (2.27 g, 6.92 mmol, published PCT patent application no. WO 2006/094842), 20 mL of CH2Cl2 and triethylamine (1.45 mL, 10.4 mmol). To this was added 2-thiophenesulfonyl chloride (1.39 mL, 7.61 mmol, Sigma-Aldrich, St. Louis, Mo.) and the mixture was stirred at room temperature for 2 h. After that time, the mixture was diluted with water (50 mL) and extracted with EtOAc (100 mL). The combined extracts were dried (MgSO4) and concentrated. This oil was purified by column chromatography (120 g silica gel, 0 to 50% EtOAc in hexanes) to give 1,1,1,3,3,3-hexafluoro-2-(4-(4-(2-thiophenylsulfonyl)-1-piperazinyl)phenyl)-2-propanol (2.35 g) as a white solid. 1H NMR (400 MHz, CDCl3) δ 7.70-7.65 (m, 1H) 7.64-7.56 (m, 3H), 7.23-7.18 (m, 1H), 7.02-6.94 (m, 2H), 3.43-3.36 (m, 4H), 3.33-3.25 (m, 4H). m/z (ESI, +ve ion) 475.0 (M+H)+. GK-GKRP EC50 (NADPH-coupled)=0.332 μM; GK-GKRP EC50 (LC MS/MS)=0.500 μM.
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([NH:8][CH3:9])[N:5]=[C:4]([N:10]2[C@H:15]([CH3:16])[CH2:14][O:13][C@H:12]([CH2:17][OH:18])[CH2:11]2)[CH:3]=1.[C:19]([C:21]1[CH:26]=[CH:25][C:24](B(O)O)=[CH:23][C:22]=1[F:30])#[N:20]>O1CCOCC1.C([O-])(O)=O.[Na+].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>[F:30][C:22]1[CH:23]=[C:24]([C:2]2[CH:3]=[C:4]([N:10]3[C@H:15]([CH3:16])[CH2:14][O:13][C@H:12]([CH2:17][OH:18])[CH2:11]3)[N:5]=[C:6]([NH:8][CH3:9])[N:7]=2)[CH:25]=[CH:26][C:21]=1[C:19]#[N:20]
Reactant: CNc1nc(Cl)cc(N2C[C@@H](CO)OC[C@H]2C)n1
Reactant: N#Cc1ccc(B(O)O)cc1F
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: C1COCCO1
Product: CNc1nc(-c2ccc(C#N)c(F)c2)cc(N2C[C@@H](CO)OC[C@H]2C)n1
Temperature: 100 °C
Reaction time: 17 h
Yield: 91.2 %

Procedure:
A mixture of {(2S,5R)-4-[6-chloro-2-(methylamino)-4-pyrimidinyl]-5-methyl-2-morpholinyl}methanol (2.24 g, 7.24 mmol), (4-cyano-3-fluorophenyl)boronic acid (2.64 g, 16.01 mmol), and Pd(PPh3)4 (0.43 g, 0.37 mmol) in 1,4-dioxane (50 mL) and saturated aqueous NaHCO3 (25 mL) was degassed with nitrogen for 10 minutes. It was then stirred at 100° C. under nitrogen for 17 hours, cooled, diluted with water (25 mL) and saturated aqueous NaHCO3 (100 mL), and extracted with EtOAc (3×100 mL). The extracts were washed with brine (150 mL), dried (Na2SO4), filtered, and concentrated in vacuo. The residue was purified by flash chromatography (90 g SiO2, 20-100% EtOAc in hexanes gradient) to give the title compound (2.36 g) as a yellow solid. LC-MS (ES) m/z=358 [M+H]+.
Reaction SMILES: [N+:1]([O-:4])([O-:3])=[O:2].[Na+:5].[S:6](=[O:10])(=[O:9])([OH:8])[OH:7].[NH4+:11]>>[N+:1]([O-:4])([O-:3])=[O:2].[NH4+:11].[S:6]([O-:10])([O-:9])(=[O:8])=[O:7].[Na+:5].[Na+:5]
Reactant: O=S(=O)(O)O
Agent: O=[N+]([O-])[O-]
Agent: [NH4+]
Agent: [Na+]
Product: O=S(=O)([O-])[O-]

Procedure:
In other known process, the sodium nitrate is reacted with sulfuric acid in order to be transformed on nitric acid which is then reacted with ammonium in order to produce ammonium nitrate and sodium sulfate which is separated by crystallization. This process is only suitable when there are plenty of cheap disposals of sodium nitrate and sulfuric acid available and when the cost of the sodium sulfate is very high.
Reaction SMILES: [NH:1]1[C:5]2=[N:6][CH:7]=[C:8]([O:10][C:11]3[CH:20]=[C:19]([N:21]4[CH2:26][CH2:25][N:24]([CH2:27][C:28]5[CH2:29][O:30][C:31]([CH3:42])([CH3:41])[CH2:32][C:33]=5[C:34]5[CH:39]=[CH:38][C:37]([Cl:40])=[CH:36][CH:35]=5)[CH2:23][CH2:22]4)[CH:18]=[CH:17][C:12]=3[C:13]([O:15]C)=[O:14])[CH:9]=[C:4]2[CH:3]=[CH:2]1.O[Li].O.Cl>O1CCCC1.CO.O.C(OCC)(=O)C>[NH:1]1[C:5]2=[N:6][CH:7]=[C:8]([O:10][C:11]3[CH:20]=[C:19]([N:21]4[CH2:22][CH2:23][N:24]([CH2:27][C:28]5[CH2:29][O:30][C:31]([CH3:42])([CH3:41])[CH2:32][C:33]=5[C:34]5[CH:35]=[CH:36][C:37]([Cl:40])=[CH:38][CH:39]=5)[CH2:25][CH2:26]4)[CH:18]=[CH:17][C:12]=3[C:13]([OH:15])=[O:14])[CH:9]=[C:4]2[CH:3]=[CH:2]1
Reactant: COC(=O)c1ccc(N2CCN(CC3=C(c4ccc(Cl)cc4)CC(C)(C)OC3)CC2)cc1Oc1cnc2[nH]ccc2c1
Agent: Cl
Agent: [Li]O
Solvent: C1CCOC1
Solvent: CO
Solvent: O
Product: CC1(C)CC(c2ccc(Cl)cc2)=C(CN2CCN(c3ccc(C(=O)O)c(Oc4cnc5[nH]ccc5c4)c3)CC2)CO1
Reaction time: 8 h

Procedure:
To a solution of EXAMPLE 15G (254 mg) in tetrahydrofuran (4 mL), methanol (2 mL) and water (2 mL) was added LiOH H2O (126 mg). The mixture was stirred overnight. The mixture was then neutralized with 5% HCl and diluted with ethyl acetate (200 mL). After washing with brine, it was dried over Na2SO4. Filtration and evaporation of solvent gave the product.
Reaction SMILES: [O:1]1[C:6]2[C:7]([CH2:11][C:12]3[N:13]=[CH:14][NH:15][CH:16]=3)=[CH:8][CH:9]=[CH:10][C:5]=2[CH2:4][O:3]C1.Cl>>[NH:15]1[CH:16]=[C:12]([CH:11]([C:7]2[C:6]([OH:1])=[C:5]([CH2:4][OH:3])[CH:10]=[CH:9][CH:8]=2)[CH2:4][CH2:5][CH2:6][CH3:7])[N:13]=[CH:14]1
Reactant: c1cc2c(c(Cc3c[nH]cn3)c1)OCOC2
Agent: Cl
Product: CCCCC(c1c[nH]cn1)c1cccc(CO)c1O

Procedure:
4-[(4H-1,3-benzodioxin-8-yl)methyl]-1H-imidazole and the hydrochloride thereof;
Reaction SMILES: [ClH:1].[C:2]([O:5][C@H:6]1[C@H:10]([O:11][C:12](=[O:14])[CH3:13])[C@H:9]([C:15]2[CH:20]=[CH:19][C:18]([NH:21]C(OC(C)(C)C)=O)=[CH:17][CH:16]=2)[N:8]([C:29]2[CH:34]=[CH:33][C:32]([F:35])=[CH:31][CH:30]=2)[C@H:7]1[C:36]1[CH:41]=[CH:40][C:39]([NH:42]C(OC(C)(C)C)=O)=[CH:38][CH:37]=1)(=[O:4])[CH3:3].CCOCC>O1CCOCC1>[ClH:1].[ClH:1].[C:12]([O:11][C@H:10]1[C@H:6]([O:5][C:2](=[O:4])[CH3:3])[C@H:7]([C:36]2[CH:37]=[CH:38][C:39]([NH2:42])=[CH:40][CH:41]=2)[N:8]([C:29]2[CH:34]=[CH:33][C:32]([F:35])=[CH:31][CH:30]=2)[C@H:9]1[C:15]1[CH:16]=[CH:17][C:18]([NH2:21])=[CH:19][CH:20]=1)(=[O:14])[CH3:13]
Reactant: CC(=O)O[C@H]1[C@H](OC(C)=O)[C@H](c2ccc(NC(=O)OC(C)(C)C)cc2)N(c2ccc(F)cc2)[C@H]1c1ccc(NC(=O)OC(C)(C)C)cc1
Agent: Cl
Solvent: C1COCCO1
Solvent: CCOCC
Product: CC(=O)O[C@H]1[C@H](OC(C)=O)[C@H](c2ccc(N)cc2)N(c2ccc(F)cc2)[C@H]1c1ccc(N)cc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 84 %

Procedure:
A solution of 4 N hydrogen chloride in dioxane (8 mL) was treated with the compound of Example 70B (136 mg, 0.21 mmol) followed by stirring at RT for 2 h. (During this time, the mono-deprotection product started precipitating, and ca. 4 mL of dichloromethane was added to speed the reaction by solublizing the mono-hydrochloride) The mixture was added to excess ether and the product collected by filtration and washed with ether. After drying in a vacuum oven at 50° C. for 18 h, these procedures afforded the title compound (92 mg, 84%) as an off-white powder. 1H NMR (400 MHz, DMSO-d6) δ 7.28 (m, 8H), 6.81 (t, J=8.9 Hz, 2H), 6.33 (m, 2H), 5.63 (m, 2H), 5.51 (dd, J=5.5, 1.9 Hz, 2H), 1.79 (s, 6H).