Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][N:2]1[CH2:14][CH:13]([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=2[F:21])[C:5]2=[CH:6][CH:7]=[C:8]3[C:12]([NH:11][CH2:10][CH2:9]3)=[C:4]2[CH2:3]1.[C:22](O)(=O)C.C=O.C([BH3-])#N.[Na+]>CO>[CH3:22][N:11]1[C:12]2[C:8](=[CH:7][CH:6]=[C:5]3[CH:13]([C:15]4[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=4[F:21])[CH2:14][N:2]([CH3:1])[CH2:3][C:4]3=2)[CH2:9][CH2:10]1
Reactant: CN1Cc2c(ccc3c2NCC3)C(c2ccccc2F)C1
Reactant: CC(=O)O
Agent: C=O
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CO
Product: CN1Cc2c(ccc3c2N(C)CC3)C(c2ccccc2F)C1

Procedure:
2.3 g (0.00814 mol) of 8-methyl-6-(fluorophenyl)-2,3,6,7,8,9-hexahydro-1H-pyrido[4,3-g]indole are dissolved in 20 ml of MeOH, and 0.977 g (0.0163 mol) of acetic acid and 0.791 ml (0.00976 mol) of formalin are added at room temperature, with stirring. The reaction mixture is subsequently stirred for 1 hour and 1.53 g (0.0244 mol) of sodium cyanoborohydride are then added in several portions. In order to bring the reaction to completion, the mixture is subsequently stirred at room temperature for 1.5 hours. The solvent is then stripped off on a rotary evaporator, H2O is added to the residue and the mixture is rendered alkaline with 1N NaOH. The aqueous phase is extracted with CH2Cl2 and dried over NaSO4 and the solvent is evaporated off on a rotary evaporator. The oily residue is chromatographed on silica gel (silica gel 60 from E. Merck, Darmstadt) using an eluent mixture of: CH2Cl2 /MeOH (2.5:0.15). The product is dried in the absence of light in a desiccator over P2O5 at 10-2 bar.
Reaction SMILES: [P:1]([O:10][CH2:11][CH2:12][Cl:13])([O:6][CH2:7][CH2:8][Cl:9])[O:2][CH2:3][CH2:4][Cl:5].C1[O:16]C1>>[P:1]([O:10][CH2:11][CH2:12][Cl:13])([O:6][CH2:7][CH2:8][Cl:9])([O:2][CH2:3][CH2:4][Cl:5])=[O:16]
Reactant: ClCCOP(OCCCl)OCCCl
Reactant: C1CO1
Product: O=P(OCCCl)(OCCCl)OCCCl

Procedure:
However, phosphorus trichloride can easily be oxidized by oxygen or oxygen-containing gases to phosphorus oxychloride. A slow, steady increase in the phosphorus oxychloride content can be observed during storage, transport and use of phosphorus trichloride. The phosphorus oxychloride lowers the quality of the phosphorus trichloride and necessarily leads to undesirable by-products during chemical processing, so that the desired end product is of lower quality and is obtained in a lesser yield. For example, in further processing to phosphorus pentachloride or phosphorus sulfochloride, all the phosphorus oxychloride reaches the end product. Because of the physical properties, subsequent separation is much more difficult than separation from phosphorus trichloride. During further processing to phosphorous acid, phosphoric acid is formed from the phosphorus oxychloride and phosphates are formed as by-products during the reaction with alcohols to phosphites. During the synthesis of tri-(2-chloroethyl) phosphite by reaction with ethylene oxide, tri-(2-chloroethyl) phosphate is formed as an interfering by-product.
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[C:10](Br)=[CH:9][N:8]2[CH:12]=[CH:13][N:14]=[C:7]2[CH:6]=1)=[O:4].[Cl:15][C:16]1[CH:21]=[C:20]([Cl:22])[CH:19]=[CH:18][C:17]=1B(O)O.C([O-])([O-])=O.[Na+].[Na+].CCOC(C)=O>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>[CH3:1][O:2][C:3]([C:5]1[C:10]([C:19]2[CH:18]=[CH:17][C:16]([Cl:15])=[CH:21][C:20]=2[Cl:22])=[CH:9][N:8]2[CH:12]=[CH:13][N:14]=[C:7]2[CH:6]=1)=[O:4]
Reactant: OB(O)c1ccc(Cl)cc1Cl
Reactant: COC(=O)c1cc2nccn2cc1Br
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: CCOC(C)=O
Solvent: COCCOC
Product: COC(=O)c1cc2nccn2cc1-c1ccc(Cl)cc1Cl
Temperature: 150 °C
Yield: 76.8 %

Procedure:
In a sealed tube, a mixture of 6-bromo-imidazo[1,2-a]pyridine-7-carboxylic acid methyl ester (505 mg, 1.98 mmol), 2,4-dichlorobenzeneboronic acid (416 mg, 2.18 mmol), Pd(PPh3)4 (114 mg, 0.10 mmol) and Na2CO3 (2.0 M solution in water, 3.5 mL) in DME (5 mL) was heated at 150° C. for 17 min in a microwave oven. The reaction mixture was cooled to RT, poured into AcOEt and washed with water. The organic layer was dried over Na2SO4, filtered, and evaporated. The remaining residue was purified by Combi-Flash Companion™ (Isco Inc.) column chromatography (SiO2; gradient elution, [hexane/DCM 1:1]/TBME 95:5→100% TBME) to yield the title compound (488 mg, 1.52 mmol, 77%). MS: 321 [M+1]+; HPLC: AtRet=1.43; TLC: RF 0.16 (hexane/DCM/TBME 1:1:2).
Reaction SMILES: [F:1][C@@H:2]1[C@@H:6]([CH2:7][OH:8])[O:5][C@@H:4]([N:9]2[CH:16]=[CH:15][C:13](=[O:14])[NH:12][C:10]2=[O:11])[CH2:3]1.[Br:17]Br>C(O)(=O)C>[Br:17][C:15]1[C:13](=[O:14])[NH:12][C:10](=[O:11])[N:9]([C@@H:4]2[O:5][C@H:6]([CH2:7][OH:8])[C@@H:2]([F:1])[CH2:3]2)[CH:16]=1
Reactant: BrBr
Reactant: O=c1ccn([C@H]2C[C@H](F)[C@@H](CO)O2)c(=O)[nH]1
Solvent: CC(=O)O
Product: O=c1[nH]c(=O)n([C@H]2C[C@H](F)[C@@H](CO)O2)cc1Br
Reaction time: 18 h
Yield: 64 %

Procedure:
The 5'-O-toluoyl derivative of 1-(2,3-dideoxy-3-fluoro-β-D-erythropentofuranosyl)uracil, prepared as described in Example 1, (200 mg, 0.574 mmol), glacial acetic acid (5 ml) and bromine (0.08 ml of an 8M solution in glacial acetic acid, 0.64 mequiv.) were stirred at 25° for 18 hours. The solution was evaporated to a glass which was treated with sodium methoxide and methanol as described in Example 1. Product was eluted from a silica gel column with 5% MeOH-CH2Cl2 as white crystals (135 mg). Recrystallization from EtOH gave title compound as white crystals (115 mg, 64% overall yield); m.p. 193.5°-194° dec.; Anal Calcd for C9H10BrFN2O4 : C, 34.97; H, 3.26; N, 9.06; Br, 25.85; F, 6.15. Found: C, 35.07; H, 3.31; N, 9.00; Br, 25.78; F, 6.04; UV λ max (H2O): 277 nM; structure further confirmed by 'H-NMR and mass spectrum.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[N:12]=[C:11]([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=2[Cl:19])[NH:10][N:9]=1.[CH3:20][O-].[Na+].CI>CO>[CH3:20][N:9]1[C:8]([C:3]2[CH:4]=[CH:5][CH:6]=[CH:7][C:2]=2[Cl:1])=[N:12][C:11]([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=2[Cl:19])=[N:10]1
Reactant: Clc1ccccc1-c1n[nH]c(-c2ccccc2Cl)n1
Reactant: C[O-]
Agent: [Na+]
Solvent: CI
Solvent: CO
Product: Cn1nc(-c2ccccc2Cl)nc1-c1ccccc1Cl
Reaction time: 72 h
Yield: 25.4 %

Procedure:
The product of stage (b) (3.0 g) and sodium methoxide (0.57 g) were dissolved in methanol (75 ml) and treated with methyl iodide (1.3 g). After standing for 3 days the solution was evaporated to dryness, treated with water and extracted into dichloromethane. The extract was washed with water and dried. Evaporation yielded 0.8 g of a solid, mp 82°-85° C., which was recrystallised twice from petroleum ether (80°-100°).
Reaction SMILES: ClCCl.[C:4]([OH:9])(=[O:8])[C:5]([CH3:7])=[CH2:6].[O:10]1[CH:14]=[CH:13][CH2:12][CH2:11]1>CS(O)(=O)=O.C(N(CC)CC)C>[C:4]([O:9][CH:11]1[CH2:12][CH2:13][CH2:14][O:10]1)(=[O:8])[C:5]([CH3:7])=[CH2:6]
Reactant: C=C(C)C(=O)O
Reactant: C1=COCC1
Agent: CS(=O)(=O)O
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: C=C(C)C(=O)OC1CCCO1
Temperature: -40 °C
Reaction time: 6 h
Yield: 57.4 %

Procedure:
To a 500-mL, 3-necked round bottomed flask equipped with a thermocouple temperature monitor, nitrogen inlet and a magnetic stirrer was added 300 mL of dichloromethane, 24.5 g (0.29 mol) of methacrylic acid and 21.4 g (0.305 mol) of 2,3-dihydrofuran. The flask was cooled under Nitrogen to −40° C. and 0.05 g of methanesulfonic acid was added. The mixture was warmed to 0° C. and stirred for 6 hours at which time it was recooled to −40° C. and an excess (1 mL) of triethylamine was added. The solution was then washed with saturated sodium bicarbonate, water and brine and dried over anhydrous magnesium sulfate. Distillation from sodium carbonate at reduced pressure resulted in 26 g (58%) of the title compound.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:9]2[C:14]([C:15]([OH:17])=O)=[C:13]([CH3:18])[NH:12][C:11](=[O:19])[NH:10]2)[CH:5]=[CH:6][C:7]=1[F:8].[F:20][C:21]1[CH:22]=[C:23]([NH:28][C:29]2[C:37]3[C:32](=[CH:33][CH:34]=[C:35]([NH2:38])[CH:36]=3)[NH:31][N:30]=2)[CH:24]=[C:25]([F:27])[CH:26]=1.C1CN([P+](Br)(N2CCCC2)N2CCCC2)CC1.F[P-](F)(F)(F)(F)F.C(N(C(C)C)CC)(C)C>C(Cl)Cl>[F:20][C:21]1[CH:22]=[C:23]([NH:28][C:29]2[C:37]3[C:32](=[CH:33][CH:34]=[C:35]([NH:38][C:15]([C:14]4[CH:9]([C:4]5[CH:5]=[CH:6][C:7]([F:8])=[C:2]([F:1])[CH:3]=5)[NH:10][C:11](=[O:19])[NH:12][C:13]=4[CH3:18])=[O:17])[CH:36]=3)[NH:31][N:30]=2)[CH:24]=[C:25]([F:27])[CH:26]=1
Reactant: Nc1ccc2[nH]nc(Nc3cc(F)cc(F)c3)c2c1
Reactant: CC1=C(C(=O)O)C(c2ccc(F)c(F)c2)NC(=O)N1
Agent: Br[P+](N1CCCC1)(N1CCCC1)N1CCCC1
Agent: F[P-](F)(F)(F)(F)F
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: CC1=C(C(=O)Nc2ccc3[nH]nc(Nc4cc(F)cc(F)c4)c3c2)C(c2ccc(F)c(F)c2)NC(=O)N1

Procedure:
The titled compound was prepared following the procedure of Example 175 using 4-(3,4-Difluoro-phenyl)-6-methyl-2-oxo-1,2,3,4-tetrahydro-pyrimidine-5-carboxylic acid, N3-(3,5-difluoro-phenyl)-1H-indazole-3,5-diamine, PyBroP and diisopropylethylamine in methylene chloride. MS (ESI) m/z=511 [M+H]+.
Reaction SMILES: [NH2:1][C:2]1[C:3]([F:17])=[C:4]([CH:13]=[CH:14][C:15]=1[Cl:16])[CH2:5][NH:6][C:7](=[O:12])[C:8]([CH3:11])([CH3:10])[CH3:9].[C:18](N1C=CC=CC1=O)(N1C=CC=CC1=O)=[S:19]>>[Cl:16][C:15]1[CH:14]=[CH:13][C:4]([CH2:5][NH:6][C:7](=[O:12])[C:8]([CH3:11])([CH3:10])[CH3:9])=[C:3]([F:17])[C:2]=1[N:1]=[C:18]=[S:19]
Reactant: CC(C)(C)C(=O)NCc1ccc(Cl)c(N)c1F
Reactant: O=c1ccccn1C(=S)n1ccccc1=O
Product: CC(C)(C)C(=O)NCc1ccc(Cl)c(N=C=S)c1F
Yield: 65 %

Procedure:
The title compound is prepared from N-(3-amino-4-chloro-2-fluoro-benzyl)-2,2-dimethyl-propionamide, 1,1′-thiocarbonyldi-2-pyridone in analogy to step Af.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]=[CH:7][C:6]([C:12]([CH:14]1[CH2:16][CH2:15]1)=[O:13])=[C:5]2Cl.Cl.[N:19]1([C@H:24]2[CH2:29][CH2:28][C@H:27]([NH2:30])[CH2:26][CH2:25]2)[CH2:23][CH2:22][CH2:21][CH2:20]1>>[Br:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]=[CH:7][C:6]([C:12]([CH:14]1[CH2:16][CH2:15]1)=[O:13])=[C:5]2[NH:30][C@H:27]1[CH2:26][CH2:25][C@H:24]([N:19]2[CH2:23][CH2:22][CH2:21][CH2:20]2)[CH2:29][CH2:28]1
Reactant: N[C@H]1CC[C@H](N2CCCC2)CC1
Reactant: O=C(c1cnc2ccc(Br)cc2c1Cl)C1CC1
Agent: Cl
Product: O=C(c1cnc2ccc(Br)cc2c1N[C@H]1CC[C@H](N2CCCC2)CC1)C1CC1

Procedure:
Following general procedure C, (6-bromo-4-chloroquinolin-3-yl)(cyclopropyl)methanone (220 mg, 0.708 mmol) was reacted with trans-4-(pyrrolidin-1-yl)cyclohexanamine hydrochloride (350 mg, 2.08 mmol) to afford the desired product (75 mg, 24%) as an off-white solid: ESI MS m/z 442 [C23H28BrN3O+H]+.
Reaction SMILES: [CH3:1][S:2][C:3]1[N:4]=[CH:5][C:6]2[CH2:12][N:11]([C:13]3[N:18]=[C:17]([C:19]([OH:21])=O)[CH:16]=[CH:15][CH:14]=3)[CH2:10][CH2:9][C:7]=2[N:8]=1.[CH:22]([C:25]1[CH:26]=[C:27]([CH:29]=[CH:30][CH:31]=1)[NH2:28])([CH3:24])[CH3:23]>>[CH:22]([C:25]1[CH:26]=[C:27]([NH:28][C:19](=[O:21])[C:17]2[CH:16]=[CH:15][CH:14]=[C:13]([N:11]3[CH2:10][CH2:9][C:7]4[N:8]=[C:3]([S:2][CH3:1])[N:4]=[CH:5][C:6]=4[CH2:12]3)[N:18]=2)[CH:29]=[CH:30][CH:31]=1)([CH3:24])[CH3:23]
Reactant: CSc1ncc2c(n1)CCN(c1cccc(C(=O)O)n1)C2
Reactant: CC(C)c1cccc(N)c1
Product: CSc1ncc2c(n1)CCN(c1cccc(C(=O)Nc3cccc(C(C)C)c3)n1)C2

Procedure:
In a manner similar to that described in Example 108, a mixture of 6-[2-(methylthio)-5,6,7,8-tetrahydropyrido[4,3-d]pyrimidin-6-yl]pyridine-2-carboxylic acid and 3-isopropylaniline were converted to the title compound (560 mg).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([F:8])[C:5]([C:9]2[C:13]([Cl:14])=[C:12]([C:15]([F:18])([F:17])[F:16])[N:11]([CH3:19])[N:10]=2)=[CH:4][C:3]=1[S:20](Cl)(=O)=O>C(O)(=O)C.[Zn]>[Cl:1][C:2]1[CH:7]=[C:6]([F:8])[C:5]([C:9]2[C:13]([Cl:14])=[C:12]([C:15]([F:18])([F:17])[F:16])[N:11]([CH3:19])[N:10]=2)=[CH:4][C:3]=1[SH:20]
Reactant: Cn1nc(-c2cc(S(=O)(=O)Cl)c(Cl)cc2F)c(Cl)c1C(F)(F)F
Agent: [Zn]
Solvent: CC(=O)O
Product: Cn1nc(-c2cc(S)c(Cl)cc2F)c(Cl)c1C(F)(F)F
Temperature: 80 °C
Reaction time: 4 h
Yield: 95.3 %

Procedure:
To a solution of 12.8 g (0.031 mole) 2-chloro-5 [4-chloro-1-methyl-5-(trifluoromethyl)-1H-pyrazol-3-yl]-4-fluorobenzenesulfonyl chloride in 100 mL acetic acid was added 40.7 g (0.62 mole) zinc powder. The slurry was stirred at 80° C. for 4 hours, allowed to cool and filtered through Celite®. The filtrate was poured into 1.0 L water, the solid filtered and dried. The solid was recrystallized from ethanol/water to give 10.2 g (95%) of 2-chloro-5-[4-chloro-1-methyl-5-(trifluoromethyl)-1H-pyrazol-3-yl]-4-fluorobenzenethiol as a yellow solid; mp 56°-58° C.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([F:8])=[CH:4][C:3]=1[CH:9]([S:28]([C:31]1[CH:36]=[CH:35][C:34]([F:37])=[CH:33][CH:32]=1)(=[O:30])=[O:29])[C:10]1[C:11]([CH3:27])=[CH:12][C:13]([C:16]([NH:18][CH2:19][O:20][CH2:21][C:22]([O:24]CC)=[O:23])=[O:17])=[N:14][CH:15]=1.O.[OH-].[Li+].Cl>O1CCCC1.O>[F:1][C:2]1[CH:7]=[CH:6][C:5]([F:8])=[CH:4][C:3]=1[CH:9]([S:28]([C:31]1[CH:36]=[CH:35][C:34]([F:37])=[CH:33][CH:32]=1)(=[O:30])=[O:29])[C:10]1[C:11]([CH3:27])=[CH:12][C:13]([C:16]([NH:18][CH2:19][O:20][CH2:21][C:22]([OH:24])=[O:23])=[O:17])=[N:14][CH:15]=1
Reactant: CCOC(=O)COCNC(=O)c1cc(C)c(C(c2cc(F)ccc2F)S(=O)(=O)c2ccc(F)cc2)cn1
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Product: Cc1cc(C(=O)NCOCC(=O)O)ncc1C(c1cc(F)ccc1F)S(=O)(=O)c1ccc(F)cc1
Temperature: 25 °C
Reaction time: 20 h
Yield: 24.1 %

Procedure:
To a mixed solution of ethyl [[[[5-[(2,5-difluorophenyl)[(4-fluorophenyl)sulfonyl]methyl]-4-methylpyridin-2-yl]carbonyl]amino]methoxy]acetate (167 mg, 0.311 mmol) in tetrahydrofuran (6 ml) and water (3 ml), lithium hydroxide monohydrate (16 mg, 0.373 mmol) was added, and the mixture was stirred for 20 hours at room temperature. 1 N hydrochloric acid (0.5 ml) and water were added to the reaction solution, and the mixture was extracted with methylene chloride. The organic layer was dried over anhydrous sodium sulfate and filtered, and then the filtrate was concentrated under reduced pressure. The resulting concentration residue was subjected to flash silica gel column chromatography, and the fraction obtained from an elution with methanol:methylene chloride (=1:10) was concentrated under reduced pressure. A mixed solution of ethyl acetate-hexane was added to the resulting concentration residue, and then the residue was collected by filtration to obtain the title compound (38 mg, 0.075 mmol, 24%) as a white powder.
Reaction SMILES: [NH2:1][C:2]1[C:7]([C:8]#[N:9])=[C:6]([C:10]2[CH:15]=[CH:14][C:13]([OH:16])=[CH:12][CH:11]=2)[C:5]([C:17]#[N:18])=[C:4]([S:19][CH2:20][CH2:21][NH2:22])[N:3]=1.[C:23](N1C=CN=C1)(=[O:25])[CH3:24].O>CN(C=O)C>[NH2:1][C:2]1[N:3]=[C:4]([S:19][CH2:20][CH2:21][NH:22][C:23](=[O:25])[CH3:24])[C:5]([C:17]#[N:18])=[C:6]([C:10]2[CH:11]=[CH:12][C:13]([OH:16])=[CH:14][CH:15]=2)[C:7]=1[C:8]#[N:9]
Reactant: N#Cc1c(N)nc(SCCN)c(C#N)c1-c1ccc(O)cc1
Reactant: CC(=O)n1ccnc1
Solvent: O
Solvent: CN(C)C=O
Product: CC(=O)NCCSc1nc(N)c(C#N)c(-c2ccc(O)cc2)c1C#N
Temperature: 25 °C
Reaction time: 5 h

Procedure:
At RT 60 mg (0.2 mmol) of 2-amino-6-[(2-aminoethyl)sulfanyl]-4-(4-hydroxyphenyl)-3,5-pyridinedicarbonitrile and 30 mg (0.3 mmol) of N-acetylimidazole are stirred in 0.5 ml of DMF for 1 hour. Water is slowly added dropwise, the mixture becomes slightly turbid and the crude product crystallizes out. The product is filtered off with suction, washed with water and dried under reduced pressure. This gives 53 mg of yellow crystals. The crystals are dissolved in 1 ml of a 1:1 mixture of CH2Cl2/CH3OH, and a few drops of concentrated ammonia are added (removal of diacetylated byproduct). The mixture is stirred at RT for 5 hours. The product crystallizes out when the reaction solution is concentrated. The product is filtered off with suction and washed with methanol.
Reaction SMILES: [N:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[NH:3][CH:2]=1.Br[CH2:11][C:12]#[N:13]>>[N:1]1([CH2:11][C:12]#[N:13])[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[N:3]=[CH:2]1
Reactant: N#CCBr
Reactant: c1ccc2[nH]cnc2c1
Product: N#CCn1cnc2ccccc21

Procedure:
The title compound is synthesized by coupling of Benzimidazole and bromoacetonitrile analogously to the preparation of Intermediate 149.2 as a colorless solid; ES-MS: M+H=158.0: CtRet=3.42.
Reaction SMILES: [N:1]([CH2:4][C@@H:5]1[CH2:7][C@H:6]1[C:8]([OH:10])=O)=[N+:2]=[N-:3].C(Cl)(=O)C([Cl:14])=O.CN(C)C=O>ClCCl>[N:1]([CH2:4][C@@H:5]1[CH2:7][C@H:6]1[C:8]([Cl:14])=[O:10])=[N+:2]=[N-:3]
Reactant: [N-]=[N+]=NC[C@@H]1C[C@H]1C(=O)O
Reactant: O=C(Cl)C(=O)Cl
Solvent: CN(C)C=O
Solvent: ClCCl
Product: [N-]=[N+]=NC[C@@H]1C[C@H]1C(=O)Cl
Yield: 97.5 %

Procedure:
A solution of trans-2-azidomethyl-1-cyclopropane carboxylic acid (2.188 g, 15.50 mmol) in dry dichloromethane (25 ml) was treated at room temperature with oxalyl chloride (1.57 ml, 18.60 mmol) and a drop of N,N-dimethylformamide. After the evolution of gas has ceased (2.5 h), the solvent was evaporated under reduced pressure and the residue was distilled under vacuum (bulb to bulb distillation) to give 2.411 g (98%) of a clear oil: bp 70°-75° C./0.8 mm Hg (air bath temperature; ir (film) νmax : 2100 (N3), 1775 cm-1 (C=O); 1Hmr (CDCl3) δ: 3.33 (2H, d, J=6, CH2N3) ~2.2-1.0 ppm (4H, m, cyclopropyl).
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[C:9]2[C:5]([CH:6]=[C:7]([C:12]3[CH:13]=[C:14]([CH2:18][NH2:19])[CH:15]=[N:16][CH:17]=3)[N:8]2[CH3:11])=[CH:4][CH:3]=1.[CH:20]([S:23](Cl)(=[O:25])=[O:24])([CH3:22])[CH3:21]>>[Cl:1][C:2]1[CH:10]=[C:9]2[C:5]([CH:6]=[C:7]([C:12]3[CH:13]=[C:14]([CH2:18][NH:19][S:23]([CH:20]([CH3:22])[CH3:21])(=[O:25])=[O:24])[CH:15]=[N:16][CH:17]=3)[N:8]2[CH3:11])=[CH:4][CH:3]=1
Reactant: Cn1c(-c2cncc(CN)c2)cc2ccc(Cl)cc21
Reactant: CC(C)S(=O)(=O)Cl
Product: CC(C)S(=O)(=O)NCc1cncc(-c2cc3ccc(Cl)cc3n2C)c1

Procedure:
C-[5-(6-Chloro-1-methyl-1H-indol-2-yl)-pyridin-3-yl]-methylamine (Example 205a) and isopropylsulfonyl chloride are processed according to the method described in Example 186f to give N-[5-(6-chloro-1-methyl-1H-indol-2-yl)-pyridin-3-ylmethyl]-isopropylsulfonamide. 1H NMR (400 MHz, MeOD) δ ppm 1.35 (d, J=6.8 Hz, 6H), 3.19-3.27 (m, 1H), 3.76 (s, 3H), 4.40 (s, 2H), 6.67 (d, J=0.6 Hz, 1H), 7.07 (dd, J=8.4, 1.8 Hz, 1H), 7.49 (d, J=1.6 Hz, 1H), 7.55 (d, J=8.5 Hz, 1H), 8.06 (t, J=2.0 Hz, 1H), 8.58 (d, J=1.9 Hz, 1H), 8.66 (d, J=2.0 Hz, 1H). HRMS (ESI) m/z 378.1036 [(M+H)+ Calcd for C18H21ClN3O2S: 378.1043].
Reaction SMILES: ClS([N:5]=C=O)(=O)=O.[CH3:8][O:9][C:10]([C@H:12]1[CH2:17][CH2:16][C@H:15]([C:18](O)=O)[CH2:14][CH2:13]1)=[O:11].CN(C=O)C>C(Cl)Cl>[C:18]([C@H:15]1[CH2:16][CH2:17][C@H:12]([C:10]([O:9][CH3:8])=[O:11])[CH2:13][CH2:14]1)#[N:5]
Reactant: O=C=NS(=O)(=O)Cl
Reactant: COC(=O)[C@H]1CC[C@H](C(=O)O)CC1
Solvent: CN(C)C=O
Solvent: ClCCl
Product: COC(=O)[C@H]1CC[C@H](C#N)CC1
Temperature: 0 °C
Reaction time: 8 h

Procedure:
Chlorosulfonyl isocyanate (1.0 mL, 0.012 mol) was added to a solution of trans-4-(methoxycarbonyl)cyclohexanecarboxylic acid (2.00 g, 0.0107 mol) in DCM cooled to 0° C. The resulting solution was heated at reflux for 15 minutes and then cooled 0° C. and treated dropwise with DMF. The mixture was stirred at room temperature overnight then poured onto ice water and the organic phase separated and washed with a saturated solution of sodium bicarbonate. The solvent was removed in vacuo and the crude material was taken up in ethyl acetate, washed with 1N aq. NaOH (10 mL) and the ethyl acetate removed in vacua. The resulting crude product was used in subsequent steps without further purification. 1H NMR (400 MHz, CHLOROFORM-d) δ ppm 1.36-1.70 (4 H, m), 2.01-2.18 (4 H, m), 2.24-2.54 (2 H, m) and 3.68 (3 H, s).
Reaction SMILES: [Br:1][CH2:2][C:3](=[O:7])[C:4]([OH:6])=[O:5].[C:8]1([C:14]([C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)=[N+]=[N-])[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1>>[Br:1][CH2:2][C:3](=[O:7])[C:4]([O:6][CH:14]([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1)=[O:5]
Reactant: O=C(O)C(=O)CBr
Reactant: [N-]=[N+]=C(c1ccccc1)c1ccccc1
Product: O=C(CBr)C(=O)OC(c1ccccc1)c1ccccc1

Procedure:
Bromopyruvic acid is treated with diphenyldiazomethane by standard methods to give benzhydryl bromopyruvate.
Reaction SMILES: [O:1]1[CH2:3][C@@H:2]1[C@@H:4]([NH:12][C:13](=[O:19])[O:14][C:15]([CH3:18])([CH3:17])[CH3:16])[CH2:5][C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1.[NH4+:20].[OH-]>CCO>[NH2:20][CH2:3][C@@H:2]([OH:1])[C@@H:4]([NH:12][C:13](=[O:19])[O:14][C:15]([CH3:18])([CH3:17])[CH3:16])[CH2:5][C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1
Reactant: CC(C)(C)OC(=O)N[C@@H](Cc1ccccc1)[C@H]1CO1
Reactant: [NH4+]
Agent: [OH-]
Solvent: CCO
Product: CC(C)(C)OC(=O)N[C@@H](Cc1ccccc1)[C@H](O)CN
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A solution of tert-butyl (S)-1-((S)-oxiran-2-yl)-2-phenylethylcarbamate (1.5 g, 5.7 mmol) in EtOH (35 mL) was added, with stirring, over 1 h to NH4OH (35 mL) at 0° C. NH3 gas was bubbled through the reaction mixture during the addition and for 1 h afterward. The reaction mixture was allowed to warm to room temperature and stirred overnight. The resulting slurry was diluted with EtOAc (80 mL), and the organic layer was washed with brine and dried (MgSO4). Concentration in vacuo, followed by trituration with 10% i-PrOH-EtOAc (overnight stirring), afforded tert-butyl (2S,3R)-4-amino-3-hydroxy-1-phenylbutan-2-ylcarbamate (0.44 g) as a white solid. The mother liquors were concentrated in vacuo and triturated again as above to give an additional quantity of tert-butyl (2S,3R)-4-amino-3-hydroxy-1-phenylbutan-2-ylcarbamate (0.57 g; 64% total yield): 1H NMR (CD3OD) d: 1.29 (s, 9H), 2.55 (m, 1H), 2.63 (m, 1H), 2.76 (m, 1H), 3.11 (m, 1H), 3.40 (m, 1H), 3.65 (m, 1H), 7.10-7.30 (m, 5H).
Reaction SMILES: Br[C:2]1[N:11]=[CH:10][CH:9]=[C:8]2[C:3]=1[CH:4]=[CH:5][C:6](=[O:12])[NH:7]2.[CH3:13][C:14]1[NH:15][C:16]([N+:19]([O-:21])=[O:20])=[CH:17][N:18]=1.C(=O)([O-])[O-].[K+].[K+]>CN1CCCC1=O>[CH3:13][C:14]1[N:15]([C:2]2[N:11]=[CH:10][CH:9]=[C:8]3[C:3]=2[CH:4]=[CH:5][C:6](=[O:12])[NH:7]3)[C:16]([N+:19]([O-:21])=[O:20])=[CH:17][N:18]=1
Reactant: Cc1ncc([N+](=O)[O-])[nH]1
Reactant: O=c1ccc2c(Br)nccc2[nH]1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN1CCCC1=O
Product: Cc1ncc([N+](=O)[O-])n1-c1nccc2[nH]c(=O)ccc12
Yield: 66.7 %

Procedure:
A mixture containing 5.6 g of 5-bromo-1,6-naphthyridin-2(1H)-one, 12.7 g of 2-methyl-5-nitro-1H-imidazole, 3.45 g of anhydrous potassium carbonate and 50 ml of N-methylpyrrolidinone was refluxed for 5.5 hours, cooled and concentrated in vacuo to remove most of the solvent. To the concentrate was added 100 ml of water and 10 ml of 35% aqueous sodium hydroxide; and, the mixture was treated with decolorizing charcoal and filtered. The filtrate was acidified with acetic acid and the precipitate was collected, washed with water, dried, recrystallized from dimethylformamide, and dried in a vacuum oven at 90°-95° C. to yield 4.5 g of 5-(2-methyl-5-nitro-1H-imidazol-1-yl)-1,6-naphthyridin-2-(1H)-one, m.p. >300° C.