Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C:9]1[CH:17]=[CH:16][C:12]([C:13]([OH:15])=[O:14])=[C:11]([F:18])[CH:10]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[Cl:19][C:20]1[CH:21]=[N+:22]([O-:40])[CH:23]=[C:24]([Cl:39])[C:25]=1[CH2:26][C@@H:27]([C:29]1[CH:34]=[CH:33][C:32]([O:35][CH3:36])=[C:31]([O:37][CH3:38])[CH:30]=1)O.C(N=C=NCCCN(C)C)C>ClCCl.CN(C)C1C=CN=CC=1>[Cl:39][C:24]1[CH:23]=[N+:22]([O-:40])[CH:21]=[C:20]([Cl:19])[C:25]=1[CH2:26][C@H:27]([O:14][C:13](=[O:15])[C:12]1[CH:16]=[CH:17][C:9]([NH:8][C:6]([O:5][C:1]([CH3:4])([CH3:2])[CH3:3])=[O:7])=[CH:10][C:11]=1[F:18])[C:29]1[CH:34]=[CH:33][C:32]([O:35][CH3:36])=[C:31]([O:37][CH3:38])[CH:30]=1
Reactant: CC(C)(C)OC(=O)Nc1ccc(C(=O)O)c(F)c1
Reactant: COc1ccc([C@@H](O)Cc2c(Cl)c[n+]([O-])cc2Cl)cc1OC
Agent: CCN=C=NCCCN(C)C
Agent: CN(C)c1ccncc1
Solvent: ClCCl
Product: COc1ccc([C@H](Cc2c(Cl)c[n+]([O-])cc2Cl)OC(=O)c2ccc(NC(=O)OC(C)(C)C)cc2F)cc1OC
Temperature: 25 °C
Reaction time: 16 h
Yield: 77.4 %

Procedure:
To a stirred solution of 4-(tert-butoxycarbonylamino)-2-fluorobenzoic acid (0.200 g, 0.78 mmol) and (1S)-2-(3,5-dichloro-1-oxidopyridin-1-ium-4-yl)-1-(3,4-dimethoxyphenyl)ethanol (0.270 g, 0.78 mmol) in dichloromethane (10.0 mL) was added 1-ethyl-3-(3-dimethylaminopropyl) carbodiimide (0.300 g, 1.57 mmol) and N,N-dimethylpyridin-4-amine (0.048 g, 0.39 mmol). The reaction was stirred at room temperature for 16 hours. The reaction was quenched by addition of saturated aqueous sodium bicarbonate solution (25.0 mL) and extracted with dichloromethane (×2). The combined organic extracts were dried on magnesium sulphate, filtered, and the solvent removed in vacuo to afford a yellow oil. The crude material was purified by silica gel chromatography eluting sequentially with iso-hexane and 10% methanol in ethyl acetate to afford the title compound as a yellow solid (0.351 g, 77%).
Reaction SMILES: [CH3:1][C:2]1[N:7]=[C:6]([SH:8])[N:5]=[C:4]([OH:9])[CH:3]=1.C(=O)([O-])[O-].[K+].[K+].Br[CH2:17][N:18]1[C:22]([Cl:23])=[CH:21][CH:20]=[N:19]1>CN(C=O)C>[Cl:23][C:22]1[N:18]([CH2:17][S:8][C:6]2[N:5]=[C:4]([OH:9])[CH:3]=[C:2]([CH3:1])[N:7]=2)[N:19]=[CH:20][CH:21]=1
Reactant: Clc1ccnn1CBr
Reactant: Cc1cc(O)nc(S)n1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: Cc1cc(O)nc(SCn2nccc2Cl)n1
Temperature: 25 °C
Reaction time: 8 h
Yield: 4 %

Procedure:
6-methyl-2-sulfanylpyrimidin-4-ol (4.8 g, 33.9 mmol) was dissolved in anhydrous DMF (180 mL), then potassium carbonate (14.0 g, 102 mmol) and 1-(bromomethyl)-5-chloro-1H-pyrazole (8.5 mmol) in DMF (20 mL) were added. The mixture was stirred overnight at room temperature. The solid was removed by filtration and washed with methanol, and the filtrate was evaporated. The residue was dissolved in DCM/MeOH and purified on silica gel using 3-10% DCM/MeOH to afford 2-{[(5-chloro-1H-pyrazol-1-yl)methyl]sulfanyl}-6-methylpyrimidin-4-ol (88 mg, 1.0% yield for 6 steps); 1H NMR (400 MHz, DMSO-d6): δ 2.24 (s, 3H), 5.85 (s, 2H), 6.10 (bs, 1H), 6.30 (d, J=2.3 Hz, 1H), 7.93 (s, 1H); LRMS (ES+) m/z 257 (45%, M+1), 259 (15%, M+3).
Reaction SMILES: [OH:1][C:2]1([CH2:27][C:28]([O:30][CH2:31][CH3:32])=[O:29])[CH2:11][CH2:10][C:9]([CH3:13])([CH3:12])[C:8]2[CH:7]=[C:6]([C:14]#[C:15][C:16]3[CH:26]=[CH:25][C:19]([C:20]([O:22][CH2:23][CH3:24])=[O:21])=[CH:18][CH:17]=3)[CH:5]=[CH:4][C:3]1=2.CC1(C)C2C=C(C#CC3C=CC(C(OC[CH2:54][Si:55](C)([CH3:57])[CH3:56])=O)=CC=3)C=CC=2C(=O)CC1>>[OH:1][C:2]1([CH2:27][C:28]([O:30][CH2:31][CH3:32])=[O:29])[CH2:11][CH2:10][C:9]([CH3:12])([CH3:13])[C:8]2[CH:7]=[C:6]([C:14]#[C:15][C:16]3[CH:17]=[CH:18][C:19]([C:20]([O:22][CH2:23][CH2:24][Si:55]([CH3:57])([CH3:56])[CH3:54])=[O:21])=[CH:25][CH:26]=3)[CH:5]=[CH:4][C:3]1=2
Reactant: CCOC(=O)CC1(O)CCC(C)(C)c2cc(C#Cc3ccc(C(=O)OCC)cc3)ccc21
Reactant: CC1(C)CCC(=O)c2ccc(C#Cc3ccc(C(=O)OCC[Si](C)(C)C)cc3)cc21
Product: CCOC(=O)CC1(O)CCC(C)(C)c2cc(C#Cc3ccc(C(=O)OCC[Si](C)(C)C)cc3)ccc21

Procedure:
Employing the same general procedure as for the preparation of ethyl 4-[(5,6,7,8-tetrahydro-5-hydroxy-8,8-dimethyl-5-carboethoxymethylnaphth-2-yl)ethynyl]benzoate (Compound 113), 0.38 g (0.89 mmol) of trimethylsilylethyl 4-[(5,6,7,8-tetrahydro-8,8-dimethyl-5-oxonaphth-2-yl)ethynyl]benzoate (Compound 116), was converted into the title compound (yellow solid) using 0.50 g (7.65 mmol) of zinc, 0.20 ml (1.78 mmol) of ethyl bromoacetate and 20 ml of dry benzene.
Reaction SMILES: C[O:2][C:3](=[O:36])[CH2:4][CH2:5][C:6]1[S:10][C:9]([CH:11]2[CH2:15][CH2:14][CH2:13][N:12]2[C:16](=[O:35])[CH2:17][C:18]2[CH:23]=[CH:22][C:21]([NH:24][C:25]([NH:27][C:28]3[CH:33]=[CH:32][CH:31]=[CH:30][C:29]=3[CH3:34])=[O:26])=[CH:20][CH:19]=2)=[N:8][CH:7]=1>CO.O1CCCC1.[OH-].[Li+]>[C:29]1([CH3:34])[CH:30]=[CH:31][CH:32]=[CH:33][C:28]=1[NH:27][C:25](=[O:26])[NH:24][C:21]1[CH:20]=[CH:19][C:18]([CH2:17][C:16]([N:12]2[CH2:13][CH2:14][CH2:15][CH:11]2[C:9]2[S:10][C:6]([CH2:5][CH2:4][C:3]([OH:36])=[O:2])=[CH:7][N:8]=2)=[O:35])=[CH:23][CH:22]=1
Reactant: COC(=O)CCc1cnc(C2CCCN2C(=O)Cc2ccc(NC(=O)Nc3ccccc3C)cc2)s1
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CO
Product: Cc1ccccc1NC(=O)Nc1ccc(CC(=O)N2CCCC2c2ncc(CCC(=O)O)s2)cc1
Reaction time: 4 h
Yield: 93.7 %

Procedure:
A solution was prepared of 3-[2-(1-{[4-(3-o-Tolyl-ureido)-phenyl]-acetyl}-pyrrolidin-2-yl)-thiazol-5-yl]-propionic acid methyl ester (0.33 g, 0.65 mmol) in methanol (4 mL), tetrahydrofuran (8 mL) and aqueous lithium hydroxide (2M, 4 mL). The solution was stirred for 4 h and partitioned between aqueous hydrochloric acid (1N, 30 mL) and ethyl acetate (100 mL). The aqueous portion was extracted with ethyl acetate (50 mL). The combined organic portions were extracted with brine (20 mL) and the solvent removed in vacuo to give the title compound (0.3 g, 94%). 1HNMR (400 MHz, CD3OD): δ7.60 (d, J=7.3 Hz, 1H), 7.46 (s, 0.3H), 7.39 (d, J=8.5 Hz, 2.7H), 7.29 (d, J=8.5 Hz, 0.6), 7.18 (m, 3H), 6.99 (m, 1.4H), 5.40 (d, J=7.0 Hz, 0.3H), 5.34 (d, J=6.0 Hz, 0.7H) 3.4-3.8 (m, 4H), 3.05 (m, 2H), 2.60 (m, 2H), 2.27 (s, 3H), 1.9-2.2 (m, 4H). MS: Calc'd for C25H26N4O4S: 492.18. Found: (M+1) 492.9.
Reaction SMILES: Cl.[F:2][C:3]1[CH:4]=[N:5][N:6]([C:8]([NH2:10])=[NH:9])[CH:7]=1.C[O-].[Na+].C([O:16][CH:17]=[C:18]([C:24](OCC)=O)[C:19]([O:21][CH2:22][CH3:23])=[O:20])C>CCO>[F:2][C:3]1[CH:4]=[N:5][N:6]([C:8]2[N:10]=[C:17]([OH:16])[C:18]([C:19]([O:21][CH2:22][CH3:23])=[O:20])=[CH:24][N:9]=2)[CH:7]=1
Reactant: N=C(N)n1cc(F)cn1
Reactant: CCOC=C(C(=O)OCC)C(=O)OCC
Agent: C[O-]
Agent: Cl
Agent: [Na+]
Solvent: CCO
Product: CCOC(=O)c1cnc(-n2cc(F)cn2)nc1O
Temperature: 25 °C
Yield: 62.8 %

Procedure:
To a solution of 28-e (2 g, 12 mmol) in EtOH was added sodium methoxide (1 g, 18 mmol) and diethyl ethoxymethylenemalonate (2.64 g, 12 mmol). The reaction was cooled to room temperature, filtered and washed with EtOH and Et2O to afford the title product, 28-f, (1.9 g, 61%).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[CH:8]=[C:7]([C:12]([OH:14])=O)[CH:6]=[CH:5]2.S(Cl)([Cl:17])=O>>[Br:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[CH:8]=[C:7]([C:12]([Cl:17])=[O:14])[CH:6]=[CH:5]2
Reactant: O=S(Cl)Cl
Reactant: O=C(O)c1ccc2cc(Br)ccc2c1
Product: O=C(Cl)c1ccc2cc(Br)ccc2c1
Temperature: 60 °C
Reaction time: 16 h

Procedure:
6-Bromonaphthalene-2-carboxylic acid (25.1 g) was suspended in thionyl chloride (200 mL), stirred at 60° C. for 16 hours and evaporated under vacuum. Solid was dissolved in dichloromethane (50 mL) and evaporated under vacuum, giving 6-bromonaphthalene-2-carbonyl chloride (27.0 g, crude) as a white solid.
Reaction SMILES: [C:1]([C:3]1[CH:4]=[CH:5][C:6]([I:12])=[C:7]([CH:11]=1)[C:8]([OH:10])=[O:9])#[N:2].S(Cl)(Cl)=O.[C:17](O)([CH3:20])([CH3:19])[CH3:18].N1C=CC=CC=1>CN(C)C=O.C(Cl)(Cl)Cl>[C:17]([O:9][C:8](=[O:10])[C:7]1[CH:11]=[C:3]([C:1]#[N:2])[CH:4]=[CH:5][C:6]=1[I:12])([CH3:20])([CH3:19])[CH3:18]
Reactant: N#Cc1ccc(I)c(C(=O)O)c1
Reactant: CC(C)(C)O
Solvent: ClC(Cl)Cl
Solvent: O=S(Cl)Cl
Solvent: c1ccncc1
Product: CC(C)(C)OC(=O)c1cc(C#N)ccc1I
Temperature: 25 °C

Procedure:
8.9 mmol of 5-Cyano-2-iodo-benzoic acid [219841-92-6] is heated at reflux with 6 ml of thionyl-chloride and 1 drop of N,N-dimethylformamide until all the solid dissolves and there is no further gas evolution. The solution is cooled to room temperature and evaporated to dryness. The residue is treated with 32 mmol of dry tert-butyl alcohol and 49 mmol of dry pyridine in 5 ml of chloroform at 0° C. under an Ar atmosphere. After the addition, the mixture is refluxed overnight, cooled, and evaporated to dryness. From the residue the title compound is identified by means of flash chromatography (SiO2 60F) on the basis of the Rf value.
Reaction SMILES: [F:1][C:2]1[N:6]([CH2:7][O:8][CH2:9][CH2:10][Si:11]([CH3:14])([CH3:13])[CH3:12])[CH:5]=[N:4][C:3]=1[CH2:15][OH:16]>ClCCl.O=[Mn]=O>[F:1][C:2]1[N:6]([CH2:7][O:8][CH2:9][CH2:10][Si:11]([CH3:12])([CH3:14])[CH3:13])[CH:5]=[N:4][C:3]=1[CH:15]=[O:16]
Reactant: C[Si](C)(C)CCOCn1cnc(CO)c1F
Agent: O=[Mn]=O
Solvent: ClCCl
Product: C[Si](C)(C)CCOCn1cnc(C=O)c1F
Temperature: 25 °C
Reaction time: 18 h
Yield: 77.9 %

Procedure:
To a stirred solution of [5-fluoro-1-(2-trimethylsilanyl-ethoxymethyl)-1H-imidazol-4-yl]-methanol (339 mg) at room temperature in dichloromethane (15 ml) under an argon atmosphere was added MnO2 (1.20 g). The black suspension was heated to reflux and stirring at that temperature was continued for 18 hours, then was cooled to room temperature and filtered. The resulting cake was washed with dichloromethane. The filtrate was concentrated to leave 5-fluoro-1-(2-trimethylsilanyl-ethoxymethyl)-1H-imidazole-4-carbaldehyde (262 mg) as light yellow viscous oil. The crude product was used in the next reaction step without further purification. MS (EI): 171.1 ([M-Si(Me)3]).
Reaction SMILES: [CH:1]([C@@H:14]1[CH2:20][C@@H:19]2[C@@H:17]([O:18]2)[CH2:16][O:15]1)([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.[CH3:21][O:22][C:23]1[CH:30]=[C:29]([O:31][CH3:32])[CH:28]=[CH:27][C:24]=1[CH2:25][NH2:26]>>[CH:1]([C@@H:14]1[CH2:20][C@@H:19]([OH:18])[C@H:17]([NH:26][CH2:25][C:24]2[CH:27]=[CH:28][C:29]([O:31][CH3:32])=[CH:30][C:23]=2[O:22][CH3:21])[CH2:16][O:15]1)([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: c1ccc(C(c2ccccc2)[C@@H]2C[C@H]3O[C@H]3CO2)cc1
Reactant: COc1ccc(CN)c(OC)c1
Product: COc1ccc(CN[C@@H]2CO[C@H](C(c3ccccc3)c3ccccc3)C[C@H]2O)c(OC)c1
Yield: 70 %

Procedure:
(1S, 4S, 6R)-4-benzhydryl-3,7-dioxa-bicyclo[4.1.0]heptane 28a (0.020 g, 0.075 mmol) was reacted with 2,4-dimethoxybenzylamine (0.25 g, 1.50 mmol) (Procedure E) to yield (2S, 4R, 5R)-2-benzhydryl-5-(2,4-dimethoxybenzylamino)-tetrahydropyran-4-ol, (−)-29e, 0.025 g (Yield; 70%, [α]D=(−)3.70, c=1, CHCl3).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([C:14]2[CH:19]([CH2:20][CH3:21])[S:18][C:17](=[O:22])[NH:16][N:15]=2)[CH:6]=[CH:7][C:8]=1[O:9][C:10]([F:13])([F:12])[F:11].[N+:23]([C:26]1[CH:33]=[CH:32][C:29]([CH2:30]Cl)=[CH:28][CH:27]=1)([O-:25])=[O:24]>>[N+:23]([C:26]1[CH:33]=[CH:32][C:29]([CH2:30][N:16]2[N:15]=[C:14]([C:5]3[CH:6]=[CH:7][C:8]([O:9][C:10]([F:12])([F:13])[F:11])=[C:3]([O:2][CH3:1])[CH:4]=3)[CH:19]([CH2:20][CH3:21])[S:18][C:17]2=[O:22])=[CH:28][CH:27]=1)([O-:25])=[O:24]
Reactant: O=[N+]([O-])c1ccc(CCl)cc1
Reactant: CCC1SC(=O)NN=C1c1ccc(OC(F)(F)F)c(OC)c1
Product: CCC1SC(=O)N(Cc2ccc([N+](=O)[O-])cc2)N=C1c1ccc(OC(F)(F)F)c(OC)c1

Procedure:
In analogy to Example 1, the reaction of 5-(3-methoxy-4-trifluoromethoxyphenyl)-6-ethyl-3,6-dihydro-1, 3,4-thiadiazin-2-one with 4-nitrobenzyl chloride ("C") gives 3-(4-nitrobenzyl)-5-(3-methoxy-4-trifluoromethoxyphenyl)-6-ethyl-3,6-dihydro-1,3,4-thiadiazin-2-one.
Reaction SMILES: [H-].[Na+].[CH3:3][C:4]1[NH:5][C:6]2[N:7]([NH:25][C:26](=[O:28])[CH:27]=2)[CH:8]([C:16]2[CH:21]=[CH:20][CH:19]=[C:18]([N+:22]([O-:24])=[O:23])[CH:17]=2)[C:9]=1[C:10]([O:12][CH:13]([CH3:15])[CH3:14])=[O:11].[CH2:29](Br)[C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1>CN(C)C=O>[CH3:3][C:4]1[NH:5][C:6]2[N:7]([N:25]([CH2:29][C:30]3[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=3)[C:26](=[O:28])[CH:27]=2)[CH:8]([C:16]2[CH:21]=[CH:20][CH:19]=[C:18]([N+:22]([O-:24])=[O:23])[CH:17]=2)[C:9]=1[C:10]([O:12][CH:13]([CH3:15])[CH3:14])=[O:11]
Reactant: CC1=C(C(=O)OC(C)C)C(c2cccc([N+](=O)[O-])c2)n2[nH]c(=O)cc2N1
Reactant: BrCc1ccccc1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CC1=C(C(=O)OC(C)C)C(c2cccc([N+](=O)[O-])c2)n2c(cc(=O)n2Cc2ccccc2)N1
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
To a suspension of sodium hydride (30 mg; 60% dispersion; 0.75 mmole) in dry dimethylformamide (4 ml) was added 1,2,4,7-tetrahydro-5-methyl-7-(3-nitrophenyl)-2-oxopyrazolo[1,5-a]pyrimidine-6-carboxylic acid, 1-methylethyl ester (180 mg; 0.5 mmole) in dimethylformamide (3 ml) at 0° C. under argon. The orange reaction mixture was allowed to stir at 0° C. for 30 minutes and benzyl bromide (70 μl; 0.6 mmole) was then added. The reaction was stirred at room temperature for one hour and then quenched with water. The resulting solution was extracted with ethyl acetate and the combined extracts were washed with water, sodium bicarbonate and brine. After drying over anhydrous magnesium sulfate, the solvent was evaporated to give a foam which was purified by preparative thin layer chromatography (40% ethyl acetate in hexanes) and the product was crystallized from dichloromethane-isopropyl ether to give a solid, melting point 183.5°-185° C.
Reaction SMILES: C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C(Cl)(Cl)(Cl)[Cl:21].O[CH2:26][CH2:27][CH2:28][N:29]([CH3:49])[C:30]([C:32]1[N:33]([CH3:48])[C:34]([C:42]2[CH:47]=[CH:46][CH:45]=[CH:44][CH:43]=2)=[C:35]2[C:40]=1[CH:39]=[CH:38][C:37]([Cl:41])=[CH:36]2)=[O:31]>O1CCOCC1>[Cl:21][CH2:26][CH2:27][CH2:28][N:29]([CH3:49])[C:30]([C:32]1[N:33]([CH3:48])[C:34]([C:42]2[CH:47]=[CH:46][CH:45]=[CH:44][CH:43]=2)=[C:35]2[C:40]=1[CH:39]=[CH:38][C:37]([Cl:41])=[CH:36]2)=[O:31]
Reactant: CN(CCCO)C(=O)c1c2ccc(Cl)cc2c(-c2ccccc2)n1C
Reactant: ClC(Cl)(Cl)Cl
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1COCCO1
Product: CN(CCCCl)C(=O)c1c2ccc(Cl)cc2c(-c2ccccc2)n1C

Procedure:
A solution of 13.6 g. of triphenylphosphine in 40 ml. of carbon tetrachloride and 24 ml. of dioxane is treated with 14.3 g. of 5-chloro-2-methyl-3-phenylisoindole-1-carboxylic acid (3-hydroxypropyl)methylamide and the mixture is subsequently boiled at reflux for 1 hour. After cooling, the mixture is concentrated to dryness under reduced pressure. The residual oil is chromatographed on 800 g. of silica gel using methylene chloride/ethyl acetate (4:1) for the elution. The homogeneous fractions yield analytically pure 5-chloro-2-methyl-3-phenylisoindole-1-carboxylic acid (3-chloropropyl)methylamide as a thick yellow oil.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[C:14]2[CH:15]=[C:16]([C:19]#[N:20])[CH:17]=[CH:18][C:13]=2[N:12]([CH3:21])[C:11](=[O:22])[CH2:10][N:9]=1>CO.N.[Ni]>[NH2:20][CH2:19][C:16]1[CH:17]=[CH:18][C:13]2[N:12]([CH3:21])[C:11](=[O:22])[CH2:10][N:9]=[C:8]([C:3]3[CH:4]=[CH:5][CH:6]=[CH:7][C:2]=3[F:1])[C:14]=2[CH:15]=1
Reactant: CN1C(=O)CN=C(c2ccccc2F)c2cc(C#N)ccc21
Agent: [Ni]
Agent: N
Solvent: CO
Product: CN1C(=O)CN=C(c2ccccc2F)c2cc(CN)ccc21

Procedure:
36.5 g (0.08 mol) of 5-(o-fluorophenyl)-2,3-dihydro-1-methyl-2-oxo-1H-1,4-benzodiazepine-7-carbonitrile, dissolved in 2700 ml of methanol and 270 ml of ammonia, are hydrogenated in an autoclave with 36.5 g of Raney-nickel at 50° and 3.5 atmospheres. The catalyst is filtered off and the solvent is removed in vacuo. There is obtained 7-(aminomethyl)-5-(o-fluorophenyl)-1,3-dihydro-1-methyl-2H-1,4-benzodiazepin-2-one as a foam.
Reaction SMILES: [NH2:1][C@H:2]1[CH2:7][CH2:6][C@H:5]([CH2:8][NH:9][C:10]2[C:15]([N+:16]([O-:18])=[O:17])=[CH:14][N:13]=[C:12]([NH:19][CH2:20][C:21]3[CH:26]=[CH:25][CH:24]=[CH:23][C:22]=3[O:27][C:28]([F:31])([F:30])[F:29])[N:11]=2)[CH2:4][CH2:3]1.[O:32]1[C:34]([CH3:36])([CH3:35])[CH:33]1O>C(O)C>[CH3:33][C:34]([OH:32])([CH3:36])[CH2:35][NH:1][C@H:2]1[CH2:3][CH2:4][C@H:5]([CH2:8][NH:9][C:10]2[C:15]([N+:16]([O-:18])=[O:17])=[CH:14][N:13]=[C:12]([NH:19][CH2:20][C:21]3[CH:26]=[CH:25][CH:24]=[CH:23][C:22]=3[O:27][C:28]([F:30])([F:31])[F:29])[N:11]=2)[CH2:6][CH2:7]1
Reactant: CC1(C)OC1O
Reactant: N[C@H]1CC[C@H](CNc2nc(NCc3ccccc3OC(F)(F)F)ncc2[N+](=O)[O-])CC1
Solvent: CCO
Product: CC(C)(O)CN[C@H]1CC[C@H](CNc2nc(NCc3ccccc3OC(F)(F)F)ncc2[N+](=O)[O-])CC1
Temperature: 100 °C

Procedure:
A reaction mixture of N4-[(trans-4-aminocyclohexyl)methyl]-5-nitro-N2-[2-(trifluoromethoxy)benzyl]pyrimidine-2,4-diamine (50 mg, 0.11 mmol) and 1,2-epoxy-2-methylpropanol (500 μL) in ethanol (1 mL) was heated to 100° C. for 1 h in a microwave. The reaction mixture was concentrated and the resulting residue was purified by silica gel preparative TLC using 10:1 CH2Cl2:MeOH as an eluent to afford 28 mg (47%) of the title compound as a white solid, m/z 513.5 [M+1]+
Reaction SMILES: [F:1][C:2]1[CH:9]=[CH:8][C:5]([C:6]#[N:7])=[C:4]([O:10][CH3:11])[CH:3]=1.C1C(=O)N([Br:19])C(=O)C1>OS(O)(=O)=O>[Br:19][C:9]1[C:2]([F:1])=[CH:3][C:4]([O:10][CH3:11])=[C:5]([CH:8]=1)[C:6]#[N:7]
Reactant: O=C1CCC(=O)N1Br
Reactant: COc1cc(F)ccc1C#N
Agent: O=S(=O)(O)O
Product: COc1cc(F)c(Br)cc1C#N
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a solution of 4-fluoro-2-methoxybenzonitrile (35 g, 0.23 mol) in 300 mL of concentrated H2SO4 was added NBS (42 g, 0.23 mol) portionwise at −10° C. and the reaction was stirred at r.t. for 2 hours. Then the reaction was poured into 2 L of ice portionwise, and the solid precipitated out was filtered. The filter cake was washed with water, then the solid was dried in vacuo to give 5-bromo-4-fluoro-2-methoxybenzonitrile.
Reaction SMILES: [CH2:1]([N:8]([C@H:16]1[CH2:21][CH2:20][C@H:19]([NH:22][C:23]2[CH:32]=[CH:31][CH:30]=[C:29]3[C:24]=2[C:25]([CH:34]=[CH2:35])=[CH:26][N:27]=[C:28]3[Cl:33])[CH2:18][CH2:17]1)[C:9](=[O:15])[O:10][C:11]([CH3:14])([CH3:13])[CH3:12])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(N(C1CCC(NC2C=CC=C3C=2C(C=C)=CN=C3)CC1)C(=O)OC(C)(C)C)C1C=CC=CC=1>>[CH2:1]([N:8]([C@H:16]1[CH2:21][CH2:20][C@H:19]([N:22]2[C:23]3=[C:24]4[C:29](=[CH:30][CH:31]=[CH:32]3)[C:28]([Cl:33])=[N:27][CH:26]=[C:25]4[CH2:34][CH2:35]2)[CH2:18][CH2:17]1)[C:9](=[O:15])[O:10][C:11]([CH3:14])([CH3:13])[CH3:12])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: C=Cc1cnc(Cl)c2cccc(N[C@H]3CC[C@H](N(Cc4ccccc4)C(=O)OC(C)(C)C)CC3)c12
Agent: C=Cc1cncc2cccc(NC3CCC(N(Cc4ccccc4)C(=O)OC(C)(C)C)CC3)c12
Product: CC(C)(C)OC(=O)N(Cc1ccccc1)[C@H]1CC[C@H](N2CCc3cnc(Cl)c4cccc2c34)CC1

Procedure:
According to the method of Example 21, Step C, the tert-butyl trans-N-benzyl-[4-(1-chloro-4-vinylisoquinolin-5-yl)aminocyclohexyl]carbamate obtained in Step A mentioned above was used for the cyclization instead of the trans-isomer of Intermediate 10 to obtain the title compound.
Reaction SMILES: [CH3:1][C:2]1[CH2:3][S:4][C@@H:5]2[CH:12]([NH:13][C:14](=[O:24])[C:15]([C:18]3[N:19]=[C:20]([NH2:23])[S:21][CH:22]=3)=[N:16][OH:17])[C:11](=[O:25])[N:6]2[C:7]=1[C:8]([OH:10])=[O:9].C([O-])(=O)C.[Na+:30]>CO>[CH3:1][C:2]1[CH2:3][S:4][C@@H:5]2[CH:12]([NH:13][C:14](=[O:24])[C:15]([C:18]3[N:19]=[C:20]([NH2:23])[S:21][CH:22]=3)=[N:16][OH:17])[C:11](=[O:25])[N:6]2[C:7]=1[C:8]([O-:10])=[O:9].[Na+:30]
Reactant: CC1=C(C(=O)O)N2C(=O)C(NC(=O)C(=NO)c3csc(N)n3)[C@H]2SC1
Agent: CC(=O)[O-]
Agent: [Na+]
Solvent: CO
Product: CC1=C(C(=O)[O-])N2C(=O)C(NC(=O)C(=NO)c3csc(N)n3)[C@H]2SC1

Procedure:
0.927 g of the product of Example 1 was dissolved in 4.8 ml of a molar solution of sodium acetate in methanol and the solution was vacuum filtered. The filter was rinsed twice with 0.6 ml of the molar solution of sodium acetate in methanol and twice with 0.6 ml of methanol and then 12 ml of absolute ethanol were slowly added to the combined filtrates. The mixture was vacuum filtered at room temperature and the recovered product was rinsed 3 times with 2 ml of ethanol and with ether and was dried to obtain 517 mg of the syn isomer of sodium 3-methyl-7-[2-(2-amino-4-thiazolyl)-2-hydroxyimino-acetamido]-ceph-3-eme-4-carboxylate. The mother liquors were diluted with 6 ml of ethanol to obtain a second yield of 58 mg of the said sodium salt.
Reaction SMILES: Br[C:2]1[CH:7]=[C:6]([C:8]([O:12][CH3:13])([O:10][CH3:11])[CH3:9])[CH:5]=[C:4]([C:14]([CH3:17])([CH3:16])[CH3:15])[C:3]=1[O:18][CH3:19].[NH:20]1[CH2:25][CH2:24][O:23][CH2:22][CH2:21]1.CC(C)([O-])C.[Na+]>COCCOC.C([O-])(=O)C.[Pd+2].C([O-])(=O)C>[C:14]([C:4]1[C:3]([O:18][CH3:19])=[C:2]([N:20]2[CH2:25][CH2:24][O:23][CH2:22][CH2:21]2)[CH:7]=[C:6]([C:8]([O:12][CH3:13])([O:10][CH3:11])[CH3:9])[CH:5]=1)([CH3:17])([CH3:16])[CH3:15]
Reactant: COc1c(Br)cc(C(C)(OC)OC)cc1C(C)(C)C
Reactant: C1COCCN1
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: CC(C)(C)[O-]
Solvent: COCCOC
Product: COc1c(N2CCOCC2)cc(C(C)(OC)OC)cc1C(C)(C)C

Procedure:
Under a nitrogen atmosphere, 2-bromo-6-tert-butyl-4-(1,1-dimethoxyethyl)anisole (650 g, 1.962 mol), palladium acetate (4.4 g 19.6 mmol, 1 mol %) and (±)-BINAP (18.3 g, 29.4 mmol, 1.5 mol %) were dissolved in 1,2-dimethoxyethane (1.96 L) at room temperature. To the resultant solution, morpholine (205 g, 2.36 mol) and sodium tert-butoxide (264 g, 2.75 mol) were added.
Reaction SMILES: [CH2:1]([O:8][C:9]1[C:14](Br)=[CH:13][CH:12]=[CH:11][C:10]=1Br)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[N:17]1[CH:22]=[CH:21][CH:20]=[C:19](B(O)O)[CH:18]=1.C(=O)([O-])[O-].[K+].[K+]>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.CN(C=O)C>[CH2:1]([O:8][C:9]1[C:14]([C:19]2[CH:18]=[N:17][CH:22]=[CH:21][CH:20]=2)=[CH:13][CH:12]=[CH:11][C:10]=1[C:19]1[CH:18]=[N:17][CH:22]=[CH:21][CH:20]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: Brc1cccc(Br)c1OCc1ccccc1
Reactant: OB(O)c1cccnc1
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: [K+]
Solvent: CN(C)C=O
Product: c1ccc(COc2c(-c3cccnc3)cccc2-c2cccnc2)cc1
Temperature: 85 °C
Reaction time: 48 h
Yield: 40.8 %

Procedure:
2,6-Dibromophenyl benzyl ether (25.61 g, 74.88 mmol), 3-pyridylboronicacid (20.25 g, 164.7 mmol), aqueous potassium carbonate (233 mL 2 M), and DMF (370 mL) were put together in a 1 liter flask. Oxygen was removed by several vacuum-argon cycles. Then Pd(PPh3)4 (5.38 g, 4.65 mmol) was added and the mixture was heated to 85° C. under an argon atmosphere. After 48 hr, the reaction mixture was cooled to rt, and poured into an ice/water mixture (1 L). This was extracted with diisopropylether (3 times 300 mL), and the combined organic layers were dried over MgSO4, filtered, and the solvent was removed in vacuo, yielding a yellow crystalline solid. Recrystallisation from diethyl ether yielded the product as a white crystalline solid (10.34 g, 41%). The residue was further purified by column chromatography (silicagel, EtOAc/n-pentane=3:2), yielding another 2.60 g (10%) of the product (total yield 51%). 1H-NMR(CDCl3):δ=8.80 (s, 2H), 8.59 (d, 2H), 7.93 (dd, 2H), 7.65 (d, 2H), 7.34 (m, 3H), 7.19 (t, 1H), 7.10 (t, 2H), 6.64 (d, 2H), 4.15 (s, 2H) ppm.