Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[C:7]([CH3:8])=[CH:6][CH:5]=[C:4]([Cl:9])[C:3]=1[NH:10][S:11]([C:14]1[N:18]=[C:17]([NH2:19])[NH:16][N:15]=1)(=[O:13])=[O:12].[C:20](OCC)(=[O:25])[CH2:21][C:22]([CH3:24])=O.Cl>CO>[Cl:1][C:2]1[C:7]([CH3:8])=[CH:6][CH:5]=[C:4]([Cl:9])[C:3]=1[NH:10][S:11]([C:14]1[N:18]=[C:17]2[N:19]=[C:22]([CH3:24])[CH:21]=[C:20]([OH:25])[N:16]2[N:15]=1)(=[O:13])=[O:12]
Reactant: CCOC(=O)CC(C)=O
Reactant: Cc1ccc(Cl)c(NS(=O)(=O)c2n[nH]c(N)n2)c1Cl
Agent: Cl
Solvent: CO
Product: Cc1cc(O)n2nc(S(=O)(=O)Nc3c(Cl)ccc(C)c3Cl)nc2n1
Reaction time: 18 h

Procedure:
A solution of 32.2 g (0.10 mol) of N-(2,6-dichloro-3-methylphenyl)-5-amino-1,2,4-triazole-3-sulfonamide and 14 ml (0.11 mol) of ethyl acetoacetate in 500 ml of methanol containing 1 ml of 12N hydrochloric acid was heated to reflux with stirring for about 18 hours. The solid present was collected by filtration and the filtrate was heated to reflux for another day. The mixture obtained was cooled in an ice bath and the solid present was collected by filtration. The filtrate was concentrated to about 200 ml by evaporation of methanol and heated to reflux overnight. The mixture obtained was filtered to collect the solid present. The filtrate was concentrated to about 150 ml, treated with about 2 ml of ethyl acetoacetate, and heated at reflux for about 3 days. The solids present were collected by filtration and dried to obtain 6.4 g, 10.0 g, 8.2 g and 11.1 g crops of the title compound for a total of 35.7 g (92 percent of theory). The first obtained crop melted at 346°-7° C. with decomposition.
Reaction SMILES: F[P-](F)(F)(F)(F)F.N1(O[P+](N(C)C)(N(C)C)N(C)C)C2C=CC=CC=2N=N1.[CH2:28]([O:30][CH:31]([C:45]([O:47]CC)=O)[NH:32][C:33](=[O:44])[C:34]1[C:35](=[C:39]([F:43])[CH:40]=[CH:41][CH:42]=1)[C:36]([OH:38])=O)[CH3:29].C(OC(C(OCC)=O)NC(=O)C1C(=CC=CC=1F)C(O)=O)C.[NH2:72][CH2:73][C:74]1[CH:81]=[CH:80][C:77]([C:78]#[N:79])=[CH:76][C:75]=1[N+:82]([O-:84])=[O:83]>>[C:78]([C:77]1[CH:80]=[CH:81][C:74]([CH2:73][NH:72][C:45](=[O:47])[CH:31]([O:30][CH2:28][CH3:29])[N:32]2[C:36](=[O:38])[C:35]3[C:34](=[CH:42][CH:41]=[CH:40][C:39]=3[F:43])[C:33]2=[O:44])=[C:75]([N+:82]([O-:84])=[O:83])[CH:76]=1)#[N:79]
Reactant: CCOC(=O)C(NC(=O)c1cccc(F)c1C(=O)O)OCC
Reactant: N#Cc1ccc(CN)c([N+](=O)[O-])c1
Agent: CCOC(=O)C(NC(=O)c1c(F)cccc1C(=O)O)OCC
Agent: CN(C)[P+](On1nnc2ccccc21)(N(C)C)N(C)C
Agent: F[P-](F)(F)(F)(F)F
Product: CCOC(C(=O)NCc1ccc(C#N)cc1[N+](=O)[O-])N1C(=O)c2cccc(F)c2C1=O

Procedure:
According to general procedure C, but using 2.2 eq. of BOP coupling reagent and adding the amine component after a delay time of 1 h, (RS)-N-(ethoxy-ethoxycarbonyl-methyl)-6-fluoro-phthalamic acid and its regioisomer (RS)-N-(ethoxy-ethoxycarbonyl-methyl)-3-fluoro-phthalamic acid (example 35.2) was reacted with 4-aminomethyl-3-nitrobenzonitrile (CAS 701269-65-0) to give (RS)-N-(4-cyano-2-nitro-benzyl)-2-ethoxy-2-(4-fluoro-1,3-dioxo-1,3-dihydro-isoindol-2-yl)-acetamide as yellow viscous oil which was further processed as follows, MS 427.3 ([M+H]+).
Reaction SMILES: [CH3:1][O:2][C:3]([O:19][CH3:20])([C:13]1[CH:18]=[CH:17][N:16]=[CH:15][CH:14]=1)[CH:4]([C:6]1[CH:11]=[CH:10][C:9]([F:12])=[CH:8][CH:7]=1)[NH2:5].[C:21]1([CH2:27][CH2:28][CH2:29][NH:30][C:31](N2C=CN=C2)=[O:32])[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1>C1(C)C=CC=CC=1.C(OCC)(=O)C>[C:21]1([CH2:27][CH2:28][CH2:29][NH:30][C:31]([NH:5][CH:4]([C:6]2[CH:7]=[CH:8][C:9]([F:12])=[CH:10][CH:11]=2)[C:3]([O:2][CH3:1])([O:19][CH3:20])[C:13]2[CH:18]=[CH:17][N:16]=[CH:15][CH:14]=2)=[O:32])[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1
Reactant: COC(OC)(c1ccncc1)C(N)c1ccc(F)cc1
Reactant: O=C(NCCCc1ccccc1)n1ccnc1
Solvent: Cc1ccccc1
Solvent: CCOC(C)=O
Product: COC(OC)(c1ccncc1)C(NC(=O)NCCCc1ccccc1)c1ccc(F)cc1
Temperature: 25 °C

Procedure:
A solution of 2,2-dimethoxy-2-(4-pyridyl)-1-(4fluorophenyl)ethanamine (51.12 g, 0.185 mol) and N-(3-phenylpropyl)-1H-imidazole-1-carboxamide (42.42 g, 0.185 mol) in toluene (300 mL) under N2, was stirred and heated to reflux temperature for 3 h. The solution was cooled to room temperature and the dark brown solution was diluted with ethyl acetate (200 mL). The mixture was washed with water (2×200 mL), brine (200 mL), and dried with Na2SO4. The solvents were removed in vacuo to yield a brown solid which was recrystallized from a solvent mixture of ethyl acetate/hexane (1:1) to yield an off-white solid.
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4]([CH:7]=[CH:8][C:9]=1[CH3:10])[CH:5]=O.C(O)(=O)[CH2:12][C:13]([OH:15])=[O:14].N1CCCCC1.Cl>N1C=CC=CC=1.O>[CH3:1][C:2]1[CH:3]=[C:4]([CH:5]=[CH:12][C:13]([OH:15])=[O:14])[CH:7]=[CH:8][C:9]=1[CH3:10]
Reactant: Cc1ccc(C=O)cc1C
Reactant: O=C(O)CC(=O)O
Agent: Cl
Solvent: c1ccncc1
Solvent: O
Solvent: C1CCNCC1
Product: Cc1ccc(C=CC(=O)O)cc1C
Temperature: 50 °C

Procedure:
A suspension of 3,4-dimethylbenzaldehyde (15.000 g; 111.793 mmol) and malonic acid (22.103 g; 212.410 mmol) in pyridine (85 ml) was heated to 50° C., under nitrogen. Then piperidine (8.5 ml; 86.079 mmol) was added dropwise (over 5 minutes) and the resulting suspension was heated to 75° C. for 2 h. The reaction mixture was cooled to 0° C., and poured into an ice-cooled solution of concentrated hydrochloric acid (12 N; 96 ml) in water (1200 ml). The precipitated colorless product was filtered off, and washed with water (3×100 ml). Remaining water was evaporated under reduced pressure, then under HV to give the dried product 3-(3,4-dimethyl-phenyl)-acrylic acid as a colorless solid (19.230 g; 98%). LC-MS: tR=0.88 min; [M+H]+: no ionisation.
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1([CH2:19][CH:20]=O)[CH2:11][CH2:10][N:9]([C:12]([O:14][C:15]([CH3:18])([CH3:17])[CH3:16])=[O:13])[CH2:8][CH2:7]1)=[O:5])[CH3:2].ClC(Cl)C.[NH2:26][C:27]1[CH:28]=[CH:29][C:30]([Br:34])=[N:31][C:32]=1[CH3:33].C(O)(=O)C.[BH-](OC(C)=O)(OC(C)=O)OC(C)=O.[Na+]>C(Cl)Cl>[CH2:1]([O:3][C:4]([C:6]1([CH2:19][CH2:20][NH:26][C:27]2[C:32]([CH3:33])=[N:31][C:30]([Br:34])=[CH:29][CH:28]=2)[CH2:7][CH2:8][N:9]([C:12]([O:14][C:15]([CH3:18])([CH3:17])[CH3:16])=[O:13])[CH2:10][CH2:11]1)=[O:5])[CH3:2]
Reactant: Cc1nc(Br)ccc1N
Reactant: CCOC(=O)C1(CC=O)CCN(C(=O)OC(C)(C)C)CC1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: CC(Cl)Cl
Solvent: CC(=O)O
Solvent: ClCCl
Product: CCOC(=O)C1(CCNc2ccc(Br)nc2C)CCN(C(=O)OC(C)(C)C)CC1
Temperature: 25 °C
Yield: 50 %

Procedure:
To a solution of 4-(2-oxo-ethyl)-piperidine-1,4-dicarboxylic acid 1-tert-butyl ester 4-ethyl ester (0.56 g, 1.87 mmol) in 1-2 dichloroethane (DCE, 6 mL) was added 5-amino-2-bromo-6-picoline (0.35 g, 1.87 mmol), acetic acid (3.1 eq) and allowed to stir at room temperature for an hour. NaBH(OAc)3 (3 equiv.) was then added in one portion and the reaction mixture was allowed to stir at room temperature for 16 hours. The reaction was diluted with DCM (10 mL), quenched with 2 M of NH4OH in water (1 mL). The layers were separated, and the aqueous layer was extracted with DCM (10 mL, 2×). The combined organic layers were washed with aqueous NaHCO3 (10 mL), brine (20 mL), dried over Na2SO4, and concentrated under vacuum. Purification over silica gel eluting with ethyl acetate in heptanes (0-75%) afforded 0.44 g (50%) of title compound.
Reaction SMILES: [N+:1]([C:4]1[CH:16]=[CH:15][C:7]([CH2:8][C:9]2[CH:14]=[CH:13][N:12]=[CH:11][CH:10]=2)=[CH:6][CH:5]=1)([O-])=O.Cl.O>C(O)C.[Pt](=O)=O>[NH:12]1[CH2:13][CH2:14][CH:9]([CH2:8][C:7]2[CH:6]=[CH:5][C:4]([NH2:1])=[CH:16][CH:15]=2)[CH2:10][CH2:11]1
Reactant: O=[N+]([O-])c1ccc(Cc2ccncc2)cc1
Agent: O=[Pt]=O
Agent: Cl
Solvent: CCO
Solvent: O
Product: Nc1ccc(CC2CCNCC2)cc1
Reaction time: 12 h
Yield: 86.3 %

Procedure:
A mixture of 4-(4-nitrobenzyl)pyridine (12.85 g, 60 mmol), platinum(IV) oxide (1.0 g), 12N hydrochloric acid (5 ml, 60 mmol), water (5 ml) in ethanol (200 ml) was hydrogenated at 40 psi in a Parr apparatus for 12 hours. The reaction mixture was concentrated in vacuo, and the residue was diluted with cold water and basified with 10% sodium hydroxide solution. The resulting mixture was extracted into ethyl acetate. The combined organic extracts were washed with water and brine, dried (Na2SO4), and concentrated in vacuo. The residue on crystallization from ethyl acetate/hexanes gave 4-(piperidin-4-ylmethyl)-phenylamine (9.85 g, 86%) as a white crystalline solid, m.p. 110-113° C.
Reaction SMILES: [O:1]1[CH2:3][C@H:2]1[CH2:4][O:5][C:6]1[CH:14]=[CH:13][CH:12]=[C:11]2[C:7]=1[CH:8]=[CH:9][NH:10]2.[O:15]([CH:22]1[CH2:27][CH2:26][NH:25][CH2:24][CH2:23]1)[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1.[C:28]([OH:33])(=[O:32])[C:29]([OH:31])=[O:30].CO>C(OCC)(=O)C>[C:28]([OH:33])(=[O:32])[C:29]([OH:31])=[O:30].[NH:10]1[C:11]2[C:7](=[C:6]([O:5][CH2:4][C@@H:2]([OH:1])[CH2:3][N:25]3[CH2:26][CH2:27][CH:22]([O:15][C:16]4[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=4)[CH2:23][CH2:24]3)[CH:14]=[CH:13][CH:12]=2)[CH:8]=[CH:9]1
Reactant: c1ccc(OC2CCNCC2)cc1
Reactant: c1cc(OC[C@@H]2CO2)c2cc[nH]c2c1
Agent: O=C(O)C(=O)O
Solvent: CO
Solvent: CCOC(C)=O
Product: O[C@H](COc1cccc2[nH]ccc12)CN1CCC(Oc2ccccc2)CC1

Procedure:
The title compound was prepared in similar fashion from (S)-(+)-4-(oxiranylmethoxy)-1H-indole and 4-(phenoxy)piperidine. The resulting free base was dissolved in ethyl acetate, and precipitated with one equivalent of oxalic acid in ethyl acetate in 69% overall yield. FDMS m/e=366 (M+ of free base). α[D]589 =-14.29 (c=0.5, methanol).
Reaction SMILES: [CH3:1][N:2]([CH2:4][C:5]1[CH:10]=[CH:9][N:8]=[C:7]([CH2:11][CH2:12][CH2:13][CH2:14][NH2:15])[CH:6]=1)[CH3:3].[N+](N[C:20]1[NH:25][C:24](=[O:26])[C:23]([CH2:27][C:28]2[CH:29]=[N:30][C:31]([CH3:34])=[CH:32][CH:33]=2)=[CH:22][N:21]=1)([O-])=O>N1C=CC=CC=1>[CH3:1][N:2]([CH2:4][C:5]1[CH:10]=[CH:9][N:8]=[C:7]([CH2:11][CH2:12][CH2:13][CH2:14][NH:15][C:20]2[NH:25][C:24](=[O:26])[C:23]([CH2:27][C:28]3[CH:29]=[N:30][C:31]([CH3:34])=[CH:32][CH:33]=3)=[CH:22][N:21]=2)[CH:6]=1)[CH3:3]
Reactant: CN(C)Cc1ccnc(CCCCN)c1
Reactant: Cc1ccc(Cc2cnc(N[N+](=O)[O-])[nH]c2=O)cn1
Solvent: c1ccncc1
Product: Cc1ccc(Cc2cnc(NCCCCc3cc(CN(C)C)ccn3)[nH]c2=O)cn1
Yield: 43.9 %

Procedure:
A mixture of 4-(4-dimethylaminomethyl-2-pyridyl)butylamine (1 g) and 2-nitroamino-5-(6-methyl-3-pyridylmethyl)-4-pyrimidone (1.26 g) in pyridine (5 ml) was refluxed for 4.5 hours. The solvent was removed in vacuo, the residue chromatographed and then crystallised from ethanol:ether (1:10) to yield 2-[4-(4-dimethylaminomethyl-2-pyridyl)butylamino]-5-(6-methyl-3-pyridylmethyl)-4-pyrimidone (0.86 g) m.p. 135°-137°.
Reaction SMILES: C[O:2][C:3](=[O:27])[C@@H:4]([O:22]C(=O)CCl)[C@H:5]([NH:14][C:15]([O:17][C:18]([CH3:21])([CH3:20])[CH3:19])=[O:16])[CH2:6][C:7]1[CH:12]=[CH:11][CH:10]=[C:9]([F:13])[CH:8]=1.[OH-].[Na+].CO>O1CCOCC1>[C:18]([O:17][C:15]([NH:14][C@H:5]([CH2:6][C:7]1[CH:12]=[CH:11][CH:10]=[C:9]([F:13])[CH:8]=1)[C@H:4]([OH:22])[C:3]([OH:27])=[O:2])=[O:16])([CH3:21])([CH3:19])[CH3:20]
Reactant: COC(=O)[C@@H](OC(=O)CCl)[C@@H](Cc1cccc(F)c1)NC(=O)OC(C)(C)C
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: C1COCCO1
Product: CC(C)(C)OC(=O)N[C@H](Cc1cccc(F)c1)[C@H](O)C(=O)O
Temperature: 25 °C
Reaction time: 4 h
Yield: 93.2 %

Procedure:
A mixture of (2S,3R)-3-tert-butoxycarbonylamino-2-(2-chloro-acetoxy)-4-(3-fluoro-phenyl)-butyric acid methyl ester (4.56 g, 11.3 mmol, 1 eq), 4N NaOH (6.5 mL, 25.9 mmol, 2.3 eq), MeOH (48 mL) and 1.4-dioxane (72 mL) was stirred at ambient temperature for 4 h after which the solvents were removed in vacuo and the residue was charged with H2O (50 mL) and washed with Et2O (100 mL). The aqueous layer was made acidic with 10% citric acid and extracted with EtOAc (2×75 mL). The combined EtOAc layers were washed with H2O (3×50 mL) brine (50 mL), dried (Na2SO4), concentrated, shaken with heptane and filtered to give the desired acid as a white solid (3.3 g, 94%).
Reaction SMILES: [N:1]1([CH:7]2[CH2:12][CH2:11][CH:10]([NH:13]C(=O)OC(C)(C)C)[CH2:9][CH2:8]2)[CH2:6][CH2:5][O:4][CH2:3][CH2:2]1.[ClH:21].CCOCC>CO>[ClH:21].[ClH:21].[N:1]1([CH:7]2[CH2:8][CH2:9][CH:10]([NH2:13])[CH2:11][CH2:12]2)[CH2:2][CH2:3][O:4][CH2:5][CH2:6]1
Reactant: CC(C)(C)OC(=O)NC1CCC(N2CCOCC2)CC1
Agent: Cl
Solvent: CO
Solvent: CCOCC
Product: NC1CCC(N2CCOCC2)CC1
Temperature: 25 °C
Reaction time: 8 h
Yield: 55 %

Procedure:
To a solution of tert-butyl N-[4-(morpholin-4-yl)cyclohexyl]carbamate (1.0 g, 3.52 mmol, 1.00 equiv) in methanol (5 mL) was added concentrated hydrochloric acid (1.5 mL) at 0° C. The resulting solution was stirred overnight at room temperature. To this mixture was slowly added ether (50 mL). The precipitates were collected by filtration and dried in an oven to give 4-(morpholin-4-yl)cyclohexan-1-amine dihydrochloride (500 mg, 55%) as a white solid.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][CH:9]2[CH2:14][CH2:13][N:12]([C:15]([O:17][C:18]([CH3:21])([CH3:20])[CH3:19])=[O:16])[CH2:11][CH2:10]2)=[CH:4][CH:3]=1.Cl[CH2:23][C:24]1[CH:29]=[CH:28][N:27]=[C:26]([C:30]2[CH:35]=[C:34]([O:36][CH3:37])[C:33]([O:38][CH3:39])=[C:32]([O:40][CH3:41])[CH:31]=2)[CH:25]=1>>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]([CH:9]2[CH2:10][CH2:11][N:12]([C:15]([O:17][C:18]([CH3:21])([CH3:20])[CH3:19])=[O:16])[CH2:13][CH2:14]2)[CH2:23][C:24]2[CH:29]=[CH:28][N:27]=[C:26]([C:30]3[CH:35]=[C:34]([O:36][CH3:37])[C:33]([O:38][CH3:39])=[C:32]([O:40][CH3:41])[CH:31]=3)[CH:25]=2)=[CH:4][CH:3]=1
Reactant: CC(C)(C)OC(=O)N1CCC(Nc2ccc(Br)cc2)CC1
Reactant: COc1cc(-c2cc(CCl)ccn2)cc(OC)c1OC
Product: COc1cc(-c2cc(CN(c3ccc(Br)cc3)C3CCN(C(=O)OC(C)(C)C)CC3)ccn2)cc(OC)c1OC

Procedure:
4-(4-Bromophenyl)amino-l-(tert-butoxycarbonyl)piperidine (711 mg) and 4-chloromethyl-2-(3,4,5-trimethoxyphenyl)pyridine (588 mg) was treated in the same manner as described in Example 9 to give light yellow amorphous of the title compound.
Reaction SMILES: C[O:2][C:3](=[O:40])[CH2:4][O:5][C:6]1[CH:11]=[CH:10][CH:9]=[C:8]([C:12]2[N:17]=[C:16]([O:18][CH3:19])[C:15]([O:20][C:21]3[CH:26]=[CH:25][CH:24]=[CH:23][C:22]=3[O:27][CH3:28])=[C:14]([NH:29][S:30]([C:33]3[CH:38]=[CH:37][C:36]([CH3:39])=[CH:35][N:34]=3)(=[O:32])=[O:31])[N:13]=2)[CH:7]=1.[OH-].[Na+].C(Cl)Cl.CCOC(C)=O>CO>[CH3:19][O:18][C:16]1[C:15]([O:20][C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][C:22]=2[O:27][CH3:28])=[C:14]([NH:29][S:30]([C:33]2[CH:38]=[CH:37][C:36]([CH3:39])=[CH:35][N:34]=2)(=[O:32])=[O:31])[N:13]=[C:12]([C:8]2[CH:7]=[C:6]([CH:11]=[CH:10][CH:9]=2)[O:5][CH2:4][C:3]([OH:40])=[O:2])[N:17]=1
Reactant: COC(=O)COc1cccc(-c2nc(NS(=O)(=O)c3ccc(C)cn3)c(Oc3ccccc3OC)c(OC)n2)c1
Agent: [Na+]
Agent: [OH-]
Solvent: ClCCl
Solvent: CCOC(C)=O
Solvent: CO
Product: COc1ccccc1Oc1c(NS(=O)(=O)c2ccc(C)cn2)nc(-c2cccc(OCC(=O)O)c2)nc1OC
Reaction time: 1 h

Procedure:
85 mg of {3-[4-methoxy-5-(2-methoxy-phenoxy)-6-(5-methyl-pyridine-2-sulfonylamino)-pyrimidin-2-yl]-phenoxy}-acetic acid methyl ester, product of example 2, dissolved in MeOH (30 ml) were treated at RT with 1N NaOH (0.9 ml) and the solution was stirred for 1 h until the transformation was complete according to TLC analysis (CH2Cl2/EtOAc: 3:1). The reaction mixture was partitioned between 1N HCl and CH2Cl2, the organic layer was dried over Na2SO4 and the solvent removed in vacuo. The residue upon triturating with ether provided the desired {3-[4-methoxy-5-(2-methoxy-phenoxy)-6-(5-methyl-pyridine-2-sulfonylamino)-pyrimidin-2-yl]-phenoxy}-acetic acid as a white solid. ISN mass spectrum, m/e 551 (M−1 calculated for C26H24N4O8S: 551).
Reaction SMILES: [Cl: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]([N+:19]([O-])=O)[CH:17]=[CH:18][C:13]=2[N:12]([CH3:22])[C:11](=[O:23])[C@H:10]([CH3:24])[N:9]=1>O1CCCC1.CO.[Ni]>[NH2:19][C:16]1[CH:17]=[CH:18][C:13]2[N:12]([CH3:22])[C:11](=[O:23])[C@H:10]([CH3:24])[N:9]=[C:8]([C:3]3[CH:4]=[CH:5][CH:6]=[CH:7][C:2]=3[Cl:1])[C:14]=2[CH:15]=1
Reactant: C[C@@H]1N=C(c2ccccc2Cl)c2cc([N+](=O)[O-])ccc2N(C)C1=O
Agent: [Ni]
Solvent: C1CCOC1
Solvent: CO
Product: C[C@@H]1N=C(c2ccccc2Cl)c2cc(N)ccc2N(C)C1=O

Procedure:
A solution of 68.2 g (0.198 mol) of (S)-5-(o-chlorophenyl)-1,3-dihydro-1,3-dimethyl-7-nitro-2H-1,4-benzodiazepin-2-one in a mixture of 400 ml of tetrahydrofuran and 950 ml of methanol is treated with Raney-nickel which has previously been washed several times with methanol and tetrahydrofuran and the suspension is hydrogenated while stirring and cooling with water, whereupon it is filtered and the filtrate is evaporated. The residue is recrystallized from ether, there being obtained (S)-7-amino-5-(o-chlorophenyl)-1,3-dihydro-1,3-dimethyl-2H-1,4-benzodiazepin-2-one of melting point 221°; [α]25D =-13.8° (1 percent solution in methylene chloride).
Reaction SMILES: [CH3:1][C:2]([C:4]1[CH:9]=[CH:8][C:7]([F:10])=[CH:6][CH:5]=1)=[O:3].Br.CS(C)=[O:14]>>[OH2:3].[F:10][C:7]1[CH:8]=[CH:9][C:4]([C:2]([CH:1]=[O:14])=[O:3])=[CH:5][CH:6]=1
Reactant: CC(=O)c1ccc(F)cc1
Reactant: CS(C)=O
Agent: Br
Product: O
Product: O=CC(=O)c1ccc(F)cc1
Temperature: 25 °C
Reaction time: 22 h
Yield: 73 %

Procedure:
4-Fluoroacetophenone (27.6 g, 0.2 moles) was dissolved in dimethylsulfoxide (140 ml). 48% Hydrobromic acid (101.1 g, 68.0 ml, 0.6 moles) was added over 20 minutes. The resulting solution was aged at 55-60° C. for 22 hours. The mixture was cooled to room temperature and partitioned between water (1.0 liters) and ethyl acetate (250 ml). The aqueous phase was extracted with ethyl acetate (2×250 ml). The combined ethyl acetate extracts were filtered and solvent switched to toluene at 60° C. under reduced pressure. The solution was diluted to 200 ml with toluene, and water (10 ml) was added. The resulting slurry was stirred at room temperature for 18 hours then at 0° C. for 1 hour. The product was collected by filtration and washed with cold toluene (50 ml). The solid was sucked down on the filter for 30 minutes and air dried to constant weight to afford 4-fluorophenylglyoxal hydrate (24.8 g) as a white solid in 73% yield.
Reaction SMILES: [Cl:1][C:2]1[CH:21]=[CH:20][CH:19]=[CH:18][C:3]=1[O:4][C:5]1[CH:17]=[CH:16][C:8]([C:9]([CH:11]=[CH:12][C:13]([OH:15])=[O:14])=[O:10])=[CH:7][CH:6]=1.[CH3:22][C:23]1C=CC(OC2C=CC(C(C=CC(O)=O)=O)=CC=2)=CC=1>>[Cl:1][C:2]1[CH:21]=[CH:20][CH:19]=[CH:18][C:3]=1[O:4][C:5]1[CH:17]=[CH:16][C:8]([C:9]([CH:11]=[CH:12][C:13]([O:15][CH2:22][CH3:23])=[O:14])=[O:10])=[CH:7][CH:6]=1
Reactant: Cc1ccc(Oc2ccc(C(=O)C=CC(=O)O)cc2)cc1
Reactant: O=C(O)C=CC(=O)c1ccc(Oc2ccccc2Cl)cc1
Product: CCOC(=O)C=CC(=O)c1ccc(Oc2ccccc2Cl)cc1

Procedure:
The procedure in Example 17(1) was followed, except that 6.05 g of 3-[4-(2-chlorophenoxy)benzoyl]acrylic acid were used in place of 3-[4-(4-methylphenoxy)benzoyl]acrylic acid, to give 5.06 g of ethyl 3-[4-(2-chlorophenoxy)benzoyl]-acrylate in the form of an oil.
Reaction SMILES: C(O)(C(F)(F)F)=O.[Cl:8][C:9]1[CH:10]=[CH:11][C:12]([CH2:31][N:32]2[CH2:35][CH:34]([OH:36])[CH2:33]2)=[C:13]([CH:30]=1)[CH2:14][NH:15][C:16](=[O:29])[C@@H:17]1[CH2:21][CH2:20][CH2:19][N:18]1C(OC(C)(C)C)=O>C(Cl)Cl>[Cl:8][C:9]1[CH:10]=[CH:11][C:12]([CH2:31][N:32]2[CH2:35][CH:34]([OH:36])[CH2:33]2)=[C:13]([CH:30]=1)[CH2:14][NH:15][C:16](=[O:29])[C@@H:17]1[CH2:21][CH2:20][CH2:19][NH:18]1
Reactant: CC(C)(C)OC(=O)N1CCC[C@H]1C(=O)NCc1cc(Cl)ccc1CN1CC(O)C1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: O=C(NCc1cc(Cl)ccc1CN1CC(O)C1)[C@@H]1CCCN1
Yield: 35.2 %

Procedure:
TFA (3 mL) was added to a stirred solution of N-{5-chloro-2-[(3-hydroxyazetidin-1-yl)methyl]benzyl}-1-(tert-butoxycarbonyl)-L-prolinamide (210 mg, 0.49 mmol) in CH2Cl2 (6 mL) at 0° C. After 90 min the solution was concentrated and the residue was partitioned between CH2Cl2 and 10% NaHCO3. The aqueous layer was saturated with NaCl and then extracted with more CH2Cl2. The combined organic layers were washed with brine, dried over (Na2SO4) and then evaporated. The reside was purified by chromatography on silica (ammonia saturated CHCl3/MeOH, 93:7) to give N-{5-chloro-2-[(3-hydroxyazetidin-1-yl)methyl]benzyl}-L-prolinamide (55.8 mg) as a glass: 1H NMR (CDCl3, 400 MHz) δ 1.71 (m, 2H), 1.93 (m, 1H), 2.16 (m, 1H), 2.92 (m, 2H), 3.05 (m, 2H), 3.39 (m, 2H), 3.61 (dd, J=12.3, 20.7 Hz, 2H), 3.72 (dd, J=6.4, 8.6 Hz, 2H), 4.28-4.46 (m, 3H), 7.12 (d, J=8.1 Hz), 7.19 (dd, J=2.2, 8.1 Hz), 7.36 (d, J=2.0 Hz, 1H), 9.09 (br s, 1H).
Reaction SMILES: [CH2:1]([C:3]1[CH:10]=[CH:9][C:6]([CH:7]=[O:8])=[CH:5][CH:4]=1)[CH3:2].[CH2:11]([Mg]Br)[CH2:12][CH3:13]>C(OCC)C>[CH2:1]([C:3]1[CH:10]=[CH:9][C:6]([CH:7]([OH:8])[CH2:11][CH2:12][CH3:13])=[CH:5][CH:4]=1)[CH3:2]
Reactant: CCc1ccc(C=O)cc1
Reactant: CCC[Mg]Br
Solvent: CCOCC
Product: CCCC(O)c1ccc(CC)cc1
Temperature: 0 °C

Procedure:
To a flame-dried flask under an argon atmosphere is added 0.69 mL of commercially available 4-ethylbenzaldehyde and charged with 15 mL of diethyl ether. The solution is cooled to 0° C. and is treated with 3.0 mL (2.0M in diethyl ether) of propylmagnesium bromide. The reaction mixture is left to warm to room temperature overnight and then quenched by the addition of aqueous ammonium chloride. After dilution with diethyl ether the phases are separated; the organic layer is washed with saturated ammonium chloride, dried (magnesium sulfate) and finally concentrated under reduced pressure. The residue is flash column chromatographed using 25% to 30% diethyl ether in hexane to yield 1.08 g of the title product as a clear, colorless oil.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[C:16]2[C:11](=[N:12][CH:13]=[C:14](Br)[CH:15]=2)[C:10]([CH3:19])([CH3:18])[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].C([Li])CCC.CON(C)[C:28](=[O:31])[CH2:29][CH3:30].O>C1COCC1.CCOC(C)=O>[C:1]([O:5][C:6]([N:8]1[C:16]2[C:11](=[N:12][CH:13]=[C:14]([C:28](=[O:31])[CH2:29][CH3:30])[CH:15]=2)[C:10]([CH3:19])([CH3:18])[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)OC(=O)N1CC(C)(C)c2ncc(Br)cc21
Reactant: CCC(=O)N(C)OC
Agent: [Li]CCCC
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Solvent: O
Product: CCC(=O)c1cnc2c(c1)N(C(=O)OC(C)(C)C)CC2(C)C
Reaction time: 0.5 h
Yield: 66.4 %

Procedure:
6-Bromo-3,3-dimethyl-2,3-dihydro-pyrrolo[3,2-b]pyridine-1-carboxylic acid tert-butyl ester (1.33 g, 4.07 mmol) in THF (20.3 mL) was cooled to −78° C. under nitrogen and butyllithium (2.5 M in hexanes, 3.75 mL, 9.4 mmol) added. The reaction was stirred at this temperature for 30 minutes. To this was added N-methoxy-N-methyl-propionamide (0.71 g, 6.1 mmol) and the reaction was stirred for 1 h. Water and EtOAc were added and the organic layer separated, washed with brine (3×) and dried with sodium sulfate, filtered and concentrated. Chromatography (silica gel, gradient elution, 0-60%, EtOAc in petrol 40-60) gave the title compound (0.823 g), MS: [M+H]+=305, as a 2:1 mixture with 3,3-dimethyl-2,3-dihydro-pyrrolo[3,2-b]pyridine-1-carboxylic acid tert-butyl ester.
Reaction SMILES: [CH:1]1[C:11]2[C:10]3[CH:12]=[CH:13][CH:14]=[CH:15][C:9]=3[CH2:8][N:7]([C:16](=[NH:20])[O:17][CH2:18][CH3:19])[CH2:6][C:5]=2[CH:4]=[CH:3][CH:2]=1.[Cl:21][C:22]1[CH:27]=[CH:26][C:25]([N:28]=[C:29]=[O:30])=[CH:24][CH:23]=1>>[Cl:21][C:22]1[CH:27]=[CH:26][C:25]([NH:28][C:29]([N:20]=[C:16]([N:7]2[CH2:6][C:5]3[CH:4]=[CH:3][CH:2]=[CH:1][C:11]=3[C:10]3[CH:12]=[CH:13][CH:14]=[CH:15][C:9]=3[CH2:8]2)[O:17][CH2:18][CH3:19])=[O:30])=[CH:24][CH:23]=1
Reactant: CCOC(=N)N1Cc2ccccc2-c2ccccc2C1
Reactant: O=C=Nc1ccc(Cl)cc1
Product: CCOC(=NC(=O)Nc1ccc(Cl)cc1)N1Cc2ccccc2-c2ccccc2C1

Procedure:
starting from ethyl 5,7-dihydro-6H-dibenz[c,e]-azepine-6-carboximidate and p-chlorophenyl isocyanate, there is obtained ethyl N-[(p-chlorophenyl)carbamoyl]-5,7-dihydro-6H-dibenz[c,e]azepine-6-carboximidate, m.p. 154°-156° C.;