Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]1([NH2:15])[N:2]=[C:3]([NH2:14])[N:4]=[C:5]2[C:10]=1[C:9]1[CH:11]=[CH:12][NH:13][C:8]=1[CH:7]=[CH:6]2.[H-].[Na+].[CH3:18][C:19]1[CH:24]=[CH:23][C:22]([CH3:25])=[CH:21][C:20]=1[S:26](Cl)(=[O:28])=[O:27]>CN(C)C=O>[CH3:18][C:19]1[CH:24]=[CH:23][C:22]([CH3:25])=[CH:21][C:20]=1[S:26]([N:13]1[C:8]2[CH:7]=[CH:6][C:5]3[C:10](=[C:1]([NH2:15])[N:2]=[C:3]([NH2:14])[N:4]=3)[C:9]=2[CH:11]=[CH:12]1)(=[O:27])=[O:28]
Reactant: Cc1ccc(C)c(S(=O)(=O)Cl)c1
Reactant: Nc1nc(N)c2c(ccc3[nH]ccc32)n1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: Cc1ccc(C)c(S(=O)(=O)n2ccc3c4c(N)nc(N)nc4ccc32)c1
Reaction time: 1.5 h

Procedure:
A solution of 11.97 g. 7H-pyrrolo[3,2-f]quinazoline-1,3-diamine, as prepared in Example 1, in 750 ml. dry dimethylformamide is stirred under nitrogen as 3.18 g. of ca. 50% sodium hydride-mineral oil is added carefully. After stirring for 1.5 hours and chilling with an ice-water bath, a solution of 13.51 g. 2,5-dimethylbenzenesulfonyl chloride in 50 ml. dry dimethylformamide is added dropwise to the chilled stirring suspension. Stirring is continued for 4 hours, while the reaction slowly warms to ambient temperature, and is quenched with 30 ml. isopropanol. After removal of solvent (in vacuo), the residue is stirred thoroughly with excess aqueous potassium carbonate solution and filtered. The solids are collected, washed well with water, rinsed with hexane, and dried. The crude product is dissolved in 2.5 liters of boiling methanol, treated with charcoal, and filtered through Celite. The filtrate is concentrated to ca. 1 liter and chilled. The crystalline solid is collected and again recrystallized from methanol and dried to afford 9.68 g. of the title compound, m.p. 271.5°-272.5° C., NMR (d DMSO): δ2.35 (singlet, 5--CH3), 2.39 (singlet, 2--CH3), 5.93 (singlet, 3--NH2), 6.88 (singlet, 1--NH2), 7.16 (doublet, J=9 cps, 5H), 7.48 (doublet, J=31/2 cps, 9H), 8.9 (doublet, J=31/2 cps, 8H) p.p.m.; λmax95%EtOH 242 shoulder (ε28,300), 257 (ε31,700), 288 shoulder (ε12,500), 350 (ε4,900) nm; λmin95%EtOH 320 (ε2,700) nm.
Reaction SMILES: [H-].[Na+].[C:3]([CH2:5][C:6]([NH:8][C:9]1[S:10][CH:11]=[CH:12][N:13]=1)=[O:7])#[N:4].[H-].[CH3:15][N:16]1[CH:20]=[CH:19][CH:18]=[C:17]1[C:21](Cl)=[O:22].Cl>COCCOC.O.CN(C)C=O>[O:22]=[C:21]([C:17]1[N:16]([CH3:15])[CH:20]=[CH:19][CH:18]=1)[CH:5]([C:6](=[O:7])[NH:8][C:9]1[S:10][CH:11]=[CH:12][N:13]=1)[C:3]#[N:4]
Reactant: N#CCC(=O)Nc1nccs1
Reactant: Cn1cccc1C(=O)Cl
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: COCCOC
Solvent: CN(C)C=O
Product: Cn1cccc1C(=O)C(C#N)C(=O)Nc1nccs1
Reaction time: 8 h

Procedure:
To the suspension of 2.1 g of 50% NaH mineral oil (washed with petroleum ether) in 25 ml of 1,2-dimethoxyethane and 15 ml of dimethylformamide was added 6.7 g of 2-(cyanoacetylamino)thiazole. After the moderately exothermic, effervescent reaction of the hydride, there was added (swirling) a solution of N-methyl-2-pyrroloyl chloride (prepared from 2.5 g of the acid) in 20 ml of 1,2-dimethoxyethane. The dark suspension resulting from the exothermic reaction was let stand overnight. After treatment with ca. 300 ml water, the filtered aqueous solution was acidified with 6 ml of 6 N HCl. The crude product was collected, redissolved in NaHCO3 solution, and the filtered solution carefully acidified with 6 N HCl. The product was collected, washed with water, dried, and triturated with methanol to give crystals, m.p. 201°-2° dec. Recrystallization from dimethylformamide-methanol gave β-oxo-α-(2-thiazolylcarbamoyl)-β-(1-methyl-2-pyrrolyl)propionitrile, m.p. 208°-9° dec.
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[C:3]([CH:10]2[CH2:15][CH2:14][NH:13][CH2:12][CH2:11]2)=[CH:2]1.Cl.[Cl:17][CH2:18][CH2:19][CH2:20][N:21]1[CH2:26][CH2:25][CH:24]([C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=2)[CH2:23][CH2:22]1.C(=O)([O-])[O-].[K+].[K+]>CN(C=O)C>[ClH:17].[C:27]1([CH:24]2[CH2:23][CH2:22][N:21]([CH2:20][CH2:19][CH2:18][N:13]3[CH2:14][CH2:15][CH:10]([C:3]4[C:4]5[C:9](=[CH:8][CH:7]=[CH:6][CH:5]=5)[NH:1][CH:2]=4)[CH2:11][CH2:12]3)[CH2:26][CH2:25]2)[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1
Reactant: c1ccc2c(C3CCNCC3)c[nH]c2c1
Reactant: ClCCCN1CCC(c2ccccc2)CC1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: c1ccc(C2CCN(CCCN3CCC(c4c[nH]c5ccccc45)CC3)CC2)cc1
Temperature: 100 °C
Reaction time: 4 h
Yield: 36.5 %

Procedure:
To a suspended solution of 4-(3-indolyl)piperidine (2.0 g, 10 mmol) and 1-(3-chloropropyl)-4-phenylpiperidine hydrochloride (3.1 g, 11.2 mmol) in DMF (60 mL) was added potassium carbonate (5.5 g, 40 mmol), and the mixture was stirred at 100° C. for 4 hours. After the precipitated salt was filtered off, the filtrate was concentrated, water (50 mL) was added to the filtrate, and the mixture was extracted with chloroform. After drying over anhydrous sodium sulfate, the chloroform layer was concentrated to afford a crude product. The crude product was purified by column chromatography on a silica gel (silica gel NH-DM 1020 produced by Fuji Silysia Chemical Ltd., eluent; chloroform) and was then recrystallized from ethyl acetate to afford a free form (1.6 g, yield: 40%) of the title compound as white crystals. After adding hydrochloric acid/methanol to a solution of the free form (1.6 g) in methanol, the mixture was concentrated and was then recrystallized from methanol/ether to afford the title compound (1.8 g) as white crystals.
Reaction SMILES: [CH:1]1([C:4]2[N:9]=[C:8]([C:10]([NH:12][C:13]3[CH:17]=[N:16][N:15]([CH3:18])[C:14]=3[C:19]([OH:21])=O)=[O:11])[C:7]([NH:22][C:23]3[CH:24]=[N:25][CH:26]=[N:27][CH:28]=3)=[N:6][CH:5]=2)[CH2:3][CH2:2]1.Cl.[CH3:30][NH:31][O:32][CH3:33]>>[CH3:33][O:32][N:31]([CH3:30])[C:19]([C:14]1[N:15]([CH3:18])[N:16]=[CH:17][C:13]=1[NH:12][C:10]([C:8]1[C:7]([NH:22][C:23]2[CH:24]=[N:25][CH:26]=[N:27][CH:28]=2)=[N:6][CH:5]=[C:4]([CH:1]2[CH2:3][CH2:2]2)[N:9]=1)=[O:11])=[O:21]
Reactant: CNOC
Reactant: Cn1ncc(NC(=O)c2nc(C3CC3)cnc2Nc2cncnc2)c1C(=O)O
Agent: Cl
Product: CON(C)C(=O)c1c(NC(=O)c2nc(C3CC3)cnc2Nc2cncnc2)cnn1C

Procedure:
The product was obtained starting from 4-{[6-cyclopropyl-3-(pyrimidin-5-ylamino)-pyrazine-2-carbonyl]-amino}-2-methyl-2H-pyrazole-3-carboxylic acid (50 mg, 131 μmol; example 236, step 3) and N,O-dimethylhydroxylamine hydrochloride (14 mg, 145 μmol) according to the method described in example 64, step 6 after purification by preparative HPLC using an acetonitrile/water gradient as yellow foam (47 mg, 84%).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([O:8][C:9]2[C:18]3[C:13](=[CH:14][C:15]([OH:21])=[C:16]([O:19][CH3:20])[CH:17]=3)[N:12]=[CH:11][N:10]=2)[CH:5]=[CH:4][C:3]=1[NH:22][C:23]([NH:25][CH2:26][CH3:27])=[O:24].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[N:47]1([CH:53](O)[CH2:54][CH3:55])[CH2:52][CH2:51][CH2:50][CH2:49][CH2:48]1.N(C(OCC)=O)=NC(OCC)=O>CN(C)C=O>[Cl:1][C:2]1[CH:7]=[C:6]([O:8][C:9]2[C:18]3[C:13](=[CH:14][C:15]([O:21][CH2:55][CH2:54][CH2:53][N:47]4[CH2:52][CH2:51][CH2:50][CH2:49][CH2:48]4)=[C:16]([O:19][CH3:20])[CH:17]=3)[N:12]=[CH:11][N:10]=2)[CH:5]=[CH:4][C:3]=1[NH:22][C:23]([NH:25][CH2:26][CH3:27])=[O:24]
Reactant: CCNC(=O)Nc1ccc(Oc2ncnc3cc(O)c(OC)cc23)cc1Cl
Reactant: CCC(O)N1CCCCC1
Agent: CCOC(=O)N=NC(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CN(C)C=O
Product: CCNC(=O)Nc1ccc(Oc2ncnc3cc(OCCCN4CCCCC4)c(OC)cc23)cc1Cl
Temperature: 25 °C
Reaction time: 2 h
Yield: 42 %

Procedure:
N-{2-Chloro-4-[(7-hydroxy-6-methoxy-4-quinazolinyl)oxy]phenyl}-N′-ethylurea (2.7 g) was dissolved in N,N-dimethylformamide (30 ml), and triphenylphosphine(3.6 g), piperidinopropanol (1.2 g), and diethyl azodicarboxylate (2.4 g) were added to the solution. The mixture was stirred at room temperature for 2 hr. Triphenylphosphine(3.6 g), piperidinopropanol (0.8 g), and diethyl azodicarboxylate (1.9 g) were then again added to the reaction solution. The mixture was stirred at room temperature for additional 10 hr. The solvent was removed by distillation under the reduced pressure, and the residue was purified by chromatography on silica gel by development with chloroform/methanol (20/1) to give 1.5 g (yield 42%) of the title compound.
Reaction SMILES: [Na].[CH:2]1[CH2:6][CH:5]=[CH:4][CH:3]=1.Br[CH2:8][C:9]([O:11][CH3:12])=[O:10]>O1CCCC1>[CH3:12][O:11][C:9](=[O:10])[CH2:8][CH:3]1[CH:2]=[CH:6][CH:5]=[CH:4]1
Reactant: C1=CCC=C1
Reactant: COC(=O)CBr
Agent: [Na]
Solvent: C1CCOC1
Product: COC(=O)CC1C=CC=C1

Procedure:
2,4-Cyclopentadienyl acetic acid methyl ester was prepared from the sodium salt of cyclopentadiene and methyl bromoacetate in tetrahydrofuran by the method of J. J. Partridge [J. Am. Chem. Soc., 95, 7171 (1973)].
Reaction SMILES: Br[C:2]1[C:7]2[S:8][C:9]3[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=3[C:6]=2[CH:5]=[CH:4][CH:3]=1.[C:15]1([N:21]2[C:33]3[CH:32]=[CH:31][C:30]([C:34]4[CH:35]=[CH:36][C:37]5[NH:38][C:39]6[C:44]([C:45]=5[CH:46]=4)=[CH:43][CH:42]=[CH:41][CH:40]=6)=[CH:29][C:28]=3[C:27]3[C:22]2=[CH:23][CH:24]=[CH:25][CH:26]=3)[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1.CC(C)([O-])C.[Na+]>C1(C)C(C)=CC=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd].C1(P(C2CCCCC2)C2C=CC=CC=2C2C(OC)=CC=CC=2OC)CCCCC1>[CH:5]1[C:6]2[C:10]3[CH:11]=[CH:12][CH:13]=[CH:14][C:9]=3[S:8][C:7]=2[C:2]([N:38]2[C:37]3[CH:36]=[CH:35][C:34]([C:30]4[CH:31]=[CH:32][C:33]5[N:21]([C:15]6[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=6)[C:22]6[C:27]([C:28]=5[CH:29]=4)=[CH:26][CH:25]=[CH:24][CH:23]=6)=[CH:46][C:45]=3[C:44]3[C:39]2=[CH:40][CH:41]=[CH:42][CH:43]=3)=[CH:3][CH:4]=1
Reactant: c1ccc(-n2c3ccccc3c3cc(-c4ccc5[nH]c6ccccc6c5c4)ccc32)cc1
Reactant: Brc1cccc2c1sc1ccccc12
Agent: [Pd]
Agent: CC(C)(C)[O-]
Agent: COc1cccc(OC)c1-c1ccccc1P(C1CCCCC1)C1CCCCC1
Solvent: Cc1ccccc1C
Product: c1ccc(-n2c3ccccc3c3cc(-c4ccc5c(c4)c4ccccc4n5-c4cccc5c4sc4ccccc45)ccc32)cc1
Yield: 75.9 %

Procedure:
A mixture of 4-bromodibenzo[b,d]thiophene (2.061 g, 7.83 mmol), 9-phenyl-9H,9′H-3,3′-bicarbazole (2 g, 4.90 mmol), and sodium t-butoxide (1.412 g, 14.69 mmol) in 200 mL of xylene was bubbled with N2 for 20 min. Pd2(dba)3 (0.045 g, 0.049 mmol) and dicyclohexyl(2′,6′-dimethoxybiphenyl-2-yl)phosphine (0.080 g, 0.196 mmol) were added and bubbled with nitrogen for another 20 min, then the mixture was heated to reflux under N2 for 24 h. The mixture was cooled and filtered through Celite. After solvent evaporation, the residue was coated on Celite and purified by column chromatography using 2:3 dichloromethane and hexanes as solvent. 9-(dibenzo[b,d]thiophen-4-yl)-9′-phenyl-9H,9′H-3,3′-bicarbazole (2.2 g. 3.72 mmol, 76% yield) was obtained. The product was further purified by recrystallization with dichloromethane and hexane.
Reaction SMILES: C1(N=C=NC2CCCCC2)CCCCC1.[CH3:16][C:17]1([CH3:26])[C@@H:19]([CH:20]=[C:21]=[CH2:22])[C@H:18]1[C:23]([OH:25])=[O:24].[CH2:27]([C:34]1[O:38][CH:37]=[C:36]([CH2:39]O)[CH:35]=1)[C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1>C(Cl)Cl.CN(C)C1C=CN=CC=1>[CH3:16][C:17]1([CH3:26])[C@@H:19]([CH:20]=[C:21]=[CH2:22])[C@H:18]1[C:23]([O:25][CH2:39][C:36]1[CH:35]=[C:34]([CH2:27][C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=2)[O:38][CH:37]=1)=[O:24]
Reactant: OCc1coc(Cc2ccccc2)c1
Reactant: C=C=C[C@H]1[C@@H](C(=O)O)C1(C)C
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: CN(C)c1ccncc1
Solvent: ClCCl
Product: C=C=C[C@H]1[C@@H](C(=O)OCc2coc(Cc3ccccc3)c2)C1(C)C
Temperature: 0 °C
Reaction time: 0.25 h
Yield: 84.5 %

Procedure:
4.06 g of dicyclohexylcarbodiimide were added at 0° C. to a solution of 1.52 g of (1R,cis)2,2-dimethyl-3-(1,2-propadienyl)-cyclopropane carboxylic acid in 40 ml of methylene chloride followed by addition of a few crystals of 4-dimethylaminopyridine and stirring at 0° C. for 15 minutes. A solution of 2.07 g of 5-benzyl-3-furyl-methanol in 10 ml of methylene chloride were added at 0° C. to the mixture which was stirred at 20° C. for 4 hours and was then filtered. The filtrate was evaporated to dryness under reduced pressure and the residue was chromatographed over silica gel. Elution with a 1-1 benzene-petroleum ether (b.p.=35° to 70° C.) yielded 2.72 g of 5-benzyl-3-furyl-methyl (1R,cis)2,2-dimethyl-3-(1,2-propadienyl)-cyclopropane-carboxylate.
Reaction SMILES: Cl[CH2:2][CH2:3][CH2:4][N:5]1[C:9]2[CH:10]=[CH:11][CH:12]=[CH:13][C:8]=2[N:7]=[N:6]1.[NH:14]1[CH2:19][CH2:18][CH:17]([C:20]2[C:24]3[CH:25]=[CH:26][CH:27]=[CH:28][C:23]=3[O:22][N:21]=2)[CH2:16][CH2:15]1.C(N(C(C)C)CC)(C)C.[I-].[K+]>C(#N)C>[N:5]1([CH2:4][CH2:3][CH2:2][N:14]2[CH2:15][CH2:16][CH:17]([C:20]3[C:24]4[CH:25]=[CH:26][CH:27]=[CH:28][C:23]=4[O:22][N:21]=3)[CH2:18][CH2:19]2)[C:9]2[CH:10]=[CH:11][CH:12]=[CH:13][C:8]=2[N:7]=[N:6]1
Reactant: ClCCCn1nnc2ccccc21
Reactant: c1ccc2c(C3CCNCC3)noc2c1
Agent: [I-]
Agent: [K+]
Solvent: CCN(C(C)C)C(C)C
Solvent: CC#N
Product: c1ccc2c(c1)nnn2CCCN1CCC(c2noc3ccccc23)CC1
Temperature: 25 °C
Yield: 69.7 %

Procedure:
1-(3-chloropropyl)-1H-benzotriazole (11.7 g, 0.06 mol) was dissolved into 150 ml of acetonitrile, 3-(piperidine-4-yl)benzisoxazole (10.1 g, 0.05 mol), diisopropylethylamine (25.8 g, 0.02 mol) and potassium iodide (8.3 g, 0.05 mol) were respectively added. The mixture was stirred and mixed, then heated and refluxed to react for 15 hours. The mixture was cooled down to ambient temperature and filtered. The filtrate was concentrated to produce oily products, and treated by chromatography with neutral Al2O3 and purified, eluted with dichloromethane to produce 12.6 g compound (I-84) with a yield of 69.7%. ESI-MS [M+H]+: m/z 362.2.
Reaction SMILES: [OH:1][CH:2]([C:14]1[CH:23]=[CH:22][C:21]2[C:20]([CH3:25])([CH3:24])[CH2:19][CH2:18][C:17]([CH3:27])([CH3:26])[C:16]=2[CH:15]=1)[C:3]#[C:4][C:5]1[CH:13]=[CH:12][C:8]([C:9]([OH:11])=[O:10])=[CH:7][CH:6]=1>[O-2].[Mn+2].ClCCl>[O:1]=[C:2]([C:14]1[CH:23]=[CH:22][C:21]2[C:20]([CH3:25])([CH3:24])[CH2:19][CH2:18][C:17]([CH3:27])([CH3:26])[C:16]=2[CH:15]=1)[C:3]#[C:4][C:5]1[CH:6]=[CH:7][C:8]([C:9]([OH:11])=[O:10])=[CH:12][CH:13]=1
Reactant: CC1(C)CCC(C)(C)c2cc(C(O)C#Cc3ccc(C(=O)O)cc3)ccc21
Agent: [Mn+2]
Agent: [O-2]
Solvent: ClCCl
Product: CC1(C)CCC(C)(C)c2cc(C(=O)C#Cc3ccc(C(=O)O)cc3)ccc21
Reaction time: 4 h

Procedure:
500 mg (1.38 mmol) of 4-(3-hydroxy-3-(5,6,7,8-tetrahydro-5,5,8,8-tetramethyl-2-naphthyl)-1-propynyl]benzoic acid, 50 ml of dichloromethane and 2.4 g (27.6 mmol) of manganese oxide were introduced into a round-bottomed flask which was placed in an ultrasonic bath for 4 hours. The reaction mixture was filtered, the filtrate was evaporated and the residue was purified by simple filtration through silica in ethyl ether. 90 mg (18%) of the expected compound, with a melting point of 208°-209° C., were recovered.
Reaction SMILES: [OH:1][CH:2](CO)[CH2:3][N:4]([CH3:44])[C:5]([C:7]1[N:16]2[C:10]([CH2:11][N:12]([C:25]([C:27]3[CH:32]=[CH:31][C:30]([C:33]4[CH:38]=[CH:37][CH:36]=[CH:35][C:34]=4[C:39]([F:42])([F:41])[F:40])=[C:29]([CH3:43])[CH:28]=3)=[O:26])[C:13]3[CH:20]=[C:19]([O:21][CH3:22])[C:18]([O:23][CH3:24])=[CH:17][C:14]=3[CH2:15]2)=[CH:9][CH:8]=1)=[O:6].[O:47]=[C:48](Cl)OC(Cl)(Cl)Cl.C(N(CC)CC)C.N(CCO)CCO>ClCCl>[OH:47][CH2:48][CH2:44][N:4]([CH2:3][CH2:2][OH:1])[C:5]([C:7]1[N:16]2[C:10]([CH2:11][N:12]([C:25]([C:27]3[CH:32]=[CH:31][C:30]([C:33]4[CH:38]=[CH:37][CH:36]=[CH:35][C:34]=4[C:39]([F:41])([F:40])[F:42])=[C:29]([CH3:43])[CH:28]=3)=[O:26])[C:13]3[CH:20]=[C:19]([O:21][CH3:22])[C:18]([O:23][CH3:24])=[CH:17][C:14]=3[CH2:15]2)=[CH:9][CH:8]=1)=[O:6]
Reactant: COc1cc2c(cc1OC)N(C(=O)c1ccc(-c3ccccc3C(F)(F)F)c(C)c1)Cc1ccc(C(=O)N(C)CC(O)CO)n1C2
Reactant: O=C(Cl)OC(Cl)(Cl)Cl
Solvent: OCCNCCO
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: COc1cc2c(cc1OC)N(C(=O)c1ccc(-c3ccccc3C(F)(F)F)c(C)c1)Cc1ccc(C(=O)N(CCO)CCO)n1C2
Reaction time: 8 h

Procedure:
A solution of N-(2,3-dihydroxypropyl)-7,8-dimethoxy-N-methyl-10-{[2-methyl-2′-trifluoromethyl-[1,1′-biphenyl]-4-yl]carbonyl}-10,11-dihydro-5H-pyrrolo[2,1-c][1,4]benzodiazepine-3-carboxamide of Example 18, Step D (0.31 mmol), diphosgene (1.1 equiv.) and triethylamine (1.5 equiv.) in dichloromethane (5 mL), was stirred at room temperature overnight. The solvent was removed in vacuo and the residue was dissolved in dichloromethane (5 mL). To the solution was added triethylamine (1.5 equiv.) and diethanolamine (1.5 equiv.) and the reaction was stirred overnight. The reaction mixture was then washed with water, dried over anhydrous magnesium sulfate, filtered and evaporated to dryness. The residue was first chromatographed on silica gel eluting with 2% methanol in dichloromethane and then rechromatographed with 2% methanol in ethyl acetate to provide the title compound (0.036 g) as a white solid, m.p. 130-132° C.
Reaction SMILES: [OH:1][NH:2][C:3](=[NH:14])[C:4]1[CH:9]=[CH:8][CH:7]=[C:6]([S:10](=[O:13])(=[O:12])[NH2:11])[CH:5]=1.[Cl:15][C:16]1[CH:21]=[CH:20][C:19]([C:22]2[CH:27]=[C:26]([C:28]([F:31])([F:30])[F:29])[N:25]=[C:24]([C:32](O)=O)[N:23]=2)=[CH:18][CH:17]=1>>[Cl:15][C:16]1[CH:17]=[CH:18][C:19]([C:22]2[CH:27]=[C:26]([C:28]([F:30])([F:29])[F:31])[N:25]=[C:24]([C:32]3[O:1][N:2]=[C:3]([C:4]4[CH:5]=[C:6]([S:10]([NH2:11])(=[O:12])=[O:13])[CH:7]=[CH:8][CH:9]=4)[N:14]=3)[N:23]=2)=[CH:20][CH:21]=1
Reactant: N=C(NO)c1cccc(S(N)(=O)=O)c1
Reactant: O=C(O)c1nc(-c2ccc(Cl)cc2)cc(C(F)(F)F)n1
Product: NS(=O)(=O)c1cccc(-c2noc(-c3nc(-c4ccc(Cl)cc4)cc(C(F)(F)F)n3)n2)c1

Procedure:
The title compound was prepared from N-hydroxy-3-sulfamoyl-benzamidine [CAS-No. 9000-88-7] (0.16 g, 0.75 mmol) and 4-(4-chloro-phenyl)-6-trifluoromethyl-pyrimidine-2-carboxylic acid (example D.1) (0.17 g, 0.5 mmol) according to the general procedure V. Obtained as a white solid (0.18 g, 75%). MS (ISN) 480.1 [(M−H)−]; mp 231° C.
Reaction SMILES: [C:1]1([O:7][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.[C:14](Cl)(=[O:24])[C:15]1[CH:23]=[CH:22][CH:21]=[C:17]([C:18](Cl)=[O:19])[CH:16]=1.C(Cl)Cl.[Cl-].[Al+3].[Cl-].[Cl-]>O>[O:7]([C:1]1[CH:2]=[CH:3][C:4]([C:14]([C:15]2[CH:23]=[CH:22][CH:21]=[C:17]([C:18](=[O:19])[C:11]3[CH:12]=[CH:13][C:8]([O:7][C:1]4[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=4)=[CH:9][CH:10]=3)[CH:16]=2)=[O:24])=[CH:5][CH:6]=1)[C:8]1[CH:9]=[CH:10][CH:11]=[CH:12][CH:13]=1
Reactant: O=C(Cl)c1cccc(C(=O)Cl)c1
Reactant: c1ccc(Oc2ccccc2)cc1
Agent: [Al+3]
Agent: [Cl-]
Solvent: O
Solvent: ClCCl
Product: O=C(c1ccc(Oc2ccccc2)cc1)c1cccc(C(=O)c2ccc(Oc3ccccc3)cc2)c1
Temperature: -5 °C
Reaction time: 1 h

Procedure:
Into a 2 liter flask equipped with a mechanical stirrer, thermometer, and nitrogen inlet and outlet, were charged 210 g (1.2338 moles) of diphenyl ether, 83.9 g (0.4132 moles) of isophthaloyl chloride, and 970 ml of methylene chloride. The solution was cooled to -5° C. by means of and acetone ice bath and then aluminum chloride (240 g, 1.8005 mole) was added in six 40 g portions. The temperature rose slightly during the addition of aluminum chloride and after the final addition the temperature was stabilized and held at 0° C. for thirty minutes. The solution was subsequently warmed to room temperature and held there for 1 hour. Afterwards, the solution was very slowly poured into agitated chilled demineralized water to deactivate the aluminum chloride (maximum water temperature reached was 28° C.). After stirring for 10 minutes, stirring was stopped and the very acidic upper layer was decanted off. The organic layer was subsequently washed several times with fresh dimeneralized water to remove the acid and filtered to remove solid impurities, e.g., elemental aluminum). Afterwards, methanol was slowly added to the organic layer (about 1/1 on a volume basis) with stirring and the product precipitated as short, white needles. Further purification was undertaken by slurrying 3X in isopropanol followed by filtration and drying. The short needles gave a DSC melting point (20° C./min) of 124° C.
Reaction SMILES: [F:1][C:2]1[CH:30]=[CH:29][C:5]([C:6]([CH:8]2[CH2:13][CH2:12][N:11]([CH2:14][CH2:15][CH2:16][CH2:17][N:18]3[C:23](=[O:24])[C:22]4=[CH:25][S:26][CH:27]=[C:21]4[NH:20][C:19]3=[O:28])[CH2:10][CH2:9]2)=[O:7])=[CH:4][CH:3]=1.[C:31]([O:35][CH3:36])(=[O:34])[CH:32]=[CH2:33].CN(C=O)C>CCOCC.CCCCCC>[F:1][C:2]1[CH:3]=[CH:4][C:5]([C:6]([CH:8]2[CH2:13][CH2:12][N:11]([CH2:14][CH2:15][CH2:16][CH2:17][N:18]3[C:23](=[O:24])[C:22]4=[CH:25][S:26][CH:27]=[C:21]4[N:20]([CH2:33][CH2:32][C:31]([O:35][CH3:36])=[O:34])[C:19]3=[O:28])[CH2:10][CH2:9]2)=[O:7])=[CH:29][CH:30]=1
Reactant: C=CC(=O)OC
Reactant: O=C(c1ccc(F)cc1)C1CCN(CCCCn2c(=O)[nH]c3cscc3c2=O)CC1
Solvent: CCOCC
Solvent: CN(C)C=O
Solvent: CCCCCC
Product: COC(=O)CCn1c(=O)n(CCCCN2CCC(C(=O)c3ccc(F)cc3)CC2)c(=O)c2cscc21
Yield: 64.6 %

Procedure:
The title compound was prepared by starting with 3-[4-[4-(4-fluorobenzoyl)piperidin-1-yl]butyl]thieno[3,4-d]pyrimidine-2,4-dione. This material (2.91 g, 6.8 mmol) was reacted with methyl acrylate as described in Example 1 using DMF as the solvent to produce 2.26 g (64.6%) of methyl 3-[3-[4-[4-(4-fluorobenzoyl)piperidin-1-yl]butyl]-2,4-dioxothieno[3,4-d]pyrimidin-1-yl]propanoate as a creamed-colored solid after trituration with ether/hexane, mp 102.5°-103.5° C.
Reaction SMILES: C([NH:8][CH2:9][C:10](O)=[O:11])(OC(C)(C)C)=O.CN(C=O)C.Cl.[NH2:19][CH2:20][C:21]1[CH:22]=[CH:23][C:24]([F:46])=[C:25]([N:27]2[C:32]([CH3:33])=[CH:31][C:30]([O:34][CH2:35][C:36]3[CH:41]=[CH:40][C:39]([F:42])=[CH:38][C:37]=3[F:43])=[C:29]([Cl:44])[C:28]2=[O:45])[CH:26]=1.Cl>CO>[ClH:44].[Cl:44][C:29]1[C:28](=[O:45])[N:27]([C:25]2[CH:26]=[C:21]([CH:22]=[CH:23][C:24]=2[F:46])[CH2:20][NH:19][C:10](=[O:11])[CH2:9][NH2:8])[C:32]([CH3:33])=[CH:31][C:30]=1[O:34][CH2:35][C:36]1[CH:41]=[CH:40][C:39]([F:42])=[CH:38][C:37]=1[F:43]
Reactant: Cc1cc(OCc2ccc(F)cc2F)c(Cl)c(=O)n1-c1cc(CN)ccc1F
Reactant: CC(C)(C)OC(=O)NCC(=O)O
Agent: Cl
Solvent: CO
Solvent: CN(C)C=O
Product: Cc1cc(OCc2ccc(F)cc2F)c(Cl)c(=O)n1-c1cc(CNC(=O)CN)ccc1F
Temperature: 0 °C
Reaction time: 0.33 h
Yield: 130.1 %

Procedure:
A 25 mL round bottomed flask equipped with stirbar and nitrogen inlet was charged with boc-glycine (105 mg, 0.6 mmol) and 8 mL of DMF. The mixture was cooled to 0° C. and isboutylchloroformate (77.5 μL, 0.6 mmol) was added and stirred for 20 min. 1-[5-(aminomethyl)-2-fluorophenyl]-3-chloro-4-[(2,4-difluorobenzyl)oxy]-6-methylpyridin-2(1H)-one hydrochloride (250 mg, 0.6 mmol) was added and stirred for 3 h. After completion of the reaction by LC-MS, concentrated HCl (2 mL) and 2 mL of methanol was added to remove the boc group. The reaction was stirred for 24 h, neutralized with 2M NaOH and extracted with ethyl acetate. The organic phase was dried with Na2SO4 and concentrated in vacuo to obtain (196 mg, 66%) of the desired product as a the HCl salt. 1H NMR (400 MHz, (CD3OD) δ 7.6 (q, J=8 and 6.5 Hz, 1H), 7.5 (m, 1H), 7.3 (m, 2H), 7.0 (m, 2H), 6.63 (s, 1H), 5.35 (s, 2H), 4.4 (q, J=15 and 13.6 Hz, 2H), 3.7 (s, 2H), 2.05 (s, 3H) ppm. ES-HRMS m/z 466.1157 (M+H calcd for C22H20ClF3N3O3 requires 466.1140).
Reaction SMILES: [NH2:1][CH2:2][C@H:3]1[N:8]([C:9]([C:11]2[N:12]=[C:13]([CH3:23])[S:14][C:15]=2[C:16]2[CH:17]=[C:18]([CH3:22])[CH:19]=[CH:20][CH:21]=2)=[O:10])[CH2:7][C@H:6]2[C@@H:4]1[CH2:5]2.[F:24][C:25]1[CH:26]=[CH:27][C:28]([O:34][CH3:35])=[C:29]([CH:33]=1)[C:30](O)=[O:31]>>[F:24][C:25]1[CH:26]=[CH:27][C:28]([O:34][CH3:35])=[C:29]([CH:33]=1)[C:30]([NH:1][CH2:2][C@H:3]1[N:8]([C:9]([C:11]2[N:12]=[C:13]([CH3:23])[S:14][C:15]=2[C:16]2[CH:17]=[C:18]([CH3:22])[CH:19]=[CH:20][CH:21]=2)=[O:10])[CH2:7][C@H:6]2[C@@H:4]1[CH2:5]2)=[O:31]
Reactant: COc1ccc(F)cc1C(=O)O
Reactant: Cc1cccc(-c2sc(C)nc2C(=O)N2C[C@@H]3C[C@@H]3[C@H]2CN)c1
Product: COc1ccc(F)cc1C(=O)NC[C@@H]1[C@H]2C[C@H]2CN1C(=O)c1nc(C)sc1-c1cccc(C)c1

Procedure:
prepared by reaction of ((1S,2S,5R)-2-Aminomethyl-3-aza-bicyclo[3.1.0]hex-3-yl)-(2-methyl-5-m-tolyl-thiazol-4-yl)-methanone with 5-Fluoro-2-methoxy-benzoic acid. LC-MS (basic): tR=0.92 min; [M+H]+=480.1.