Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [ClH:1].CS[C:4]1[N:5]2[CH:17]=[CH:16][N:15]=[C:6]2[S:7][C:8]2[CH:14]=[CH:13][CH:12]=[CH:11][C:9]=2[N:10]=1.[OH:18][CH2:19][CH2:20][N:21]1[CH2:26][CH2:25][NH:24][CH2:23][CH2:22]1.C(O)CCCC>>[ClH:1].[ClH:1].[OH:18][CH2:19][CH2:20][N:21]1[CH2:26][CH2:25][N:24]([C:4]2[N:5]3[CH:17]=[CH:16][N:15]=[C:6]3[S:7][C:8]3[CH:14]=[CH:13][CH:12]=[CH:11][C:9]=3[N:10]=2)[CH2:23][CH2:22]1
Reactant: OCCN1CCNCC1
Reactant: CSC1=Nc2ccccc2Sc2nccn21
Agent: Cl
Solvent: CCCCCO
Product: OCCN1CCN(C2=Nc3ccccc3Sc3nccn32)CC1

Procedure:
A mixture of 5 g of 5-methylthio-imidazo[2,1-b][1,3,5]benzothiadiazepine hydrochloride, 2.86 g of N-β-hydroxyethylpiperazine, and 175 ml of amyl alcohol is refluxed under nitrogen for 48 hrs. with stirring. The solvent is removed under vacuum, the residue is triturated with methylene chloride, washed with 2N sodium hydroxide solution, dried over MgSO4, and evaporated to dryness. The residue is dissolved in 5 ml of methanol and treated with 2N ethereal hydrochloric acid solutions to give 5-(4-β-hydroxyethylpiperazino)-imidazo[2,1-b][1,3,5]benzothiadiaz epine dihydrochloride melting at 212°-214°.
Reaction SMILES: [Cl:1][C:2]1[CH:19]=[CH:18][C:5]([CH2:6][C:7]2[NH:8][C:9](=[O:17])[C:10]([C:15]#[N:16])=[C:11](SC)[N:12]=2)=[CH:4][CH:3]=1.[NH:20]1[CH2:24][CH2:23][CH2:22][CH2:21]1>>[Cl:1][C:2]1[CH:19]=[CH:18][C:5]([CH2:6][C:7]2[NH:8][C:9](=[O:17])[C:10]([C:15]#[N:16])=[C:11]([N:20]3[CH2:24][CH2:23][CH2:22][CH2:21]3)[N:12]=2)=[CH:4][CH:3]=1
Reactant: C1CCNC1
Reactant: CSc1nc(Cc2ccc(Cl)cc2)[nH]c(=O)c1C#N
Product: N#Cc1c(N2CCCC2)nc(Cc2ccc(Cl)cc2)[nH]c1=O

Procedure:
In analogy to the preparation of Example 1, 100 mg (0.34 mmol) of 2-(4-chlorobenzyl)-4-(methylsulphanyl)-6-oxo-1,6-dihydropyrimidine-5-carbonitrile are reacted with 244 mg (3.43 mmol) of pyrrolidine to give 45 mg (42% of theory) of the title compound.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][C:6](=[O:11])[C:5]2=[O:12].O1C2=CC3C(=O)C(=O)NC=3C=C2OCC1.Br[CH:29]([C:36]1[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=1)[C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1.BrCC1OC(C(F)(F)F)=CC=1>>[Br:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[N:7]([CH:29]([C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1)[C:36]1[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=1)[C:6](=[O:11])[C:5]2=[O:12]
Reactant: O=C1Nc2ccc(Br)cc2C1=O
Reactant: BrC(c1ccccc1)c1ccccc1
Agent: FC(F)(F)c1ccc(CBr)o1
Agent: O=C1Nc2cc3c(cc2C1=O)OCCO3
Product: O=C1C(=O)N(C(c2ccccc2)c2ccccc2)c2ccc(Br)cc21

Procedure:
Following the procedure as described in PREPARATION 26A and making non-critical variations using 5-bromoisatin to replace 2,3-dihydro-6H-[1,4]dioxino[2,3-f]indole-7,8-dione, and bromodiphenylmethane to replace 2-(bromomethyl)-5-(trifluoromethyl)furan, 5-bromo-1-(diphenylmethyl)-1H-indole-2,3-dione was obtained (76%): 1H NMR (300 MHz, CDCl3) δ 7.74-7.67 (m, 1H), 7.46-7.20 (m, 11H), 6.96 (s, 1H), 6.37 (d, J=8.5 Hz, 1H).
Reaction SMILES: Br[C:2]1[CH:3]=[CH:4][C:5]([CH2:8][S:9][C:10]2[C:20]3[CH2:19][CH2:18][N:17](C(OC(C)(C)C)=O)[CH2:16][CH2:15][C:14]=3[CH:13]=[CH:12][C:11]=2[Cl:28])=[N:6][CH:7]=1.[NH:29]1[CH2:33][CH2:32][CH2:31][CH2:30]1>>[ClH:28].[Cl:28][C:11]1[CH:12]=[CH:13][C:14]2[CH2:15][CH2:16][NH:17][CH2:18][CH2:19][C:20]=2[C:10]=1[S:9][CH2:8][C:5]1[CH:4]=[CH:3][C:2]([N:29]2[CH2:33][CH2:32][CH2:31][CH2:30]2)=[CH:7][N:6]=1
Reactant: C1CCNC1
Reactant: CC(C)(C)OC(=O)N1CCc2ccc(Cl)c(SCc3ccc(Br)cn3)c2CC1
Product: Cl
Product: Clc1ccc2c(c1SCc1ccc(N3CCCC3)cn1)CCNCC2

Procedure:
Use a method similar to the Example 369, using 6-(5-bromopyridin-2-ylmethylthio)-3-tert-butoxycarbonyl-7-chloro-2,3,4,5-tetrahydro-1H-benzo[d]azepine and pyrrolidine to give the title compound as a pale yellow solid. MS (ES+) m/z: 374 (M+H)+.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[C@@H:12]([C@H:13]([OH:20])[C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[CH2:11][CH2:10][C@H:9]1[CH2:21][C:22]1[CH:30]=[CH:29][C:25]([C:26](O)=[O:27])=[CH:24][CH:23]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[N:31]1([CH:36]2[CH2:41][CH2:40]NC[CH2:37]2)[CH:35]=[CH:34][CH:33]=[N:32]1.C1C=[N:46][C:45]2N(O)N=NC=2C=1.C(Cl)CCl.CCN(C(C)C)C(C)C>CN(C=O)C>[OH:20][C@H:13]([C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)[C@H:12]1[CH2:11][CH2:10][C@@H:9]([CH2:21][C:22]2[CH:30]=[CH:29][C:25]([C:26]([N:46]3[CH2:37][CH:36]([N:31]4[CH:35]=[CH:34][CH:33]=[N:32]4)[CH2:41][CH2:40][CH2:45]3)=[O:27])=[CH:24][CH:23]=2)[N:8]1[C:6]([O:5][C:1]([CH3:4])([CH3:3])[CH3:2])=[O:7]
Reactant: c1cnn(C2CCNCC2)c1
Reactant: On1nnc2cccnc21
Reactant: CC(C)(C)OC(=O)N1[C@H](Cc2ccc(C(=O)O)cc2)CC[C@@H]1[C@H](O)c1ccccc1
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Solvent: ClCCCl
Product: CC(C)(C)OC(=O)N1[C@H](Cc2ccc(C(=O)N3CCCC(n4cccn4)C3)cc2)CC[C@@H]1[C@H](O)c1ccccc1
Temperature: 25 °C
Reaction time: 16 h
Yield: 81 %

Procedure:
To a solution of 4-{((2S,5R)-1-(tert-butoxycarbonyl)-5-[(R)-hydroxy(phenyl)methyl]pyrrolidin-2-yl)methyl}benzoic acid (82 mg, 0.2 mmol) and 4-(1H-pyrazol-1-yl)piperidine (30 mg, 0.2 mmol) in 1.5 mL anhydrous DMF was added a 0.5 M solution of HOAt in DMF (0.4 mL, 0.2 mmol) followed by EDC (78 mg, 0.4 mmol) and DIEA (70 μL, 0.4 mmol). The resulting mixture was stirred at RT under nitrogen atmosphere for 16 h. The mixture was washed with water and extracted with dichloromethane (2×5 mL). The organics were combined, dried over sodium sulfate, filtered and concentrated in vacuum. The residue was purified by preparative TLC plate (1000 uM) eluting with 5% MeOH in dichloromethane to afford the title compound (88 mg, 81%). ESI-MS calculated for C32H40N4O4: Exact Mass: 544.30. Found 545.30 (MH)4 and 567.28 (MNa)+,
Reaction SMILES: [CH:1]1[C:14]2[C:13](=[O:15])[C:12]3[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=3)[C:6](=[O:16])[C:5]=2[CH:4]=[CH:3][C:2]=1[C:17]([OH:19])=O.S(Cl)([Cl:22])=O>ClCCl>[CH:1]1[C:14]2[C:13](=[O:15])[C:12]3[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=3)[C:6](=[O:16])[C:5]=2[CH:4]=[CH:3][C:2]=1[C:17]([Cl:22])=[O:19]
Reactant: O=S(Cl)Cl
Reactant: O=C(O)c1ccc2c(c1)C(=O)c1ccccc1C2=O
Solvent: ClCCl
Product: O=C(Cl)c1ccc2c(c1)C(=O)c1ccccc1C2=O

Procedure:
Anthraquinone-2-carboxylic acid (2.52 g, 10 mmol) was suspended in dichloro methane (100 ml). Thionyl chloride (50 ml) was added and the mixture heated to reflux in a nitrogen atmosphere for several hours giving a clear yellow solution. Dichloro methane and excess thionyl chloride was removed in vacuo giving a yellow solid. The solid was filtered off, washed several times with petroleum ether and dried in vacuo. Yield 2.69 g (99% from anthraquinone-2-carboxylic acid); MP: 143-144.5° C.; TLC (analyzed as the methyl ester: a small sample of the acid chloride was dissolved in dry methanol and analyzed immediately using ethyl acetate as eluent); Rf =0.68. MS (FAB+): 307.1 (MH+).
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]([CH3:16])[CH:7]=[C:8]([N+:13]([O-])=O)[C:9]=1[C:10]([OH:12])=[O:11])([O-])=O.[H][H]>CO.[Pd]>[NH2:1][C:4]1[CH:5]=[C:6]([CH3:16])[CH:7]=[C:8]([NH2:13])[C:9]=1[C:10]([OH:12])=[O:11]
Reactant: Cc1cc([N+](=O)[O-])c(C(=O)O)c([N+](=O)[O-])c1
Reactant: [H][H]
Agent: [Pd]
Solvent: CO
Product: Cc1cc(N)c(C(=O)O)c(N)c1
Yield: 81 %

Procedure:
3,5-dinitro-p-toluic acid (10.0 gm.) is dissolved in methanol (300 ml.) and 5% palladium on charcoal (1.0 gm.) added. Reduction is carried out in a Parr apparatus for one hour at 40 psi of hydrogen. The product precipitates and the reaction mixture warmed until solution is complete. The catalyst is removed by filtration, washed with a few cc of methanol and the filtrate cooled to 0°. The product precipitates in fine needles and is collected by filtration, washed with a few ml. of methanol and dried (5.95 gm., 81% yield, m.p. 218°-220° dec.). The thin layer chromatogram (Silica gel, 5% methanol in chloroform) shows the material to be homogeneous.
Reaction SMILES: Br[CH:2]([CH:5]1[CH2:10][CH2:9][N:8]([C:11]([O:13][C:14]([CH3:17])([CH3:16])[CH3:15])=[O:12])[CH2:7][CH2:6]1)[CH:3]=O.[CH3:18][NH:19][C:20]([NH:22][CH3:23])=[S:21]>C(O)C>[CH3:23][N:22]1[CH:3]=[C:2]([CH:5]2[CH2:10][CH2:9][N:8]([C:11]([O:13][C:14]([CH3:17])([CH3:16])[CH3:15])=[O:12])[CH2:7][CH2:6]2)[S:21]/[C:20]/1=[N:19]\[CH3:18]
Reactant: CNC(=S)NC
Reactant: CC(C)(C)OC(=O)N1CCC(C(Br)C=O)CC1
Solvent: CCO
Product: C/N=c1\sc(C2CCN(C(=O)OC(C)(C)C)CC2)cn1C
Yield: 68 %

Procedure:
tert-Butyl 4-(1-bromo-2-oxoethyl)piperidine-1-carboxylate (WO 0059502: 21.0 g) and a solution of N,N′-dimethylthiourea (6.0 g) in ethanol (300 mL) were heated under reflux. The reaction solution was concentrated, and the residue was dissolved in ethyl acetate and water. The aqueous layer was collected by separation. The aqueous layer was basified with an aqueous potassium carbonate solution, and extracted with chloroform. The extract was dried over anhydrous sodium sulfate, and then the solvent was distilled off to give the title compound (12.2 g) as a pale yellow solid.
Reaction SMILES: C(OC([N:8]1[CH2:13][CH2:12][CH:11]([N:14]([CH2:17][C:18]2[CH:23]=[CH:22][CH:21]=[C:20]([C:24]3[CH:29]=[CH:28][N:27]=[C:26](Cl)[N:25]=3)[CH:19]=2)[CH2:15][CH3:16])[CH2:10][CH2:9]1)=O)(C)(C)C.[S:31]1[CH:35]=[CH:34][CH:33]=[C:32]1[CH2:36][CH2:37][NH2:38]>>[CH2:15]([N:14]([CH2:17][C:18]1[CH:19]=[C:20]([C:24]2[CH:29]=[CH:28][N:27]=[C:26]([NH:38][CH2:37][CH2:36][C:32]3[S:31][CH:35]=[CH:34][CH:33]=3)[N:25]=2)[CH:21]=[CH:22][CH:23]=1)[CH:11]1[CH2:10][CH2:9][NH:8][CH2:13][CH2:12]1)[CH3:16]
Reactant: CCN(Cc1cccc(-c2ccnc(Cl)n2)c1)C1CCN(C(=O)OC(C)(C)C)CC1
Reactant: NCCc1cccs1
Product: CCN(Cc1cccc(-c2ccnc(NCCc3cccs3)n2)c1)C1CCNCC1

Procedure:
Intermediate 84 was coupled with 2-thiophen-2-yl-ethylamine following procedure F. The product was deprotected following procedure G2. LC-MS showed the product had the expected M+H+ of 422.
Reaction SMILES: Cl.[NH2:2][C@H:3]1[CH2:8][CH2:7][C@H:6]([NH:9][C:10]([C:12]2[C:16]3=[N:17][CH:18]=[CH:19][C:20]([C:21]4[CH:26]=[C:25]([F:27])[CH:24]=[CH:23][C:22]=4[O:28][CH2:29][CH:30]4[CH2:32][CH2:31]4)=[C:15]3[NH:14][C:13]=2[CH3:33])=[O:11])[CH2:5][CH2:4]1.C([O:37][CH2:38][C:39](Cl)=[O:40])(=O)C>>[CH:30]1([CH2:29][O:28][C:22]2[CH:23]=[CH:24][C:25]([F:27])=[CH:26][C:21]=2[C:20]2[CH:19]=[CH:18][N:17]=[C:16]3[C:12]([C:10]([NH:9][C@H:6]4[CH2:7][CH2:8][C@H:3]([NH:2][C:38](=[O:37])[CH2:39][OH:40])[CH2:4][CH2:5]4)=[O:11])=[C:13]([CH3:33])[NH:14][C:15]=23)[CH2:31][CH2:32]1
Reactant: Cc1[nH]c2c(-c3cc(F)ccc3OCC3CC3)ccnc2c1C(=O)N[C@H]1CC[C@H](N)CC1
Reactant: CC(=O)OCC(=O)Cl
Agent: Cl
Product: Cc1[nH]c2c(-c3cc(F)ccc3OCC3CC3)ccnc2c1C(=O)N[C@H]1CC[C@H](NC(=O)CO)CC1

Procedure:
Starting from N-(trans-4-aminocyclohexyl)-7-[2-(cyclopropylmethoxy)-5-fluorophenyl]-2-methyl-1H-pyrrolo[3,2-b]pyridine-3-carboxamide hydrochloride (example D.f8) and commercially available 2-chloro-2-oxoethyl acetate the title compound is obtained as colorless solid.
Reaction SMILES: C[C@@:2]([N:12]1[CH:16]=[CH:15][N:14]=[C:13]1[NH:17][C:18](=[O:29])[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][C:20]=1[S:25]([OH:28])(=[O:27])=[O:26])([CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH3:11])[C:3]([O-:5])=[O:4].[K].[OH-].[Na+]>O.C(O)C>[S:25]([C:20]1[CH:21]=[CH:22][CH:23]=[CH:24][C:19]=1[C:18]([NH:17][C:13]1[N:12]([C@H:2]([CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH3:11])[C:3]([OH:5])=[O:4])[CH:16]=[CH:15][N:14]=1)=[O:29])([OH:28])(=[O:26])=[O:27]
Reactant: CCCCCC[C@](C)(C(=O)[O-])n1ccnc1NC(=O)c1ccccc1S(=O)(=O)O
Agent: [K]
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CCO
Product: CCCCCC[C@H](C(=O)O)n1ccnc1NC(=O)c1ccccc1S(=O)(=O)O
Reaction time: 3 h
Yield: 43.3 %

Procedure:
The potassium salt (22.5 g) was dissolved in a mixture of 200 mL H2O and 100 mL of ethanol. To this solution was added 1N NaOH (53 mL). The reaction was allowed to stir for 3 hours. Ethanol was then removed in vacuo, and the aqueous acidified to pH=1.5 with 5N HCl. This solution was extratced with 10% ethanol/ethyl acetate (3×200 mL). The organic was dried (Na2SO4) and concentrated in vacuo to give 8.65 g (46% for two steps) of (R)-[(2-sulfobenzoyl)amino-1H-imidazol-1-yl]-octanoic acid as a white solid. MS.
Reaction SMILES: [Br:1][CH:2]([C:6]12[CH2:15][CH:10]3[CH2:11][CH:12]([CH2:14][CH:8]([CH2:9]3)[CH2:7]1)[CH2:13]2)[C:3]([OH:5])=[O:4].[OH:16]S(O)(=O)=O.[N+]([O-])(O)=O>O>[Br:1][CH:2]([C:6]12[CH2:15][CH:10]3[CH2:11][CH:12]([CH2:14][C:8]([OH:16])([CH2:9]3)[CH2:7]1)[CH2:13]2)[C:3]([OH:5])=[O:4]
Reactant: O=S(=O)(O)O
Reactant: O=C(O)C(Br)C12CC3CC(CC(C3)C1)C2
Solvent: O
Solvent: O=[N+]([O-])O
Product: O=C(O)C(Br)C12CC3CC(CC(O)(C3)C1)C2
Temperature: 28 °C

Procedure:
α-Bromotricyclo[3.3.1.13,7]decane-1-acetic acid (Formula O) is then reacted with H2SO4 and HNO3 to produce α-bromo-3-hydroxytricyclo[3.3.1.13,7]decane-1-acetic acid (Formula Q). More specifically, α-bromo-3-hydroxytricyclo[3.3.1.13,7]decane-1-acetic acid (Formula Q) is prepared from α-bromotricyclo[3.3.1.13,7]decane-1-acetic acid (Formula O) by first charging an Erlen-Meyer flask with H2SO4. The flask is then cooled in an ice bath and 50% HNO3 is added to the flask. The solid α-bromotricyclo[3.3.1.13,7]decane-1-acetic acid (Formula O) is then added to the mixture in portions which maintain the temperature under 28° C. The reaction is then heated to 60° C. with stirring until a clear solution is obtained. When the reaction is complete, it is cooled to and maintained at room temperature. Water is then added to quench the reaction. The resulting slurry is cooled in an ice bath and then filtered to obtain α-bromo-3-hydroxytricyclo[3.3.1.13,7]decane-1-acetic acid (Formula Q). See also Example 18 herein.
Reaction SMILES: COC1C=C(OC)C=CC=1C[O:6][N:7]1[C:12](=[O:13])[C:11]2[O:14][C:15]3[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=3[C:10]=2[NH:9][C:8]1=[O:21].[CH2:28](Br)[C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1>>[CH2:28]([N:9]1[C:10]2[C:16]3[CH:17]=[CH:18][CH:19]=[CH:20][C:15]=3[O:14][C:11]=2[C:12](=[O:13])[N:7]([OH:6])[C:8]1=[O:21])[C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1
Reactant: COc1ccc(COn2c(=O)[nH]c3c(oc4ccccc43)c2=O)c(OC)c1
Reactant: BrCc1ccccc1
Product: O=c1c2oc3ccccc3c2n(Cc2ccccc2)c(=O)n1O

Procedure:
Following general procedure B2 and D1, 3-(2,4-Dimethoxy-benzyloxy)-1H-benzo[4,5]furo[3,2-d]pyrimidine-2,4-dione was alkylated with benzyl bromide and subsequently deprotected to provide the title compound as a white solid. 1H NMR (d6-DMSO, 300 MHz) δ 5.57 (s, 2H); 7.22-7.39 (m, 6H); 7.61 (dd, J=8 Hz, 1H); 7.78-7.82 (m, 2H); Ret. time=2.36 min., m/z=309.0.
Reaction SMILES: CS([C:5]1[N:10]=[C:9]([C:11]2[CH:16]=[CH:15][C:14]([S:17]([CH3:20])(=[O:19])=[O:18])=[CH:13][CH:12]=2)[CH:8]=[C:7]([C:21]([F:24])([F:23])[F:22])[N:6]=1)(=O)=O.[O:25]1[CH2:30][CH2:29][CH:28]([NH2:31])[CH2:27][CH2:26]1.O>CN1CCCC1=O>[CH3:20][S:17]([C:14]1[CH:15]=[CH:16][C:11]([C:9]2[CH:8]=[C:7]([C:21]([F:24])([F:23])[F:22])[N:6]=[C:5]([NH:31][CH:28]3[CH2:29][CH2:30][O:25][CH2:26][CH2:27]3)[N:10]=2)=[CH:12][CH:13]=1)(=[O:19])=[O:18]
Reactant: CS(=O)(=O)c1ccc(-c2cc(C(F)(F)F)nc(S(C)(=O)=O)n2)cc1
Reactant: NC1CCOCC1
Solvent: CN1CCCC1=O
Solvent: O
Product: CS(=O)(=O)c1ccc(-c2cc(C(F)(F)F)nc(NC3CCOCC3)n2)cc1
Reaction time: 1 h
Yield: 39.6 %

Procedure:
To a solution of 2-(methylsulfonyl)-4-[4-(methylsulfonyl)phenyl]-6-(trifluoromethyl)pyrimidine (0.277 g, 0.73 mmol) in N-methylpyrrolidone (1.25 ml) was added tetrahydro-2H-pyran-4-amine (0.147 g, 2 eq.), the mixture was stirred for 1 hour and then water (1.25 ml) was added dropwise. This resulted in a precipitate being formed, which was collected by filtration, and dried in vacuo (0.258 g). This material was then purified by autopurification to give the title compound as a colourless solid (0.116 g, 40%).
Reaction SMILES: Cl[C:2]1[C:8]([Cl:9])=[C:7]([CH3:10])[C:6]([Cl:11])=[C:5](Cl)[C:3]=1[NH2:4].C1(O)C=CC=CC=1.[H][H].Cl>[Pd].O.C1(C)C=CC=CC=1.[Ta]>[Cl:9][C:8]1[CH:2]=[C:3]([CH:5]=[C:6]([Cl:11])[C:7]=1[CH3:10])[NH2:4]
Reactant: Cc1c(Cl)c(Cl)c(N)c(Cl)c1Cl
Reactant: [H][H]
Agent: [Pd]
Agent: [Ta]
Agent: Cl
Solvent: Oc1ccccc1
Solvent: O
Solvent: Cc1ccccc1
Product: Cc1c(Cl)cc(N)cc1Cl
Yield: 98 %

Procedure:
61.5 parts of 2,3,5,6-tetrachloro-4-methylaniline, 180 parts of phenol and 15 parts of a 1% strength palladium/charcoal catalyst are reacted with hydrogen under a maximum pressure of 50 bar at 180° C. in a tantalum autoclave, in the presence of a small amount of hydrochloric acid, in the course of 5 hours, while stirring. After the pressurized vessel has been cooled and the pressure released, the mixture is diluted with 300 parts of water and 200 parts of toluene, rendered alkaline, heated to 90°, and separated from the catalyst. The catalyst is boiled up with toluene, and the combined toluene solutions are distilled. 44 parts of 3,5-dichloro-4-methylaniline, bp. 146°-155°/18 mbar, 98% strength, are obtained; yield: 98% of theory.
Reaction SMILES: [OH:1][C:2]1[N:3]=[C:4](SC)[N:5]([CH3:9])[C:6](=[O:8])[CH:7]=1.[CH3:12][OH:13].Cl>CCOCC>[OH:1][C:2]1[N:3]=[C:4]([O:13][CH3:12])[N:5]([CH3:9])[C:6](=[O:8])[CH:7]=1
Reactant: CO
Reactant: CSc1nc(O)cc(=O)n1C
Agent: Cl
Solvent: CCOCC
Product: COc1nc(O)cc(=O)n1C
Reaction time: 240 h
Yield: 40 %

Procedure:
A mixture of 172 g (1 mol) of 1,6-dihydro-4-hydroxy-1-methyl-2-methylthio-6-oxo-pyrimidine, 700 ml of methanol and 5 ml of a solution of hydrogen chloride in ether was boiled for 10 days under reflux. The reaction mixture was then filtered while still hot and the filtrate is evaporated in vacuo. The residue was triturated with ether and the crystalline product was filtered off. In this way, 71 g (40% of theory) of 1,6-dihydro-4-hydroxy-1-methyl-2-methoxy-6-oxo-pyrimidine were obtained in the form of colorless crystals of melting point 170°-171° C. ##STR11##
Reaction SMILES: Br[C:2]1[CH:3]=[CH:4][C:5]2[C:6]3[C:16](=[O:17])[NH:15][CH2:14][CH2:13][CH2:12][C:7]=3[N:8]([CH3:11])[C:9]=2[CH:10]=1.[F:18][C:19]1[CH:20]=[CH:21][C:22]([CH2:25][O:26][C:27]2[CH:32]=[CH:31][NH:30][C:29](=[O:33])[CH:28]=2)=[N:23][CH:24]=1>>[F:18][C:19]1[CH:20]=[CH:21][C:22]([CH2:25][O:26][C:27]2[CH:32]=[CH:31][N:30]([C:2]3[CH:3]=[CH:4][C:5]4[C:6]5[C:16](=[O:17])[NH:15][CH2:14][CH2:13][CH2:12][C:7]=5[N:8]([CH3:11])[C:9]=4[CH:10]=3)[C:29](=[O:33])[CH:28]=2)=[N:23][CH:24]=1
Reactant: O=c1cc(OCc2ccc(F)cn2)cc[nH]1
Reactant: Cn1c2c(c3ccc(Br)cc31)C(=O)NCCC2
Product: Cn1c2c(c3ccc(-n4ccc(OCc5ccc(F)cn5)cc4=O)cc31)C(=O)NCCC2
Yield: 21.8 %

Procedure:
8-Bromo-6-methyl-2,3,4,5-tetrahydroazepino[4,3-b]indol-1(6H)-one (100 mg, 0.340 mmol) and 4-((5-fluoropyridin-2-yl)methoxy)pyridin-2(1H)-one (102 mg, 0.510 mmol) were reacted following the procedure for Example 2 (step d) to provide the title compound (32 mg, 21%) as a white solid: 1H NMR (300 MHz, DMSO-d6) δ 8.53 (d, J=8.6 Hz, 1H), 8.48 (s, 1H), 7.51-7.46 (m, 2H), 7.37-7.31 (m, 2H), 7.13-7.17 (dd, J=8.5, 1.8 Hz, 1H), 6.12-6.03 (m, 2H), 5.93-5.86 (m, 1H), 5.17 (s, 2H), 3.66 (s, 3H), 3.42-3.34 (m, 2H), 3.09 (t, J=6.8 Hz, 2H), 2.28-2.19 (m, 2H); ESI MS m/z 433 [M+H]+; HPLC (Method B) 98.7% (AUC), tR=13.8 min.
Reaction SMILES: [NH2:1][CH:2]1[CH2:7][CH2:6][N:5]([C:8]2[C:9]3[CH:31]=[C:30]([Cl:32])[CH:29]=[CH:28][C:10]=3[N:11]([CH3:27])[C:12](=[O:26])[CH:13]([CH2:15][C:16]3[CH:25]=[CH:24][C:23]4[C:18](=[CH:19][CH:20]=[CH:21][CH:22]=4)[CH:17]=3)[N:14]=2)[CH2:4][CH2:3]1.C(N(CC)CC)C.[C:40](Cl)(=[O:47])[C:41]1[CH:46]=[CH:45][CH:44]=[CH:43][CH:42]=1>ClCCl>[Cl:32][C:30]1[CH:29]=[CH:28][C:10]2[N:11]([CH3:27])[C:12](=[O:26])[CH:13]([CH2:15][C:16]3[CH:25]=[CH:24][C:23]4[C:18](=[CH:19][CH:20]=[CH:21][CH:22]=4)[CH:17]=3)[N:14]=[C:8]([N:5]3[CH2:4][CH2:3][CH:2]([NH:1][C:40](=[O:47])[C:41]4[CH:46]=[CH:45][CH:44]=[CH:43][CH:42]=4)[CH2:7][CH2:6]3)[C:9]=2[CH:31]=1
Reactant: CN1C(=O)C(Cc2ccc3ccccc3c2)N=C(N2CCC(N)CC2)c2cc(Cl)ccc21
Reactant: O=C(Cl)c1ccccc1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CN1C(=O)C(Cc2ccc3ccccc3c2)N=C(N2CCC(NC(=O)c3ccccc3)CC2)c2cc(Cl)ccc21
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 57.7 %

Procedure:
5-(4-Aminopiperidin-1-yl)-7-chloro-1-methyl-3-(naphthalen-2-ylmethyl)-1H-benzo[e][1,4]diazepin-2(3H)-one (50 mg, 0.11 mmol) was dissolved in dichloromethane (2 mL) and triethylamine (31 μL, 0.22 mmol), a solution of benzoyl chloride (10 μL, 0.11 mmol) in dichloromethane (0.2 mL) was added dropwise, and stirred at ambient temperature for 30 minutes. To the solution was added silica gel and the mixture was concentrated. Column chromatography eluting with a gradient of 50-100% ethyl acetate in hexanes provided N-(1-(7-chloro-1-methyl-3-(naphthalen-2-ylmethyl)-2-oxo-2,3-dihydro-1H-benzo[e][1,4]diazepin-5-yl)piperidin-4-yl)benzamide (35 mg, 57% yield). ESI m/z measured 551.2224 [M+H]+. calculated 551.2214.
Reaction SMILES: [OH:1][C:2]1[CH:15]=[C:14]([OH:16])[CH:13]=[CH:12][C:3]=1[C:4]([C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1)=[O:5].N1C=CC=CC=1.CCOCC.[C:28]([N:32]=[N:33][C:34]([C:41]#[N:42])([CH3:40])[CH2:35][CH2:36][C:37](Cl)=[O:38])([CH3:31])([CH3:30])[CH3:29]>O>[C:28]([N:32]=[N:33][C:34]([C:41]#[N:42])([CH3:40])[CH2:35][CH2:36][C:37]([O:16][C:14]1[CH:13]=[CH:12][C:3]([C:4]([C:6]2[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=2)=[O:5])=[C:2]([OH:1])[CH:15]=1)=[O:38])([CH3:31])([CH3:29])[CH3:30]
Reactant: O=C(c1ccccc1)c1ccc(O)cc1O
Reactant: CC(C)(C)N=NC(C)(C#N)CCC(=O)Cl
Solvent: O
Solvent: c1ccncc1
Solvent: CCOCC
Product: CC(C)(C)N=NC(C)(C#N)CCC(=O)Oc1ccc(C(=O)c2ccccc2)c(O)c1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 99 %

Procedure:
To a solution of 4.7 g. (0.022 m) of 2,4-dihydroxybenzophenone and 2.5 ml. of pyridine in 35 ml. of ether in a 4 neck 100 ml. round bottom flask containing a thermometer, condenser and magnetic stirring bar was added 4.0 g. (0.0218 m) of 4-t-butylazo-4-cyanovaleryl chloride dropwise with cooling so the temperature did not rise above 25° C. After completion of the addition the reaction mixture was stirred 1/2 hour at room temperature and then diluted with 100 ml. of water. The ether layer was separated, washed consecutively with 5% HCl, water, and 10% NaHCO3 solution and saturated sodium chloride solution. The ether was evaporated off and the residue dissolved in methylene chloride, dried over anhydrous sodium sulfate, filtered and the methylene chloride stripped off under reduced pressure. The product weighted 8.8 g. (99% yield) and was a viscous syrup. The infrared spectrum was in agreement with the structure of the desired product.
Reaction SMILES: [CH2:1]([O:8][C@H:9]1[C@@H:14]([NH:15][C:16]([C:18]2[NH:19][CH:20]=[CH:21][N:22]=2)=[O:17])[CH2:13][CH2:12][N:11]([C:23]2[S:24][C:25]([C:28]([O:30]CC)=[O:29])=[CH:26][N:27]=2)[CH2:10]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[OH-].[Li+]>CO.ClCCl>[CH2:1]([O:8][C@H:9]1[C@@H:14]([NH:15][C:16]([C:18]2[NH:22][CH:21]=[CH:20][N:19]=2)=[O:17])[CH2:13][CH2:12][N:11]([C:23]2[S:24][C:25]([C:28]([OH:30])=[O:29])=[CH:26][N:27]=2)[CH2:10]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CCOC(=O)c1cnc(N2CC[C@H](NC(=O)c3ncc[nH]3)[C@H](OCc3ccccc3)C2)s1
Agent: [Li+]
Agent: [OH-]
Solvent: CO
Solvent: ClCCl
Product: O=C(N[C@H]1CCN(c2ncc(C(=O)O)s2)C[C@H]1OCc1ccccc1)c1ncc[nH]1
Temperature: 70 °C
Reaction time: 0.33 h
Yield: 63.8 %

Procedure:
Ethyl cis(±)-2-{3-(benzyloxy)-4-[(1H-imidazol-2-ylcarbonyl)amino]piperidin-1-yl}-1,3-thiazole-5-carboxylate obtained in Example (90f) (0.25 g, 0.55 mmol) was dissolved in methanol (5 mL) and dichloromethane (1 mL). A 2 N aqueous lithium hydroxide solution (5 mL, 10 mmol) was added, and the mixture was stirred at 70° C. for 20 minutes. The organic solvent was evaporated under reduced pressure, and 1 N hydrochloric acid was added until the pH of the solution was about 4. Purification by reverse phase chromatography (elution solvent: acetonitrile/water=1/1, 4/1) gave 0.15 g of the title compound as a white solid (66%).
Reaction SMILES: C([O:8][C:9]1[CH:16]=[CH:15][C:12]([C:13]#[N:14])=[CH:11][C:10]=1[O:17][CH2:18][CH2:19][CH2:20][CH2:21][O:22]CC1C=CC=CC=1)C1C=CC=CC=1>FC(F)(F)C(O)=O.CSC.O>[OH:8][C:9]1[CH:16]=[CH:15][C:12]([C:13]#[N:14])=[CH:11][C:10]=1[O:17][CH2:18][CH2:19][CH2:20][CH2:21][OH:22]
Reactant: N#Cc1ccc(OCc2ccccc2)c(OCCCCOCc2ccccc2)c1
Solvent: O=C(O)C(F)(F)F
Solvent: O
Solvent: CSC
Product: N#Cc1ccc(O)c(OCCCCO)c1
Temperature: 25 °C
Reaction time: 18 h
Yield: 46.7 %

Procedure:
4-Benzyloxy-3-(4-benzyloxybutoxy)benzonitrile (4.0 g) was dissolved in a mixed solvent of trifluoroacetic acid (9 mL), dimethylsulfide (0.5 mL) and water (5 mL), and the mixture was stirred at room temperature for 18 hours. The solvent was removed under reduced pressure, and the obtained residue was purified by column chromatography on silica gel (eluent: ethyl acetate/hexane=1/5) to give the title compound (1.0 g).