Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C([S:9][CH2:10][CH2:11][C:12]([NH:14][C:15]([CH3:20])([CH3:19])[C:16]([OH:18])=[O:17])=[O:13])(=O)C1C=CC=CC=1.[OH-].[NH4+]>O>[SH:9][CH2:10][CH2:11][C:12]([NH:14][C:15]([CH3:20])([CH3:19])[C:16]([OH:18])=[O:17])=[O:13]
Reactant: CC(C)(NC(=O)CCSC(=O)c1ccccc1)C(=O)O
Agent: [NH4+]
Agent: [OH-]
Solvent: O
Product: CC(C)(NC(=O)CCS)C(=O)O

Procedure:
2.8 g. of the product of Example 1 is treated with a mixture of 20 ml. water and 20 ml. of concentrated ammonium hydroxide solution under an argon blanket for one hour. The benzmide precipitate is filtered and the filtrate is extracted twice with ethyl acetate. The aqueous phase is concentrated in vacuo, acidified with concentrated hydrochloric acid and extracted with ethyl acetate. The organic layer is dried and concentrated to dryness in vacuo and the residual product 2-[(3-mercaptopropanoyl)amino]-2-methylpropanoic acid, is crystallized from acetonitrile, yield 1.2 g., m.p. 169°-170°.
Reaction SMILES: [C:1]([NH:5][S:6]([C:9]1[C:10]([C:15]2[CH:20]=[CH:19][C:18](B3OC(C)(C)C(C)(C)O3)=[C:17]([F:30])[CH:16]=2)=[CH:11][CH:12]=[CH:13][CH:14]=1)(=[O:8])=[O:7])([CH3:4])([CH3:3])[CH3:2].[NH2:31][C:32]1[N:37]=[C:36]([C:38]#[N:39])[C:35](Br)=[CH:34][CH:33]=1>>[NH2:31][C:32]1[N:37]=[C:36]([C:38]#[N:39])[C:35]([C:18]2[CH:19]=[CH:20][C:15]([C:10]3[C:9]([S:6]([NH:5][C:1]([CH3:2])([CH3:3])[CH3:4])(=[O:7])=[O:8])=[CH:14][CH:13]=[CH:12][CH:11]=3)=[CH:16][C:17]=2[F:30])=[CH:34][CH:33]=1
Reactant: N#Cc1nc(N)ccc1Br
Reactant: CC(C)(C)NS(=O)(=O)c1ccccc1-c1ccc(B2OC(C)(C)C(C)(C)O2)c(F)c1
Product: CC(C)(C)NS(=O)(=O)c1ccccc1-c1ccc(-c2ccc(N)nc2C#N)c(F)c1

Procedure:
The title compound was prepared using analogous conditions to those described in Example 6 utilizing N-(tert-butyl)-3′-fluoro-4′-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-[1,1′-biphenyl]-2-sulfonamide and 6-amino-3-bromo-2-cyanopyridine. MS (ESI): mass calcd. for C22H21FN4O2S, 424.14; m/z found, 424.9 [M+H]+. 1H NMR (500 MHz, DMSO-d6) δ 8.11-8.04 (d, J=7.9, 1H), 7.71-7.64 (m, 1H), 7.64-7.58 (m, 2H), 7.54-7.48 (m, 1H), 7.45-7.36 (dd, J=19.2, 9.2, 2H), 7.36-7.30 (dd, J=7.9, 1.6, 1H), 6.89-6.83 (d, J=8.7, 1H), 6.83-6.75 (d, J=10.0, 3H), 1.03 (s, 9H).
Reaction SMILES: CC1C=C[C:5]([S:8]([N-]Cl)(=O)=O)=CC=1.O.O.O.[Na+].Cl.[Br:18][C:19]1[C:20]([NH:34][CH:35]([CH3:37])[CH3:36])=[N:21][C:22]([NH:25][C:26]2[CH:31]=[CH:30][C:29](C)=[CH:28][C:27]=2S)=[N:23][CH:24]=1>C(#N)C.C(OCC)(=O)C>[Br:18][C:19]1[C:20]([NH:34][CH:35]([CH3:37])[CH3:36])=[N:21][C:22]([NH:25][C:26]2[CH:31]=[CH:30][C:29]([S:8][CH3:5])=[CH:28][CH:27]=2)=[N:23][CH:24]=1
Reactant: Cc1ccc(S(=O)(=O)[N-]Cl)cc1
Reactant: Cc1ccc(Nc2ncc(Br)c(NC(C)C)n2)c(S)c1
Agent: Cl
Agent: [Na+]
Solvent: O
Solvent: CC#N
Solvent: CCOC(C)=O
Product: CSc1ccc(Nc2ncc(Br)c(NC(C)C)n2)cc1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
1.36 g (4.8 mmol) of chloramine-T trihydrate (Aldrich) are added to a suspension of 1.56 g (4.0 mmol) of the hydrochloride of 5-bromo-N4-isopropyl-N2-(4-methyl-sulphanylphenyl)pyrimidine-2,4-diamine in 20 ml of acetonitrile at room temperature. The mixture is stirred at room temperature for 16 hours and then diluted with ethyl acetate. The mixture is filtered with suction and the filter cake is washed with ethyl acetate. The combined organic phases are dried (Na2SO4), filtered and concentrated. The resulting residue is purified by HPLC:
Reaction SMILES: [S:1]1[C:5](=[O:6])[CH2:4][C:3]2[CH:7]=[CH:8][CH:9]=[CH:10][C:2]1=2.[H-].[Na+].CCCCCC.[S:19]1[CH:23]=[CH:22][CH:21]=[C:20]1[CH2:24][C:25](Cl)=[O:26]>O=P(N(C)C)(N(C)C)N(C)C>[OH:6][C:5]1[S:1][C:2]2[CH:10]=[CH:9][CH:8]=[CH:7][C:3]=2[C:4]=1[C:25](=[O:26])[CH2:24][C:20]1[S:19][CH:23]=[CH:22][CH:21]=1
Reactant: O=C1Cc2ccccc2S1
Reactant: O=C(Cl)Cc1cccs1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)P(=O)(N(C)C)N(C)C
Solvent: CCCCCC
Product: O=C(Cc1cccs1)c1c(O)sc2ccccc12

Procedure:
In a sulfonating flask under a nitrogen atmosphere, 15 g of benzo[b]thiophene-2(3H)-one (100 mmol) are dissolved in 150 ml of distilled hexametapol. The light-yellow solution is cooled to 5°. 8.9 g of a sodium hydride suspension (55%) that has been de-oiled with n-hexane are then added in portions while stirring. The resulting suspension is stirred for 15 minutes at 20°, during which time the evolution of gas is observed. The suspension is then cooled to -10°and 17.65 g of 2-(2-thienyl)-acetic acid chloride are added, the internal temperature being maintained at below 0°. After the cooling has been removed, the mixture is stirred for 1 hour. The reaction mixture is poured onto 2 liters of ice-water and 60 ml of 2N hydrochloric acid, and then 500 ml of toluene are added. The separated organic phase is extractedtwice with water and then three times using 200 ml of 5% soda solution eachtime. The alkaline phase is filtered and poured onto ice and 2N hydrochloric acid, and the crystals that are formed are filtered off and dried. Chromatography over silica gel and recrystallisation from methanol yield 2-hydroxy-3-[2-(2-thienyl)-acetyl]-benzo[b]thiophene, ##STR7##
Reaction SMILES: [C:1]([CH2:8][N:9]1[CH2:20][CH2:19][N:18]2[CH2:21][CH2:22][CH2:23][N:12]([CH2:13][CH2:14][N:15]([CH2:24][C:25]([O:27]C(C)(C)C)=[O:26])[CH2:16][CH2:17]2)[CH2:11][CH2:10]1)([O:3]C(C)(C)C)=[O:2]>Cl>[C:25]([CH2:24][N:15]1[CH2:14][CH2:13][N:12]2[CH2:23][CH2:22][CH2:21][N:18]([CH2:19][CH2:20][N:9]([CH2:8][C:1]([OH:3])=[O:2])[CH2:10][CH2:11]2)[CH2:17][CH2:16]1)([OH:27])=[O:26]
Reactant: CC(C)(C)OC(=O)CN1CCN2CCCN(CC1)CCN(CC(=O)OC(C)(C)C)CC2
Agent: Cl
Product: O=C(O)CN1CCN2CCCN(CC1)CCN(CC(=O)O)CC2
Temperature: 100 °C
Reaction time: 24 h
Yield: 141.5 %

Procedure:
Compound 5 (1.12 g, 2.54 mmol) was dissolved in 6 N HCl (60 mL), and slowly heated to 100° C. with stirring for 24 hours. After evaporation of all the solvents, the crude product was recrystallized from ethanol/diethyl ether to give white solid 6 (1.18 g, 98% yield) (4 equiv HCl calculated on the basis of mass).
Reaction SMILES: [CH2:1]([O:8][C:9]1[C:18](=[O:19])[N:17]2[C:12]([CH:13]([CH3:20])[O:14][CH2:15][CH2:16]2)=[N:11][C:10]=1[C:21]([OH:23])=O)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.FC(F)(F)C(O)=O.[NH2:31][CH2:32][C:33]1[CH:42]=[CH:41][C:40]([F:43])=[CH:39][C:34]=1[C:35]([NH:37][CH3:38])=[O:36].C(N(CC)CC)C.F[P-](F)(F)(F)(F)F.N1(O[P+](N2CCCC2)(N2CCCC2)N2CCCC2)C2C=CC=CC=2N=N1>ClCCl.C(OCC)(=O)C>[F:43][C:40]1[CH:41]=[CH:42][C:33]([CH2:32][NH:31][C:21]([C:10]2[N:11]=[C:12]3[N:17]([C:18](=[O:19])[C:9]=2[O:8][CH2:1][C:2]2[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=2)[CH2:16][CH2:15][O:14][CH:13]3[CH3:20])=[O:23])=[C:34]([C:35](=[O:36])[NH:37][CH3:38])[CH:39]=1
Reactant: CC1OCCn2c1nc(C(=O)O)c(OCc1ccccc1)c2=O
Reactant: CNC(=O)c1cc(F)ccc1CN
Agent: F[P-](F)(F)(F)(F)F
Agent: c1ccc2c(c1)nnn2O[P+](N1CCCC1)(N1CCCC1)N1CCCC1
Solvent: O=C(O)C(F)(F)F
Solvent: CCOC(C)=O
Solvent: ClCCl
Product: CNC(=O)c1cc(F)ccc1CNC(=O)c1nc2n(c(=O)c1OCc1ccccc1)CCOC2C
Reaction time: 3 h
Yield: 100.2 %

Procedure:
A mixture of intermediate 27, 3-benzyloxy-9-methyl-4-oxo-4,6,7,9-tetrahydropyrimido[2,1-c][1,4]oxazine-2-carboxylic acid (0.172 g, 0.54 mmol) and intermediate 39, 2-(aminomethyl)-5-fluoro-N-methylbenzamide trifluoroacetate salt (0.177 g, 0.60 mmol) in dichloromethane (10 ml) was treated at 22° C. with triethylamine (0.17 ml, 1.22 mmol) followed by benzotriazole-1-yloxy-tris-pyrrolidino-phosphonium hexafluorophosphate (PyBOP) (0.340 g, 0.65 mmol). After 3 h, the reaction mixture was diluted with ethyl acetate, washed with saturated sodium bicarbonate and brine then dried over anhydrous magnesium sulfate. Evaporation of the solvent followed by chromatography of the residue on silica gel (elution gradient ethyl acetate 50-100% in toluene) gave 0.260 g (100% yield) of the title amide as a white solid. 1HNMR 400 MHz (CDCl3) δ (ppm): 1.70 (3H, d, J=6.6 Hz, CH3), 3.01 (3H, d, J=4.7 Hz, NCH3), 3.89 (2H, m, CH2), 4.14 (1H, m, CH), 4.29 (1H, m, CH), 4.53 (2H, d, J=6.7 Hz, NCH2), 4.69 (1H, q, J=6.6 Hz, OCH), 5.35 (2H, s, OCH2), 6.69 (1H, broad q, NH), 7.09 (1H, m, aromatic), 7.16 (1H, m, aromatic), 7.32 (3H, m, aromatics), 7.42 (1H, m, aromatic), 7.47 (2H, m, aromatics), 8.61 (1H, broad t, NH). HRMS (ESI+) calculated for C25H26FN4O5 [M+H+]: 481.1887: found: 481.1884.
Reaction SMILES: [NH2:1][C:2]1[C:3]2[S:10][CH:9]=[C:8](/[CH:11]=[CH:12]/[C:13]3[CH:14]=[C:15]([CH:19]=[CH:20][C:21]=3[CH3:22])[C:16]([OH:18])=O)[C:4]=2[N:5]=[CH:6][N:7]=1.[F:23][C:24]([F:33])([F:32])[C:25]1[CH:26]=[C:27]([NH2:31])[CH:28]=[CH:29][CH:30]=1.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F>CN(C=O)C.C(OCC)(=O)C>[NH2:1][C:2]1[C:3]2[S:10][CH:9]=[C:8](/[CH:11]=[CH:12]/[C:13]3[CH:14]=[C:15]([CH:19]=[CH:20][C:21]=3[CH3:22])[C:16]([NH:31][C:27]3[CH:28]=[CH:29][CH:30]=[C:25]([C:24]([F:23])([F:32])[F:33])[CH:26]=3)=[O:18])[C:4]=2[N:5]=[CH:6][N:7]=1
Reactant: Nc1cccc(C(F)(F)F)c1
Reactant: Cc1ccc(C(=O)O)cc1/C=C/c1csc2c(N)ncnc12
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: Cc1ccc(C(=O)Nc2cccc(C(F)(F)F)c2)cc1/C=C/c1csc2c(N)ncnc12
Temperature: 25 °C
Reaction time: 18 h
Yield: 82.5 %

Procedure:
(E)-3-(2-(4-aminothieno[3,2-d]pyrimidine-7-yl)vinyl)-4-methylbenzoic acid (30 mg, 0.096 mmol) was dissolved in DMF (1 mL), 3-(trifluoromethyl)benzeneamine (16 mg, 0.096 mmol), HATU (110 mg, 0.289 mmol) and TEA (67 μL, 0.48 mmol) was added thereto and stirred at room temperature for 18 hours. The reaction mixture was diluted with ethyl acetate and washed with brine. The organic layer was dried with MgSO4, filtered and concentrated. The resulting mixture was purified by silica gel chromatography to obtain the title compound (36 mg, 82% yield).
Reaction SMILES: [C:1]([C:6]1([S:12][CH2:13][C:14]2[CH:19]=[CH:18][C:17]([O:20][CH3:21])=[CH:16][CH:15]=2)[CH2:11][CH2:10][CH2:9][CH2:8][CH2:7]1)([O:3]CC)=[O:2].[OH-].[Na+].C(O)C.O.[OH-].[Li+]>O.O1CCCC1>[C:1]([C:6]1([S:12][CH2:13][C:14]2[CH:19]=[CH:18][C:17]([O:20][CH3:21])=[CH:16][CH:15]=2)[CH2:11][CH2:10][CH2:9][CH2:8][CH2:7]1)([OH:3])=[O:2]
Reactant: CCOC(=O)C1(SCc2ccc(OC)cc2)CCCCC1
Agent: [Li+]
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CCO
Solvent: O
Product: COc1ccc(CSC2(C(=O)O)CCCCC2)cc1
Temperature: 60 °C

Procedure:
Dissolve 1-(carboethoxy)-1-(4-methoxybenzylthio)cyclohexane (1.45 g, 4.7 mmol) in water (2.5 mL) and tetrahydrofuran (10 mL). Treat with 2.5N sodium hydroxide (4 mL, 10 mmol). Heat at 60° C. for 2 hours, add 95% ethanol (10 mL) and lithium hydroxide monohydrate (0.42 g, 10 mmol) Heat to a gentle reflux for 20 hours, cool and evaporate the solvent in vacuo. Partition between water (50 mL) and ether (50 mL). Separate the aqueous phase and acidify to pH 1. Extract with methylene chloride (50 mL), dry (Na2SO4) and evaporate the solvent in vacuo to give 1-(carboxy)-1-(4-methoxybenzylthio)cyclohexane as a white solid (l.21 g, 92%).
Reaction SMILES: [NH2:1][CH2:2][C:3]1[CH:32]=[CH:31][C:6]([C:7]([N:9]([CH2:14][CH2:15][N:16]2[CH2:21][CH2:20][CH:19]([C:22](=[O:30])[C:23]3[CH:28]=[CH:27][C:26]([F:29])=[CH:25][CH:24]=3)[CH2:18][CH2:17]2)[CH2:10][CH2:11][O:12][CH3:13])=[O:8])=[CH:5][CH:4]=1.[C:33]([NH:40][C@H:41]([C:43](O)=[O:44])[CH3:42])([O:35][C:36]([CH3:39])([CH3:38])[CH3:37])=[O:34].CCN=C=NCCCN(C)C.Cl.C(=O)(O)[O-].[Na+]>C(Cl)Cl.O>[C:36]([O:35][C:33]([NH:40][C@@H:41]([CH3:42])[C:43]([NH:1][CH2:2][C:3]1[CH:4]=[CH:5][C:6]([C:7]([N:9]([CH2:14][CH2:15][N:16]2[CH2:17][CH2:18][CH:19]([C:22](=[O:30])[C:23]3[CH:24]=[CH:25][C:26]([F:29])=[CH:27][CH:28]=3)[CH2:20][CH2:21]2)[CH2:10][CH2:11][O:12][CH3:13])=[O:8])=[CH:31][CH:32]=1)=[O:44])=[O:34])([CH3:39])([CH3:38])[CH3:37]
Reactant: C[C@H](NC(=O)OC(C)(C)C)C(=O)O
Reactant: COCCN(CCN1CCC(C(=O)c2ccc(F)cc2)CC1)C(=O)c1ccc(CN)cc1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: O=C([O-])O
Solvent: ClCCl
Solvent: O
Product: COCCN(CCN1CCC(C(=O)c2ccc(F)cc2)CC1)C(=O)c1ccc(CNC(=O)[C@H](C)NC(=O)OC(C)(C)C)cc1
Reaction time: 4 h
Yield: 72.6 %

Procedure:
4-Aminomethyl-N-{2-[4-(4-fluorobenzoyl)piperidino]ethyl}-N-(2-methoxyethyl)benzamide (120 mg, 0.245 mmol) was dissolved in methylene chloride (5 ml) to which were subsequently added Boc-L-alanine (46.4 mg, 0.245 mmol) and EDC hydrochloride (52 mg, 0.270 mmol) while cooling in an ice bath. After 4 hours of stirring at the same temperature, the reaction solution was mixed with water (10 ml), adjusted to pH 8 with saturated sodium bicarbonate aqueous solution and then extracted with methylene chloride. Thereafter, the resulting organic layer was dried on anhydrous sodium carbonate, the solvent was removed by evaporation, and the resulting residue was purified by a silica gel column chromatography (ethyl acetate) to obtain 109 mg (68.9%) of the title compound in a colorless amorphous form.
Reaction SMILES: [CH3:1][C:2]1[N:3]=[C:4]([NH:7][C:8]([C:10]2[CH:15]=[C:14](B3OC(C)(C)C(C)(C)O3)[CH:13]=[C:12]([CH3:25])[N:11]=2)=[O:9])[S:5][CH:6]=1.Br[C:27]1[CH:32]=[C:31]([CH3:33])[N:30]=[C:29]([C:34]#[N:35])[CH:28]=1>>[CH3:1][C:2]1[N:3]=[C:4]([NH:7][C:8]([C:10]2[CH:15]=[C:14]([C:27]3[CH:28]=[C:29]([C:34]#[N:35])[N:30]=[C:31]([CH3:33])[CH:32]=3)[CH:13]=[C:12]([CH3:25])[N:11]=2)=[O:9])[S:5][CH:6]=1
Reactant: Cc1cc(Br)cc(C#N)n1
Reactant: Cc1cc(B2OC(C)(C)C(C)(C)O2)cc(C(=O)Nc2nc(C)cs2)n1
Product: Cc1cc(-c2cc(C)nc(C(=O)Nc3nc(C)cs3)c2)cc(C#N)n1

Procedure:
The title compound, was prepared from 6-Methyl-4-(4,4,5,5-tetramethyl-[1,3,2]dioxa-borolan-2-yl)-pyridine-2-carboxylic acid (4-methyl-thiazol-2-yl)-amide in accordance with the general method of example 131, step 2 using 4-Bromo-6-methyl-pyridine-2-carbonitrile instead of 3-Trifluoromethyl-5-bromopyridine to yield the final compound as a yellow solid, MS (ISP): m/e=350.3 (M+H)+.
Reaction SMILES: Cl[C:2]1[N:3]=[CH:4][C:5]2[C:10]([CH:11]=1)=[C:9]([C:12]1[CH:13]=[N:14][N:15]([CH3:17])[CH:16]=1)[CH:8]=[CH:7][CH:6]=2.[CH3:18][O:19][C:20]1[CH:26]=[C:25]([O:27][CH:28]2[CH2:33][CH2:32][N:31]([CH3:34])[CH2:30][CH2:29]2)[CH:24]=[CH:23][C:21]=1[NH2:22]>>[CH3:18][O:19][C:20]1[CH:26]=[C:25]([O:27][CH:28]2[CH2:33][CH2:32][N:31]([CH3:34])[CH2:30][CH2:29]2)[CH:24]=[CH:23][C:21]=1[NH:22][C:2]1[N:3]=[CH:4][C:5]2[C:10]([CH:11]=1)=[C:9]([C:12]1[CH:13]=[N:14][N:15]([CH3:17])[CH:16]=1)[CH:8]=[CH:7][CH:6]=2
Reactant: COc1cc(OC2CCN(C)CC2)ccc1N
Reactant: Cn1cc(-c2cccc3cnc(Cl)cc23)cn1
Product: COc1cc(OC2CCN(C)CC2)ccc1Nc1cc2c(-c3cnn(C)c3)cccc2cn1
Yield: 5 %

Procedure:
The title compound was prepared according to Method 3 (Example 27) using 3-Chloro-5-(1-methyl-1H-pyrazol-4-yl)isoquinoline (Preparation 7) and 2-methoxy-4-(1-methylpiperidin-4-yloxy)aniline at 100° C. for 3 hours. The reaction mixture was concentrated onto silica gel in vacuo and purified by silica gel column chromatography eluting with 0-100% EtOAc in cyclohexane followed by 0-10% MeOH in CH2Cl2 and finally eluting with 10% 1M NH3/MeOH in DCM to afford the title compound (5 mg, 5%).
Reaction SMILES: C[O:2][C:3](=[O:13])[CH2:4][CH2:5][N:6]([CH3:12])[CH2:7][CH2:8][CH2:9][CH2:10][CH3:11].Br.[ClH:15]>O>[CH3:12][N:6]([CH2:7][CH2:8][CH2:9][CH2:10][CH3:11])[CH2:5][CH2:4][C:3]([OH:13])=[O:2].[ClH:15]
Reactant: CCCCCN(C)CCC(=O)OC
Agent: Br
Agent: Cl
Solvent: O
Product: CCCCCN(C)CCC(=O)O

Procedure:
The hydrolysis can be performed by refluxing the N-methyl-N-pentyl-β-alanine methyl ester in a diluted mineral acid, but can also be performed by refluxing in water at least until no ester can be detected any further. Formation of the hydrohalogenide such as the hydrobromide or the hydrochloride, preferably of the hydrochloride (X═Cl) can be effected by addition of an aqueous solution of the appropriate mineral acid. The resulting N-methyl-N-pentyl-β-alanine hydrohalogenide, e.g., hydrochloride, can be isolated by distilling of the water and by a crystallization of the residue in a suitable solvent such as toluene/acetone or methyl ethyl ketone, preferably in methyl ethyl ketone.
Reaction SMILES: [O:1]=[S:2]1(=[O:16])[C:8]2[CH:9]=[CH:10][CH:11]=[CH:12][C:7]=2[CH2:6][N:5]([C:13](=O)[CH3:14])[CH2:4][CH2:3]1.P(Cl)(Cl)(Cl)=O.[NH2:22][C:23]1[CH:30]=[CH:29][C:28]([CH3:31])=[CH:27][C:24]=1[C:25]#[N:26].C(=O)(O)[O-].[Na+]>ClCCl.O>[O:1]=[S:2]1(=[O:16])[C:8]2[CH:9]=[CH:10][CH:11]=[CH:12][C:7]=2[CH2:6][N:5](/[C:13](=[N:22]/[C:23]2[CH:30]=[CH:29][C:28]([CH3:31])=[CH:27][C:24]=2[C:25]#[N:26])/[CH3:14])[CH2:4][CH2:3]1
Reactant: CC(=O)N1CCS(=O)(=O)c2ccccc2C1
Reactant: Cc1ccc(N)c(C#N)c1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Solvent: O=P(Cl)(Cl)Cl
Solvent: ClCCl
Product: C/C(=N\c1ccc(C)cc1C#N)N1CCS(=O)(=O)c2ccccc2C1
Temperature: 25 °C
Reaction time: 0.33 h
Yield: 17 %

Procedure:
To a stirred solution of 1-(1,1-dioxido-2,3-dihydro-1,4-benzothiazepin-4(5H)-yl)ethanone (6.0 g, 25.0 mmol) in dry dichloromethane (100 mL) was added phosphorus oxychloride (2.5 mL, 27.3 mmol) at 10° C. After being stirred for 20 minutes at room temperature, a solution of 2-amino-5-methylbenzonitrile (3.3 g, 25.0 mmol) in dry dichloromethane (40 mL) was added and the resulting suspension was heated under reflux for 24 hours. After being cooled to room temperature, the reaction mixture was diluted with water (50 mL), basified with a saturated aqueous solution of sodium bicarbonate to about pH 8. The separated aqueous layer was extracted with dichloromethane (100 mL). The combined organic layers were washed with brine, dried over sodium sulfate and concentrated in vacuo. The residue was purified by column chromatography on silica gel (eluting with 16% ethyl acetate in petroleum ether) to give 1.5 g of the product as a white solid.
Reaction SMILES: [CH2:1]([O:3][C:4]1[N:8]=[C:7]([CH:9]2[CH2:14][CH:13]([C:15]3[CH:20]=[CH:19][C:18]([C:21]([F:24])([F:23])[F:22])=[CH:17][CH:16]=3)[CH2:12][N:11]([C:25]([N:27]3[CH2:32][CH2:31][S:30][CH2:29][CH2:28]3)=[O:26])[CH2:10]2)[O:6][N:5]=1)[CH3:2].ClC1C=CC=C(C(OO)=[O:41])C=1>>[CH2:1]([O:3][C:4]1[N:8]=[C:7]([CH:9]2[CH2:14][CH:13]([C:15]3[CH:20]=[CH:19][C:18]([C:21]([F:24])([F:22])[F:23])=[CH:17][CH:16]=3)[CH2:12][N:11]([C:25]([N:27]3[CH2:28][CH2:29][S:30](=[O:41])[CH2:31][CH2:32]3)=[O:26])[CH2:10]2)[O:6][N:5]=1)[CH3:2]
Reactant: CCOc1noc(C2CC(c3ccc(C(F)(F)F)cc3)CN(C(=O)N3CCSCC3)C2)n1
Reactant: O=C(OO)c1cccc(Cl)c1
Product: CCOc1noc(C2CC(c3ccc(C(F)(F)F)cc3)CN(C(=O)N3CCS(=O)CC3)C2)n1

Procedure:
65.0 mg (0.138 mmol) of the compound from Example 44 were reacted according to General Method 2 with 42.9 mg (0.124 mmol) of meta-chloroperbenzoic acid. Yield: 50.8 mg (72% of theory)
Reaction SMILES: [NH2:1][N:2]1[N:11]=[C:10]([C:12]2[CH:17]=[CH:16][C:15]([CH3:18])=[CH:14][C:13]=2[CH3:19])[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[C:3]1=[O:20].[Cl:21][C:22]1[CH:27]=[CH:26][C:25]([CH2:28][C:29](O)=[O:30])=[CH:24][CH:23]=1>>[Cl:21][C:22]1[CH:27]=[CH:26][C:25]([CH2:28][C:29]([NH:1][N:2]2[N:11]=[C:10]([C:12]3[CH:17]=[CH:16][C:15]([CH3:18])=[CH:14][C:13]=3[CH3:19])[C:9]3[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=3)[C:3]2=[O:20])=[O:30])=[CH:24][CH:23]=1
Reactant: O=C(O)Cc1ccc(Cl)cc1
Reactant: Cc1ccc(-c2nn(N)c(=O)c3ccccc23)c(C)c1
Product: Cc1ccc(-c2nn(NC(=O)Cc3ccc(Cl)cc3)c(=O)c3ccccc23)c(C)c1

Procedure:
The product of Example 159A and 2-(4-chlorophenyl)acetic acid were treated using a method similar to that described in Example 17C to give the title compound. 1H NMR (400 MHz, DMSO-d6) δ ppm 11.68 (s, 1H), 8.37-8.40 (m, 1H), 7.85-7.97 (m, 2H), 7.34-7.45 (m, 4H), 7.25-7.31 (m, 1H), 7.19-7.24 (m, 2H), 7.14-7.18 (m, 1H), 3.69 (s, 2H), 2.37 (s, 3H), 2.04 (s, 3H); MS (APCI+) M/Z 418 (M+H)+.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[C:6]([CH3:8])[C:5]([Cl:9])=[CH:4][C:3]=1[C:10]([OH:13])([CH3:12])[CH3:11].Cl[CH2:15][O:16][CH2:17][CH3:18].CCN(C(C)C)C(C)C.O>C(Cl)Cl>[Br:1][C:2]1[CH:7]=[C:6]([CH3:8])[C:5]([Cl:9])=[CH:4][C:3]=1[C:10]([O:13][CH2:15][O:16][CH2:17][CH3:18])([CH3:11])[CH3:12]
Reactant: CCOCCl
Reactant: Cc1cc(Br)c(C(C)(C)O)cc1Cl
Solvent: O
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: CCOCOC(C)(C)c1cc(Cl)c(C)cc1Br
Temperature: 40 °C
Reaction time: 8 h
Yield: 77.6 %

Procedure:
A mixture of 2-(2-bromo-5-chloro-4-methylphenyl)propan-2-ol (4.5 g 17.1 mmol), (chloromethoxy)ethane (3.2 g, 34.2 mmol) and DIPEA (6.6 g, 51.3 mmol) in DCM (50 mL) was stirred at 40° C. overnight under argon. Water (50 mL) was added and the mixture was extracted with DCM (2×50 mL). The combined organic layers were washed with brine, dried over Na2SO4, filtered and concentrated under reduced pressure. The residue was purified by silica gel column chromatography eluted with PE-EA (10:1) to give 1-bromo-4-chloro-2-(2-(ethoxymethoxy)propan-2-yl)-5-methylbenzene (4.27 g, yield 77.5%). 1H NMR (400 MHz, DMSO-d6): δ 7.67 (s, 1H), 7.50 (s, 1H), 4.59 (s, 2H), 3.55 (q, 2H), 2.29 (s, 3H), 1.65 (s, 6H), 1.08 (t, 3H) ppm; MS: m/z=344.8 (M+Na+, ESI+).
Reaction SMILES: CC(C)([O-])C.[K+].[N:7]1([CH:12]([C:18]2[CH:25]=[CH:24][C:21]([C:22]#[N:23])=[CH:20][CH:19]=2)[CH2:13][CH2:14][CH2:15][CH2:16]Cl)[CH:11]=[CH:10][N:9]=[CH:8]1>O1CCCC1>[C:22]([C:21]1[CH:24]=[CH:25][C:18]([C:12]2([N:7]3[CH:11]=[CH:10][N:9]=[CH:8]3)[CH2:16][CH2:15][CH2:14][CH2:13]2)=[CH:19][CH:20]=1)#[N:23]
Reactant: N#Cc1ccc(C(CCCCCl)n2ccnc2)cc1
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: C1CCOC1
Product: N#Cc1ccc(C2(n3ccnc3)CCCC2)cc1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
A solution of potassium tert-butoxide (1.10 g) in tetrahydrofuran (50 mL) is added dropwise to a solution of 4-[1-(1-imidazolyl)-5-chloropentyl]benzonitrile (2.50 g) in tetrahydrofuran at 0° (ice-bath). The reaction is allowed to proceed at 0° for 30 minutes and is then allowed to warm to room temperature during 3 hours. The reaction is then quenched with water (100 mL) and the mixture is subsequently extracted with ethyl acetate (100 mL). The organic extract is extracted with 3N hydrochloric acid (3×30 mL) and the combined acid extracts are made basic with 6N sodium hydroxide. The crude product is extracted into ethyl acetate (3×30 mL) and the combined extracts are dried (MgSO4) and evaporated to afford 1-(4-cyanophenyl)-1-(1-imidazolyl)cyclopentane as an oil. The compound is dissolved in acetone and treated with ethereal HCl to afford the hydrochloride salt, m.p. 217°-219°.
Reaction SMILES: [CH3:1][C@@H:2]1[C@@H:7]([CH3:8])[N:6](C)[CH2:5][CH2:4][N:3]1[C:10](OCC1C=CC=CC=1)=O>CO>[CH3:10][N:3]1[CH2:4][CH2:5][NH:6][C@H:7]([CH3:8])[C@H:2]1[CH3:1]
Reactant: C[C@@H]1[C@@H](C)N(C(=O)OCc2ccccc2)CCN1C
Solvent: CO
Product: C[C@@H]1[C@@H](C)NCCN1C
Yield: 156.6 %

Procedure:
Phenylmethyl (2R,3R)-2,3,4-trimethyl-1-piperazinecarboxylate (328 mg, 1.25 mmol) was dissolved in 20 mL of MeOH, degassed and placed under argon. 10% Pd/C (81 mg) was added, and the contents were thoroughly degassed and placed under a hydrogen balloon for approximately 3 hrs. The contents were then degassed and filtered through Celite, and the Celite pad was washed with DCM and MeOH. After 2.75 mL 1N HCl was added, the resulting filtrate was concentrated in vacuo to provide the hydrochloride salt of (2R,3R)-1,2,3-trimethylpiperazine (251 mg, 100%). LCMS: (M+H)+: 129.1.
Reaction SMILES: Cl[C:2]1[CH:11]=[CH:10][C:9]2[C:4](=[CH:5][CH:6]=[CH:7][C:8]=2[N+:12]([O-:14])=[O:13])[N:3]=1.O.[NH3:16].C1COCC1>[Na+].[Cl-]>[NH2:16][C:2]1[CH:11]=[CH:10][C:9]2[C:4](=[CH:5][CH:6]=[CH:7][C:8]=2[N+:12]([O-:14])=[O:13])[N:3]=1
Reactant: O=[N+]([O-])c1cccc2nc(Cl)ccc12
Reactant: N
Agent: [Cl-]
Agent: [Na+]
Solvent: O
Solvent: C1CCOC1
Product: Nc1ccc2c([N+](=O)[O-])cccc2n1

Procedure:
450 mg (2.2 mmol) of 2-chloro-5-nitroquinoline, 10 ml of 25% ammonia water and 10 ml of THF are stirred in a pressure vessel for 8 hours at 120° C. The batch is diluted with NaCl solution and extracted with ethyl acetate. The combined organic phases are dried (Na2SO4) and concentrated by evaporation: 370 mg of product.
Reaction SMILES: [F:1][C:2]1[CH:10]=[CH:9][C:5]([C:6](Cl)=[O:7])=[CH:4][CH:3]=1.[CH2:11]([OH:13])[CH3:12]>>[F:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([O:13][CH2:11][CH3:12])=[O:7])=[CH:4][CH:3]=1
Reactant: O=C(Cl)c1ccc(F)cc1
Reactant: CCO
Product: CCOC(=O)c1ccc(F)cc1

Procedure:
A mixture containing 35 g of 4-fluorobenzoyl chloride in 50 ml of 100% ethanol is refluxed for 15 minutes. 35 g of the ethyl 4-fluorobenzoate obtained are mixed with 22 g of imidazole and 61 g of potassium carbonate in 35 ml of DMSO. The mixture is heated for 18 hours at 120°-130° C. and 500 ml of iced water are then added. A precipitate forms and the expected product crystallizes from iso ether.