Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]1[C:7]2=[C:8]3[C:12](=[CH:13][CH:14]=[C:6]2[O:5][CH2:4][CH2:3][N:2]1C(OC(C)(C)C)=O)[NH:11][CH:10]=[CH:9]3.[H-].[Na+].CN(C=O)C.[S:29]1[C:33]2[CH:34]=[CH:35][CH:36]=[CH:37][C:32]=2[CH:31]=[C:30]1[S:38](Cl)(=[O:40])=[O:39]>N.CO>[S:29]1[C:33]2[CH:34]=[CH:35][CH:36]=[CH:37][C:32]=2[CH:31]=[C:30]1[S:38]([N:11]1[C:12]2[C:8](=[C:7]3[CH2:1][NH:2][CH2:3][CH2:4][O:5][C:6]3=[CH:14][CH:13]=2)[CH:9]=[CH:10]1)(=[O:40])=[O:39]
Reactant: O=S(=O)(Cl)c1cc2ccccc2s1
Reactant: CC(C)(C)OC(=O)N1CCOc2ccc3[nH]ccc3c2C1
Agent: N
Agent: [H-]
Agent: [Na+]
Solvent: CO
Solvent: CN(C)C=O
Product: O=S(=O)(c1cc2ccccc2s1)n1ccc2c3c(ccc21)OCCNC3
Temperature: 25 °C
Reaction time: 0.33 h
Yield: 9.9 %

Procedure:
tert-Butyl 1,3,4,8-tetrahydro-2H-[1,4]oxazepino[6,7-e]indole-2-carboxylate (Intermediate 18, 14 mg, 0.050 mmol), NaH (60% in mineral oil, 6.4 mg, 0.10 mmol) and dry DMF (0.2 mL) were shaken at room temperature for 10 minutes. 1-Benzothiophene-2-sulfonyl chloride (23 mg, 0.10 mmol, in 0.15 mL of dry DMF) was added to the solution. The reaction mixture was shaken at room temperature for another 20 minutes and a mixture of MeOH/1 M HCl (3:1, 1 mL) was added. The reaction mixture was stirred overnight and evaporated. The residue was dissolved in 1 M NH3 in MeOH (1 mL, 1 mmol) and MeOH (1 mL). The crude product was purified by preparative HPLC (XTerra C18, 50 mM NH4HCO3 pH 10-CH3CN) to give the title compound as an off-white solid (1.9 mg). MS m/z 385 [M+H]+.
Reaction SMILES: [S:1]([CH2:5][C:6]1[CH:11]=[CH:10][C:9]([CH2:12][C:13]([OH:15])=O)=[CH:8][CH:7]=1)(=[O:4])(=[O:3])[NH2:2].[N:16]1([C:22]2[C:23]3[CH:30]=[C:29]([CH2:31][C:32]([F:35])([F:34])[F:33])[S:28][C:24]=3[N:25]=[CH:26][N:27]=2)[CH2:21][CH2:20][NH:19][CH2:18][CH2:17]1.CCN=C=NCCCN(C)C>CN(C1C=CN=CC=1)C.C(Cl)Cl>[O:15]=[C:13]([N:19]1[CH2:18][CH2:17][N:16]([C:22]2[C:23]3[CH:30]=[C:29]([CH2:31][C:32]([F:34])([F:33])[F:35])[S:28][C:24]=3[N:25]=[CH:26][N:27]=2)[CH2:21][CH2:20]1)[CH2:12][C:9]1[CH:8]=[CH:7][C:6]([CH2:5][S:1]([NH2:2])(=[O:3])=[O:4])=[CH:11][CH:10]=1
Reactant: FC(F)(F)Cc1cc2c(N3CCNCC3)ncnc2s1
Reactant: NS(=O)(=O)Cc1ccc(CC(=O)O)cc1
Agent: CCN=C=NCCCN(C)C
Agent: CN(C)c1ccncc1
Solvent: ClCCl
Product: NS(=O)(=O)Cc1ccc(CC(=O)N2CCN(c3ncnc4sc(CC(F)(F)F)cc34)CC2)cc1
Yield: 110.4 %

Procedure:
23 mg of 2-(4-(sulfamoylmethyl)phenyl)acetic acid (0.1 mmol), 20 mg of 4-(piperazin-1-yl)-6-(2,2,2-trifluoroethyl)thieno[2,3-d]pyrimidine (0.067 mmol), 20 mg of EDCI (0.1 mmol) and 4 mg of DMAP (0.033 mmol) was stirred in 2 mL of DCM. After 2 hs reaction mixture was concentrated and residue was loaded on silica gel column. Elution with DCM-MeOH 9:1 and evaporation of fraction produced 38 mg of (4-(2-oxo-2-(4-(6-(2,2,2-trifluoroethyl)thieno[2,3-d]pyrimidin-4-yl)piperazin-1-yl)ethyl)phenyl)methanesulfonamide (compound 44). 1H NMR (400 MHz, CDCl3): δ 8.44 (s, 1H), 7.36 (d, 2H, J=8 Hz), 7.25 (d, 2H, J=8 Hz), 7.20 (s, 1H), 4.88 (s, 2H), 4.26 (s, 1H), 3.5-4.0 (m, 10H). ESI MS [MH+]: 514.1. Its monohydrochloride salt was obtained by adding 1 equivalent of 1N HCl solution in diethyl ether to a solution of compound in ethanol.
Reaction SMILES: [O:1]=[C:2]([C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1)[CH2:3][N:4]1[CH2:9][CH2:8][N:7]([C:10]([O:12][C:13]([CH3:16])([CH3:15])[CH3:14])=[O:11])[CH2:6][CH2:5]1.CC(O[CH:28](N(C)C)[N:29]([CH3:31])[CH3:30])(C)C>>[CH3:28][N:29]([CH3:31])[CH:30]=[C:3]([N:4]1[CH2:9][CH2:8][N:7]([C:10]([O:12][C:13]([CH3:16])([CH3:15])[CH3:14])=[O:11])[CH2:6][CH2:5]1)[C:2](=[O:1])[C:17]1[CH:18]=[CH:19][CH:20]=[CH:21][CH:22]=1
Reactant: CC(C)(C)OC(=O)N1CCN(CC(=O)c2ccccc2)CC1
Reactant: CN(C)C(OC(C)(C)C)N(C)C
Product: CN(C)C=C(C(=O)c1ccccc1)N1CCN(C(=O)OC(C)(C)C)CC1
Temperature: 55 °C

Procedure:
To the compound tert-butyl 4-(2-oxo-2-phenylethyl)piperazine-1-carboxylate (18 g) taken in round bottom flask, Bredereck's reagent (1 1.33 g) was added very slowly under nitrogen atmosphere. The reaction mixture was stirred at 55° C. for over-night. The progress of reaction was monitored by TLC. After consumption of starting material, diethyl ether was added to the reaction mixture. The resulting solid was filtered and dried under reduced pressure to afford tert-butyl 4-(1-(dimethylamino)-3-oxo-3-phenylprop-1-en-2-yl)piperazine-1-carboxylate as pure product.
Reaction SMILES: Cl.[CH3:2][C:3]1[CH:17]=[C:6]2[C:7]3[CH:13]([CH2:14][CH2:15][NH2:16])[CH2:12][CH2:11][C:8]=3[CH:9]=[CH:10][N:5]2[N:4]=1.C(N(CC)CC)C.[C:25](OC(=O)C)(=[O:27])[CH3:26]>O1CCCC1.C(=O)([O-])O.[Na+]>[CH3:2][C:3]1[CH:17]=[C:6]2[C:7]3[CH:13]([CH2:14][CH2:15][NH:16][C:25](=[O:27])[CH3:26])[CH2:12][CH2:11][C:8]=3[CH:9]=[CH:10][N:5]2[N:4]=1
Reactant: Cc1cc2c3c(ccn2n1)CCC3CCN
Reactant: CC(=O)OC(C)=O
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: CC(=O)NCCC1CCc2ccn3nc(C)cc3c21
Reaction time: 0.25 h
Yield: 45 %

Procedure:
To a mixture of 2-(2-methyl-8,9-dihydro-7H-cyclopenta[c]pyrazolo[1,5-a]pyridin-9-yl)ethanamine hydrochloride obtained in Reference Example 43 and triethylamine (1.36 mL, 9.76 mmol) in tetrahydrofuran (5 mL) was added acetic anhydride (115 μL, 1.22 mmol) under ice-cooling, and the mixture was stirred for 15 min. The reaction solution was diluted with saturated aqueous sodium hydrogen carbonate solution, and the mixture was extracted with ethyl acetate. The extract was dried over anhydrous sodium sulfate, and the solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate/hexane=50/50→100/0) and recrystallization (ethyl acetate/diisopropyl ether) to give the title compound (56.6 mg, total yield from Reference Example 43, 45%).
Reaction SMILES: Cl.[NH2:2][C:3]1[CH:8]=[CH:7][C:6]([N:9]2[C:18](=[O:19])[C:17]3[C:12](=[CH:13][C:14](F)=[C:15]([F:20])[CH:16]=3)[NH:11][C:10]2=[O:22])=[CH:5][CH:4]=1.[CH3:23][NH2:24]>CS(C)=O>[NH2:2][C:3]1[CH:8]=[CH:7][C:6]([N:9]2[C:18](=[O:19])[C:17]3[C:12](=[CH:13][C:14]([NH:24][CH3:23])=[C:15]([F:20])[CH:16]=3)[NH:11][C:10]2=[O:22])=[CH:5][CH:4]=1
Reactant: Nc1ccc(-n2c(=O)[nH]c3cc(F)c(F)cc3c2=O)cc1
Reactant: CN
Agent: Cl
Solvent: CS(C)=O
Product: CNc1cc2[nH]c(=O)n(-c3ccc(N)cc3)c(=O)c2cc1F
Temperature: 22 °C
Reaction time: 0.25 h
Yield: 76.5 %

Procedure:
The PP1-R2000 (200 L HP reactor) was charged with compound 5b (18 Kg, 1.0 eq.) and pressurized with 100±5 psig of nitrogen. Vent the nitrogen from the reactor through the atmospheric vent line then open the condenser valve and then charged dimethyl sulfoxide into the reactor (>99.7%, 105 Kg) under blanket of argon. The reactor contents were agitated at 22° C. (19-25° C.) for 15 mins. and then pulled maximum achievable vacuum on the 200 L HP reactor and close all the valves. Using the established vacuum charged to the 200 L HP reactor methylamine (33% wt % in absolute ethanol, 37.2 Kg) at a rate that maintains the internal temperature at 25±5° C. and kept a nitrogen blanket on the reagent solution during charging. After rinsing the charging line with dimethyl sulfoxide (5 Kg) closed the 200 L HP reactor condenser valve and heated the reactor contents to 110±5° C. The contents of the reactor were agitated for at least 5 hrs. at 110±5° C. In-process HPLC taken after 5 hr 40 mins. showed compound 5b content of 0.09%, indicating completion of the reaction (in-process specification ≦1%). The contents of 200 L HP reactor were cooled to 25±5° C. While the 200 L reactor is cooling, closed all the valves of the PP1-R1000 reactor (2000 L GL reactor) and charged with process filtered water (550 Kg). The contents of the 200 L HP reactor were transferred to the 2000 L GL reactor over 15 minutes followed by rinsing the charging line with process filtered water (50 Kg). The contents of the 2000 L GL reactor were agitated for 2 hrs at 5±5° C. The filterable solids obtained were filtered onto PPF200 (GL nutsche filter) fitted with Mel-Tuf 1149-12 filter paper under vacuum. The wet filter cake was discharged and transferred into pre-lined vacuum trays with Dupont's fluorocarbon film (Kind 100 A). Clamped down the special oven paper (KAVON 992) over the vacuum trays containing the wet compound 6 and transferred to the vacuum oven tray dryer. The oven temperature was set to 55° C. and compound 6 dried to a constant weight for 12 hrs. The product 5c was discharged (12.70 Kg) in 76.5% yield (expected 85-95%). HPLC shows 98.96% purity and 1H NMR confirmed the structure for compound 5c. 1H NMR (DMSO): δ 11.10 (s, 1H), 7.36 (d, 1H), 6.78 (d, 2H), 6.75 (m, 1H), 6.56 (d, 2H), 6.20 (d, 1H), 5.18 (d, 2H), 2.76 (d, 3H).
Reaction SMILES: [CH2:1]([C:6]1[CH:14]=[CH:13][C:9]([C:10]([OH:12])=O)=[CH:8][CH:7]=1)[CH2:2][CH2:3][CH2:4][CH3:5].[C:15]([C:17]1[CH:22]=[CH:21][C:20]([SH:23])=[CH:19][CH:18]=1)#[N:16].C1(N=C=NC2CCCCC2)CCCCC1>CN(C)C1C=CN=CC=1>[CH2:1]([C:6]1[CH:7]=[CH:8][C:9]([C:10]([S:23][C:20]2[CH:21]=[CH:22][C:17]([C:15]#[N:16])=[CH:18][CH:19]=2)=[O:12])=[CH:13][CH:14]=1)[CH2:2][CH2:3][CH2:4][CH3:5]
Reactant: CCCCCc1ccc(C(=O)O)cc1
Reactant: N#Cc1ccc(S)cc1
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: CN(C)c1ccncc1
Product: CCCCCc1ccc(C(=O)Sc2ccc(C#N)cc2)cc1

Procedure:
Quantities: compound 17 (0.51 g, 3.8 mmol), compound 10 (0.87 g, 4.5 mmol), 4-(dimethylamino)pyridine (0.19 g, 1.6 mmol). N,N'-dicyclohexylcarbodiimide (0.94 g, 4.6 mmol).
Reaction SMILES: [C:1]([N:5]1[C:10](=[O:11])[C:9]([CH:12](Br)Br)=[C:8]([Cl:15])[CH:7]=[N:6]1)([CH3:4])([CH3:3])[CH3:2].C[O:17]CCO>[N+]([O-])([O-])=O.[Ag+]>[C:1]([N:5]1[C:10](=[O:11])[C:9]([CH:12]=[O:17])=[C:8]([Cl:15])[CH:7]=[N:6]1)([CH3:4])([CH3:3])[CH3:2]
Reactant: COCCO
Reactant: CC(C)(C)n1ncc(Cl)c(C(Br)Br)c1=O
Agent: [Ag+]
Agent: O=[N+]([O-])[O-]
Product: CC(C)(C)n1ncc(Cl)c(C=O)c1=O

Procedure:
Into 300 ml of a 2-methoxyethanol solution of 27.4 g of 2-tert-butyl-5-chloro-4-dibromomethylpyridazin-3-(2H)-one, 200 ml of an aqueous solution of 39 g of silver nitrate was dropwise added at 10° C. over a period of 10 minutes, and the mixture was reacted for one hour under heating and refluxing. After cooling, insoluble matters were filtered off, and 500 ml of benzene was added to the filtrate. The mixture was washed with water, and the extract layer was dried over anhydrous sodium sulfate. The benzene was distilled off under reduced pressure to obtain 12.2 g of 2-tert-butyl-5-chloro-4-formylpyridazin-3-(2H)-one having a melting point of from 61° to 66° C.
Reaction SMILES: CN(C=O)C.[C:6](Cl)(=O)[C:7]([Cl:9])=[O:8].[CH3:12][O:13][C:14]([C:16]1[C:25]2[C:20](=[CH:21][C:22](CC(O)=O)=[CH:23][CH:24]=2)[CH:19]=[CH:18][CH:17]=1)=[O:15]>C(Cl)Cl>[CH3:12][O:13][C:14]([C:16]1[C:25]2[C:20](=[CH:21][C:22]([CH2:6][C:7]([Cl:9])=[O:8])=[CH:23][CH:24]=2)[CH:19]=[CH:18][CH:17]=1)=[O:15]
Reactant: COC(=O)c1cccc2cc(CC(=O)O)ccc12
Reactant: O=C(Cl)C(=O)Cl
Solvent: CN(C)C=O
Solvent: ClCCl
Product: COC(=O)c1cccc2cc(CC(=O)Cl)ccc12
Temperature: 0 °C

Procedure:
140 μl (1.8 mMol) DMF are added to an ice-cooled solution of 3.6 ml (43 mMol) oxalylchloride in 150 CH2Cl2. Then a suspension of 8.8 g (36 mMol) 6-carboxymethyl-naphthalene-1-carboxylic acid methyl ester in 400 ml CH2Cl2 is added during 1 h. After 1.5 h stirring in the ice-bath, the reaction mixture is concentrated in vacuo, yielding the title compound.
Reaction SMILES: [Na].Cl.C(O[C:6](=[NH:8])[CH3:7])C.[CH3:9][C:10]1[CH:19]=[CH:18][C:13]([C:14]([NH:16][NH2:17])=[O:15])=[CH:12][CH:11]=1>C(O)C>[NH:8]=[C:6]([N:16]([C:14](=[O:15])[C:13]1[CH:12]=[CH:11][C:10]([CH3:9])=[CH:19][CH:18]=1)[NH2:17])[CH3:7]
Reactant: CCOC(C)=N
Reactant: Cc1ccc(C(=O)NN)cc1
Agent: Cl
Agent: [Na]
Solvent: CCO
Product: CC(=N)N(N)C(=O)c1ccc(C)cc1
Reaction time: 8 h
Yield: 15.7 %

Procedure:
1.65 g (72 mmol) sodium are dissolved in 80 mL ethanol. 8.89 g (72 mmol) ethylacetimidate hydrochloride in 160 mL ethanol are added at ambient temperature and the precipitated sodium chloride is filtered off. The filtrate is combined with 6.00 g (40 mmol) 4-methyl-benzoic acid hydrazide and stirred overnight. The reaction mixture is evaporated down and cooled. The precipitated solid is filtered off and washed with cold ethanol and diethyl ether (5.7 g white solid). A further 1.2 g of solid are obtained from the filtrate after distillation of the solvent and recrystallisation from ethanol.
Reaction SMILES: Cl.[NH2:2][C@:3](OC(C)(C)C)([CH2:7][C:8]([N:10]([CH2:33][CH:34]([CH3:36])[CH3:35])[NH:11][C:12](=[O:32])[C@@H:13]([C@@H:18]([C:28](=[O:31])[NH:29][OH:30])[CH2:19]/[CH:20]=[CH:21]/[C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1)[CH2:14][CH:15]([CH3:17])[CH3:16])=[O:9])[C:4]([OH:6])=[O:5].[F:42][C:43]([F:48])([F:47])[C:44]([OH:46])=[O:45]>ClCCl>[F:42][C:43]([F:48])([F:47])[C:44]([OH:46])=[O:45].[NH2:2][C@@H:3]([CH2:7][C:8]([N:10]([CH2:33][CH:34]([CH3:36])[CH3:35])[NH:11][C:12](=[O:32])[C@@H:13]([C@@H:18]([C:28](=[O:31])[NH:29][OH:30])[CH2:19]/[CH:20]=[CH:21]/[C:22]1[CH:23]=[CH:24][CH:25]=[CH:26][CH:27]=1)[CH2:14][CH:15]([CH3:16])[CH3:17])=[O:9])[C:4]([OH:6])=[O:5]
Reactant: CC(C)C[C@@H](C(=O)NN(CC(C)C)C(=O)C[C@](N)(OC(C)(C)C)C(=O)O)[C@H](C/C=C/c1ccccc1)C(=O)NO
Agent: Cl
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CC(C)C[C@@H](C(=O)NN(CC(C)C)C(=O)C[C@H](N)C(=O)O)[C@H](C/C=C/c1ccccc1)C(=O)NO
Temperature: 25 °C
Reaction time: 4 h

Procedure:
A solution of 0.050 g of (E)-2(S)-amino-3-[[2-[2(R)-[1(S)-(hydroxycarbamoyl)-4-phenyl-3-butenyl]-4-methylvaleryl]-1-isobutylhydrazino]carbonyl]tert.butoxypropionate hydrogen chloride in 1 ml of dichloromethane was treated with 0.400 mL of trifluoroacetic acid. The mixture was stirred for 4 hours at room temperature and evaporated. The residue was triturated with diethyl ether, filtered off and dried to give 0.022 g of (E)-2(S)-amino-3-[[2-[2(R)-[1(S)-(hydroxycarbamoyl)-4-phenyl-3-butenyl]-4-methylvaleryl]-1-isobutylhydrazino]carbonyl]propionic acid trifluoroacetate in the form of a white solid.
Reaction SMILES: [CH2:1]([N:7]1[C:12](=[O:13])[C:11]2[C:14]3[CH2:20][CH2:19][CH2:18][CH2:17][C:15]=3[S:16][C:10]=2[NH:9][C:8]1=[O:21])[CH2:2][CH2:3][CH2:4][CH2:5][CH3:6].[H-].[Na+].Br[CH2:25][C:26]([O:28][CH2:29][CH3:30])=[O:27]>C(Cl)(Cl)Cl>[CH2:29]([O:28][C:26]([CH2:25][N:9]1[C:10]2[S:16][C:15]3[CH2:17][CH2:18][CH2:19][CH2:20][C:14]=3[C:11]=2[C:12](=[O:13])[N:7]([CH2:1][CH2:2][CH2:3][CH2:4][CH2:5][CH3:6])[C:8]1=[O:21])=[O:27])[CH3:30]
Reactant: CCOC(=O)CBr
Reactant: CCCCCCn1c(=O)[nH]c2sc3c(c2c1=O)CCCC3
Agent: [H-]
Agent: [Na+]
Solvent: ClC(Cl)Cl
Product: CCCCCCn1c(=O)c2c3c(sc2n(CC(=O)OCC)c1=O)CCCC3
Yield: 77 %

Procedure:
A 1.2 g quantity of 3-hexyl-5,6,7,8-tetrahydrobenzothieno[2,3-d]pyrimidin-2,4(1H,3H)-dione (Compound III-9), 0.14 g of 50% sodium hydride and 1.0 g of ethyl bromoacetate were allowed to react with each other in the same manner as in Reference Example 5. The residue obtained by concentration was subjected to silica gel column chromatography using chloroform as an eluent. Then 1.2 g of 1-ethoxycarbonylmethyl-3-hexyl-5,6,7,8-tetrahydrobenzothieno[2,3-d]pyrimidin-2,4(1H,3H)-dione was obtained in a yield of 77%.
Reaction SMILES: Br[C:2]1[C:10]2[N:9]3[CH2:11][CH2:12][NH:13][C:14](=[O:15])[C:8]3=[CH:7][C:6]=2[CH:5]=[C:4]([C:16]#[N:17])[CH:3]=1.[F:18][C:19]([F:30])([F:29])[C:20]1[CH:21]=[C:22](B(O)O)[CH:23]=[CH:24][CH:25]=1>>[O:15]=[C:14]1[C:8]2=[CH:7][C:6]3[CH:5]=[C:4]([C:16]#[N:17])[CH:3]=[C:2]([C:24]4[CH:23]=[CH:22][CH:21]=[C:20]([C:19]([F:30])([F:29])[F:18])[CH:25]=4)[C:10]=3[N:9]2[CH2:11][CH2:12][NH:13]1
Reactant: N#Cc1cc(Br)c2c(c1)cc1n2CCNC1=O
Reactant: OB(O)c1cccc(C(F)(F)F)c1
Product: N#Cc1cc(-c2cccc(C(F)(F)F)c2)c2c(c1)cc1n2CCNC1=O

Procedure:
The title compound, off-white solid (78 mg, 88%), MS (ISP) m/z=356.5 [(M+H)+], mp 279.5° C., was prepared in accordance with the general method of example 1 from 6-bromo-1-oxo-1,2,3,4-tetrahydro-pyrazino[1,2-a]indole-8-carbonitrile (intermediate 15) (72.5 mg, 0.25 mmol) and commercially available 3-trifluoromethyl-phenylboronic acid (61.7 mg, 0.325 mmol).
Reaction SMILES: [CH2:1]([C:3]1[CH:8]=[CH:7][C:6]([OH:9])=[CH:5][C:4]=1[OH:10])[CH3:2].[CH3:11][O:12][C:13]1[CH:18]=[CH:17][C:16]([CH2:19][C:20](O)=[O:21])=[CH:15][CH:14]=1.B(F)(F)F.C([O-])(=O)C.[Na+]>>[CH2:1]([C:3]1[C:4]([OH:10])=[CH:5][C:6]([OH:9])=[C:7]([C:20](=[O:21])[CH2:19][C:16]2[CH:17]=[CH:18][C:13]([O:12][CH3:11])=[CH:14][CH:15]=2)[CH:8]=1)[CH3:2]
Reactant: CCc1ccc(O)cc1O
Reactant: COc1ccc(CC(=O)O)cc1
Agent: CC(=O)[O-]
Agent: FB(F)F
Agent: [Na+]
Product: CCc1cc(C(=O)Cc2ccc(OC)cc2)c(O)cc1O
Temperature: 50 °C

Procedure:
4-Ethylbenzene-1,3-diol (17.5 g, 159 mmol) and 4-methoxyphenylacetic acid (26.4 g, 159 mmol) was heated with boron trifluoride dietherate solution (100.7 ml, 795 mmol) to 90° C. for 3 hours. The mixture was then cooled to 50° C. before it was added to a stirred solution of 10% aqueous sodium acetate (11). The resulting mixture was stirred at room temperature over night at room temperature. The resulting solid was filtered off dissolved in a minimum volume of methanol and pre-absorbed onto silica gel. For the initial purification the crude material was chromatographed, eluting with an increasingly polar mixture of methylene chloride/methanol (95/5 to 90/10). The fractions containing product were grouped into two groups, evaporated under vacuum to give a solid which was triturated with diethyl ether in a further purification step. The title compound was obtained in three portions of varying purity as an off white solid from combined purest fractions (10.78 g, 26.2%) the less pure fractions (7.56 g, 18.4%) and from the combined, evaporated mother liquors after renewed trituration with iso-hexane/diethylether to give the title product (6.32 g, 15.4%). 1H NMR Spectrum (purest solid): δH (300 MHz, CDCl3) 1.22 (3H t, J=7.5 Hz), 1.63 (1H, s), 2.57 (2H q, J=7.5 Hz), 3.79 (3H, s), 4.16 (2H d, J=3.0 Hz), 5.52 (1H, s), 6.30 (1H, s), 6.85-6.90 (2H, m), 7.16-7.21 (2H, m), 7.59 (1H, s), 12.51 (1H, s); Mass Spectrum: (M+H−) 258.20.
Reaction SMILES: [CH2:1]1[O:9][C@@H:2]1[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.[Cl:10][C:11]1[CH:20]=[C:19]([SH:21])[CH:18]=[CH:17][C:12]=1[C:13]([O:15][CH3:16])=[O:14]>>[Cl:10][C:11]1[CH:20]=[C:19]([S:21][CH2:1][C@H:2]([OH:9])[C:3]2[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=2)[CH:18]=[CH:17][C:12]=1[C:13]([O:15][CH3:16])=[O:14]
Reactant: COC(=O)c1ccc(S)cc1Cl
Reactant: c1ccc([C@@H]2CO2)cc1
Product: COC(=O)c1ccc(SC[C@H](O)c2ccccc2)cc1Cl

Procedure:
150 mg of (R)-styrene oxide was reacted with methyl 2-chloro-4-mercaptobenzoate via Procedure S to afford (R)-methyl 2-chloro-4-(2-hydroxy-2-phenylethylthio)benzoate. 190 mg of (R)-methyl-2-chloro-4-(2-hydroxy-2-phenylethylthio)benzoate was hydrolyzed via Procedure M to give (R)-2-chloro-4-(2-hydroxy-2-phenylethylthio)benzoic acid. 170 mg of (R)-2-chloro-4-(2-hydroxy-2-phenylethylthio)benzoic acid was reacted via Procedure R to give (R)-2-chloro-4-(2-hydroxy-2-phenylethylsulfonyl)benzoic acid. 60 mg of 4-chloro-3-(pyridine-2-yl)aniline was coupled to (R)-2-chloro-4-(2-hydroxy-2-phenylethylsulfonyl)benzoic acid via Procedure G. The product was purified on reverse phase HPLC to yield (R)-2-chloro-N-(4-chloro-3-(pyridin-2-yl)phenyl)-4-(2-hydroxy-2-phenylethylsulfonyl)benzamide. MS (Q1) 527.2 (M)+.
Reaction SMILES: [Br:1]Br.[F:3][C:4]1[CH:5]=[C:6]([C:12]2[CH:16]=[C:15]([NH:17][C:18]([C@@H:20]3[CH2:22][C@H:21]3[CH3:23])=[O:19])[S:14][N:13]=2)[CH:7]=[CH:8][C:9]=1[O:10][CH3:11].[O-]S([O-])(=S)=O.[Na+].[Na+]>ClCCl.CCOC(C)=O>[Br:1][C:16]1[C:12]([C:6]2[CH:7]=[CH:8][C:9]([O:10][CH3:11])=[C:4]([F:3])[CH:5]=2)=[N:13][S:14][C:15]=1[NH:17][C:18]([C@@H:20]1[CH2:22][C@H:21]1[CH3:23])=[O:19]
Reactant: COc1ccc(-c2cc(NC(=O)[C@@H]3C[C@H]3C)sn2)cc1F
Reactant: BrBr
Agent: O=S([O-])([O-])=S
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: ClCCl
Product: COc1ccc(-c2nsc(NC(=O)[C@@H]3C[C@H]3C)c2Br)cc1F
Yield: 97.1 %

Procedure:
Add bromine (0.15 mL, 0.47 g, 2.94 mmol) to (R,R)—N-[3-(3-fluoro-4-methoxy-phenyl)isothiazol-5-yl]-2-methylcyclopropanecarboxamide (0.45 g, 1.47 mmol) in dichloromethane (3 mL) dropwise. Monitor by TLC and stop bromine addition when complete. Dilute the reaction mixture with EtOAc (100 mL) and pour into aqueous Na2S2O3 (1 N). Collect the organic phase, wash with brine (50 mL) and water (80 mL), and evaporate. Chromatograph over silica gel, eluting with 10-50% EtOAc in hexane, to afford (R,R)—N-[4-bromo-3-(3-fluoro-4-methoxyphenyl)isothiazol-5-yl]-2-methyl-cyclopropanecarboxamide. Yield: 97.1%. ES-MS: m/e 387.0 (m+1).
Reaction SMILES: Cl[CH2:2][C:3]([N:5]1[C:11]2[CH:12]=[CH:13][CH:14]=[CH:15][C:10]=2[NH:9][C:8](=[O:16])[C:7]2[N:17]([CH3:21])[N:18]=[C:19]([CH3:20])[C:6]1=2)=[O:4].[CH3:22][N:23]1[CH2:28][CH2:27][NH:26][CH2:25][CH2:24]1.C(=O)(O)[O-].[Na+]>C1(C)C=CC=CC=1>[CH3:21][N:17]1[C:7]2[C:8](=[O:16])[NH:9][C:10]3[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=3[N:5]([C:3](=[O:4])[CH2:2][N:26]3[CH2:27][CH2:28][N:23]([CH3:22])[CH2:24][CH2:25]3)[C:6]=2[C:19]([CH3:20])=[N:18]1
Reactant: CN1CCNCC1
Reactant: Cc1nn(C)c2c1N(C(=O)CCl)c1ccccc1NC2=O
Agent: O=C([O-])O
Agent: [Na+]
Solvent: Cc1ccccc1
Product: Cc1nn(C)c2c1N(C(=O)CN1CCN(C)CC1)c1ccccc1NC2=O
Yield: 52 %

Procedure:
3.5 g of 4-chloroacetyl-1,3-dimethyl-1,4,9,10-tetrahydropyrazolo[4,3-b][1,5]benzodiazepin-10-one, 8.1 g of N-methylpiperazine and 50 ml of toluene are stirred at 80° C. for 2 hours. 60 ml of dilute sodium bicarbonate solution are added to the mixture, the layers are separated and the aqueous phase is extracted by shaking it with toluene several times more before concentrating it to dryness in vacuo. The residue is stirred with 100 ml of isopropanol and is filtered; the filtrate is concentrated in vacuo. The residue (4.0 g) is purified by stirring it with diethyl ether and by recrystallizing it from toluene, which yields 2.2 g of 1,3-dimethyl-4-[(4-methylpiperazin-1-yl)acetyl]-1,4,9,10-tetrahydropyrazolo[4,3-b][1,5]benzodiazepin-10-one, mp 186° to 188° C.; succinate, mp 172° to 174° C.
Reaction SMILES: [O:1]=[C:2]1[C:6](=[CH:7][C:8]2[CH:13]=[CH:12][C:11]([N:14]3[CH2:19][CH2:18][C:17](=O)[CH2:16][CH2:15]3)=[CH:10][CH:9]=2)[S:5][C:4]([N:21]2[CH2:26][CH2:25][CH2:24][CH2:23][CH2:22]2)=[N:3]1.[NH2:27][CH2:28][C@H:29]([OH:44])[CH2:30][O:31][C:32]1[CH:41]=[CH:40][C:39]([OH:42])=[C:38]2[C:33]=1[CH2:34][CH2:35][C:36](=[O:43])[NH:37]2>>[OH:42][C:39]1[CH:40]=[CH:41][C:32]([O:31][CH2:30][C@@H:29]([OH:44])[CH2:28][NH:27][CH:17]2[CH2:18][CH2:19][N:14]([C:11]3[CH:10]=[CH:9][C:8]([CH:7]=[C:6]4[S:5][C:4]([N:21]5[CH2:22][CH2:23][CH2:24][CH2:25][CH2:26]5)=[N:3][C:2]4=[O:1])=[CH:13][CH:12]=3)[CH2:15][CH2:16]2)=[C:33]2[C:38]=1[NH:37][C:36](=[O:43])[CH2:35][CH2:34]2
Reactant: O=C1CCN(c2ccc(C=C3SC(N4CCCCC4)=NC3=O)cc2)CC1
Reactant: NC[C@H](O)COc1ccc(O)c2c1CCC(=O)N2
Product: O=C1CCc2c(OC[C@@H](O)CNC3CCN(c4ccc(C=C5SC(N6CCCCC6)=NC5=O)cc4)CC3)ccc(O)c2N1

Procedure:
The title compound was prepared from 1-[4-(4-oxo-2-piperidin-1-yl-4H-thiazol-5-ylidenemethyl)-phenyl]-piperidin-4-one (which was obtained in Intermediate 25) and 5-((2S)-3-amino-2-hydroxy-propoxy)-8-hydroxy-3,4-dihydro-1H-quinolin-2-one (which was obtained in Intermediate 12) according to the procedure of Example 1 as a yellowish solid; mp>120° C. (dec.); 1H NMR (300 MHz, DMSO-d6) δ 1.20-1.40 (m, 2 H), 1.55-1.70 (m, 6 H), 1.85-2.00 (m, 2 H), 2.43 (t, J=7.9 Hz, 2.55-2.90 (m, 9 H), 3.60 (br s, 2 H), 3.70-3.95 (m, 6 H), 6.44 (d, J=9.0 Hz, 1 H), 6.69 (d, J=9.0 Hz, 1 H), 7.02 (d, J=9.0 Hz, 2 H), 7.44 (d, J=9.0 Hz, 2 H), 7.50 (s, 1 H), 8.82 (s, 1 H); MS (ES) m/z: 303.6 ((M+2H)2+, 100%); 606.1 (MH+, 10%); HRMS Calcd. for C32H40N5O5S (MH+): 606.2750. Found: 606.2711.