Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]([CH2:8][CH2:9][CH2:10][CH2:11][N:12]2[CH:16]=[CH:15][N:14]=[CH:13]2)[CH:5]=[CH:6][CH:7]=1.Cl[CH2:18][C:19]1[N:20]=[C:21](/[CH:24]=[CH:25]/[C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=2)[O:22][CH:23]=1>>[N:12]1([CH2:11][CH2:10][CH2:9][CH2:8][C:4]2[CH:3]=[C:2]([CH:7]=[CH:6][CH:5]=2)[O:1][CH2:18][C:19]2[N:20]=[C:21](/[CH:24]=[CH:25]/[C:26]3[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=3)[O:22][CH:23]=2)[CH:16]=[CH:15][N:14]=[CH:13]1
Reactant: ClCc1coc(/C=C/c2ccccc2)n1
Reactant: Oc1cccc(CCCCn2ccnc2)c1
Product: C(=C/c1nc(COc2cccc(CCCCn3ccnc3)c2)co1)\c1ccccc1
Yield: 70 %

Procedure:
In substantially the same manner as in Working Example 72, 1-[4-(3-hydroxyphenyl)butyl]imidazole was allowed to react with 4-chloromethyl-2-[(E)-2-phenylethenyl]oxazole to give 4-[3-[4-(1-imidazolyl)butyl]phenoxymethyl]-2-[(E)-2-phenylethenyl]oxazole. The yield was 70%. Recrystallization from ethyl acetate-hexane gave colorless prisms, mp 75-76° C.
Reaction SMILES: Br[C:2]1[CH:11]=[CH:10][C:9]([N+:12]([O-:14])=[O:13])=[CH:8][C:3]=1[C:4]([O:6][CH3:7])=[O:5].[Cl:15][C:16]1[CH:17]=[CH:18][C:19]([O:25][CH3:26])=[C:20](B(O)O)[CH:21]=1>C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[CH3:7][O:6][C:4]([C:3]1[C:2]([C:18]2[CH:17]=[C:16]([Cl:15])[CH:21]=[CH:20][C:19]=2[O:25][CH3:26])=[CH:11][CH:10]=[C:9]([N+:12]([O-:14])=[O:13])[CH:8]=1)=[O:5]
Reactant: COC(=O)c1cc([N+](=O)[O-])ccc1Br
Reactant: COc1ccc(Cl)cc1B(O)O
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Product: COC(=O)c1cc([N+](=O)[O-])ccc1-c1cc(Cl)ccc1OC
Yield: 55 %

Procedure:
This compound was prepared in a manner similar to that of methyl-(5'-fluoro-2'-methoxy-4-nitro-2-biphenyl)carboxylate (EXAMPLE 107) from methyl 2-bromo-5-nitrobenzoate (1.25 g, 4.8 mmol, 1.0 equivuiv), tetrakis(triphenylphosphine)palladium (Aldrich: 0.16 g, 0.14 mmol, 2.9 mol %), and 5-chloro-2-methoxyphenylboronic acid (1.30 g, 6.9 mmol, 1.5 equivuiv) to afford 0.85 g (55%) of methyl-5'-chloro-2'-methoxy-4-nitro-2-biphenylcarboxylate as a yellow-orange solid. Data for methyl-5'-chloro-2'-methoxy-4-nitro-2-biphenylcarboxylate: 1H NMR (400 MHz, CDCl3): 8.73 (d, J=2.4, 1 H); 8.38 (dd, J=8.5, 2.5, 1 H); 7.49 (d, J=8.5, 1 H); 7.36 (dd, J=8.7, 2.5, 1 H); 7.23 (d, J=2.5, 1 H); 6.85 (d, J=8.7, 1 H); 3.76 (s, 3 H); 3.70 (s, 3 H).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]=[CH:7][CH:6]=[C:5]2Cl.Cl.[CH3:14][O:15][C@@H:16]1[CH2:20][CH2:19][NH:18][CH2:17]1>>[Br:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]=[CH:7][CH:6]=[C:5]2[N:18]1[CH2:19][CH2:20][C@@H:16]([O:15][CH3:14])[CH2:17]1
Reactant: Clc1ccnc2ccc(Br)cc12
Reactant: CO[C@@H]1CCNC1
Agent: Cl
Product: CO[C@@H]1CCN(c2ccnc3ccc(Br)cc23)C1
Yield: 44.8 %

Procedure:
500 mg 6-bromo-4-chloroquinoline and 300 mg (3R)-3-methoxy pyrrolidine monohydrochloride were reacted by the same method as in Production Example 82, to give 284 mg of the title compound as a yellow oil.
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]([CH3:27])[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:34](Cl)(=[O:37])[CH2:35][CH3:36]>>[CH:30]1([CH2:29][O:28][C:22]2[CH:23]=[CH:24][C:25]([CH3:27])=[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:34](=[O:37])[CH2:35][CH3:36])[CH2:4][CH2:5]4)=[O:11])=[C:13]([CH3:33])[NH:14][C:15]=23)[CH2:31][CH2:32]1
Reactant: Cc1ccc(OCC2CC2)c(-c2ccnc3c(C(=O)N[C@H]4CC[C@H](N)CC4)c(C)[nH]c23)c1
Reactant: CCC(=O)Cl
Agent: Cl
Product: CCC(=O)N[C@H]1CC[C@H](NC(=O)c2c(C)[nH]c3c(-c4cc(C)ccc4OCC4CC4)ccnc23)CC1

Procedure:
Starting from N-(trans-4-aminocyclohexyl)-7-[2-(cyclopropylmethoxy)-5-methylphenyl]-2-methyl-1H-pyrrolo[3,2-b]pyridine-3-carboxamide hydrochloride (example D.f19) and commercially available propionyl chloride the title compound is obtained as colorless solid.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]2[CH2:12][CH2:11][N:10]([CH2:13][C:14]([OH:16])=O)[C:9]2=[O:17])=[CH:4][CH:3]=1.C(Cl)(=O)C(Cl)=O.[F:24][C:25]([F:34])([F:33])[C:26]1[CH:27]=[CH:28][C:29]([NH2:32])=[N:30][CH:31]=1.CN1CCOCC1>ClCCl>[F:1][C:2]1[CH:3]=[CH:4][C:5]([CH:8]2[CH2:12][CH2:11][N:10]([CH2:13][C:14]([NH:32][C:29]3[CH:28]=[CH:27][C:26]([C:25]([F:33])([F:24])[F:34])=[CH:31][N:30]=3)=[O:16])[C:9]2=[O:17])=[CH:6][CH:7]=1
Reactant: Nc1ccc(C(F)(F)F)cn1
Reactant: O=C(O)CN1CCC(c2ccc(F)cc2)C1=O
Agent: O=C(Cl)C(=O)Cl
Solvent: ClCCl
Solvent: CN1CCOCC1
Product: O=C(CN1CCC(c2ccc(F)cc2)C1=O)Nc1ccc(C(F)(F)F)cn1
Reaction time: 0.5 h

Procedure:
To a suspension of 2-(3-(4-fluorophenyl)-2-oxopyrrolidin-1-yl)acetic acid (0.088 g, 0.370 mmol; Example 216A) in dichloromethane (1 mL) was added oxalyl dichloride (0.308 mL, 0.617 mmol). After 30 minutes, the reaction was concentrated and dried. This residue was dissolved in dichloromethane (1 mL) and 5-(trifluoromethyl)pyridin-2-amine (0.050 g, 0.308 mmol) was added followed by 4-methylmorpholine (0.068 mL, 0.617 mmol). After stirring for 30 minutes, the reaction was loaded onto a GraceResolv™ 12 g silica gel column (Grace Davison Discovery Sciences) and the product eluted with a gradient of 5% ethyl acetate/hexanes to 100% ethyl acetate/hexanes (Flow=20 mL/minute) over 30 minutes to give the title compound. 1H NMR (300 MHz, CDCl3) δ 8.67 (s, 1H), 8.57-8.52 (m, 1H), 8.28 (d, J=8.7, 1H), 7.92 (dd, J=2.3, 8.8, 1H), 7.35-7.21 (m, 2H), 7.09-6.99 (m, 2H), 4.25 (d, J=16.0, 1H), 4.18 (d, J=16.0, 1H), 3.78 (t, J=9.0, 1H), 3.69-3.59 (m, 2H), 2.63 (m, 1H), 2.23 (m, 1H); MS (ESI+) m/z 382.0 (M+H)+.
Reaction SMILES: F[C:2]1[CH:9]=[CH:8][C:7]([Br:10])=[CH:6][C:3]=1[CH:4]=O.[CH2:11]([NH2:14])[CH2:12][NH2:13]>O>[Br:10][C:7]1[CH:8]=[CH:9][C:2]2[NH:14][CH2:11][CH2:12][N:13]=[CH:4][C:3]=2[CH:6]=1
Reactant: O=Cc1cc(Br)ccc1F
Reactant: NCCN
Solvent: O
Product: Brc1ccc2c(c1)C=NCCN2
Temperature: 140 °C

Procedure:
A 5 mL microwave tube was charged with 2-fluoro-5-bromobenzaldehyde (1 g) and ethylenediamine (3 mL). The mixture was heated to 140° C. for 300 s using microwave irradiation. The reaction was diluted with water and extracted with diethyl ether. The organics were extracted with 1N HCl, and the pH of the aqueous layer was adjusted to ˜8 with 2.5M NaOH. The basic water layer was extracted again with diethyl ether. The organics were dried over magnesium sulfate, filtered and concentrated to dryness. Reconcentration from diethyl ether afforded 7-bromo-2,3-dihydro-1H-1,4-benzodiazepine as a yellow crystalline solid. H1 NMR (d6-dmso): 8.04 (s, 1H), 7.46 (d, 1H), 7.19 (dd, 1H), 7.07 (br t, 1H), 6.64 (d, 1H), 3.82 (m, 2H), 3.17 (m, 2H). Mass (ES+)=225.0 (100%).
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[CH:13]=[CH:12][CH:11]=[CH:10][C:9]2=[O:14])=[CH:4][C:3]=1[F:15].C[Si]([N-][Si](C)(C)C)(C)C.[Li+].[CH2:26]([O:28][C:29]([CH:31]1[CH:36]2[CH:32]1[C:33](=[O:45])[N:34]([C:38]1[CH:43]=[CH:42][C:41]([Cl:44])=[CH:40][CH:39]=1)[C:35]2=[O:37])=[O:30])[CH3:27].Cl>C1COCC1>[CH2:26]([O:28][C:29]([CH:31]1[CH:36]([C:35](=[O:37])[NH:1][C:2]2[CH:7]=[CH:6][C:5]([N:8]3[CH:13]=[CH:12][CH:11]=[CH:10][C:9]3=[O:14])=[CH:4][C:3]=2[F:15])[CH:32]1[C:33](=[O:45])[NH:34][C:38]1[CH:39]=[CH:40][C:41]([Cl:44])=[CH:42][CH:43]=1)=[O:30])[CH3:27]
Reactant: Nc1ccc(-n2ccccc2=O)cc1F
Reactant: CCOC(=O)C1C2C(=O)N(c3ccc(Cl)cc3)C(=O)C12
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: Cl
Agent: [Li+]
Solvent: C1CCOC1
Product: CCOC(=O)C1C(C(=O)Nc2ccc(Cl)cc2)C1C(=O)Nc1ccc(-n2ccccc2=O)cc1F
Reaction time: 0.5 h
Yield: 24 %

Procedure:
A solution of 7 g (34 mmol) of 1-(4-amino-3-fluoro-phenyl)-1H-pyridin-2-one (prepared according to C. F. Bigge et al., patent application WO 2003045912) in 25 ml of THF was cooled to −78° C. and treated dropwise with 41 ml of a 1M lithium bis(trimethylsilyl)amide-solution in THF and stirred for 30 min. To this solution 9.5 g (32 mmol) of (1RS, 5SR, 6R)-3-(4-chloro-phenyl)-2,4-dioxo-3-aza-bicyclo[3.1.0]hexane-6-carboxylic acid ethyl ester were added portionwise and the mixture was allowed to reach room temperature within a few hours. The mixture was then poured into a diluted aqueous HCl-solution (ca. 0.2 M) and extracted with AcOEt. The combined organic phases were dried with Na2SO4. Evaporation of the solvent and chromatography on silica gel with dichloromethane and then with a gradient of dichloromethane/MeOH from 98:2 to 95:5 gave 4.1 g (24%) of the title compound. Light brown solid. MS: 496 (M−H)−.
Reaction SMILES: [N:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[NH:3][CH:2]=1.[CH2:10]1[O:12][CH2:11]1>CN(C)C(=O)C>[N:1]1([CH2:10][CH2:11][OH:12])[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[N:3]=[CH:2]1
Reactant: c1ccc2[nH]cnc2c1
Reactant: C1CO1
Solvent: CC(=O)N(C)C
Product: OCCn1cnc2ccccc21
Temperature: 100 °C
Reaction time: 16 h

Procedure:
A mixture of 118 g of benzimidazole, 48.5 g of ethylene oxide, and 400 g of N,N-dimethylacetamide was heated and stirred in an autoclave at 100° C. for 16 hours. The solvent was distilled off in vacuo, yielding crude 2-(1H-benzimidazol-1-yl)ethanol.
Reaction SMILES: [C:1]([O:5][C:6](=[O:28])[NH:7][CH:8]1[CH2:17][CH2:16][C:15]2[C:10](=[CH:11][C:12]([C:18]#[N:19])=[CH:13][CH:14]=2)[CH:9]1[CH2:20][C:21]1[CH:26]=[CH:25][C:24](Cl)=[CH:23][CH:22]=1)([CH3:4])([CH3:3])[CH3:2]>CO.[Ni]>[C:1]([O:5][C:6](=[O:28])[NH:7][CH:8]1[CH2:17][CH2:16][C:15]2[C:10](=[CH:11][C:12]([CH2:18][NH2:19])=[CH:13][CH:14]=2)[CH:9]1[CH2:20][C:21]1[CH:22]=[CH:23][CH:24]=[CH:25][CH:26]=1)([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)NC1CCc2ccc(C#N)cc2C1Cc1ccc(Cl)cc1
Agent: [Ni]
Solvent: CO
Product: CC(C)(C)OC(=O)NC1CCc2ccc(CN)cc2C1Cc1ccccc1
Temperature: 25 °C
Reaction time: 4 h

Procedure:
Tert-butyl[1-(4-chlorobenzyl)-7-cyano-1,2,3,4-tetrahydronaphthalen-2-yl]carbamate (52 mg, 0.131 mmol, cf. example 30d) were dissolved in methanol (5 mL). Raney nickel (about 30 mg) was added and the reaction mixture was stirred at room temperature for 4 h under an atmosphere of hydrogen. The catalyst was removed by filtration. The solvent was evaporated in vacuo. The crude product was used without further purification for the next step. Yield: 32 mg (0.087 mmol, 67%).
Reaction SMILES: [CH2:1]([O:8][C:9]([N:11]1[CH2:15][C@H:14]([O:16][S:17]([CH3:20])(=[O:19])=[O:18])[CH2:13][C@H:12]1[CH2:21][O:22][CH2:23][C:24](=[O:30])[CH2:25][C:26]([O:28][CH3:29])=[O:27])=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[BH4-].[Na+].[CH3:33]C(C)=O>C(O)C>[CH2:1]([O:8][C:9]([N:11]1[CH2:15][C@H:14]([O:16][S:17]([CH3:20])(=[O:19])=[O:18])[CH2:13][C@H:12]1[CH2:21][O:22][CH2:23][CH:24]([OH:30])[CH2:25][C:26]([O:28][CH2:29][CH3:33])=[O:27])=[O:10])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CC(C)=O
Reactant: COC(=O)CC(=O)COC[C@@H]1C[C@@H](OS(C)(=O)=O)CN1C(=O)OCc1ccccc1
Agent: [BH4-]
Agent: [Na+]
Solvent: CCO
Product: CCOC(=O)CC(O)COC[C@@H]1C[C@@H](OS(C)(=O)=O)CN1C(=O)OCc1ccccc1
Reaction time: 6 h

Procedure:
To a solution of (2S,4R)-1-benzyloxycarbonyl-2-[{3-(methoxycarbonyl)-2-oxopropyl}oxymethyl]-4-methanesulfonyloxypyrrolidine (7 g) in ethanol (80 ml) was added by portions sodium borohydride (1.2 g) at 0° C. After 6 hours, to the reaction mixture was carefully added dropwise acetone (30 ml) at 0° C. and then the solvent was evaporated in vacuo. To the resultant residue were added ethyl acetate (100 ml) and water (50 ml). The organic layer was separated, washed with brine (50 ml) and dried over magnesium sulfate. Evaporation of the solvent gave a residue, which was chromatographed on silica gel (500 ml) eluting with a mixture of dichloromethane and methanol (18:1 V/V) to give (2S,4R)-1-benzyloxycarbonyl-2-[{3-(ethoxycarbonyl)-2-hydroxypropyl}oxymethyl]-4-methanesulfonyloxypyrrolidine (5.1 g).
Reaction SMILES: [CH:1]1([S:4]([N:7]2[CH2:12][CH2:11][N:10]([C:13]([C:15]3[NH:16][C:17]4[C:22]([CH:23]=3)=[CH:21][C:20]([C:24]([N:26]3[CH2:31][CH2:30][N:29]([CH:32]([CH3:34])[CH3:33])[CH2:28][CH2:27]3)=[O:25])=[CH:19][CH:18]=4)=[O:14])[CH2:9][CH2:8]2)(=[O:6])=[O:5])[CH2:3][CH2:2]1.[Cl:35][C:36]1[CH:41]=[C:40](B(O)O)[CH:39]=[CH:38][N:37]=1>>[Cl:35][C:36]1[CH:41]=[C:40]([N:16]2[C:17]3[C:22](=[CH:21][C:20]([C:24]([N:26]4[CH2:27][CH2:28][N:29]([CH:32]([CH3:34])[CH3:33])[CH2:30][CH2:31]4)=[O:25])=[CH:19][CH:18]=3)[CH:23]=[C:15]2[C:13]([N:10]2[CH2:9][CH2:8][N:7]([S:4]([CH:1]3[CH2:2][CH2:3]3)(=[O:5])=[O:6])[CH2:12][CH2:11]2)=[O:14])[CH:39]=[CH:38][N:37]=1
Reactant: OB(O)c1ccnc(Cl)c1
Reactant: CC(C)N1CCN(C(=O)c2ccc3[nH]c(C(=O)N4CCN(S(=O)(=O)C5CC5)CC4)cc3c2)CC1
Product: CC(C)N1CCN(C(=O)c2ccc3c(c2)cc(C(=O)N2CCN(S(=O)(=O)C4CC4)CC2)n3-c2ccnc(Cl)c2)CC1
Yield: 61 %

Procedure:
The title compound was synthesized in analogy to example 5, from (4-cyclopropanesulfonyl-piperazin-1-yl)-[5-(4-isopropyl-piperazine-1-carbonyl)-1H-indol-2-yl]-methanone (example 33) and 2-chloropyridine-4-boronic acid to afford the desired product as light-brown foam (61%). MS (ISP): 599.4 (M+H)+.
Reaction SMILES: Cl.[F:2][C:3]1[CH:12]=[C:11]2[C:6]([CH2:7][CH2:8][N:9]=[CH:10]2)=[CH:5][CH:4]=1.[CH3:13][C:14]([C:16]1[CH2:21][CH2:20][CH2:19][CH2:18][CH:17]=1)=[O:15].O>C(O)C>[F:2][C:3]1[CH:4]=[CH:5][C:6]2[CH2:7][CH2:8][N:9]3[CH:10]([CH2:13][C:14](=[O:15])[CH:16]4[CH2:21][CH2:20][CH2:19][CH2:18][CH:17]43)[C:11]=2[CH:12]=1
Reactant: Fc1ccc2c(c1)C=NCC2
Reactant: CC(=O)C1=CCCCC1
Agent: Cl
Solvent: CCO
Solvent: O
Product: O=C1CC2c3cc(F)ccc3CCN2C2CCCCC12
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A mixture of 19.5 g (0.1 mole) of 3,4-dihydro-7-fluoroisoquinoline hydrochloride and 18.6 g (0.15 mole) of 1-cyclohexen-1-yl methyl ketone in 22 ml of ethanol is refluxed with stirring overnight then cooled to room temperature. The solution is poured into water, whereupon a suspension of undissolved material forms, and is extracted with ether. The aqueous layer and its suspended solid are stirred and treated with ammonium hydroxide solution to pH 8.5 to 9.0. The suspended solid is broken up, collected by decantation washed with water, dissolved in methylene chloride, dried over sodium sulfate and evaporated. The remaining residue is dissolved in benzene and chromatographed on alumina and eluted with benzene. The resulting solid is triturated with hexane and dried to give 2,3,4,4a,6,7,11b, 12,13,13a-decahydro-10-fluoro-1H-dibenzo[a,f]quinolizin-13-one, M.P. 130°-136°C.
Reaction SMILES: Cl[C:2]1[N:3]=[C:4]([N:22]2[CH2:27][CH2:26][O:25][CH2:24][CH2:23]2)[C:5]2[S:10][C:9]([CH2:11][N:12]3[CH2:17][CH2:16][N:15]([S:18]([CH3:21])(=[O:20])=[O:19])[CH2:14][CH2:13]3)=[CH:8][C:6]=2[N:7]=1.CC1(C)C(C)(C)OB([C:36]2[CH:37]=[CH:38][C:39]([NH:42][C:43](=[O:45])[CH3:44])=[N:40][CH:41]=2)O1>>[O:25]1[CH2:26][CH2:27][N:22]([C:4]2[C:5]3[S:10][C:9]([CH2:11][N:12]4[CH2:17][CH2:16][N:15]([S:18]([CH3:21])(=[O:20])=[O:19])[CH2:14][CH2:13]4)=[CH:8][C:6]=3[N:7]=[C:2]([C:36]3[CH:37]=[CH:38][C:39]([NH:42][C:43](=[O:45])[CH3:44])=[N:40][CH:41]=3)[N:3]=2)[CH2:23][CH2:24]1
Reactant: CS(=O)(=O)N1CCN(Cc2cc3nc(Cl)nc(N4CCOCC4)c3s2)CC1
Reactant: CC(=O)Nc1ccc(B2OC(C)(C)C(C)(C)O2)cn1
Product: CC(=O)Nc1ccc(-c2nc(N3CCOCC3)c3sc(CN4CCN(S(C)(=O)=O)CC4)cc3n2)cn1

Procedure:
2-Chloro-6-(4-methanesulfonyl-piperazin-1-ylmethyl)-4-morpholin-4-yl-thieno[3,2-d]pyrimidine, prepared via General Procedure B-3, was reacted with N-[5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridine-2-yl]-acetamide via General Procedure A. Purification on silica and ether trituration gave 233. NMR (CDCl3): 2.25 (3H, s), 2.67-2.71 (4H, m), 2.81 (3H, s), 3.29-3.33 (4H, m), 3.89 (2H, s), 3.89-3.93 (4H, m), 4.08-4.12 (4H, m), 7.35 (1H, s), 7.97 (1H, br. s), 8.28 (1H, d), 8.71 (1H, d), 9.30 (1H, s). MS (ESI+): MH+532.28 (100%)
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:14]=[CH:13][C:12]([S:15]([N:18]2[CH2:23][CH:22]([OH:24])[CH2:21][CH2:20][CH:19]2[C:25]([OH:27])=[O:26])(=[O:17])=[O:16])=[CH:11][CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[H-].[Na+].I[CH3:31].Cl>C1COCC1.CN1CCCC1=O>[CH2:1]([O:8][C:9]1[CH:10]=[CH:11][C:12]([S:15]([N:18]2[CH2:23][CH:22]([O:24][CH3:31])[CH2:21][CH2:20][CH:19]2[C:25]([OH:27])=[O:26])(=[O:16])=[O:17])=[CH:13][CH:14]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: O=C(O)C1CCC(O)CN1S(=O)(=O)c1ccc(OCc2ccccc2)cc1
Reactant: CI
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CN1CCCC1=O
Product: COC1CCC(C(=O)O)N(S(=O)(=O)c2ccc(OCc3ccccc3)cc2)C1
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 73 %

Procedure:
A mixture of 1-(4-benzyloxy-benzenesulfonyl)-5-hydroxy-piperidine-2-carboxylic acid (0.10 g, 0.26 mmol) and 1:1 THF-N-methylpyrrolidin-2-one (1 mL) was treated with NaH (0.031 g, 0.78 mmol, 60% dispersion in mineral oil). After stirring for 10 min, the mixture was warmed to room temperature, stirred for 20 min and treated with iodomethane (0.016 mL, 0.26 mmol). After stirring fro 3 h, the mixture was treated with an additional 0.010 g of NaH and 0.015 mL of iodomethane. The resulting mixture was stirred for 24 h, acidified with 1M HCl, extracted 3× with ethyl acetate, and the combined organic layers were dried over Na2SO4, filtered and concentrated in vacuo. Purification of the residue by radial chromatography (1:1 to 2:1 ethyl acetate hexane containing 1% of acetic acid, 2 mm silica gel plate) afforded 0.077 g (75%) of 1-(4-benzyloxy-benzenesulfonyl)-5-methoxy-piperidine-2-carboxylic acid as a colorless syrup:
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[C:8](=[O:12])[NH:7][C:6](=[O:13])/[C:5]/2=[CH:14]\NC1C=NC(C2C[C@H](C)N[C@H](C)C2)=C(C)C=1.BrC1C=C2C(=CC=1)[C:38](=[O:42])NC(=O)C2=CNC1C=CC(N2CC(C)NC(C)C2)=CC=1>>[Br:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[C:8](=[O:12])[NH:7][C:6](=[O:13])/[C:5]/2=[CH:14]/[O:42][CH3:38]
Reactant: Cc1cc(N/C=C2\C(=O)NC(=O)c3ccc(Br)cc32)cnc1C1C[C@@H](C)N[C@@H](C)C1
Reactant: CC1CN(c2ccc(NC=C3C(=O)NC(=O)c4ccc(Br)cc43)cc2)CC(C)N1
Product: CO/C=C1/C(=O)NC(=O)c2ccc(Br)cc21

Procedure:
Using the procedure described for the preparation of 4Z)-6-bromo-4-({[4-(3,5-dimethylpiperazin-1-yl)phenyl]amino}methylene)isoquinoline-1,3(2H,4H)-dione, 900 mg (86% yield) of solid is obtained from 630 mg (2.23 mmol) of (4E)-6-bromo-4-(methoxymethylene)isoquinoline-1,3(2H,4H)-dione, and 0.14 g (0.608 mmol) of 6-[(2R,6S)-2,6-dimethylpiperidin-4-yl]-5-methylpyridin-3-yl}amine; mp: 194-195° C.;
Reaction SMILES: C([Li])CCC.Br[C:7]1[CH:8]=[C:9]2[CH:15]=[CH:14][N:13]([Si:16]([CH:23]([CH3:25])[CH3:24])([CH:20]([CH3:22])[CH3:21])[CH:17]([CH3:19])[CH3:18])[C:10]2=[N:11][CH:12]=1.C1C=CC(S(N(S(C2C=CC=CC=2)(=O)=O)[F:36])(=O)=O)=CC=1>C1COCC1.CCCCCC>[F:36][C:7]1[CH:8]=[C:9]2[CH:15]=[CH:14][N:13]([Si:16]([CH:23]([CH3:25])[CH3:24])([CH:20]([CH3:22])[CH3:21])[CH:17]([CH3:19])[CH3:18])[C:10]2=[N:11][CH:12]=1
Reactant: CC(C)[Si](C(C)C)(C(C)C)n1ccc2cc(Br)cnc21
Reactant: O=S(=O)(c1ccccc1)N(F)S(=O)(=O)c1ccccc1
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: CCCCCC
Product: CC(C)[Si](C(C)C)(C(C)C)n1ccc2cc(F)cnc21
Temperature: -78 °C
Reaction time: 1 h
Yield: 50.1 %

Procedure:
2.5M Butyl lithium (4.4 mL, 10.8 mmol) was added dropwise to a stirred solution of 5-bromo-1-(triisopropylsilyl)-1H-pyrrolo[2,3-b]pyridine (2.55 g, 7.23 mmol) in THF (65 mL) over 10 min at −78° C. under nitrogen in three necked flask. The resulting solution was stirred at −78° C. for 1 h and solid N-fluorobenzenesulfonimide (2.84 g, 9.03 mmol) was added in one portion and stirred at −78° C. for 2 h. The solvent was evaporated and the crude material was dissolved in water (50 mL) and extracted with EtOAc (3×25 mL). The organic extract was dried and concentrated under reduced pressure to give a residue which was suspended in hexane (5 mL) and filtered. The filtrate was chromatographed (Biotage HPFC) on silica gel eluting with hexane to give 5-fluoro-1-(triisopropylsilyl)-1H-pyrrolo[2,3-b]pyridine (1.06 g, 50.2%) as a viscous oil.; Mass Spec.; MS 293 (M+1); 1H NMR(CDCl3,500 MHz) 8.11(d,1H), 7.51(dd,1H), 7.34(d,1H), 6.50(d,1H), 1.84(q,3H), 1.10(d,18H).
Reaction SMILES: CC1C=CC(S(O)(=O)=O)=CC=1.C1(C)C=CC(S(O[CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][N:28]2[C:33](=[O:34])[CH2:32][O:31][CH2:30][C:29]2=[O:35])(=O)=O)=CC=1.[NH:37]1[CH2:42][CH2:41][CH2:40][CH2:39][CH2:38]1>C(O)(C)(C)C>[N:37]1([CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][N:28]2[C:29](=[O:35])[CH2:30][O:31][CH2:32][C:33]2=[O:34])[CH2:42][CH2:41][CH2:40][CH2:39][CH2:38]1
Reactant: C1CCNCC1
Reactant: Cc1ccc(S(=O)(=O)OCCCCCCN2C(=O)COCC2=O)cc1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: CC(C)(C)O
Product: O=C1COCC(=O)N1CCCCCCN1CCCCC1

Procedure:
p-toluenesulfonate. To a solution of 19.6 grams (53.2 millimoles) of 6-(3,5-dioxomorpholino)hexyl p-toluenesulfonate in 54 milliliters of tertiary butyl alcohol was added 5.3 milliliters of tertiary (53 millimoles) of piperidine in 54 milliliters of tertiary butyl alcohol. The reaction mixture was heated at reflux temperature for about 22 hours to obtain 4-(6-piperidinohexyl)-3,5-dioxomorpholine.p-toluenesulfonate product which crystallized from tertiary butyl alcohol-ether mixture in a yield of 13.45 grams (56 percent) as an off-white solid, m.p. 125°-128° C. A portion of this product after purification by (a) chromatographing on Silicar CC4 Special (Silica gel, product of Mallinkrodt) employing 10:1 dichloromethanemethanol as eluant, (b) recovering from the effluent and (c) recrystallizing from tertiary butyl alcohol-ether, was a white solid, m.p. 121°-122.5° C.
Reaction SMILES: C[C:2]1([CH3:9])[O:6][C@H:5]([CH2:7][OH:8])[CH2:4][O:3]1.[OH-].[K+].Br[CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18]CC.O>C1C=CC=CC=1>[CH2:2]([O:3][CH2:4][C@H:5]([CH2:7][OH:8])[OH:6])[CH2:9][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH3:18]
Reactant: CCCCCCCCBr
Reactant: CC1(C)OC[C@@H](CO)O1
Agent: [K+]
Agent: [OH-]
Solvent: c1ccccc1
Solvent: O
Product: CCCCCCCCOC[C@@H](O)CO
Temperature: 25 °C

Procedure:
21 ml of (R)-(−)-2,2-dimethyl-1,3-dioxolane-4-methanol, 29 grams of powdered potassium hydroxide and 32 ml of 1-bromooctane were stirred in 150 ml benzene and refluxed for 6 hours, while removing the water formed by azeotropic distillation. The volume of the solvent was gradually reduced to about 100 ml. The reaction mixture was then cooled to room temperature and 200 ml water was added. The reaction mixture was then extracted thrice with 150 ml diethyl ether, the combined organic phase was washed with 100 ml water, and the solvent was then removed under reduced pressure. The obtained residue was dissolved in 100 ml of a 90:10:5 (v/v) mixture of methanol:water:concentrated hydrochloric acid, and the resulting solution was refluxed for 2 hours, followed by cooling to room temperature and addition of 100 ml water. The product was extracted thrice with 150 ml chloroform, washed consecutively with 150 ml water, 150 ml of saturated aqueous solution of sodium bicarbonate, and again with 100 ml water. The solvent was dried over anhydrous Na2SO4, filtered, and removed under reduced pressure, yielding 34 grams of (S)-1-octyl-glycerol.