Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C(OC([N:8]([C:10]1([C@@H:13]2[CH2:17][CH2:16][NH:15][CH2:14]2)[CH2:12][CH2:11]1)[CH3:9])=O)(C)(C)C.C(N(CC)CC)C.[CH:25]1([N:28]2[C:37]3[C:32](=[CH:33][CH:34]=[C:35](F)[C:36]=3[CH3:38])[C:31](=[O:40])[C:30]([C:41]([OH:43])=[O:42])=[CH:29]2)[CH2:27][CH2:26]1>CS(C)=O>[CH:25]1([N:28]2[C:37]3[C:32](=[CH:33][CH:34]=[C:35]([N:15]4[CH2:16][CH2:17][C@@H:13]([C:10]5([NH:8][CH3:9])[CH2:11][CH2:12]5)[CH2:14]4)[C:36]=3[CH3:38])[C:31](=[O:40])[C:30]([C:41]([OH:43])=[O:42])=[CH:29]2)[CH2:26][CH2:27]1
Reactant: Cc1c(F)ccc2c(=O)c(C(=O)O)cn(C3CC3)c12
Reactant: CN(C(=O)OC(C)(C)C)C1([C@@H]2CCNC2)CC1
Solvent: CS(C)=O
Solvent: CCN(CC)CC
Product: CNC1([C@@H]2CCN(c3ccc4c(=O)c(C(=O)O)cn(C5CC5)c4c3C)C2)CC1
Temperature: 70 °C
Reaction time: 0.5 h
Yield: 53.2 %

Procedure:
After adding 3-(R)-[1-[N-(tert-butoxycarbonyl)-N-(methyl)amino]cyclopropyl]pyrrolidine (880 mg, 3.25 mmol) and triethylamine (1.0 ml) to dried dimethyl sulfoxide (5 ml), 1-cyclopropyl-7-fluoro-8-methyl-1,4-dihydro-4-oxoquinoline-3-carboxylic acid (425 mg, 1.63 mmol) was added thereto and heated under reflux in an oil bath of 70° C. for 38 hours under a nitrogen atmosphere. After concentrating the reaction solution under a reduced pressure, the residue was dissolved in ethyl acetate (200 ml). After washing the organic layer with a 10% aqueous citric acid solution (100 ml), the organic layer was dried over anhydrous sodium sulfate. After filtering, the filtrate was concentrated under a reduced pressure, and after adding dropwise concentrated hydrochloric acid (6 ml) to the residue while cooling with ice, it was stirred at room temperature for 30 minutes. After adding 1 mol/l hydrochloric acid (12 ml) to the reaction solution and washing the yellow acidic aqueous solution with chloroform (50 ml×3), the pH was adjusted to 12.0 with an aqueous sodium hydroxide solution. After adjusting the pH of the basic aqueous solution to 7.4 with 1 mol/l hydrochloric acid, extraction with chloroform (100 ml×3) was performed. After drying over anhydrous sodium sulfate, the solvent was evapolated under a reduced pressure. The residue thus obtained was then purified by recrystallization from a mixed solvent of methanol/2-propanol, and then dried under a reduced pressure. 331 mg (53%) of the title compound was thereby obtained in the form of yellow crystals.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][C:6]([CH3:11])=[C:5]2[C:12]([OH:14])=O.[NH2:15][CH:16]1[CH2:21][CH2:20][N:19]([CH2:22][CH2:23][C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)[CH2:18][CH2:17]1>O1CCCC1>[F:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][C:6]([CH3:11])=[C:5]2[C:12]([NH:15][CH:16]1[CH2:21][CH2:20][N:19]([CH2:22][CH2:23][C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)[CH2:18][CH2:17]1)=[O:14]
Reactant: NC1CCN(CCc2ccccc2)CC1
Reactant: Cc1[nH]c2ccc(F)cc2c1C(=O)O
Solvent: C1CCOC1
Product: Cc1[nH]c2ccc(F)cc2c1C(=O)NC1CCN(CCc2ccccc2)CC1
Yield: 47.4 %

Procedure:
A solution of 4.0 g of 5-fluoro-2-methylindole-3-carboxylic acid and 4.2 g of 4-amino-1-(2-phenylethyl)piperidine in 80 ml of tetrahydrofuran was allowed to stand for a while to precipitate a salt. To the suspension was added 4.7 g of dicyclohexylcarbodiimide and the mixture was stirred under reflux for 3 hours. After cooling, the precipitated dicyclohexylurea was filtered off and the filtrate was concentrated. The residue was crystallized by treatment of hexane. The crystals were filtered with suction and recrystallized from ethyl acetate to yield 3.7 g of 5-fluoro-2-methyl-N-[1-(2-phenylethyl)-4-piperidyl]indole-3-carboxamide, melting at 159°-162° C. The crude product (3.9 g) was recovered from the mother liquor.
Reaction SMILES: [CH3:1][C:2]1([CH3:28])[CH2:7][CH:6]([NH:8][C:9]2[N:14]=[C:13]([C:15]3[CH:20]=[CH:19][C:18]([CH2:21][CH2:22][C:23](=[O:25])[CH3:24])=[CH:17][CH:16]=3)[CH:12]=[CH:11][N:10]=2)[CH2:5][C:4]([CH3:27])([CH3:26])[NH:3]1.[BH4-].[Na+]>CO>[CH3:27][C:4]1([CH3:26])[CH2:5][CH:6]([NH:8][C:9]2[N:14]=[C:13]([C:15]3[CH:20]=[CH:19][C:18]([CH2:21][CH2:22][CH:23]([OH:25])[CH3:24])=[CH:17][CH:16]=3)[CH:12]=[CH:11][N:10]=2)[CH2:7][C:2]([CH3:28])([CH3:1])[NH:3]1
Reactant: CC(=O)CCc1ccc(-c2ccnc(NC3CC(C)(C)NC(C)(C)C3)n2)cc1
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Product: CC(O)CCc1ccc(-c2ccnc(NC3CC(C)(C)NC(C)(C)C3)n2)cc1

Procedure:
The title compound was prepared by reduction of 4-{4-[2-(2,2,6,6-tetramethyl-piperidin-4-ylamino)-pyrimidin-4-yl]-phenyl}-butan-2-one with sodium borohydride in MeOH. Yield: 196 mg (100%).
Reaction SMILES: [C:1]1(=[O:12])[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH2:4][C:3](=[O:11])O1.[NH2:13][CH2:14][CH2:15][CH2:16][NH:17][CH2:18][CH2:19][CH2:20][NH2:21]>>[O:12]=[C:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH2:4][C:3](=[O:11])[N:13]1[CH2:14][CH2:15][CH2:16][NH:17][CH2:18][CH2:19][CH2:20][N:21]1[C:3](=[O:11])[CH2:4][C:5]2[C:10](=[CH:9][CH:8]=[CH:7][CH:6]=2)[C:1]1=[O:12]
Reactant: NCCCNCCCN
Reactant: O=C1Cc2ccccc2C(=O)O1
Product: O=C1Cc2ccccc2C(=O)N1CCCNCCCN1C(=O)Cc2ccccc2C1=O

Procedure:
N,N-Bis-[3-(3,4-dihydro-1,3-dioxo-2(1H)-isoquinolyl)-propyl]-amine was prepared analogous to Example 30 from 2.44 gm of isochroman-1,3-dione and N,N-bis-(3-amino-propyl)-amine. The hydrochloride was precipitated from acetone with ethereal hydrochloric acid. M.p. of the hydrochloride: 135° -140° C; yield: 0.17 gm (2.5% of the theory).
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:14]=[CH:13][C:12]([NH:15][C:16]2[CH:24]=[CH:23][C:22]([O:25][CH3:26])=[CH:21][C:17]=2[C:18]([OH:20])=[O:19])=[CH:11][CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:27](Cl)(Cl)=[O:28]>>[CH2:1]([O:8][C:9]1[CH:10]=[CH:11][C:12]([N:15]2[C:27](=[O:28])[O:20][C:18](=[O:19])[C:17]3=[CH:21][C:22]([O:25][CH3:26])=[CH:23][CH:24]=[C:16]23)=[CH:13][CH:14]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: COc1ccc(Nc2ccc(OCc3ccccc3)cc2)c(C(=O)O)c1
Reactant: O=C(Cl)Cl
Product: COc1ccc2c(c1)c(=O)oc(=O)n2-c1ccc(OCc2ccccc2)cc1
Yield: 79 %

Procedure:
N-(4-Benzyloxyphenyl)-5-methoxyisatoic anhydride [VIII; R=5-CH3O, R"=H, OR°=4-OCH2C6H5 ] was prepared from 2-(4-benzyloxyphenylamino)-5-methoxybenzoic acid and phosgene according to the procedure of Example 1, part (b), and was obtained in 79% yield as a colorless solid used directly in the next reaction.
Reaction SMILES: [Cl:1][C:2]1[C:3]([F:10])=[N:4][C:5](F)=[C:6]([Cl:8])[CH:7]=1.CCCCCC.[H-].[Na+].[CH2:19]([O:23][CH2:24][CH2:25][O:26][CH2:27][CH2:28][OH:29])[CH2:20][CH2:21][CH3:22]>>[CH2:19]([O:23][CH2:24][CH2:25][O:26][CH2:27][CH2:28][O:29][C:5]1[C:6]([Cl:8])=[CH:7][C:2]([Cl:1])=[C:3]([F:10])[N:4]=1)[CH2:20][CH2:21][CH3:22]
Reactant: CCCCOCCOCCO
Reactant: Fc1nc(F)c(Cl)cc1Cl
Agent: [H-]
Agent: [Na+]
Solvent: CCCCCC
Product: CCCCOCCOCCOc1nc(F)c(Cl)cc1Cl
Temperature: 25 °C

Procedure:
A mixture was prepared by admixing 12.9 grams (0.07 mole) of 3,5-dichloro-2,6-difluoropyridine, 100 milliliters of diethyleneglycol n-butyl ether and 3.3 grams (0.75 mole) of a hexane slurry of sodium hydride. The sodium hydride was a 53 percent oil dispersion and had been washed 3 times with 10 milliliter portions of hexane. Considerable foaming occurred and after foaming ceased, the reaction mixture was stirred for ~10 minutes at room temperature and thereafter diluted with 200 milliliters of water. The mixture was extracted 3 times with 100 milliliter portions of hexane, the extracts combined and dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The oil which remained as a residue was vacuum distilled to yield 14.3 grams of 2-[2-(2-butoxyethoxy)ethoxy]-3,5-dichloro-6-fluoropyridine as a water-white product. The product had a boiling point of 113°-124° C. at 0.3 millimeters of mercury (mm). Upon analysis, the product was found to have carbon, hydrogen and nitrogen contents of 47.55, 5.37 and 4.36 percent, respectively, as compared with the theoretical contents of 47.87, 5.56 and 4.29 percent, respectively, as calculated for the above named compound.
Reaction SMILES: C(=O)(O)O.C(OC(C1CC[N:13](C(N)=O)[CH2:12]C1)=O)C.N([C:23]1[CH:49]=[CH:48][C:26]([C:27]([NH:29][CH:30]([C:45]([OH:47])=[O:46])[CH2:31][C:32]2[CH:37]=[CH:36][CH:35]=[C:34]([O:38][C:39]3[CH:44]=[CH:43][CH:42]=[CH:41][CH:40]=3)[CH:33]=2)=[O:28])=[CH:25][CH:24]=1)C(N)=N.C1CCCCC=1>CO.[Pd]>[NH2:13][CH2:12][C@H:23]1[CH2:24][CH2:25][C@H:26]([C:27]([NH:29][CH:30]([C:45]([OH:47])=[O:46])[CH2:31][C:32]2[CH:37]=[CH:36][CH:35]=[C:34]([O:38][C:39]3[CH:44]=[CH:43][CH:42]=[CH:41][CH:40]=3)[CH:33]=2)=[O:28])[CH2:48][CH2:49]1
Reactant: CCOC(=O)C1CCN(C(N)=O)CC1
Reactant: N=C(N)Nc1ccc(C(=O)NC(Cc2cccc(Oc3ccccc3)c2)C(=O)O)cc1
Agent: [Pd]
Agent: O=C(O)O
Solvent: C1=CCCCC1
Solvent: CO
Product: NC[C@H]1CC[C@H](C(=O)NC(Cc2cccc(Oc3ccccc3)c2)C(=O)O)CC1

Procedure:
A solution of the compound (III) (0.62 g), a palladium black (0.15 g), and cyclohexene (2 ml) in methanol (30 ml) was allowed to react under reflux of methanol for 1.5 hours. The reaction mixture was suction filtered while hot to remove the solid materials, followed by concentrating in vacuo. N-(trans-4-aminomethylcyclohexylcarbonyl)-3-phenoxy-DL-phenylalanine (0.30 g) was obtained in the form of a white powder.
Reaction SMILES: Cl[CH2:2][CH:3]1[O:8][CH2:7][C@@H:6]2[CH2:9][S:10][CH2:11][N:5]2[CH2:4]1.[F:12][C:13]([F:18])([F:17])[C:14]([OH:16])=[O:15].[Cl:19][C:20]1[CH:21]=[C:22]([NH:27][C:28]2[C:37]3[C:32](=[CH:33][C:34]([OH:40])=[C:35]([O:38][CH3:39])[CH:36]=3)[N:31]=[CH:30][N:29]=2)[CH:23]=[CH:24][C:25]=1[Cl:26].C(=O)([O-])[O-].[K+].[K+]>CN(C)C(=O)C>[F:12][C:13]([F:18])([F:17])[C:14]([OH:16])=[O:15].[Cl:19][C:20]1[CH:21]=[C:22]([NH:27][C:28]2[C:37]3[C:32](=[CH:33][C:34]([O:40][CH2:2][CH:3]4[O:8][CH2:7][C@@H:6]5[CH2:9][S:10][CH2:11][N:5]5[CH2:4]4)=[C:35]([O:38][CH3:39])[CH:36]=3)[N:31]=[CH:30][N:29]=2)[CH:23]=[CH:24][C:25]=1[Cl:26]
Reactant: ClCC1CN2CSC[C@H]2CO1
Reactant: COc1cc2c(Nc3ccc(Cl)c(Cl)c3)ncnc2cc1O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(=O)N(C)C
Solvent: O=C(O)C(F)(F)F
Product: COc1cc2c(Nc3ccc(Cl)c(Cl)c3)ncnc2cc1OCC1CN2CSC[C@H]2CO1
Yield: 9.6 %

Procedure:
A solution of (8aR)-6-(chloromethyl)tetrahydro-1H-[1,3]thiazolo[4,3-c][1,4]oxazine (11.6 mg, 0.0599 mmol), 4-[(3,4-dichlorophenyl)amino]-6-(methyloxy)quinazolin-7-ol trifluoroacetate (salt) (30.0 mg, 0.0644 mmol), and potassium carbonate (45.0 mg, 0.326 mmol) in N,N-dimethylacetamide (1.0 mL) was heated in a sealed tube to 150° C. for 12 h. The crude reaction mixture was directly purified via reverse-phase preparative HPLC (acetonitrile/water/0.1%-TFA). Lyophillization of the pure fractions yielded 3.5 mg (8.9%) of N-(3,4-dichlorophenyl)-6-(methyloxy)-7-{[(8aR)-tetrahydro-1H-[1,3]thiazolo[4,3-c][1,4]oxazin-6-ylmethyl]oxy} quinazolin-4-amine trifluoroacetate. 1H NMR (400 MHz, d6-DMSO): 8.80 (s, 1H), 8.11 (s, 1H), 7.99 (s, 1H), 7.74 (s, 2H), 7.29 (s, 1H), 4.29 (d, 2H), 4.11 (m, 2H), 4.00 (s, 3H), 3.96 (m, 1H), 2.99 (m, 2H), 2.56 (t, 1H), 2.367 (m, 1H); MS (EI) for C22H22N4O3SCl2: 492 (MH+).
Reaction SMILES: ClC1C=CC=C(C(OO)=[O:9])C=1.[OH:12][CH:13]([CH2:26][C:27]1[CH:32]=[CH:31][N:30]=[CH:29][N:28]=1)[C:14]([CH3:25])([CH3:24])[O:15][C:16]1[CH:23]=[CH:22][C:19]([C:20]#[N:21])=[CH:18][CH:17]=1>ClCCl>[C:20]([C:19]1[CH:18]=[CH:17][C:16]([O:15][C:14]([CH3:24])([CH3:25])[CH:13]([OH:12])[CH2:26][C:27]2[N+:28]([O-:9])=[CH:29][N:30]=[CH:31][CH:32]=2)=[CH:23][CH:22]=1)#[N:21]
Reactant: O=C(OO)c1cccc(Cl)c1
Reactant: CC(C)(Oc1ccc(C#N)cc1)C(O)Cc1ccncn1
Solvent: ClCCl
Product: CC(C)(Oc1ccc(C#N)cc1)C(O)Cc1ccnc[n+]1[O-]
Temperature: 20 °C
Reaction time: 16 h
Yield: 19.4 %

Procedure:
3.77 g of m-chloroperbenzoic acid were added to a solution of 4.78 g of 4-[2-hydroxy-1,1-dimethyl-3-(4pyrimidinyl)propoxy]benzonitrile in 75 ml of dichloromethane and the mixture was stirred at 20° C. for 16 hours. A further 0.38 g of m-chloroperbenzoic acid was added and the mixture was stirred at 20° C. for 24 hours. The mixture was then washed in succession with water and sodium chloride solution. The organic solution was evaporated and the residue was chromatographed on silica gel using diethyl ether/methanol (9:1) for the elution to give 0.98 g of 6-[3-(4-cyanophenoxy)-2-hydroxy-3-methylbutyl]pyrimidine 1-oxide in the form of a white solid of melting point 105°-107.5° C. (from ethyl acetate).
Reaction SMILES: [CH3:1][C@H:2]([N:9]1[CH2:13][CH2:12][C:11]([CH2:21][C:22]2[CH:27]=[CH:26][C:25]([F:28])=[CH:24][CH:23]=2)([CH2:14][CH2:15]OS(C)(=O)=O)[C:10]1=[O:29])[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.[CH2:30]([O:32][CH2:33][CH2:34][N:35]1[C:39]2[CH:40]=[CH:41][CH:42]=[CH:43][C:38]=2[N:37]=[C:36]1[NH:44][CH:45]1[CH2:50][CH2:49][NH:48][CH2:47][CH2:46]1)[CH3:31]>>[CH3:1][C@H:2]([N:9]1[CH2:13][CH2:12][C:11]([CH2:14][CH2:15][N:48]2[CH2:47][CH2:46][CH:45]([NH:44][C:36]3[N:35]([CH2:34][CH2:33][O:32][CH2:30][CH3:31])[C:39]4[CH:40]=[CH:41][CH:42]=[CH:43][C:38]=4[N:37]=3)[CH2:50][CH2:49]2)([CH2:21][C:22]2[CH:23]=[CH:24][C:25]([F:28])=[CH:26][CH:27]=2)[C:10]1=[O:29])[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1
Reactant: CCOCCn1c(NC2CCNCC2)nc2ccccc21
Reactant: C[C@@H](c1ccccc1)N1CCC(CCOS(C)(=O)=O)(Cc2ccc(F)cc2)C1=O
Product: CCOCCn1c(NC2CCN(CCC3(Cc4ccc(F)cc4)CCN([C@@H](C)c4ccccc4)C3=O)CC2)nc2ccccc21

Procedure:
Prepare by the method of Example 1.6 using 1-((S)-α-methylbenzyl)-3-(4-fluorophenylmethyl)-3-(2-methanesulfonyloxyethyl)-2-oxopyrrolidine (Rf=0.71 silica gel, ethyl acetate) (0.45 g, 1.06 mmol) and (1-(2-ethoxyethyl)-1H-benzimidazol-2-yl) (piperidin-4-yl)amine to give a diastereomer of the title compound.
Reaction SMILES: [C:1]12([C:11](Cl)=[O:12])[CH2:10][CH:5]3[CH2:6][CH:7]([CH2:9][CH:3]([CH2:4]3)[CH2:2]1)[CH2:8]2.[F:14][C:15]1[CH:21]=[CH:20][C:18]([NH2:19])=[CH:17][CH:16]=1.C(N(CC)CC)C>C(OCC)C>[F:14][C:15]1[CH:21]=[CH:20][C:18]([NH:19][C:11]([C:1]23[CH2:10][CH:5]4[CH2:6][CH:7]([CH2:9][CH:3]([CH2:4]4)[CH2:2]2)[CH2:8]3)=[O:12])=[CH:17][CH:16]=1
Reactant: O=C(Cl)C12CC3CC(CC(C3)C1)C2
Reactant: Nc1ccc(F)cc1
Solvent: CCN(CC)CC
Solvent: CCOCC
Product: O=C(Nc1ccc(F)cc1)C12CC3CC(CC(C3)C1)C2

Procedure:
Subject 2.29 g. of adamantane carboxylic acid chloride (11.5 mmoles) 1.11 g. (10 mmoles) of p-fluoro-aniline and 4.0 ml. of triethylamine to the process of Example 11. Crystallize the residue obtained thereby from ethyl ether to yield the title product, m.p. 170°-171° C.
Reaction SMILES: [CH2:1]([N:3]1[C:12]2[C:7](=[C:8]([F:16])[C:9]([F:15])=[C:10](F)[C:11]=2[F:13])[C:6](=[O:17])[C:5]([C:18]([OH:20])=[O:19])=[CH:4]1)[CH3:2].[NH:21]1[CH2:25][CH2:24][CH:23]([CH2:26][NH2:27])[CH2:22]1>C(#N)C.C(OCC)C>[NH2:27][CH2:26][CH:23]1[CH2:24][CH2:25][N:21]([C:10]2[C:11]([F:13])=[C:12]3[C:7]([C:6](=[O:17])[C:5]([C:18]([OH:20])=[O:19])=[CH:4][N:3]3[CH2:1][CH3:2])=[C:8]([F:16])[C:9]=2[F:15])[CH2:22]1
Reactant: NCC1CCNC1
Reactant: CCn1cc(C(=O)O)c(=O)c2c(F)c(F)c(F)c(F)c21
Solvent: CC#N
Solvent: CCOCC
Product: CCn1cc(C(=O)O)c(=O)c2c(F)c(F)c(N3CCC(CN)C3)c(F)c21
Temperature: 45 °C
Reaction time: 18 h
Yield: 80.5 %

Procedure:
To 1.0 g (3.5 mmol) of 1-ethyl-5,6,7,8-tetrafluoro-1,4-dihydro-4-oxo-3-quinolinecarboxylic acid in 20 ml of acetonitrile was added 1.05 g (6.9 mmol) of 1,8-diazobicyclo[5.4.0]undec-7-ene and 0.35 g (3.5 mmol) of 3-pyrrolidinemethanamine and the mixture was stirred at 45° C. for 18 hours, then refluxed one hour. The mixture was cooled, diluted with 50 ml of diethyl ether, and filtered. The solids were washed with ethanol and then diethyl ether to give 1.04 g (82%) of the title compound, mp>170° C. (decomposition).
Reaction SMILES: Cl[C:2]1[N:3]=[C:4]([N:24]2[CH2:29][CH2:28][O:27][CH2:26][CH2:25]2)[C:5]2[S:10][C:9]([CH2:11][N:12]3[CH2:17][CH2:16][CH:15]([N:18]4[CH2:23][CH2:22][CH2:21][CH2:20][CH2:19]4)[CH2:14][CH2:13]3)=[CH:8][C:6]=2[N:7]=1.CC1(C)C(C)(C)OB([C:38]2[CH:39]=[N:40][C:41]([NH2:44])=[N:42][CH:43]=2)O1>>[O:27]1[CH2:28][CH2:29][N:24]([C:4]2[C:5]3[S:10][C:9]([CH2:11][N:12]4[CH2:17][CH2:16][CH:15]([N:18]5[CH2:23][CH2:22][CH2:21][CH2:20][CH2:19]5)[CH2:14][CH2:13]4)=[CH:8][C:6]=3[N:7]=[C:2]([C:38]3[CH:39]=[N:40][C:41]([NH2:44])=[N:42][CH:43]=3)[N:3]=2)[CH2:25][CH2:26]1
Reactant: CC1(C)OB(c2cnc(N)nc2)OC1(C)C
Reactant: Clc1nc(N2CCOCC2)c2sc(CN3CCC(N4CCCCC4)CC3)cc2n1
Product: Nc1ncc(-c2nc(N3CCOCC3)c3sc(CN4CCC(N5CCCCC5)CC4)cc3n2)cn1

Procedure:
1′-(2-Chloro-4-morpholin-4-yl-thieno[3,2-d]pyrimidin-6-ylmethyl)-[1,4′]bipiperidinyl (Example 24) was reacted with 5-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-pyrimidin-2-ylamine in General Procedure A. Purification on silica yielded 114. NMR (CDCl3): 1.50 (m, 2H, CH2), 1.58-1.70 (m, 6H, 3×CH2), 1.80 (m, 2H, CH2), 2.12 (m, 2H, CH2), 2.30 (m, H, CH), 2.53 (m, 4H, 2×CH2), 3.05 (m, 2H, CH2), 3.82 (s, 2H, CH2), 3.89-3.91 (m, 4H, 2×CH2), 4.03-4.06 (m, 4H, 2×CH2), 5.23 (sbr, 2H, NH2), 7.26 (s, H, ArH), 9.30 (s, 2H, 2×ArH). MS: (ESI+): MH+=495.49
Reaction SMILES: [Cl:1][C:2]1[C:11]([C:12]2[N:13]([C:23]([O:25][C:26]([CH3:29])([CH3:28])[CH3:27])=[O:24])[C:14]3[C:19]([CH:20]=2)=[CH:18][C:17]([CH2:21][OH:22])=[CH:16][CH:15]=3)=[CH:10][C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[N:3]=1>ClCCl.O=[Mn]=O>[Cl:1][C:2]1[C:11]([C:12]2[N:13]([C:23]([O:25][C:26]([CH3:29])([CH3:28])[CH3:27])=[O:24])[C:14]3[C:19]([CH:20]=2)=[CH:18][C:17]([CH:21]=[O:22])=[CH:16][CH:15]=3)=[CH:10][C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[N:3]=1
Reactant: CC(C)(C)OC(=O)n1c(-c2cc3ccccc3nc2Cl)cc2cc(CO)ccc21
Agent: O=[Mn]=O
Solvent: ClCCl
Product: CC(C)(C)OC(=O)n1c(-c2cc3ccccc3nc2Cl)cc2cc(C=O)ccc21
Reaction time: 1 h

Procedure:
A mixture of tert-butyl 2-(2-chloro-3-quinolinyl)-5-(hydroxymethyl)-1H-indole-1-carboxylate (7-2, 800 mg, 1.96 mmol, 1 equiv) and MnO2 (850 mg, 9.8 mmol, 5.00 equiv) in dichloromethane (100 mL) was heated at reflux for 1.5 h. Additional MnO2 (700 mg, 8.05 mmol, 4.10 equiv) was added and heating was continued for 1 h. The catalyst was filtered and washed with dichloromethane (100 mL). The combined filtrate was concentrated to give tert-butyl 2-(2-chloro-3-quinolinyl)-5-formyl-1H-indole-1-carboxylate (8-1) as a white foam. 1H NMR (500 MHz, CDCl3) δ 10.11 (s, 1H), 8.47 (d, 1H, J=8.8 Hz), 8.22 (s, 1H), 8.16 (d, 1H, J=1.0 Hz), 8.09 (d, 1H, J=8.6 Hz), 7.95 (dd, 1H, J=8.8, 1.7 Hz), 7.89 (d, 1 H, J=8.1 Hz), 7.81 (br t, 1H, J=7.6 Hz), 7.64 (br t, 1H, J=7.5 Hz), 6.80 (s, 1H), 1.27 (s, 9H).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]=[CH:7][C:6]([C:12]([CH:14]1[CH2:16][CH2:15]1)=[O:13])=[C:5]2Cl.[CH3:18][N:19]([CH2:21][C:22]1[CH:28]=[CH:27][C:25]([NH2:26])=[CH:24][CH:23]=1)[CH3:20]>>[Br:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]=[CH:7][C:6]([C:12]([CH:14]1[CH2:16][CH2:15]1)=[O:13])=[C:5]2[NH:26][C:25]1[CH:24]=[CH:23][C:22]([CH2:21][N:19]([CH3:20])[CH3:18])=[CH:28][CH:27]=1
Reactant: O=C(c1cnc2ccc(Br)cc2c1Cl)C1CC1
Reactant: CN(C)Cc1ccc(N)cc1
Product: CN(C)Cc1ccc(Nc2c(C(=O)C3CC3)cnc3ccc(Br)cc23)cc1
Yield: 49.9 %

Procedure:
Following general procedure C, (6-bromo-4-chloroquinolin-3-yl)(cyclopropyl)methanone (320 mg, 1.03 mmol) was reacted with 4-[(dimethylamino)methyl]aniline (210 mg, 1.54 mmol) to afford the desired product (218 mg, 50%) as a yellow solid: ESI MS m/z 425 [C22H22BrN3O+H]+.
Reaction SMILES: Cl.[CH:2]1([CH2:5][O:6][C:7]2[CH:12]=[C:11]([O:13][CH3:14])[CH:10]=[CH:9][C:8]=2[C:15]2[CH:20]=[CH:19][N:18]=[C:17]3[C:21]([C:25]([NH:27][CH:28]4[CH2:33][CH2:32][NH:31][CH2:30][CH2:29]4)=[O:26])=[C:22]([CH3:24])[NH:23][C:16]=23)[CH2:4][CH2:3]1.[CH3:34][O:35][CH2:36][C:37](Cl)=[O:38]>>[CH:2]1([CH2:5][O:6][C:7]2[CH:12]=[C:11]([O:13][CH3:14])[CH:10]=[CH:9][C:8]=2[C:15]2[CH:20]=[CH:19][N:18]=[C:17]3[C:21]([C:25]([NH:27][CH:28]4[CH2:29][CH2:30][N:31]([C:37](=[O:38])[CH2:36][O:35][CH3:34])[CH2:32][CH2:33]4)=[O:26])=[C:22]([CH3:24])[NH:23][C:16]=23)[CH2:4][CH2:3]1
Reactant: COCC(=O)Cl
Reactant: COc1ccc(-c2ccnc3c(C(=O)NC4CCNCC4)c(C)[nH]c23)c(OCC2CC2)c1
Agent: Cl
Product: COCC(=O)N1CCC(NC(=O)c2c(C)[nH]c3c(-c4ccc(OC)cc4OCC4CC4)ccnc23)CC1

Procedure:
Starting from 7-[2-(cyclopropylmethoxy)-4-methoxyphenyl]-2-methyl-N-(piperidin-4-yl)-1H-pyrrolo[3,2-b]pyridine-3-carboxamide hydrochloride (example D.f11) and commercially methoxy-acetyl chloride the title compound is obtained as colorless solid.
Reaction SMILES: [CH3:1][C:2]1([CH3:9])[NH:6][C:5](=[O:7])[NH:4][C:3]1=[O:8].C(=O)([O-])[O-].[K+].[K+].[Cl:16][CH2:17][CH2:18]Cl>CN(C)C=O>[Cl:16][CH2:17][CH2:18][N:4]1[C:3](=[O:8])[C:2]([CH3:9])([CH3:1])[NH:6][C:5]1=[O:7]
Reactant: CC1(C)NC(=O)NC1=O
Reactant: ClCCCl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CC1(C)NC(=O)N(CCCl)C1=O

Procedure:
A mixture of 1,664 g of 5,5-dimethyl-hydantoin (13.0 mols), 897 g of anhydrous potassium carbonate (6.5 mols), 5,148 g of 1,2-dichloroethane (52 mols) and 1,458 ml of dimethylformamide is reacted for 18 hours and 20 minutes at 90° C to 100° C internal temperature (external temperature 155° C), whilst constantly removing the resulting water of reaction by azeotropic circulatory distillation. Water of reaction eliminated: 110 g (94.0% of theory). Thereafter the reaction mixture, whilst still hot, is separated by filtration from the potassium chloride produced, the filtrate concentrated on a rotary evaporator at 100° C and the residue is dried to constant weight at 100° C and 10-1 mm Hg.
Reaction SMILES: [CH:1]1([C:4]2[C:5]([N:24]([C:29]3[CH:30]=[CH:31][C:32]([N+:39]([O-])=O)=[C:33]([CH:38]=3)[C:34]([O:36][CH3:37])=[O:35])[S:25]([CH3:28])(=[O:27])=[O:26])=[CH:6][C:7]3[O:11][C:10]([C:12]4[CH:17]=[CH:16][C:15]([F:18])=[CH:14][CH:13]=4)=[C:9]([C:19](=[O:22])[NH:20][CH3:21])[C:8]=3[CH:23]=2)[CH2:3][CH2:2]1.[H][H]>C1COCC1.CCO>[NH2:39][C:32]1[CH:31]=[CH:30][C:29]([N:24]([C:5]2[C:4]([CH:1]3[CH2:3][CH2:2]3)=[CH:23][C:8]3[C:9]([C:19](=[O:22])[NH:20][CH3:21])=[C:10]([C:12]4[CH:13]=[CH:14][C:15]([F:18])=[CH:16][CH:17]=4)[O:11][C:7]=3[CH:6]=2)[S:25]([CH3:28])(=[O:27])=[O:26])=[CH:38][C:33]=1[C:34]([O:36][CH3:37])=[O:35]
Reactant: CNC(=O)c1c(-c2ccc(F)cc2)oc2cc(N(c3ccc([N+](=O)[O-])c(C(=O)OC)c3)S(C)(=O)=O)c(C3CC3)cc12
Reactant: [H][H]
Solvent: C1CCOC1
Solvent: CCO
Product: CNC(=O)c1c(-c2ccc(F)cc2)oc2cc(N(c3ccc(N)c(C(=O)OC)c3)S(C)(=O)=O)c(C3CC3)cc12
Yield: 75 %

Procedure:
A stirred suspension of 59.5 g (102 mmol) of methyl 5-(N-(5-cyclopropyl-2-(4-fluorophenyl)-3-(methylcarbamoyl)benzofuran-6-yl)methylsulfonamido)-2-nitrobenzoate and 6.0 g of 10% Pd(C) in 1.2 L of 2:1 THF/EtOH was saturated with hydrogen by bubbling hydrogen gas through for 10 minutes and then subjected to balloon hydrogenation at RT. After 6 hours LCMS indicated complete reaction. After 24 hours the mixture was purged with nitrogen, catalyst removed by filtration through celite, and the filtrate concentrated to dryness at reduced pressure to give a light yellow solid. This material was recrystallized from hot EtOAc to afford 42.2 g of methyl 2-amino-5-(N-(5-cyclopropyl-2-(4-fluorophenyl)-3-(methylcarbamoyl)benzofuran-6-yl)methylsulfonamido)benzoate as a white solid. The filtrate was concentrated to dryness at reduced pressure to give an additional 13.0 g of methyl 2-amino-5-(N-(5-cyclopropyl-2-(4-fluorophenyl)-3-(methylcarbamoyl)benzofuran-6-yl)methylsulfonamido)benzoate as a light yellow foam determined to be 95% pure by LCMS. The two batches were combined for a total yield of 55.2 g (98%) of methyl 2-amino-5-(N-(5-cyclopropyl-2-(4-fluorophenyl)-3-(methylcarbamoyl)benzofuran-6-yl)methylsulfonamido)benzoate. 1H NMR (400 MHz, DMSO-d6) δ ppm 8.46 (q, J=4.42 Hz, 1H) 8.16 (s, 1H) 7.91-8.00 (m, 3H) 7.61 (dd, J=8.98, 2.73 Hz, 1H) 7.41 (t, J=8.88 Hz, 2H) 7.15 (s, 1H) 6.76-6.86 (m, 3H) 3.79 (s, 3H) 3.28 (s, 3H) 2.83 (d, J=4.68 Hz, 3H) 2.25-2.38 (m, 1H) 0.82-1.10 (m, 3H) 0.42 (m, 1H). LCMS(ESI): 552 (M+H+).
Reaction SMILES: [NH2:1][C:2]1[N:7]=[C:6]([C:8]2[O:9][CH:10]=[CH:11][CH:12]=2)[C:5]([C:13]#[N:14])=[C:4](S(C)=O)[N:3]=1.Cl.[Br:19][C:20]1[CH:27]=[CH:26][C:23]([CH2:24][NH2:25])=[CH:22][CH:21]=1.C1CCN2C(=NCCC2)CC1>COCCOC>[NH2:1][C:2]1[N:3]=[C:4]([NH:25][CH2:24][C:23]2[CH:26]=[CH:27][C:20]([Br:19])=[CH:21][CH:22]=2)[C:5]([C:13]#[N:14])=[C:6]([C:8]2[O:9][CH:10]=[CH:11][CH:12]=2)[N:7]=1
Reactant: NCc1ccc(Br)cc1
Reactant: CS(=O)c1nc(N)nc(-c2ccco2)c1C#N
Agent: Cl
Solvent: C1CCC2=NCCCN2CC1
Solvent: COCCOC
Product: N#Cc1c(NCc2ccc(Br)cc2)nc(N)nc1-c1ccco1

Procedure:
From 2-amino-4-furan-2-yl-6-methanesulfinyl-pyrimidine-5-carbonitrile, 4-bromobenzylamine hydrochloride and DBU in DME. ES-MS m/e (%): 372 (M{81Br}+H+, 95), 370 (M{79Br}+H+, 100).