Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C([NH:4][C:5]1[CH:10]=[C:9]([O:11][C:12]2[C:17]([F:18])=[CH:16][C:15]([NH:19][C:20]([C:22]3[C:23](=[O:38])[N:24]([C:31]4[CH:36]=[CH:35][C:34]([F:37])=[CH:33][CH:32]=4)[CH:25]=[CH:26][C:27]=3[O:28][CH2:29][CH3:30])=[O:21])=[C:14]([F:39])[CH:13]=2)[CH:8]=[CH:7][N:6]=1)(=O)C.C([O-])([O-])=O.[K+].[K+]>CCO>[NH2:4][C:5]1[CH:10]=[C:9]([O:11][C:12]2[C:17]([F:18])=[CH:16][C:15]([NH:19][C:20]([C:22]3[C:23](=[O:38])[N:24]([C:31]4[CH:32]=[CH:33][C:34]([F:37])=[CH:35][CH:36]=4)[CH:25]=[CH:26][C:27]=3[O:28][CH2:29][CH3:30])=[O:21])=[C:14]([F:39])[CH:13]=2)[CH:8]=[CH:7][N:6]=1
Reactant: CCOc1ccn(-c2ccc(F)cc2)c(=O)c1C(=O)Nc1cc(F)c(Oc2ccnc(NC(C)=O)c2)cc1F
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCO
Product: CCOc1ccn(-c2ccc(F)cc2)c(=O)c1C(=O)Nc1cc(F)c(Oc2ccnc(N)c2)cc1F
Yield: 37.9 %

Procedure:
A mixture of Example 1 (1.00 g, 1.86 mmol) and K2CO3 (1.000 g, 7.24 mmol) in EtOH (4 mL) was heated at 120° C. under microwave irradiation for 1 h. The reaction mixture was filtered, washed with EtOH and the filtrate was evaporated to dryness. The crude was stirred in water (15 mL) for a few minutes and collected by filtration. The residue was further purified by successive crystallization from MeOH and MeCN to provide N-(4-((2-aminopyridin-4-yl)oxy)-2,5-difluorophenyl)-4-ethoxy-1-(4-fluorophenyl)-2-oxo-1,2-dihydropyridine-3-carboxamide (350 mg, 38.0% yield) as a white solid. MS (ESI) m/z: 497.1 (M+H+).
Reaction SMILES: Cl.C([N:5]1[C@@H:13]2[C@@H:8]([C:9]3[C:17]([OH:18])=[CH:16][CH:15]=[CH:14][C:10]=3[CH2:11][CH2:12]2)[CH2:7][CH2:6]1)CC.[CH3:19][N:20]([CH3:24])[C:21]([Cl:23])=[O:22].C(N(CC)CC)C.C(=O)([O-])O.[Na+]>CN(C)C1C=CN=CC=1.C1(C)C=CC=CC=1>[ClH:23].[CH3:19][N:20]([CH3:24])[C:21](=[O:22])[O:18][C:17]1[C:9]2[C@@H:8]3[C@H:13]([CH2:12][CH2:11][C:10]=2[CH:14]=[CH:15][CH:16]=1)[NH:5][CH2:6][CH2:7]3
Reactant: CN(C)C(=O)Cl
Reactant: CCCN1CC[C@@H]2c3c(O)cccc3CC[C@@H]21
Agent: CN(C)c1ccncc1
Agent: Cl
Agent: O=C([O-])O
Solvent: Cc1ccccc1
Solvent: CCN(CC)CC
Product: CN(C)C(=O)Oc1cccc2c1[C@H]1CCN[C@H]1CC2
Yield: 101.1 %

Procedure:
A mixture of 1.10 g (0.004 mol) of rac-cis-2,3,3a,4,5,9b-hexahydro-3-propyl-1H-benzo[e]indol-9-ol hydrochloride, 0.61 g (0.005 mol) of dimethylcarbamoyl chloride, 1.4 ml (0.01 mol) of triethylamine and 0.61 g (0.005 mol) of 4-dimethylaminopyridine in 40 ml of toluene was boiled under reflux for 4 hours and then poured into a saturated aqueous sodium hydrogen carbonate solution, whereupon the mixture was extracted with methylene chloride. The extract was dried with sodium sulphate, filtered and evaporated in a vacuum. The residue was purified by chromatography over silica gel with methylene chloride/methanol (99:1) and over aluminum oxide with methylene chloride and dissolved in ethanol. After the addition of ethanolic HCl the solvent was distilled off. There were obtained 1.20 g (86%) of rac-cis-2,3,3a,4,5,9b-hexahydro-1H-benzo[e]indol-9-yl dimethylcarbamate hydrochloride as a foam.
Reaction SMILES: [CH3:1][N:2]1C(=O)O[C:5](=[O:6])[C:4]2=[CH:10][CH:11]=[CH:12][CH:13]=[C:3]12.[CH3:14][NH2:15]>C1COCC1>[CH3:14][NH:15][C:5](=[O:6])[C:4]1[CH:10]=[CH:11][CH:12]=[CH:13][C:3]=1[NH:2][CH3:1]
Reactant: Cn1c(=O)oc(=O)c2ccccc21
Reactant: CN
Solvent: C1CCOC1
Product: CNC(=O)c1ccccc1NC
Reaction time: 18 h

Procedure:
A solution of N-methylisatoic anhydride (5 g, 28 mmol) in THF (100 mL) was treated with methylamine (THF solution, 2.0 M, 60 mL). The mixture was stirred for 18 h and the solvent was evaporated. The residue was partitioned between ethyl acetate (100 ml) and water (50 ml). The organic layer was washed once with brine (30 ml), dried over sodium sulfate, and concentrated to give N-methyl-2-methylamino-benzamide (5 g, 30 mmol): 1H NMR (300 MHz, CDCl3): δ 7.3 (m, 2H), 6.67 (d, 1H), 6.58 (t, 1H), 2.96 (d, 3H), 2.86 (d, 3H); MS (m/e) 165 (M+1).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:14]=[C:7]2[C:8]([O:10]C(=O)[NH:12][C:6]2=[CH:5][CH:4]=1)=O.Cl.[CH3:16][O:17][C:18](=[O:25])[C@@H:19]([NH2:24])[CH2:20][CH2:21][CH2:22][CH3:23].C(N(CC)CC)C>CN(C=O)C.CCOC(C)=O>[CH3:16][O:17][C:18](=[O:25])[C@@H:19]([NH:24][C:8](=[O:10])[C:7]1[CH:14]=[C:3]([O:2][CH3:1])[CH:4]=[CH:5][C:6]=1[NH2:12])[CH2:20][CH2:21][CH2:22][CH3:23]
Reactant: CCCC[C@H](N)C(=O)OC
Reactant: COc1ccc2[nH]c(=O)oc(=O)c2c1
Agent: Cl
Solvent: CCN(CC)CC
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: CCCC[C@H](NC(=O)c1cc(OC)ccc1N)C(=O)OC
Temperature: 25 °C
Reaction time: 16 h
Yield: 26.9 %

Procedure:
To a mixture of 5-methoxy-isatoic anhydride (1.0 g, 5.18 mmol) and (S)-2-amino-hexanoic acid methyl ester hydrochloride (1.4 g, 7.71 mmol) (prepared according to example A) in DMF (10 mL) is added triethylamine (2.0 mL, 11.48 mmol). The mixture is stirred at room temperature for 16 hours. The reaction mixture is diluted with EtOAc (100 mL) and washed with H2O (50 mL×3). The organic layer is dried over sodium sulfate, concentrated and the residue is purified by flash chromatography with 60% EtOAc in Hexane as the eluent to afford (S)-2-(2-amino-5-methoxy-benzoylamino)-hexanoic acid methyl ester (410 mg, 27%).
Reaction SMILES: [CH:1]1(/[C:7](/[CH2:14][CH3:15])=[CH:8]/[C:9](OCC)=[O:10])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[H-].[Al+3].[Li+].[H-].[H-].[H-]>CCOCC>[CH:1]1(/[C:7](/[CH2:14][CH3:15])=[CH:8]/[CH2:9][OH:10])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: CCOC(=O)/C=C(\CC)C1CCCCC1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: CCOCC
Product: CC/C(=C\CO)C1CCCCC1
Reaction time: 0.08 h
Yield: 86.7 %

Procedure:
To a solution of (E)-ethyl 3-cyclohexylpent-2-enoate (2.3 g, 10.9 mmol) in Et2O (22 mL), was added lithium aluminum hydride (1.0 M in Et2O, 10.9 mL, 10.9 mmol) dropwise. After 5 minutes, the reaction mixture was slowly quenched with 1 mL of MeOH and poured into 100 mL of a saturated solution of potassium sodium tartrate. The aqueous layer was extracted with 100 mL Et2O (3×). The combined organics were dried over Na2SO4, filtered and concentrated. The product was purified by flash chromatography (10% EtOAc/hexanes) to provide a clear oil (1.59 g, 87% yield) that was a 3:1 mixture of E:Z isomers. Major isomer: IR (film) 3421, 2929, 2854, 1732, 1684, 1635, 1449, 1235, 1164, 864, 749 cm−1; 1H NMR (300 MHz, CDCl3) δ 5.33 (t, 1H, J=6.7 Hz, CHCH2OH), 4.17 (d, 2H, J=6.9 Hz, CH2OH), 2.07 (q, 2H, J=7.4 Hz, CH2CH3), 1.99 to 1.63 (m, 6H), 1.48-1.08 (m, 6H), 0.97 (t, 3H, J=7.4 Hz, CH2CH3); 13C NMR (75 MHz, CDCl3) δ 151.1, 121.2, 59.4, 44.8, 32.6, 31.6, 26.9, 26.7, 26.4, 23.1, 14.7; HRMS (EI+) exact mass calculated for [M]+ (C11H20O) requires m/z 168.1514, found m/z 168.1520.
Reaction SMILES: [C:1]([C:9]1[CH:34]=[C:33]([Br:35])[CH:32]=[CH:31][C:10]=1[C:11]([N:13]([CH2:20][C:21]1[CH:26]=[CH:25][C:24]([S:27]([CH3:30])(=[O:29])=[O:28])=[CH:23][CH:22]=1)[CH2:14][C:15](=[O:19])[CH2:16][CH2:17][CH3:18])=[O:12])(=O)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.N12CCCN=C1CCCCC2>C1(C)C=CC=CC=1>[Br:35][C:33]1[CH:34]=[C:9]2[C:10](=[CH:31][CH:32]=1)[C:11](=[O:12])[N:13]([CH2:20][C:21]1[CH:26]=[CH:25][C:24]([S:27]([CH3:30])(=[O:29])=[O:28])=[CH:23][CH:22]=1)[C:14]([C:15](=[O:19])[CH2:16][CH2:17][CH3:18])=[C:1]2[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CCCC(=O)CN(Cc1ccc(S(C)(=O)=O)cc1)C(=O)c1ccc(Br)cc1C(=O)c1ccccc1
Solvent: C1CCC2=NCCCN2CC1
Solvent: Cc1ccccc1
Product: CCCC(=O)c1c(-c2ccccc2)c2cc(Br)ccc2c(=O)n1Cc1ccc(S(C)(=O)=O)cc1
Yield: 72.3 %

Procedure:
[Step 3] To a solution (40 ml) of 2-benzoyl-4-bromo-N-(4-methanesulfonylbenzyl)-N-(2-oxopentyl)benzamide (2.0 g) in toluene was added 1,8-diazabicyclo[5.4.0]undeca-7-ene (1.1 g), and the mixture was heated under reflux for 48 hrs. The reaction mixture was concentrated under reduced pressure. To the residue were added water and 10% hydrochloric acid, and the mixture was extracted with ethyl acetate. The organic layer was washed with water, saturated aqueous sodium hydrogen carbonate, water and saturated brine, and dried over anhydrous sodium sulfate. The solvent was evaporated under reduced pressure, and the residue was purified by recrystallization (THF-diisopropyl ether) to give the title compound (1.4 g).
Reaction SMILES: [CH3:1][O:2][CH2:3][CH2:4][O:5][CH2:6][CH2:7][O:8][C:9]1[N:14]=[C:13]([NH2:15])[N:12]=[C:11]([NH2:16])[C:10]=1[N:17]=O.[ClH:19]>[Pd].C(O)C>[ClH:19].[ClH:19].[CH3:1][O:2][CH2:3][CH2:4][O:5][CH2:6][CH2:7][O:8][C:9]1[N:14]=[C:13]([NH2:15])[N:12]=[C:11]([NH2:16])[C:10]=1[NH2:17]
Reactant: COCCOCCOc1nc(N)nc(N)c1N=O
Agent: [Pd]
Agent: Cl
Solvent: CCO
Product: COCCOCCOc1nc(N)nc(N)c1N
Reaction time: 16 h
Yield: 84.1 %

Procedure:
1.5 g (0.04 mol %) of palladium on carbon (5%) was added to a solution of 11.3 g (0.044 mol) of 6-[2-(2-methoxyethoxyl)ethoxy]-5-nitrosopyrimidine-2,4-diamine from step 5.2 in 400 ml of ethanol, and shaking was performed at room temperature for 16 h under hydrogen-1 atmosphere. Then the reaction mixture was poured into 80 ml of diluted hydrochloric acid (0.23 mol), the catalyst was filtered off, and the filtrate was concentrated almost to dryness. The precipitated crystals were sucked off and post-washed with ethanol. 6-[2-(2-methoxyethoxyl)ethoxy]pyrimidine-2,4,5-triamine, dihydrochloride (11.7 g, 84%) was obtained as white crystals.
Reaction SMILES: [F:1][C:2]1[CH:26]=[CH:25][C:5]([O:6][C:7]2[CH:12]=[CH:11][C:10]([S:13]([NH:16][C:17]3([C:22]([OH:24])=[O:23])[CH2:21][CH2:20][CH2:19][CH2:18]3)(=[O:15])=[O:14])=[CH:9][CH:8]=2)=[CH:4][CH:3]=1.[CH3:27][C:28](=[CH2:30])[CH3:29].S(=O)(=O)(O)O>C(Cl)Cl>[C:28]([O:23][C:22]([C:17]1([NH:16][S:13]([C:10]2[CH:11]=[CH:12][C:7]([O:6][C:5]3[CH:25]=[CH:26][C:2]([F:1])=[CH:3][CH:4]=3)=[CH:8][CH:9]=2)(=[O:14])=[O:15])[CH2:21][CH2:20][CH2:19][CH2:18]1)=[O:24])([CH3:30])([CH3:29])[CH3:27]
Reactant: O=C(O)C1(NS(=O)(=O)c2ccc(Oc3ccc(F)cc3)cc2)CCCC1
Reactant: C=C(C)C
Agent: O=S(=O)(O)O
Solvent: ClCCl
Product: CC(C)(C)OC(=O)C1(NS(=O)(=O)c2ccc(Oc3ccc(F)cc3)cc2)CCCC1
Temperature: 25 °C
Reaction time: 22 h
Yield: 95 %

Procedure:
To a solution of 1-[4-(4-fluoro-phenoxy) benzenesulfonylamino]-cyclopentanecarboxylic acid (10.22 g, 27 mmole) in 100 mL methylene chloride at -78□ C. was condensed 40 mL of isobutylene. Concentrated sulfuric acid (0.3 mL) was added and the mixture allowed to warm to ambient temperature and stirred for 22 hours. The mixture was then washed with 3×50 mL 2N NaOH and the organic layer dried over magnesium sulfate and evaporated to give 11.17 g (95%) of 1-[4-(4-fluoro-phenoxy)-benzenesulfonylamino]-cyclopentanecarboxylic acid tert-butyl ester. 1H NMR (CDCl3) □ 7.74-7.77 (m, 2H), 6.85-7.13 (m, 6H), 4.95 (s, 1H), 1.92-2.02 (m, 2H), 1.78-1.88 (m, 2H), 1.50-1.65 (m, 4H), 1.35 (s, 9H).
Reaction SMILES: [C:1]([O:5][C:6](=[O:40])[N:7]([C@H:9]([C:11](=[O:39])[NH:12][C@@H:13]1[C:19](=[O:20])[N:18]([CH2:21][C:22]2[C:31]3[C:26](=[C:27](Br)[CH:28]=[CH:29][CH:30]=3)[CH:25]=[CH:24][C:23]=2[O:33][CH3:34])[C:17]2[CH:35]=[CH:36][CH:37]=[CH:38][C:16]=2[NH:15][CH2:14]1)[CH3:10])[CH3:8])([CH3:4])([CH3:3])[CH3:2].FC(F)(F)C(O)=O.N[C@@H]1C(=O)N(CC2C3C(=CC=CC=3)C=CC=2OC)C2C=CC=CC=2NC1.N(C(OC(C)(C)C)=O)(C)[C@H](C(O)=O)C>>[C:1]([O:5][C:6](=[O:40])[N:7]([C@H:9]([C:11](=[O:39])[NH:12][C@@H:13]1[C:19](=[O:20])[N:18]([CH2:21][C:22]2[C:31]3[C:26](=[CH:27][CH:28]=[CH:29][CH:30]=3)[CH:25]=[CH:24][C:23]=2[O:33][CH3:34])[C:17]2[CH:35]=[CH:36][CH:37]=[CH:38][C:16]=2[NH:15][CH2:14]1)[CH3:10])[CH3:8])([CH3:2])([CH3:3])[CH3:4]
Reactant: COc1ccc2c(Br)cccc2c1CN1C(=O)[C@@H](NC(=O)[C@H](C)N(C)C(=O)OC(C)(C)C)CNc2ccccc21
Agent: COc1ccc2ccccc2c1CN1C(=O)[C@@H](N)CNc2ccccc21
Agent: C[C@@H](C(=O)O)N(C)C(=O)OC(C)(C)C
Solvent: O=C(O)C(F)(F)F
Product: COc1ccc2ccccc2c1CN1C(=O)[C@@H](NC(=O)[C@H](C)N(C)C(=O)OC(C)(C)C)CNc2ccccc21
Yield: 73.2 %

Procedure:
In a similar manner to that described for the preparation of {(S)-1-[(S)-1-(5-bromo-2-methoxy-naphthalen-1-ylmethyl)-2-oxo-2,3,4,5-tetrahydro-1H-benzo[b][1,4]diazepin-3-ylcarbamoyl]-ethyl}-methyl-carbamic acid tert-butyl ester (Intermediate 12), (S)-3-amino-1-(2-methoxy-naphthalen-1-ylmethyl)-1,3,4,5-tetrahydro-benzo[b][1,4]diazepin-2-one trifluoroacetate salt (Step 1 above) (460 mg) and Boc-N-Me-Ala-OH (223.3 mg, 1.1 mmol) were converted to the title compound (390 mg, 73.2%) obtained as a white solid. LC-MS: 533 (M+H).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][N:11]([C:14]2[CH:19]=[CH:18][C:17]([N+:20]([O-])=O)=[C:16]([CH3:23])[N:15]=2)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].CO.[H][H]>C1COCC1.[Pd]>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][N:11]([C:14]2[CH:19]=[CH:18][C:17]([NH2:20])=[C:16]([CH3:23])[N:15]=2)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: [H][H]
Reactant: Cc1nc(N2CCN(C(=O)OC(C)(C)C)CC2)ccc1[N+](=O)[O-]
Agent: [Pd]
Solvent: C1CCOC1
Solvent: CO
Product: Cc1nc(N2CCN(C(=O)OC(C)(C)C)CC2)ccc1N
Reaction time: 7 h
Yield: 99 %

Procedure:
Mix a slurry of 4-(6-methyl-5-nitro-pyridin-2-yl)-piperazine-1-carboxylic acid tert-butyl ester (46.00 g, 142.7 mmol) in THF (750 mL) at room temperature with Pd/C (5% Aldrich, 3.04 g, 1.43 mmol) then place under a hydrogen atmosphere (Parr shaker, 40-45 psi) for 6 hours. Add MeOH (250 mL), and subject the slurry to an atmosphere of hydrogen for 4 hours at room temperature. Add additional catalyst (3.04 g), then place the mixture under hydrogen for 7 hours. Filter the mixture through a pad of Celite 521®, washing with THF and MeOH then concentrate under reduced pressure to provide the title compound a pale pink solid. (41.58 g, 99% yield, MS(ES+): m/z=293 [M+H]).
Reaction SMILES: [CH3:1][C@H:2]1[CH2:7][CH2:6][C@H:5]([NH:8][C:9](=[O:29])[CH:10]=[CH:11][C:12]2[CH:17]=[CH:16][C:15]([O:18][CH2:19][CH2:20][N:21]3[CH2:26][CH2:25][CH2:24][CH2:23][CH2:22]3)=[C:14]([O:27][CH3:28])[CH:13]=2)[CH2:4][CH2:3]1>[C].[Pd].CO>[CH3:1][C@H:2]1[CH2:3][CH2:4][C@H:5]([NH:8][C:9](=[O:29])[CH2:10][CH2:11][C:12]2[CH:17]=[CH:16][C:15]([O:18][CH2:19][CH2:20][N:21]3[CH2:22][CH2:23][CH2:24][CH2:25][CH2:26]3)=[C:14]([O:27][CH3:28])[CH:13]=2)[CH2:6][CH2:7]1
Reactant: COc1cc(C=CC(=O)N[C@H]2CC[C@H](C)CC2)ccc1OCCN1CCCCC1
Agent: [Pd]
Solvent: CO
Product: COc1cc(CCC(=O)N[C@H]2CC[C@H](C)CC2)ccc1OCCN1CCCCC1

Procedure:
Using 1 g of N-(trans-4-methylcyclohexyl)-4-(2-piperidinoethoxy)-3-methoxycinnamamide (Example 142), 0.05 g of 10% palladium-carbon, and 100 ml of methanol, a reaction similar to that conducted in Example 147 was carried out. The product obtained was recrystallized from methylene chloride/ether, yielding 0.91 g of N-(trans-4-methylcyclohexyl)-3-[4-(2-piperidinoethoxy)-3-methoxyphenyl]propionamide (a compound of the present invention) as white crystal, which had the following physiochemical properties:
Reaction SMILES: [Cl:1][C:2]1[S:3][C:4]([CH2:7]Cl)=[CH:5][CH:6]=1.BrCC1CCCCO1.[O:17]=[C:18]1[C:26]2([C:30]3=[CH:31][C:32]4[O:36][CH2:35][O:34][C:33]=4[CH:37]=[C:29]3[O:28][CH2:27]2)[C:25]2[C:20](=[C:21]([C:38]#[N:39])[CH:22]=[CH:23][CH:24]=2)[NH:19]1>>[Cl:1][C:2]1[S:3][C:4]([CH2:7][N:19]2[C:20]3[C:25](=[CH:24][CH:23]=[CH:22][C:21]=3[C:38]#[N:39])[C:26]3([C:30]4=[CH:31][C:32]5[O:36][CH2:35][O:34][C:33]=5[CH:37]=[C:29]4[O:28][CH2:27]3)[C:18]2=[O:17])=[CH:5][CH:6]=1
Reactant: ClCc1ccc(Cl)s1
Reactant: N#Cc1cccc2c1NC(=O)C21COc2cc3c(cc21)OCO3
Agent: BrCC1CCCCO1
Product: N#Cc1cccc2c1N(Cc1ccc(Cl)s1)C(=O)C21COc2cc3c(cc21)OCO3

Procedure:
Following the procedure as described in EXAMPLE 4 and making non-critical variations using 2-chloro-5-(chloromethyl)thiophene to replace 2-(bromomethyl)tetrahydro-2H-pyran, and 2′-oxo-1′,2′-dihydrospiro[furo[2,3-f][1,3]benzodioxole-7,3′-indole]-7′-carbonitrile to replace 5,6-dihydrospiro[benzo[1,2-b:5,4-b′]difuran-3,3′-indol]-2″(1′H)-one, 1′-[(5-chloro-2-thienyl)methyl]-2′-oxo-1′,2′-dihydrospiro[furo[2,3-f][1,3]benzodioxole-7,3′-indole]-7′-carbonitrile was obtained (78%) as a colorless solid: mp 192-193° C. (diethyl ether); 1H NMR (300 MHz, DMSO-d6) δ 7.72 (dd, J=8.0, 1.1 Hz, 1H), 7.54 (dd, J=7.4, 1.1 Hz, 1H), 7.21 (dd, J=7.7, 7.7 Hz, 1H), 7.03 (s, 2H), 6.73 (s, 1H), 6.35 (s, 1H), 5.95 (dd, J=4.0, 0.7 Hz, 2H), 5.29 (d, J=1.5 Hz, 2H), 4.78 (dd, J=20.4, 9.6 Hz, 2H); 13C NMR (75 MHz, DMSO-d6) δ 177.0, 155.5, 148.7, 143.2, 141.8, 137.6, 133.6, 133.2, 128.8, 127.9, 126.6, 126.5, 123.7, 118.5, 116.9, 103.0, 101.5, 93.4, 92.6, 79.5, 56.4, 40.0; MS (ES+) m/z 437.3 (M+1), 439.3 (M+1).
Reaction SMILES: [CH3:1][C:2]1[N:11]=[C:10]([N:12]2[CH2:18][C:17]3[CH:19]=[C:20](B(O)O)[CH:21]=[CH:22][C:16]=3[O:15][CH2:14][CH2:13]2)[C:9]2[CH2:8][C:7]([CH3:27])([CH3:26])[CH2:6][CH2:5][C:4]=2[N:3]=1.[NH2:28][C:29]1[C:34]([S:35]([N:38]([CH3:40])[CH3:39])(=[O:37])=[O:36])=[CH:33][C:32](Br)=[CH:31][N:30]=1>>[NH2:28][C:29]1[C:34]([S:35]([N:38]([CH3:40])[CH3:39])(=[O:37])=[O:36])=[CH:33][C:32]([C:20]2[CH:21]=[CH:22][C:16]3[O:15][CH2:14][CH2:13][N:12]([C:10]4[C:9]5[CH2:8][C:7]([CH3:27])([CH3:26])[CH2:6][CH2:5][C:4]=5[N:3]=[C:2]([CH3:1])[N:11]=4)[CH2:18][C:17]=3[CH:19]=2)=[CH:31][N:30]=1
Reactant: Cc1nc2c(c(N3CCOc4ccc(B(O)O)cc4C3)n1)CC(C)(C)CC2
Reactant: CN(C)S(=O)(=O)c1cc(Br)cnc1N
Product: Cc1nc2c(c(N3CCOc4ccc(-c5cnc(N)c(S(=O)(=O)N(C)C)c5)cc4C3)n1)CC(C)(C)CC2

Procedure:
Prepared according to the method of example 5 by using 4-(2,6,6-trimethyl-5,6,7,8-tetrahydroquinazolin-4-yl)-2,3,4,5-tetrahydrobenzo[f][1,4]oxazepin-7-ylboronic acid (reagent preparation 23) and 2-amino-5-bromo-N,N-dimethylpyridine-3-sulfonamide (reagent preparation 25) in step 1. 1H NMR (400 MHz, methanol-d4): 8.47 (s, 1H), 8.04 (s, 1H), 7.52 (s, 1H), 7.41 (d, 1H), 7.06 (d, 1H), 4.71 (s, 2H), 4.31 (m, 2H), 4.00 (m, 2H), 2.80 (s, 6H), 2.75 (m, 2H), 2.45 (s, 2H), 2.40 (s, 3H), 1.67 (m, 2H), 0.91 (s, 6H); MS (EI) for C27H34N6O3S: 523 (MH+).
Reaction SMILES: C(N(CC)C(C)C)(C)C.C1CN([P+](ON2N=NC3C=CC=CC2=3)(N2CCCC2)N2CCCC2)CC1.F[P-](F)(F)(F)(F)F.[CH3:43][C@H:44]1[NH:49][C@@H:48]([CH3:50])[CH2:47][N:46]([C:51]2[C:60]([O:61][CH3:62])=[C:59]3[C:54]([C:55](=[O:71])[C:56]([C:68](O)=[O:69])=[CH:57][N:58]3[CH2:63][C:64]([F:67])([F:66])[F:65])=[CH:53][C:52]=2[F:72])[CH2:45]1.[Cl:73][C:74]1[CH:81]=[C:80]([Cl:82])[CH:79]=[CH:78][C:75]=1[CH2:76][NH2:77].C(#N)C>CN(C)C=O.C(OCC)(=O)C>[Cl:73][C:74]1[CH:81]=[C:80]([Cl:82])[CH:79]=[CH:78][C:75]=1[CH2:76][NH:77][C:68]([C:56]1[C:55](=[O:71])[C:54]2[C:59](=[C:60]([O:61][CH3:62])[C:51]([N:46]3[CH2:45][CH:44]([CH3:43])[NH:49][CH:48]([CH3:50])[CH2:47]3)=[C:52]([F:72])[CH:53]=2)[N:58]([CH2:63][C:64]([F:66])([F:67])[F:65])[CH:57]=1)=[O:69]
Reactant: COc1c(N2C[C@@H](C)N[C@@H](C)C2)c(F)cc2c(=O)c(C(=O)O)cn(CC(F)(F)F)c12
Reactant: NCc1ccc(Cl)cc1Cl
Agent: F[P-](F)(F)(F)(F)F
Agent: c1ccc2c(c1)nnn2O[P+](N1CCCC1)(N1CCCC1)N1CCCC1
Solvent: CCOC(C)=O
Solvent: CC#N
Solvent: CCN(C(C)C)C(C)C
Product: COc1c(N2CC(C)NC(C)C2)c(F)cc2c(=O)c(C(=O)NCc3ccc(Cl)cc3Cl)cn(CC(F)(F)F)c12
Temperature: 25 °C
Reaction time: 8 h
Yield: 0.1 %

Procedure:
Under argon, 7.52 g (58.2 mmol) of N,N-diisopropylethylamine and 7.71 g (14.81 mmol) of PyBOP are added to 5.20 g (10.58 mmol) of 7-(cis-3,5-dimethylpiperazin-1-yl)-6-fluoro-8-methoxy-1-(2,2,2-trifluoroethyl)-4-oxo-1,4-dihydroquinoline-3-carboxylic acid hydroformate (Example 31A) and 3.73 g (21.2 mmol) of 2,4-dichlorobenzylamine in 10.7 ml of dimethylformamide and the mixture is stirred at room temperature overnight. The reaction mixture is diluted with 1500 ml of ethyl acetate and washed three times with water. The combined aqueous phases are extracted once with ethyl acetate. The combined organic phases are washed with a saturated sodium chloride solution, dried over sodium sulfate and concentrated. The residue is stirred with 30 ml of acetonitrile. The solid is then collected by filtration and dried under high vacuum. 6.80 mg of the target compound are obtained as a cocrystallisate with 1 eq. of acetonitrile. For smaller quantities the residue after extraction can be purified by preparative HPLC (by one of the methods 5 to 8).
Reaction SMILES: [Cl:1][C:2]1[CH:20]=[C:19]([F:21])[CH:18]=[CH:17][C:3]=1[C:4]([NH:6][C:7]1[CH:12]=[CH:11][C:10]([F:13])=[C:9]([N+:14]([O-])=O)[CH:8]=1)=[O:5].O.O.Cl[Sn]Cl.Cl.[OH-].[Na+]>C(O)C>[NH2:14][C:9]1[CH:8]=[C:7]([NH:6][C:4](=[O:5])[C:3]2[CH:17]=[CH:18][C:19]([F:21])=[CH:20][C:2]=2[Cl:1])[CH:12]=[CH:11][C:10]=1[F:13]
Reactant: O=C(Nc1ccc(F)c([N+](=O)[O-])c1)c1ccc(F)cc1Cl
Agent: Cl
Agent: Cl[Sn]Cl
Agent: [Na+]
Solvent: O
Solvent: CCO
Product: Nc1cc(NC(=O)c2ccc(F)cc2Cl)ccc1F
Temperature: 60 °C
Yield: 88.4 %

Procedure:
Add 2-chloro-4-fluoro-N-(4-fluoro-3-nitrophenyl)benzamide (Preparation 11, 1 g, 3.2 mmol) to a warm solution (55° C.) of SnCl2.2H2O (3.6 g, 16 mmol) in ethanol (25 mL). Add concentrated HCl (25 mL). Stir and heat the mixture at 60° C. for 30 min. Cool and then basicify the mixture to pH 14 with aqueous NaOH. Extract the product three times with ethyl acetate (3×150 mL). Combine the organic layers and dry over anhydrous sodium sulfate. Evaporate the solvent under reduced pressure. Further purify the residue by chromatography on silica gel, using a gradient of 10-50% ethyl acetate in hexanes to obtain the title intermediate (800 mg, 89% yield): mass spectrum (ion spray): m/z=283.0 (M+1).
Reaction SMILES: [NH2:1][C:2]1[S:3][CH:4]=[C:5]([CH2:7][C:8]([O:10][CH2:11][CH3:12])=[O:9])[N:6]=1.[Br:13][C:14]1[CH:18]=[C:17]([Cl:19])[S:16][C:15]=1[S:20](Cl)(=[O:22])=[O:21]>>[Br:13][C:14]1[CH:18]=[C:17]([Cl:19])[S:16][C:15]=1[S:20]([NH:1][C:2]1[S:3][CH:4]=[C:5]([CH2:7][C:8]([O:10][CH2:11][CH3:12])=[O:9])[N:6]=1)(=[O:22])=[O:21]
Reactant: O=S(=O)(Cl)c1sc(Cl)cc1Br
Reactant: CCOC(=O)Cc1csc(N)n1
Product: CCOC(=O)Cc1csc(NS(=O)(=O)c2sc(Cl)cc2Br)n1

Procedure:
The title compound was prepared from ethyl 2-amino-4-thiazolylacetate and 3-bromo-5-chlorothiophene-2-sulfonyl chloride as described in the synthetic METHOD B to give a yellow solid (29.0 mg) with purity >90%. MS (pos) m/z 445.0, 447.0.
Reaction SMILES: [CH2:1]([O:3][C:4]([C@@:6]1([CH3:12])[CH2:11][CH2:10][CH2:9][NH:8][CH2:7]1)=[O:5])[CH3:2].[CH2:13](Cl)[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1.C([O-])([O-])=O.[K+].[K+].O>CN(C=O)C>[CH2:1]([O:3][C:4]([C@@:6]1([CH3:12])[CH2:11][CH2:10][CH2:9][N:8]([CH2:13][C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[CH2:7]1)=[O:5])[CH3:2]
Reactant: CCOC(=O)[C@@]1(C)CCCNC1
Reactant: ClCc1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: CCOC(=O)[C@@]1(C)CCCN(Cc2ccccc2)C1
Yield: 92.3 %

Procedure:
(S)-3-Methylpiperidine-3-carboxylic acid ethyl ester (1.16 g, 6.8 mmol), benzyl chloride (0.82 ml, 7.1 mmol), K2CO3 (1.22 g, 8.8 mmol) and KI (0.056 g) were stirred and heated in DMF (50 ml) for 2.5 h. The cooled solution was poured into water and extracted with EtOAc (3×50 ml). The combined extracts were washed several times with water and finally with brine. Drying, filtering and evaporation of the solvent gave 1.64 g of the target compound as a yellowish oil.
Reaction SMILES: C[O:2][C:3]1[C:8]([NH:9][C:10]([NH:12][C:13]2[CH:18]=[CH:17][CH:16]=[C:15]([C:19]([F:22])([F:21])[F:20])[CH:14]=2)=[O:11])=[CH:7][CH:6]=[C:5]([O:23][CH3:24])[N:4]=1.B(Br)(Br)Br>ClCCl>[OH:2][C:3]1[C:8]([NH:9][C:10]([NH:12][C:13]2[CH:18]=[CH:17][CH:16]=[C:15]([C:19]([F:20])([F:22])[F:21])[CH:14]=2)=[O:11])=[CH:7][CH:6]=[C:5]([O:23][CH3:24])[N:4]=1
Reactant: COc1ccc(NC(=O)Nc2cccc(C(F)(F)F)c2)c(OC)n1
Agent: BrB(Br)Br
Solvent: ClCCl
Product: COc1ccc(NC(=O)Nc2cccc(C(F)(F)F)c2)c(O)n1
Temperature: 25 °C
Yield: 43.8 %

Procedure:
1-(2,6-dimethoxy-pyridin-3-yl)-3-(3-trifluoromethyl-phenyl)-urea (0.5 g) was suspended in dry dichloromethane (10 ml), BBr3 (0.14 ml) was added and the solution stirred at room temperature. After 5 hours more BBr3 (50 μl) was added and after a further hour the reaction was diluted with more dichloromethane and quenched with ice-water. The mixture was extracted with ethyl acetate, dried over MgSO4, filtered and concentrated to provide a light purple residue. This was preloaded onto silica and chromatographed to provide 1-(2-Hydroxy-6-methoxy-pyridin-3-yl)-3-(3-trifluoromethyl-phenyl)-urea as a white solid (210 mg). Mp.=223-224° C.