Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH:1]([NH:4][C:5]1[N:6]=[N:7][C:8]([C:11]#[CH:12])=[CH:9][CH:10]=1)([CH3:3])[CH3:2].[Cl:13][C:14]1[CH:19]=[CH:18][C:17]([C:20]2[NH:24][C:23]3[CH:25]=[C:26]([CH2:29][N:30]4[CH2:35][CH2:34][N:33]([CH3:36])[CH2:32][CH2:31]4)[CH:27]=[CH:28][C:22]=3[N:21]=2)=[CH:16][C:15]=1I>>[Cl:13][C:14]1[CH:19]=[CH:18][C:17]([C:20]2[NH:24][C:23]3[CH:25]=[C:26]([CH2:29][N:30]4[CH2:35][CH2:34][N:33]([CH3:36])[CH2:32][CH2:31]4)[CH:27]=[CH:28][C:22]=3[N:21]=2)=[CH:16][C:15]=1[C:12]#[C:11][C:8]1[N:7]=[N:6][C:5]([NH:4][CH:1]([CH3:3])[CH3:2])=[CH:10][CH:9]=1
Reactant: CN1CCN(Cc2ccc3nc(-c4ccc(Cl)c(I)c4)[nH]c3c2)CC1
Reactant: C#Cc1ccc(NC(C)C)nn1
Product: CC(C)Nc1ccc(C#Cc2cc(-c3nc4ccc(CN5CCN(C)CC5)cc4[nH]3)ccc2Cl)nn1

Procedure:
The title compound was synthesized from N-isopropyl-6-ethynylpyridazin-3-amine and 2-(4-chloro-3-iodophenyl)-6-((4-methylpiperazin-1-yl)methyl)-1H-benzo[d]imidazole in a manner similar to that described for in Example 1. The title compound was obtained as a khaki solid. Mp: 127-128° C.; 1H NMR (300 MHz, CDCl3) δ: 8.11-8.13 (1H, d, J=6.0 Hz), 7.82 (1H, s), 7.64 (2H, m), 7.53 (1H, s), 7.35-7.38 (1H, d, J=9.0 Hz), 7.29-7.32 (1H, d, J=9.0 Hz), 6.66-6.69 (1H, d, J=9.0 Hz), 5.22 (1H, s), 4.12-4.14 (1H, m), 3.62 (2H, s), 2.51 (8H, brs), 2.31 (3H, s), 1.25-1.31 (6H, m). HRMS (ESI-TOF+): m/z [M+H]+ calcd for C28H31ClN7: 500.2324. found: 500.2313.
Reaction SMILES: [OH-].[Na+].CC(O)C.[F:7][C:8]1[CH:31]=[CH:30][C:11]([NH:12][C:13]2[CH:22]=[C:21]([S:23][C:24]3[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=3)[CH:20]=[CH:19][C:14]=2[C:15]([O:17]C)=[O:16])=[CH:10][CH:9]=1.Cl>C(OCC)(=O)C>[F:7][C:8]1[CH:31]=[CH:30][C:11]([NH:12][C:13]2[CH:22]=[C:21]([S:23][C:24]3[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=3)[CH:20]=[CH:19][C:14]=2[C:15]([OH:17])=[O:16])=[CH:10][CH:9]=1
Reactant: COC(=O)c1ccc(Sc2ccccc2)cc1Nc1ccc(F)cc1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCOC(C)=O
Solvent: CC(C)O
Product: O=C(O)c1ccc(Sc2ccccc2)cc1Nc1ccc(F)cc1
Temperature: 25 °C
Yield: 79.3 %

Procedure:
10% Sodium hydroxide aqueous solution 1.0 mL was added to a suspension of 2-propanol 2.0 mL of methyl 2-(4-fluoroanilino)-4-(phenylthio)benzoate 0.21 g at room temperature, and it was heated and refluxed for 2 hours. After the reaction mixture was cooled to room temperature, 1.0 mol/L hydrochloric acid and ethyl acetate were added to it. The organic layer was separated and collected,dried over anhydrous magnesium sulfate, the solvent was removed under reduced pressure to give 2-(4-fluoroanilino)-4-(phenylthio)benzoic acid 0.16 g of pale yellow solid.
Reaction SMILES: CS([C:5]1[N:10]=[C:9]([C:11]2[N:15]3[CH:16]=[CH:17][N:18]=[C:19]([N:20]4[CH2:25][CH2:24][N:23]([CH3:26])[CH2:22][CH2:21]4)[C:14]3=[N:13][CH:12]=2)[CH:8]=[CH:7][N:6]=1)(=O)=O.[C:27]([O:31][C:32](=[O:45])[NH:33][CH2:34][CH2:35][CH:36]([NH2:44])[C:37]1[CH:42]=[CH:41][CH:40]=[C:39]([Cl:43])[CH:38]=1)([CH3:30])([CH3:29])[CH3:28]>>[C:27]([O:31][C:32](=[O:45])[NH:33][CH2:34][CH2:35][CH:36]([C:37]1[CH:42]=[CH:41][CH:40]=[C:39]([Cl:43])[CH:38]=1)[NH:44][C:5]1[N:10]=[C:9]([C:11]2[N:15]3[CH:16]=[CH:17][N:18]=[C:19]([N:20]4[CH2:25][CH2:24][N:23]([CH3:26])[CH2:22][CH2:21]4)[C:14]3=[N:13][CH:12]=2)[CH:8]=[CH:7][N:6]=1)([CH3:30])([CH3:28])[CH3:29]
Reactant: CC(C)(C)OC(=O)NCCC(N)c1cccc(Cl)c1
Reactant: CN1CCN(c2nccn3c(-c4ccnc(S(C)(=O)=O)n4)cnc23)CC1
Product: CN1CCN(c2nccn3c(-c4ccnc(NC(CCNC(=O)OC(C)(C)C)c5cccc(Cl)c5)n4)cnc23)CC1
Temperature: 140 °C
Reaction time: 2 h

Procedure:
The mixture of 3-(2-methanesulfonyl-pyrimidin-4-yl)-8-(4-methyl-piperazin-1-yl)-imidazo[1,2-a]pyrazine (from Example 46 supra) (100 mg, 0.27 mmol) and [3-amino-3-(3-chloro-phenyl)-propyl]-carbamic acid tert-butyl ester (from Example 62 supra) (307 mg, 1.08 mmol) was heated at 140° C. with stirring for 2 hours. The oil was purified by chromatography (silica gel, 10 g, 200-300 mesh, eluting with dichloromethane:methanol, 50:1 to 20:1) to afford crude (3-(3-chloro-phenyl)-3-{4-[8-(4-methyl-piperazin-1-yl)-imidazo[1,2-a]pyrazin-3-yl]-pyrimidin-2-ylamino}-propyl)-carbamic acid tert-butyl ester. (Yield 123 mg). LC-MS: [M+H]+ 578.
Reaction SMILES: [CH:1]([N:4]1[C:8]([C:9]2[N:18]=[C:17]3[N:11]([CH2:12][CH2:13][O:14][C:15]4[CH:22]=[C:21]([O:23][C:24]([CH3:30])([CH2:27][CH2:28][OH:29])[CH2:25][OH:26])[CH:20]=[CH:19][C:16]=43)[CH:10]=2)=[N:7][C:6]([CH3:31])=[N:5]1)([CH3:3])[CH3:2].CCN(CC)CC.[CH3:39][S:40](Cl)(=[O:42])=[O:41]>C(Cl)Cl>[CH:1]([N:4]1[C:8]([C:9]2[N:18]=[C:17]3[N:11]([CH2:12][CH2:13][O:14][C:15]4[CH:22]=[C:21]([O:23][C:24]([CH3:30])([CH2:25][O:26][S:40]([CH3:39])(=[O:42])=[O:41])[CH2:27][CH2:28][O:29][S:40]([CH3:39])(=[O:42])=[O:41])[CH:20]=[CH:19][C:16]=43)[CH:10]=2)=[N:7][C:6]([CH3:31])=[N:5]1)([CH3:3])[CH3:2]
Reactant: CS(=O)(=O)Cl
Reactant: Cc1nc(-c2cn3c(n2)-c2ccc(OC(C)(CO)CCO)cc2OCC3)n(C(C)C)n1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: Cc1nc(-c2cn3c(n2)-c2ccc(OC(C)(CCOS(C)(=O)=O)COS(C)(=O)=O)cc2OCC3)n(C(C)C)n1
Temperature: 25 °C
Reaction time: 1.5 h

Procedure:
To a solution of 2-[2-(2-isopropyl-5-methyl-2H-[1,2,4]triazol-3-yl)-4,5-dihydro-6-oxa-1,3a-diazabenzo[e]azulen-8-yloxy]-2-methylbutane-1,4-diol (14 mg, 0.0318 mmol) and Et3N (13 uL, 0.095 mmol) in DCM (2 mL) at 0° C. was added methanesulfonyl chloride (6.0 uL, 0.080 mmol) and stirring at RT was continued for 1.5 h. The mixture was diluted with DCM, washed with a saturated solution of NaHCO3, followed by water, then dried (Na2SO4) and concentrated in vacuo affording Methanesulfonic acid 3-[2-(2-isopropyl-5-methyl-2H-[1,2,4]triazol-3-yl)-4,5-dihydro-6-oxa-1,3a-diazabenzo[e]azulen-8-yloxy]-4-methanesulfonyloxy-3-methylbutyl ester as a colorless gum (23 mg, quantitative). LCMS: RT 2.99 min [M+H]+ 584.1
Reaction SMILES: [CH:1]([N:4]1[C:8]([C:9]2[N:18]=[C:17]3[N:11]([CH2:12][CH2:13][O:14][C:15]4[CH:22]=[C:21]([CH2:23][OH:24])[CH:20]=[CH:19][C:16]=43)[CH:10]=2)=[N:7][CH:6]=[N:5]1)([CH3:3])[CH3:2].CC(OI1(OC(C)=O)(OC(C)=O)OC(=O)C2C=CC=CC1=2)=O>C(Cl)Cl>[CH:1]([N:4]1[C:8]([C:9]2[N:18]=[C:17]3[N:11]([CH2:12][CH2:13][O:14][C:15]4[CH:22]=[C:21]([CH:23]=[O:24])[CH:20]=[CH:19][C:16]=43)[CH:10]=2)=[N:7][CH:6]=[N:5]1)([CH3:3])[CH3:2]
Reactant: CC(C)n1ncnc1-c1cn2c(n1)-c1ccc(CO)cc1OCC2
Agent: CC(=O)OI1(OC(C)=O)(OC(C)=O)OC(=O)c2ccccc21
Solvent: ClCCl
Product: CC(C)n1ncnc1-c1cn2c(n1)-c1ccc(C=O)cc1OCC2
Yield: 118.9 %

Procedure:
A solution of [2-(2-isopropyl-2H-[1,2,4]triazol-3-yl)-4,5-dihydro-6-oxa-1,3a-diaza-benzo[e]azulen-8-yl]-methanol (0.294 g, 0.91 mmol) and Dess-Martin periodinane (3.32 mL, 1.0 mmol, 3M solution in DCM) in DCM (15 mL) was stirred at RT for 1.5 h then washed with 1M sodium hydroxide. The aqueous phase was extracted with DCM and the combined organic extracts dried (Na2SO4) and concentrated in vacuo to give 2-(2-Isopropyl-2H-[1,2,4]triazol-3-yl)-4,5-dihydro-6-oxa-1,3a-diaza-benzo[e]azulene-8-carbaldehyde (0.35 g, quant.). LCMS: RT=3.07 min, [M+H]+=324.
Reaction SMILES: F[C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][N:11]=1)[N:8]=[CH:7][C:6]([C:12]#[N:13])=[C:5]2[NH:14][C:15]1[CH:20]=[CH:19][CH:18]=[C:17]([CH:21]([CH3:23])[CH3:22])[CH:16]=1.[CH3:24][O:25][C:26]1[CH:31]=[CH:30][C:29]([CH2:32][NH2:33])=[CH:28][CH:27]=1>>[CH:21]([C:17]1[CH:16]=[C:15]([NH:14][C:5]2[C:4]3[C:9](=[CH:10][N:11]=[C:2]([NH:33][CH2:32][C:29]4[CH:30]=[CH:31][C:26]([O:25][CH3:24])=[CH:27][CH:28]=4)[CH:3]=3)[N:8]=[CH:7][C:6]=2[C:12]#[N:13])[CH:20]=[CH:19][CH:18]=1)([CH3:23])[CH3:22]
Reactant: CC(C)c1cccc(Nc2c(C#N)cnc3cnc(F)cc23)c1
Reactant: COc1ccc(CN)cc1
Product: COc1ccc(CNc2cc3c(Nc4cccc(C(C)C)c4)c(C#N)cnc3cn2)cc1
Yield: 25 %

Procedure:
Following the procedure described above in Example 34, 6-fluoro-4-[(3-isopropylphenyl)amino]-1,7-naphthyridine-3-carbonitrile was reacted with (4-methoxyphenyl)methanamine. The crude product was purified by flash column chromatography (1% methanol in methylene chloride) to give a yellow solid (0.209 g, 25%). 1H NMR (400 MHz, DMSO-D6) δ ppm 1.2 (d, J=6.8 Hz, 6 H) 2.8 (none, 1 H) 2.9 (dq, J=6.9 Hz, 1 H) 3.7 (s, 3 H) 4.4 (d, J=6.3 Hz, 2 H) 6.9 (m, 2 H) 7.1 (m, 2 H) 7.1 (dd, J=4.3, 2.5 Hz, 2 H) 7.3 (m, 4 H) 8.2 (s, 1 H) 8.8 (s, 1 H) 9.6 (s, 1 H)
Reaction SMILES: C([O:3][C:4](=[O:21])[C@@H:5]([O:19][CH3:20])[CH2:6][C:7]1[CH:12]=[CH:11][C:10]([C:13]#[C:14][CH2:15][CH2:16][CH2:17][OH:18])=[CH:9][CH:8]=1)C.[C:22]1([C:28]2[CH:33]=[CH:32][C:31](O)=[CH:30][CH:29]=2)[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1>>[C:22]1([C:28]2[CH:29]=[CH:30][CH:31]=[CH:32][CH:33]=2)[CH:27]=[CH:26][C:25]([O:18][CH2:17][CH2:16][CH2:15][C:14]#[C:13][C:10]2[CH:9]=[CH:8][C:7]([CH2:6][C@H:5]([O:19][CH3:20])[C:4]([OH:3])=[O:21])=[CH:12][CH:11]=2)=[CH:24][CH:23]=1
Reactant: Oc1ccc(-c2ccccc2)cc1
Reactant: CCOC(=O)[C@H](Cc1ccc(C#CCCCO)cc1)OC
Product: CO[C@@H](Cc1ccc(C#CCCCOc2ccc(-c3ccccc3)cc2)cc1)C(=O)O

Procedure:
The title compound was prepared from (2S)-3-[4-(5-hydroxy-pent-1-ynyl)-phenyl]-2-methoxy-propionic acid ethyl ester and 4-phenylphenol via the standard Mitsunobu coupling-hydrolysis procedure (Standard Procedure A) to produce a white oily solid. 1H-NMR (200.15 MHz, CDCl3): δ 7.56–7.28 (m, 9H), 7.15 (d, 2H, J=8.4), 6.98 (d, 2H, J=8.8), 4.15 (t, 2H, J=6.2), 3.97 (dd, 1H, J=7.7, 4.4), 3.36 (s, 3H), 3.11 (dd, 1H, J=14.3, 4.4), 2.97 (dd, 1H, J=14.3, 7.7), 2.62 (t, 2H, J=7.0), 2.08 (qn, 2H, J=6.6).
Reaction SMILES: [OH:1][C@H:2]1[C@H:6]([O:7][CH3:8])[CH2:5][N:4]([C:9]([O:11][CH2:12][C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)=[O:10])[CH2:3]1.[CH3:19][C:20]1[CH:25]=[CH:24][C:23]([S:26](Cl)(=[O:28])=[O:27])=[CH:22][CH:21]=1.C(N(CC)CC)C>CN(C)C1C=CN=CC=1.C(Cl)Cl>[CH3:8][O:7][C@H:6]1[C@H:2]([O:1][S:26]([C:23]2[CH:24]=[CH:25][C:20]([CH3:19])=[CH:21][CH:22]=2)(=[O:28])=[O:27])[CH2:3][N:4]([C:9]([O:11][CH2:12][C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)=[O:10])[CH2:5]1
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Reactant: CO[C@@H]1CN(C(=O)OCc2ccccc2)C[C@H]1O
Agent: CN(C)c1ccncc1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CO[C@@H]1CN(C(=O)OCc2ccccc2)C[C@H]1OS(=O)(=O)c1ccc(C)cc1
Temperature: 25 °C
Yield: 83 %

Procedure:
(+/−)-Trans-Benzyl 3-hydroxy-4-methoxypyrrolidine-1-carboxylate (7.7 g, 30.6 mmol) and N,N-dimethylpyridin-4-amine (0.374 g, 3.06 mmol) were dissolved in DCM (75 mL). Cooled to 0 deg. Celsius and added 4-methylbenzene-1-sulfonyl chloride (8.76 g, 46 mmol) and triethylamine (6.41 ml, 46.0 mmol). The reaction was stirred to warm to RT overnight. The solvent was removed and the residue was passed thru a pad of silica to give the product, (+/−)-Trans-benzyl 3-methoxy-4-(tosyloxy)pyrrolidine-1-carboxylate (10.3 g, 25.4 mmol, 83% yield).
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([C:8]2[CH:9]=[C:10]3[CH:16]=[CH:15][NH:14][C:11]3=[N:12][CH:13]=2)[CH:5]=[CH:4][C:3]=1[C:17]1[CH2:22][CH2:21][N:20]([C:23]([O:25][C:26]([CH3:29])([CH3:28])[CH3:27])=[O:24])[CH2:19][CH:18]=1>C(OCC)(=O)C.CO.[OH-].[Pd+2].[OH-]>[F:1][C:2]1[CH:7]=[C:6]([C:8]2[CH:9]=[C:10]3[CH:16]=[CH:15][NH:14][C:11]3=[N:12][CH:13]=2)[CH:5]=[CH:4][C:3]=1[CH:17]1[CH2:22][CH2:21][N:20]([C:23]([O:25][C:26]([CH3:29])([CH3:28])[CH3:27])=[O:24])[CH2:19][CH2:18]1
Reactant: CC(C)(C)OC(=O)N1CC=C(c2ccc(-c3cnc4[nH]ccc4c3)cc2F)CC1
Agent: [Pd+2]
Agent: [OH-]
Solvent: CO
Solvent: CCOC(C)=O
Product: CC(C)(C)OC(=O)N1CCC(c2ccc(-c3cnc4[nH]ccc4c3)cc2F)CC1
Reaction time: 168 h
Yield: 99.4 %

Procedure:
To a solution of tert-butyl 4-(2-fluoro-4-(1H-pyrrolo[2,3-b]pyridin-5-yl)phenyl)-5,6-dihydropyridine-1(2H)-carboxylate (320 mg, 0.814 mmol) in ethyl acetate/methanol 20/20 mL was added palladium hydroxide (160 mg) and stirred under hydrogen atmosphere for 7 days. The catalyst was filtered through celite and the solvent was distilled off to get 320 mg (99.37% yield) of the titled compound. MS: m/z=396.3 (M+1).
Reaction SMILES: [H-].[Na+].Cl[C:4]1[N:9]=[C:8]([C:10]2[C:18]([C:19]3[CH:24]=[CH:23][C:22]([F:25])=[CH:21][CH:20]=3)=[C:13]3[CH:14]=[CH:15][CH:16]=[CH:17][N:12]3[N:11]=2)[CH:7]=[CH:6][CH:5]=1.CN([CH:29]=[O:30])C>CO>[F:25][C:22]1[CH:23]=[CH:24][C:19]([C:18]2[C:10]([C:8]3[CH:7]=[CH:6][CH:5]=[C:4]([O:30][CH3:29])[N:9]=3)=[N:11][N:12]3[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=23)=[CH:20][CH:21]=1
Reactant: Fc1ccc(-c2c(-c3cccc(Cl)n3)nn3ccccc23)cc1
Reactant: CN(C)C=O
Agent: [H-]
Agent: [Na+]
Solvent: CO
Product: COc1cccc(-c2nn3ccccc3c2-c2ccc(F)cc2)n1
Temperature: 25 °C
Reaction time: 4 h
Yield: 97 %

Procedure:
Add sodium hydride (20.7 mg, 60% dispersion in mineral oil, 0.52 mmol) to a solution of 2-(6-chloro-pyridin-2-yl)-3-(4-fluoro-phenyl)-pyrazolo[1,5-a]pyridine (33.5 mg, 0.10 mmol) in DMF (2.5 mL) and methanol (2.5 mL) at room temperature. Stir the reaction mixture at room temperature for 4 hours and at 80° C. for 48 hours. Cool to room temperature and concentrate in vacuo. Add water (20 mL) and extract the aqueous solution with methylene chloride (3×20 mL). Dry the combined organic layers with sodium sulfate and concentrate. Purify by flash column chromatography (SiO2, 50% ethyl acetate/hexanes) to give the title compound 31 mg (97%) as an off-white solid.
Reaction SMILES: [CH:1]1([P:7]([CH:27]2[CH2:32][CH2:31][CH2:30][CH2:29][CH2:28]2)[C@@H:8]2[CH2:12][NH:11][C@H:10]([CH2:13][P:14]([C:21]3[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=3)[C:15]3[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=3)[CH2:9]2)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[C:33]([O:37][C:38](=O)[O:39]C(C)(C)C)([CH3:36])([CH3:35])[CH3:34].C(N(CC)CC)C>C(Cl)Cl>[C:33]([O:37][C:38]([N:11]1[CH2:12][C@@H:8]([P:7]([CH:1]2[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]2)[CH:27]2[CH2:28][CH2:29][CH2:30][CH2:31][CH2:32]2)[CH2:9][C@H:10]1[CH2:13][P:14]([C:21]1[CH:22]=[CH:23][CH:24]=[CH:25][CH:26]=1)[C:15]1[CH:16]=[CH:17][CH:18]=[CH:19][CH:20]=1)=[O:39])([CH3:36])([CH3:35])[CH3:34]
Reactant: CC(C)(C)OC(=O)OC(C)(C)C
Reactant: c1ccc(P(C[C@@H]2C[C@H](P(C3CCCCC3)C3CCCCC3)CN2)c2ccccc2)cc1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CC(C)(C)OC(=O)N1C[C@@H](P(C2CCCCC2)C2CCCCC2)C[C@H]1CP(c1ccccc1)c1ccccc1

Procedure:
To a solution of (2S,4S)-4-dicyclohexylphosphino-2-diphenylphosphinomethylpyrrolidine [IV′] (46 mg, 0.1 mmol) dissolved in 1 ml of methylene chloride was added a solution of di-tert-butylcarbonate (24 mg, 0.11 mmol) dissolved in 11 mg (0.11 mmol) of triethylamine and 2 ml of methylene chloride and the resultant mixture was stirred for 2 to 3 hours at room temperature under nitrogen atmosphere. The reaction solution was concentrated under vacuum to afford white crystalline BCPM (50 mg, 86%), mp. 171 to 174° C.
Reaction SMILES: [Cl:1][C:2]1[CH:11]=[CH:10][C:9]2[CH2:8][CH2:7][CH2:6][CH:5]([OH:12])[C:4]=2[N:3]=1.ClC1C=CC=C(C(OO)=[O:21])C=1>ClCCl>[Cl:1][C:2]1[CH:11]=[CH:10][C:9]2[CH2:8][CH2:7][CH2:6][CH:5]([OH:12])[C:4]=2[N+:3]=1[O-:21]
Reactant: OC1CCCc2ccc(Cl)nc21
Reactant: O=C(OO)c1cccc(Cl)c1
Solvent: ClCCl
Product: [O-][n+]1c(Cl)ccc2c1C(O)CCC2
Temperature: 25 °C
Reaction time: 20 h
Yield: 98 %

Procedure:
To an ice-cold solution of 2-chloro-5,6,7,8-tetrahydroquinolin-8-ol (300 mg, 1.634 mmol) in dichloromethane (5 mL) was added 3-chloroperbenzoic acid (604 mg, 2.451 mmol) in small portions over a period of 5 min. The reaction mixture was slowly warmed to RT and stirred for 20 h. The reaction was quenched by the addition of water. The aqueous phase was removed and the organic layer was washed with a 10% aqueous sodium thiosulfate solution (2×), with a 2M sodium carbonate solution (2×), and with brine (1×). The organic layer was dried over sodium sulfate, filtered, and evaporated to dryness furnishing a beige solid. Amount 320 mg. Yield 98%.
Reaction SMILES: [CH3:1][C:2]1[S:3][C:4]2[CH:11]=[CH:10][C:9]3[CH:12]=[C:13]([CH2:16][CH2:17][CH3:18])[CH:14]=[CH:15][C:8]=3[C:7](=[O:19])[C:5]=2[N:6]=1.[BH4-].[Na+]>CS(C)=O.O1CCOCC1>[CH3:1][C:2]1[S:3][C:4]2[CH:11]=[CH:10][C:9]3[CH:12]=[C:13]([CH2:16][CH2:17][CH3:18])[CH:14]=[CH:15][C:8]=3[CH:7]([OH:19])[C:5]=2[N:6]=1
Reactant: CCCc1ccc2c(=O)c3nc(C)sc3ccc2c1
Agent: [BH4-]
Agent: [Na+]
Solvent: C1COCCO1
Solvent: CS(C)=O
Product: CCCc1ccc2c(c1)C=Cc1sc(C)nc1C2O
Temperature: 25 °C
Reaction time: 24 h

Procedure:
To a solution of the product from step (x) (3.1 g) in dry dimethylsulphoxide (30 ml) and dry 1,4-dioxane (90 ml) was added sodium borohydride (0.7 g). After stirring at room temperature for 24 h the reaction mixture was quenched with water and extracted with ethyl acetate. The organic layer was washed with saturated sodium bicarbonate solution, then brine. The organic layer was collected and dried over magnesium sulphate and solvent removed under reduced pressure to leave a pale yellow gum.
Reaction SMILES: [CH:1]1[CH:6]=[C:5]2[C:7]([N:9]([CH2:12][CH2:13]Br)[C:10](=[O:11])[C:4]2=[CH:3][CH:2]=1)=[O:8].[F:15][C:16]1[CH:22]=[CH:21][C:19]([NH2:20])=[CH:18][CH:17]=1.CN(C=O)C.C(=O)([O-])[O-].[Na+].[Na+]>O>[F:15][C:16]1[CH:22]=[CH:21][C:19]([NH:20][CH2:13][CH2:12][N:9]2[C:7](=[O:8])[C:5]3[C:4](=[CH:3][CH:2]=[CH:1][CH:6]=3)[C:10]2=[O:11])=[CH:18][CH:17]=1
Reactant: Nc1ccc(F)cc1
Reactant: O=C1c2ccccc2C(=O)N1CCBr
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: O=C1c2ccccc2C(=O)N1CCNc1ccc(F)cc1
Temperature: 80 °C
Reaction time: 8 h

Procedure:
To a 50 mL round-bottomed flask was added n-(2-bromoethyl)phthalimide, 95% (508 mg, 1999 μmol, Aldrich), 4-fluoroaniline (193 μL, 1999 μmol, Aldrich), DMF (2 mL), sodium carbonate (336 mg, 3999 μmol). The reaction mixture was stirred at 80° C. for overnight. The reaction mixture was diluted with water (20 mL) and extracted with EtOAc (2×40 mL). The organic extract was washed with water (20 mL), saturated NaCl (20 mL), dried over Na2SO4, filtered and concentrated in vacuo and the residue was purified by silica gel chromatography, eluting with 30% EtOAc/hexanes to give 2-(2-(4-fluorophenylamino)ethyl)iso-indoline-1,3-dione. MS (ESI pos. ion) m/z: 285 (M+1).
Reaction SMILES: C[O:2][C:3](=O)[CH2:4][C:5]([NH:7][C:8]1[CH:13]=[CH:12][C:11]([O:14][CH2:15][C:16]2[CH:21]=[CH:20][CH:19]=[C:18]([F:22])[CH:17]=2)=[CH:10][CH:9]=1)=[O:6].[OH-].[NH4+:25]>O1CCCC1>[F:22][C:18]1[CH:17]=[C:16]([CH:21]=[CH:20][CH:19]=1)[CH2:15][O:14][C:11]1[CH:12]=[CH:13][C:8]([NH:7][C:5](=[O:6])[CH2:4][C:3]([NH2:25])=[O:2])=[CH:9][CH:10]=1
Reactant: [NH4+]
Reactant: COC(=O)CC(=O)Nc1ccc(OCc2cccc(F)c2)cc1
Agent: [OH-]
Solvent: C1CCOC1
Product: NC(=O)CC(=O)Nc1ccc(OCc2cccc(F)c2)cc1
Reaction time: 2.5 h
Yield: 51 %

Procedure:
99 mg (0.31 mmol) N-[4-(3-fluoro-benzyloxy)-phenyl]-malonamic acid methyl ester (example 1) is dissolved in a mixture of 0.5 ml tetrahydrofuran and 1.0 ml of aqueous ammonium hydroxide (25%). The reaction vessel is capped and kept at 60° C. for 2.5 h. The reaction mixture is cooled, evaporated to dryness and diluted with water. Filtration provides 48 mg (51%) of the title compound as a light yellow solid. MS: m/e=303.2 (M++H).
Reaction SMILES: Br[C:2]1[C:10]2[C:5](=[C:6]([CH:12]([O:14][CH2:15][C:16]3([C:29]4[CH:34]=[CH:33][C:32]([F:35])=[CH:31][CH:30]=4)[CH2:21][CH2:20][N:19]([C:22]([O:24][C:25]([CH3:28])([CH3:27])[CH3:26])=[O:23])[CH2:18][CH2:17]3)[CH3:13])[CH:7]=[C:8]([Cl:11])[CH:9]=2)[N:4]([CH2:36][O:37][CH2:38][CH2:39][Si:40]([CH3:43])([CH3:42])[CH3:41])[N:3]=1.[CH:44]1(B(O)O)[CH2:46][CH2:45]1>O1CCCC1.[Pd].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>[Cl:11][C:8]1[CH:9]=[C:10]2[C:5](=[C:6]([CH:12]([O:14][CH2:15][C:16]3([C:29]4[CH:34]=[CH:33][C:32]([F:35])=[CH:31][CH:30]=4)[CH2:21][CH2:20][N:19]([C:22]([O:24][C:25]([CH3:28])([CH3:27])[CH3:26])=[O:23])[CH2:18][CH2:17]3)[CH3:13])[CH:7]=1)[N:4]([CH2:36][O:37][CH2:38][CH2:39][Si:40]([CH3:43])([CH3:42])[CH3:41])[N:3]=[C:2]2[CH:44]1[CH2:46][CH2:45]1
Reactant: OB(O)C1CC1
Reactant: CC(OCC1(c2ccc(F)cc2)CCN(C(=O)OC(C)(C)C)CC1)c1cc(Cl)cc2c(Br)nn(COCC[Si](C)(C)C)c12
Agent: [Pd]
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: CC(OCC1(c2ccc(F)cc2)CCN(C(=O)OC(C)(C)C)CC1)c1cc(Cl)cc2c(C3CC3)nn(COCC[Si](C)(C)C)c12
Temperature: 100 °C

Procedure:
(±)-tert-Butyl 4-((1-(3-bromo-5-chloro-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-indazol-7-yl)ethoxy)methyl)-4-(4-fluorophenyl)piperidine-1-carboxylate (100 mg, 0.14 mmol), cyclopropylboronic acid (18.5 mg, 0.22 mmol), and tetrakis(triphenylphosphine) palladium(0) (16.6 mg, 0.01 mmol) were combined in dry tetrahydrofuran (3 mL) in a microwave tube and sealed. The mixture was flushed with nitrogen then 0.5 mL of a 1 N potassium hydroxide aqueous solution was introduced. The mixture was heated at 100° C. for 1 h via microwave. After cooling to room temperature, the reaction mixture was diluted with ethyl acetate, washed with water (2×), then brine (2×), dried over sodium sulfate, and concentrated. Flash chromatography on silica gel (15% ethyl acetate/hexanes) gave 65 mg (69%). 1H-NMR (CDCl3, 500 MHz) δ 7.58 (d, J=1.8 Hz, 1H), 7.21-7.23 (m, 2H), 6.97-7.01 (m, 3H), 5.50 (qAB, JAB=11.9 Hz, 2H), 5.00 (q, J=6.4 Hz, 1H), 3.69 (m, 2H), 3.33-3.45 (m, 2H), 3.19-3.27 (m, 2H), 3.01-3.06 (m, 2H), 2.01-2.14 (m, 3H), 1.79-1.89 (m, 2H), 1.43 (s, 9H), 1.41 (m, 3H), 0.96-1.01 (m, 4H), 0.67-0.83 (m, 2H), 0.09 (s, 9H). Mass spec.: 658.67 (MH)+.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]2[C:11]3([O:15][N:14]([CH3:16])[C:13]([NH2:17])=[N:12]3)[CH2:10][CH:9]([CH:18]3[CH2:23][CH2:22][CH2:21][O:20][CH2:19]3)[O:8][C:5]2=[CH:6][CH:7]=1.[CH:24]([C:27]1[CH:28]=[C:29](B(O)O)[CH:30]=[CH:31][CH:32]=1)([CH3:26])[CH3:25]>O1CCOCC1.C([O-])([O-])=O.[Cs+].[Cs+].Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>[CH:24]([C:27]1[CH:32]=[C:31]([C:2]2[CH:3]=[C:4]3[C:11]4([O:15][N:14]([CH3:16])[C:13]([NH2:17])=[N:12]4)[CH2:10][CH:9]([CH:18]4[CH2:23][CH2:22][CH2:21][O:20][CH2:19]4)[O:8][C:5]3=[CH:6][CH:7]=2)[CH:30]=[CH:29][CH:28]=1)([CH3:26])[CH3:25]
Reactant: CC(C)c1cccc(B(O)O)c1
Reactant: CN1OC2(CC(C3CCCOC3)Oc3ccc(Br)cc32)N=C1N
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: C1COCCO1
Product: CC(C)c1cccc(-c2ccc3c(c2)C2(CC(C4CCCOC4)O3)N=C(N)N(C)O2)c1
Temperature: 120 °C
Yield: 16.9 %

Procedure:
Pd(PPh3)2Cl2 (5 mg) in a 10 mL flask under Ar was treated sequentially with the 6-bromo-2′-methyl-2-(tetrahydro-2H-pyran-3-yl)-2′H-spiro[chroman-4,5′-[1,2,4]oxadiazol]-3′-amine (40 mg, 0.105 mmol) in 1,4-dioxane (1 mL), Cs2CO3 (2 N, 0.2 mL) and 3-isopropylphenylboronic acid (25.8 mg, 144 mmol). The mixture was heated at 120° C. under Ar in a microwave reactor for 30 minutes. The reaction mixture was concentrated in vacuo to give the residue, which was purified by preparative TLC and preparative HPLC to give 6-(3-isopropylphenyl)-2′-methyl-2-(tetrahydro-2H-pyran-3-yl)-2′H-spiro[chroman-4,5′-[1,2,4]oxadiazol]-3′-amine (7.5 mg, 18%). 1H NMR (MeOD): 1.31 (d, 6H), 1.68 (m, 2H), 1.92-2.07 (m, 3H), 2.43-2.72 (m, 1H), 2.96 (m, 1H), 3.34 (s, 3H), 3.45-3.58 (m, 2H), 3.83-4.01 (m, 2H), 4.12-4.23 (m, 2H), 6.98 (m, 1H), 7.21 (m, 1H), 7.38 (m, 3H), 7.63 (m, 1H), 7.79 (m, 1H).
Reaction SMILES: [CH3:1][C:2]1[N:7]2[N:8]=[N:9][N:10]=[C:6]2[C:5]2[N:11]=[C:12]([CH2:29][CH2:30][CH3:31])[N:13]([CH2:14][CH2:15][CH2:16][S:17]([C:20]3[CH:28]=[CH:27][C:23]([C:24]([OH:26])=O)=[CH:22][CH:21]=3)(=[O:19])=[O:18])[C:4]=2[C:3]=1[CH3:32].C(Cl)(=O)C(Cl)=O.[NH:39]1[CH2:44][CH2:43][O:42][CH2:41][CH2:40]1>ClCCl>[CH3:1][C:2]1[N:7]2[N:8]=[N:9][N:10]=[C:6]2[C:5]2[N:11]=[C:12]([CH2:29][CH2:30][CH3:31])[N:13]([CH2:14][CH2:15][CH2:16][S:17]([C:20]3[CH:28]=[CH:27][C:23]([C:24]([N:39]4[CH2:44][CH2:43][O:42][CH2:41][CH2:40]4)=[O:26])=[CH:22][CH:21]=3)(=[O:19])=[O:18])[C:4]=2[C:3]=1[CH3:32]
Reactant: CCCc1nc2c(c(C)c(C)n3nnnc23)n1CCCS(=O)(=O)c1ccc(C(=O)O)cc1
Reactant: C1COCCN1
Agent: O=C(Cl)C(=O)Cl
Solvent: ClCCl
Product: CCCc1nc2c(c(C)c(C)n3nnnc23)n1CCCS(=O)(=O)c1ccc(C(=O)N2CCOCC2)cc1
Temperature: 0 °C
Reaction time: 2 h
Yield: 29.1 %

Procedure:
Under a nitrogen atmosphere, a mixture of 4-[3-(5,6-dimethyl-8-propyl-7H-imidazo[4,5-c]tetrazolo[1,5-a]pyridin-7-yl)propane-1-sulfonyl]benzoic acid (2.26 g, 4.95 mmol) and dichloromethane (50 mL) was cooled to 0° C. Oxalyl chloride (0.95 mL, 10.9 mmol) was added dropwise, and the reaction was stirred for two hours at room temperature. To one-third of the solution was added morpholine (0.43 mL, 4.9 mmol), and the reaction was stirred under nitrogen overnight. Additional morpholine (1.0 mL, 11 mmol) was added, and the reaction was stirred for two hours. A white precipitate formed, which was isolated by filtration, washed with ethyl acetate and water, and then dried for two hours in a vacuum oven at 80° C. to provide 0.75 g of {4-[3-(5,6-dimethyl-8-propyl-7H-imidazo[4,5-c]tetrazolo[1,5-a]pyridin-7-yl)propane-1-sulfonyl]phenyl}morpholin-4-ylmethanone as a white solid.