Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]2[C:9](=[C:10]([O:23][CH3:24])[C:11]=1[N:12]1[CH2:17][CH2:16][CH:15]([C:18]([O:20]CC)=[O:19])[CH2:14][CH2:13]1)[N:8]([CH2:25][CH2:26][F:27])[CH:7]=[C:6]([C:28]([NH:30][CH2:31][C:32]1[CH:37]=[CH:36][C:35]([O:38][C:39]([F:42])([F:41])[F:40])=[CH:34][C:33]=1[CH3:43])=[O:29])[C:5]2=[O:44].[OH-].[Li+].Cl>O1CCOCC1.C(OCC)(=O)C.O>[F:1][C:2]1[CH:3]=[C:4]2[C:9](=[C:10]([O:23][CH3:24])[C:11]=1[N:12]1[CH2:13][CH2:14][CH:15]([C:18]([OH:20])=[O:19])[CH2:16][CH2:17]1)[N:8]([CH2:25][CH2:26][F:27])[CH:7]=[C:6]([C:28]([NH:30][CH2:31][C:32]1[CH:37]=[CH:36][C:35]([O:38][C:39]([F:42])([F:40])[F:41])=[CH:34][C:33]=1[CH3:43])=[O:29])[C:5]2=[O:44]
Reactant: CCOC(=O)C1CCN(c2c(F)cc3c(=O)c(C(=O)NCc4ccc(OC(F)(F)F)cc4C)cn(CCF)c3c2OC)CC1
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: C1COCCO1
Solvent: O
Solvent: CCOC(C)=O
Product: COc1c(N2CCC(C(=O)O)CC2)c(F)cc2c(=O)c(C(=O)NCc3ccc(OC(F)(F)F)cc3C)cn(CCF)c12
Temperature: 25 °C

Procedure:
60 mg (0.096 mmol) of the compound of Example 4 are dissolved in 2.35 ml of dioxane, 480 μl (5 eq.) of a 1M solution of lithium hydroxide are added, and the mixture is stirred at RT until the reaction is complete (4 h). The reaction mixture is acidified with 1N hydrochloric acid and diluted with ethyl acetate and water. Following phase separation, the organic phase is washed once again with water and then with a saturated sodium chloride solution, dried over magnesium sulfate and freed from solvents on a rotary evaporator. The residue is dried under high vacuum. 54 mg (94% of theory) of the title compound are obtained.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([Cl:8])[C:5]([O:9][CH2:10][C:11]#[CH:12])=[CH:4][C:3]=1[N:13]1[C:22](=[O:23])[N:16]2[CH2:17][CH2:18][CH2:19][CH:20](O)[C:15]2=[N:14]1.C(N(S(F)(F)[F:30])CC)C>ClCCl>[Cl:1][C:2]1[CH:7]=[C:6]([Cl:8])[C:5]([O:9][CH2:10][C:11]#[CH:12])=[CH:4][C:3]=1[N:13]1[C:22](=[O:23])[N:16]2[CH2:17][CH2:18][CH2:19][CH:20]([F:30])[C:15]2=[N:14]1
Reactant: CCN(CC)S(F)(F)F
Reactant: C#CCOc1cc(-n2nc3n(c2=O)CCCC3O)c(Cl)cc1Cl
Solvent: ClCCl
Product: C#CCOc1cc(-n2nc3n(c2=O)CCCC3F)c(Cl)cc1Cl
Temperature: -78 °C
Reaction time: 4 h
Yield: 90.2 %

Procedure:
To a solution of 300 mg (0.847 mmol) of 5,6,7,8-tetrahydro-2-[2,4-dichloro-5-(2-propynyloxy)phenyl]-8-hydroxy-1,2,4-triazolo[4,3-α]pyridin-3(2H)-one in 10 mL of dichloromethane was added 123 mL (0.930 mmol) of diethylaminosulfur trifluoride (DAST) at -78° C. The reaction mixture was stirred at -78° C. for 4h. The mixture was warmed to room temperature, quenched with ice, and extracted with dichloromethane. The organic layers were dried (MgSO4), and concentrated under reduced pressure. The crude product was flash chromatographed over silica gel, eluting with a 98:2 v:v mixture of dichloromethane and methanol to give 272 mg of the title product of Step 4 as a yellow solid. 19F NMR (CDCl3, 300 MHz) δ-172; 1H NMR (CDCl3, 300 MHz) δ 7.55 (s,1H), 7.2 (s,1H), 5.6, 5.5 (2m, J=70 Hz,1H), 4.8 (s,2H), 4.0 (m,1H), 3.55 (m,1H), 2.6 (m,1H), 2.5-1.8 (m,4H).
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][N:5]=[CH:4][C:3]=1[N:8]1[CH2:12][CH2:11][NH:10][C:9]1=[O:13].Br[C:15]1[S:23][C:22]2[CH:21]=[CH:20][N:19]=[C:18]([O:24][CH3:25])[C:17]=2[CH:16]=1.N[C@@H]1CCCC[C@H]1N.P([O-])([O-])([O-])=O.[K+].[K+].[K+]>[Cu](I)I.O1CCOCC1>[CH3:25][O:24][C:18]1[C:17]2[CH:16]=[C:15]([N:10]3[CH2:11][CH2:12][N:8]([C:3]4[CH:4]=[N:5][CH:6]=[CH:7][C:2]=4[CH3:1])[C:9]3=[O:13])[S:23][C:22]=2[CH:21]=[CH:20][N:19]=1
Reactant: Cc1ccncc1N1CCNC1=O
Reactant: COc1nccc2sc(Br)cc12
Agent: I[Cu]I
Agent: N[C@@H]1CCCC[C@H]1N
Agent: O=P([O-])([O-])[O-]
Solvent: C1COCCO1
Product: COc1nccc2sc(N3CCN(c4cnccc4C)C3=O)cc12
Yield: 42 %

Procedure:
Using the same reaction conditions as in Example 14, 1-(4-methyl-pyridin-3-yl)-imidazolidin-2-one (I-14b: 62 mg, 0.3498 mmol) was reacted with 2-bromo-4-methoxy-thieno[3,2-c]pyridine (85.4 mg, 0.3498 mmol), 1,4-dioxane (50 mL), copper iodide (6.6 mg, 0.03498 mmol), trans-1,2-diamino cyclohexane (12 mg, 0.1049 mmol) and potassium phosphate (185.6 mg, 0.8747 mmol) to afford the crude product. Purification by column chromatography on silica gel (1% MeOH in CHCl3) afforded 50 mg of the product (40% yield).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][C:9]2[CH:18]=[C:17]3[C:12]([C:13]([OH:34])=[C:14]([C:29](OCC)=[O:30])[C:15](=[O:28])[N:16]3[CH2:19][CH2:20][N:21]3[CH2:26][CH2:25][CH2:24][CH2:23][C:22]3=[O:27])=[N:11][CH:10]=2)=[CH:4][CH:3]=1.[NH2:35][CH2:36][CH2:37][CH2:38][N:39]1[CH2:43][CH2:42][CH2:41][C:40]1=[O:44]>>[F:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][C:9]2[CH:18]=[C:17]3[C:12]([C:13]([OH:34])=[C:14]([C:29]([NH:35][CH2:36][CH2:37][CH2:38][N:39]4[CH2:43][CH2:42][CH2:41][C:40]4=[O:44])=[O:30])[C:15](=[O:28])[N:16]3[CH2:19][CH2:20][N:21]3[CH2:26][CH2:25][CH2:24][CH2:23][C:22]3=[O:27])=[N:11][CH:10]=2)=[CH:4][CH:3]=1
Reactant: CCOC(=O)c1c(O)c2ncc(Cc3ccc(F)cc3)cc2n(CCN2CCCCC2=O)c1=O
Reactant: NCCCN1CCCC1=O
Product: O=C(NCCCN1CCCC1=O)c1c(O)c2ncc(Cc3ccc(F)cc3)cc2n(CCN2CCCCC2=O)c1=O

Procedure:
This compound was prepared from ethyl 7-[(4-fluorophenyl)methyl]-4-hydroxy-2-oxo-1-[2-(2-oxo-1-piperidinyl)ethyl]-1,2-dihydro-1,5-naphthyridine-3-carboxylate and 1-(3-aminopropyl)-2-pyrrolidinone using methods similar to Example 563 to provide a white solid: 1H NMR (d6-DMSO) δ 10.28 (1H, t, J=6 Hz), 8.53 (1H, s), 8.16 (1H, s), 7.38 (2H, dd, J=6, 8 Hz), 7.11 (2H, t, J=9 Hz), 4.35 (2H, t, J=6 Hz), 4.13 (2H, s), 3.47 (2H, t, J=7 Hz), 3.18-3.35 (8H, m), 2.19 (2H, t, J=9 Hz), 2.02 (2H, t, J=5 Hz), 1.84-1.94 (2H, m), 1.69-1.76 (2H, m), 1.49-1.62 (4H, m); ES+ MS: 564 (M+H+).
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][C:8]=2[NH2:10])[CH:3]=[N:2]1>C(O)C.[Rh]>[NH:1]1[C:9]2[CH:8]([NH2:10])[CH2:7][CH2:6][CH2:5][C:4]=2[CH:3]=[N:2]1
Reactant: Nc1cccc2cn[nH]c12
Agent: [Rh]
Solvent: CCO
Product: NC1CCCc2cn[nH]c21
Yield: 27.7 %

Procedure:
Combine 1H-indazol-7-ylamine (5.0 g, 37.6 mmol) and 5% Rh/C (2.45 g) in ethanol (120 mL) and heat at 120° C. for 48 hours under ˜1000 psi H2. Cool the reaction and filter through hyflo. Remove the solvent in vacuo and purify the crude product with 5% 2 M NH3 in MeOH in CH2Cl2 to afford 1.43 g (28%) of the titled product. MS (m/z): 138 (M+1).
Reaction SMILES: [C:1]1([C:11]2([CH:16]=[O:17])[CH2:15][CH2:14][CH2:13][CH2:12]2)[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][CH:2]=1.[BH4-].[Na+].C(OCC)(=O)C>CO.CCCCCC>[C:1]1([C:11]2([CH2:16][OH:17])[CH2:15][CH2:14][CH2:13][CH2:12]2)[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][CH:2]=1
Reactant: O=CC1(c2cccc3ccccc23)CCCC1
Agent: [BH4-]
Agent: [Na+]
Solvent: CCCCCC
Solvent: CCOC(C)=O
Solvent: CO
Product: OCC1(c2cccc3ccccc23)CCCC1
Yield: 86.7 %

Procedure:
A solution of 1-naphthalen-1-yl-cyclopentanecarbaldehyde (339) (10 g, 44.6 mmol) in methanol (150 mL) was cooled to 0° C. and NaBH4 (3.373 g, 89.2 mmol) was added in portions (8 portions). After the addition was completed the reaction mixture was allowed to stir at room temperature for 1 h (silica TLC, 10% ethyl acetate in hexane; Rf=0.3). The reaction mixture was quenched with aqueous NH4Cl solution and concentrated in vacuo as much as possible; diluted with water (100 mL) and extracted with ethyl acetate (2×100 mL). The organic part was washed with brine (50 mL), dried and concentrated in vacuo to get a crude mass which was purified by CombiFlash using gradient eluent mixture of ethyl acetate and hexane to get pure (1-naphthalen-1-yl-cyclopentyl)-methanol (340) (8.75 g, 87%) as a white solid.
Reaction SMILES: [CH:1]1([C:4]2[C:5]([N:24]3[CH2:29][CH2:28][N:27](C(OC(C)(C)C)=O)[CH2:26][CH2:25]3)=[C:6]3[C:12]([CH2:13][CH3:14])=[N:11][N:10]([CH2:15][C:16]4[CH:21]=[CH:20][C:19]([O:22][CH3:23])=[CH:18][CH:17]=4)[C:7]3=[N:8][CH:9]=2)[CH2:3][CH2:2]1.C(O)(C(F)(F)F)=O>C(Cl)Cl>[CH:1]1([C:4]2[C:5]([N:24]3[CH2:25][CH2:26][NH:27][CH2:28][CH2:29]3)=[C:6]3[C:12]([CH2:13][CH3:14])=[N:11][N:10]([CH2:15][C:16]4[CH:17]=[CH:18][C:19]([O:22][CH3:23])=[CH:20][CH:21]=4)[C:7]3=[N:8][CH:9]=2)[CH2:2][CH2:3]1
Reactant: CCc1nn(Cc2ccc(OC)cc2)c2ncc(C3CC3)c(N3CCN(C(=O)OC(C)(C)C)CC3)c12
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CCc1nn(Cc2ccc(OC)cc2)c2ncc(C3CC3)c(N3CCNCC3)c12
Temperature: 25 °C
Reaction time: 1 h
Yield: 95 %

Procedure:
tert-Butyl 4-(5-cyclopropyl-3-ethyl-1-(4-methoxybenzyl)-1H-pyrazolo[3,4-b]pyridin-4-yl)piperazine-1-carboxylate (0.21 g, 0.43 mmol) was placed in DCM (5 mL). TFA (1.5 mL) was then added, and the reaction was stirred at room temperature for 1 hour and concentrated to dryness. The crude product was then azeotroped with toluene (3×) and dried to give the crude 5-cyclopropyl-3-ethyl-1-(4-methoxybenzyl)-4-(piperazin-1-yl)-1H-pyrazolo[3,4-b]pyridine (0.16 g, 96% yield).
Reaction SMILES: [CH3:1][C:2]1[NH:3][C:4]2[C:9]([CH:10]=1)=[C:8]([C:11]([F:14])([F:13])[F:12])[C:7]([C:15]#[N:16])=[CH:6][CH:5]=2.Cl[CH2:18][C:19]1[CH:23]=[C:22]([C:24]2[CH:29]=[CH:28][CH:27]=[C:26]([C:30]([F:33])([F:32])[F:31])[CH:25]=2)[O:21][N:20]=1>>[CH3:1][C:2]1[N:3]([CH2:18][C:19]2[CH:23]=[C:22]([C:24]3[CH:29]=[CH:28][CH:27]=[C:26]([C:30]([F:32])([F:31])[F:33])[CH:25]=3)[O:21][N:20]=2)[C:4]2[C:9]([CH:10]=1)=[C:8]([C:11]([F:12])([F:14])[F:13])[C:7]([C:15]#[N:16])=[CH:6][CH:5]=2
Reactant: Cc1cc2c(C(F)(F)F)c(C#N)ccc2[nH]1
Reactant: FC(F)(F)c1cccc(-c2cc(CCl)no2)c1
Product: Cc1cc2c(C(F)(F)F)c(C#N)ccc2n1Cc1cc(-c2cccc(C(F)(F)F)c2)on1

Procedure:
Synthesized as described in Example 4 using 2-methyl-4-(trifluoromethyl)-1H-indole-5-carbonitrile (Example 120) and 3-(chloromethyl)-5-[3-(trifluoromethyl)phenyl]isoxazole (Example 324C): 1H NMR (400 MHz, CDCl3) δ 7.91 (s, 1H), 7.86 (d, J=7.7 Hz, 1H), 7.68 (d, J=7.6 Hz, 1H), 7.57 (m, 3H), 6.66 (s, 1H), 6.17 (s, 1H), 5.44 (s, 2H), 2.58 (s, 3H); MS (ES) m/z 450 (M+1).
Reaction SMILES: [NH2:1][C:2]1[N:7]=[CH:6][N:5]=[C:4]2[N:8]([CH2:26][C@@H:27]3[CH2:31][CH2:30][CH2:29][N:28]3[C:32](=[O:36])[CH2:33][C:34]#[N:35])[N:9]=[C:10]([C:11]3[CH:16]=[CH:15][C:14]([O:17][C:18]4[CH:23]=[CH:22][CH:21]=[C:20]([F:24])[CH:19]=4)=[CH:13][C:12]=3[F:25])[C:3]=12.[CH3:37][C:38]([NH:42][C:43](=[O:49])[O:44][C:45]([CH3:48])([CH3:47])[CH3:46])([CH3:41])[CH:39]=O.N1CCCCC1>O1CCOCC1.CC(O)=O>[NH2:1][C:2]1[N:7]=[CH:6][N:5]=[C:4]2[N:8]([CH2:26][C@@H:27]3[CH2:31][CH2:30][CH2:29][N:28]3[C:32](=[O:36])[C:33]([C:34]#[N:35])=[CH:41][C:38]([NH:42][C:43](=[O:49])[O:44][C:45]([CH3:48])([CH3:47])[CH3:46])([CH3:37])[CH3:39])[N:9]=[C:10]([C:11]3[CH:16]=[CH:15][C:14]([O:17][C:18]4[CH:23]=[CH:22][CH:21]=[C:20]([F:24])[CH:19]=4)=[CH:13][C:12]=3[F:25])[C:3]=12
Reactant: CC(C)(C=O)NC(=O)OC(C)(C)C
Reactant: N#CCC(=O)N1CCC[C@H]1Cn1nc(-c2ccc(Oc3cccc(F)c3)cc2F)c2c(N)ncnc21
Solvent: CC(=O)O
Solvent: C1CCNCC1
Solvent: C1COCCO1
Product: CC(C)(C=C(C#N)C(=O)N1CCC[C@H]1Cn1nc(-c2ccc(Oc3cccc(F)c3)cc2F)c2c(N)ncnc21)NC(=O)OC(C)(C)C
Temperature: 110 °C
Reaction time: 6 h
Yield: 18.2 %

Procedure:
To a solution of 3-((S)-2-((4-amino-3-(2-fluoro-4-(3-fluorophenoxy)phenyl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl)methyl)pyrrolidin-1-yl)-3-oxopropanenitrile (245 mg, 0.5 mmol, 1 equiv) and tert-butyl 2-methyl-1-oxopropan-2-ylcarbamate (935 mg, 5 mmol, 10 equiv) in dioxane (30 mL) was added 0.5 mL piperidine, 1 drop AcOH and 2 g of 4 A molecular sieves. The resulting mixture was stirred for 6 h at 110° C. The solids was filtered out, the filtrate was diluted with 200 mL of ethyl acetate, washed with brine, dried over Na2SO4, concentrated and purified with silica gel column (ethyl acetate/MeOH 10/1) to give 60 mg of tert-butyl 5-((S)-2-((4-amino-3-(2-fluoro-4-(3-fluorophenoxy)phenyl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl)methyl)pyrrolidin-1-yl)-4-cyano-2-methyl-5-oxopent-3-en-2-ylcarbamate as white solid.
Reaction SMILES: [NH2:1][C@H:2]1[CH2:7][CH2:6][CH2:5][N:4]([C:8]([O:10][C:11]([CH3:14])([CH3:13])[CH3:12])=[O:9])[CH2:3]1.[Cl:15][C:16]1[N:21]=[C:20](Cl)[C:19]([F:23])=[CH:18][N:17]=1.C(N(C(C)C)CC)(C)C>C(O)(C)C>[Cl:15][C:16]1[N:21]=[C:20]([NH:1][C@H:2]2[CH2:7][CH2:6][CH2:5][N:4]([C:8]([O:10][C:11]([CH3:14])([CH3:13])[CH3:12])=[O:9])[CH2:3]2)[C:19]([F:23])=[CH:18][N:17]=1
Reactant: Fc1cnc(Cl)nc1Cl
Reactant: CC(C)(C)OC(=O)N1CCC[C@H](N)C1
Solvent: CC(C)O
Solvent: CCN(C(C)C)C(C)C
Product: CC(C)(C)OC(=O)N1CCC[C@H](Nc2nc(Cl)ncc2F)C1
Temperature: 80 °C
Reaction time: 17 h

Procedure:
To a solution of tert-butyl (3S)-3-aminopiperidine-1-carboxylate (8.1 g, 40.4 mmol) and 2,4-dichloro-5-fluoro-pyrimidine (6.6 g, 39.8 mmol) in isopropanol (80 mL) was added N,N-diisopropyl-N-ethylamine (9.0 mL, 51.7 mmol). The reaction mixture was warmed to 80° C. and stirred for 17 hours. All volatiles were removed at reduced pressure and the residue was dissolved in EtOAc. The organic layer was partitioned with water and the layers were separated. The organic phase was washed with brine, dried (MgSO4), filtered and concentrated in vacuo. The resulting residue was dissolved in CH2Cl2 and purified by silica gel chromatography (0-50% EtOAc/Hexanes) to afford the desired product, 5a.
Reaction SMILES: [C:1]([C:5]1[CH:10]=[CH:9][C:8]([C:11]2[S:12][CH:13]=[C:14]([CH:20]=[O:21])[C:15]=2[O:16]COC)=[CH:7][CH:6]=1)([CH3:4])([CH3:3])[CH3:2].Cl.O>O1CCOCC1>[C:1]([C:5]1[CH:6]=[CH:7][C:8]([C:11]2[S:12][CH:13]=[C:14]([CH:20]=[O:21])[C:15]=2[OH:16])=[CH:9][CH:10]=1)([CH3:4])([CH3:2])[CH3:3]
Reactant: COCOc1c(C=O)csc1-c1ccc(C(C)(C)C)cc1
Agent: Cl
Solvent: C1COCCO1
Solvent: O
Product: CC(C)(C)c1ccc(-c2scc(C=O)c2O)cc1
Temperature: 80 °C
Reaction time: 1 h
Yield: 69.8 %

Procedure:
To 2-(4-t-butylphenyl)-3-methoxymethyloxy-4-formylthiophene (0.20 g, 0.66 mmol) in 1,4-dioxane (1.3 mL), 1 M hydrochloric acid (0.66 mL, 0.66 mmol) was added dropwise, and the reaction solution was stirred at 65° C. for 1 hour and at 80° C. for 1 hour. After addition of water, the reaction solution was extracted with ethyl acetate, and the organic layer was washed with saturated aqueous sodium chloride, dried over anhydrous sodium sulfate, concentrated and purified by silica gel column chromatography (chloroform) to give the desired product as a reddish brown oil (0.12 g, yield 68%).
Reaction SMILES: CN(C)C=O.[C:6]([NH2:12])([NH2:11])=[N:7][C:8](N)=[NH:9].[CH2:13]([N:15]=[C:16]=[S:17])[CH3:14]>O>[NH2:12][C:6]1[N:7]=[C:8]([NH2:9])[N:15]([CH2:13][CH3:14])[C:16](=[S:17])[N:11]=1
Reactant: N=C(N)N=C(N)N
Reactant: CCN=C=S
Solvent: CN(C)C=O
Solvent: O
Product: CCn1c(N)nc(N)nc1=S
Temperature: 100 °C
Yield: 104.9 %

Procedure:
To 15 ml of dry dimethylformamide were dissolved 1.52 g of diguanide and 1.31 g of ethylisothiocyanate, and the solution was heated at 100° C. for 4 hours. After cooling, the solution was added to 60 ml of water to produce white precipitates, which subsequently was dried to obtain 2.7 g of the title compound having the characteristics of:
Reaction SMILES: [CH:1]1([NH:6][C:7]2[CH:8]=[C:9]([CH3:22])[CH:10]=[C:11]3[C:15]=2[NH:14][C:13]([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][N:17]=2)=[CH:12]3)[CH2:5][CH2:4][CH2:3][CH2:2]1.[CH2:23]=O>>[CH:1]1([N:6]([CH3:23])[C:7]2[CH:8]=[C:9]([CH3:22])[CH:10]=[C:11]3[C:15]=2[NH:14][C:13]([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][N:17]=2)=[CH:12]3)[CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: C=O
Reactant: Cc1cc(NC2CCCC2)c2[nH]c(-c3ccccn3)cc2c1
Product: Cc1cc(N(C)C2CCCC2)c2[nH]c(-c3ccccn3)cc2c1

Procedure:
Cyclopentyl-[5-methyl-2-(pyridin-2-yl)-1H-indol-7-yl]-amine prepared in Example 1 and formaldehyde were reacted according to the same procedure as Step B of Example 1 to give the title compound.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([S:11][CH2:12][C:13]#[N:14])[CH:6]=[CH:7][C:8]=1[O:9][CH3:10].[BH4-].[Na+].B(F)(F)F.CCOCC.C(Cl)Cl.CO>C1COCC1>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([S:11][CH2:12][CH2:13][NH2:14])[CH:6]=[CH:7][C:8]=1[O:9][CH3:10]
Reactant: COc1ccc(SCC#N)cc1OC
Agent: FB(F)F
Agent: [BH4-]
Agent: [Na+]
Solvent: CCOCC
Solvent: C1CCOC1
Solvent: CO
Product: COc1ccc(SCCN)cc1OC
Temperature: 25 °C
Reaction time: 3 h
Yield: 46.9 %

Procedure:
To a cold (0° C.) solution of (3,4-dimethoxy-phenylsulfanyl)-acetonitrile (7.53 g, 36.0 mmol) in anhydrous THF (41 ml), was added portionwise NaBH4 (1.22 g, 32.0 mmol) and dropwise a solution of BF3.OEt2 (5.37 ml, 20.0 mmol) in anhydrous THF (13.4 ml) over 30 min. The resulting mixture was stirred at RT for 3 h under nitrogen. The mixture was concentrated in vacuo, the residue was dissolved in CH2Cl2 and washed with HCl 37%. The aqueous phase was neutralized with NaOH 30% and extracted with CH2Cl2. The combined organic phases were dried over anhydrous MgSO4, filtered and concentrated to give a crude oil. Flash chromatography (CH2Cl2/MeOH: 9/1) gave the title product (3.6 g, 46%).
Reaction SMILES: [C:1]([NH:4][C:5]1[CH:15]=[CH:14][C:8]([CH2:9][O:10]C(=O)C)=[CH:7][CH:6]=1)(=[O:3])[CH3:2].[Li+].[OH-]>C1COCC1>[OH:10][CH2:9][C:8]1[CH:7]=[CH:6][C:5]([NH:4][C:1](=[O:3])[CH3:2])=[CH:15][CH:14]=1
Reactant: CC(=O)Nc1ccc(COC(C)=O)cc1
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Product: CC(=O)Nc1ccc(CO)cc1
Temperature: 25 °C
Reaction time: 27 h

Procedure:
The product from Example 197a (4.00 g, 19.3 mmol) in THF (40 mL) was added aqueous LiOH solution (0.91 g, 21.2 mmol dropwise at room temperature over 10 minutes. The mixture was allowed to stir at room temperature for 27 hours and then evaporated. The aqueous residue was diluted with H2O, adjusted to pH 4 with 10% HCl, and then extracted with EtOAc. The extract was washed with brine, dried over MgSO4, filtered and concentrated under vacuum giving the title compound which was purified by washing with cold EtOAc to give the title compound as colorless crystals (2.92 g, 92%).
Reaction SMILES: [CH2:1]([NH:5][CH2:6][C:7]([O:9][CH2:10][CH3:11])=[O:8])[CH:2]=[CH:3][CH3:4].Cl[C:13]([CH2:18][CH3:19])=[C:14]([CH3:17])[CH:15]=O.C(N(CC)CC)C.CC(C)([O-])C.[K+].[Cl-].[NH4+]>C(O)C>[CH2:1]([N:5]1[C:13]([CH2:18][CH3:19])=[C:14]([CH3:17])[CH:15]=[C:6]1[C:7]([O:9][CH2:10][CH3:11])=[O:8])[CH:2]=[CH:3][CH3:4]
Reactant: CC=CCNCC(=O)OCC
Reactant: CCC(Cl)=C(C)C=O
Agent: CC(C)(C)[O-]
Agent: [Cl-]
Agent: [K+]
Solvent: CCO
Solvent: CCN(CC)CC
Product: CC=CCn1c(C(=O)OCC)cc(C)c1CC
Yield: 27.1 %

Procedure:
3.74 g (0.024 mole) of ethyl N-(2-butenyl)glycinate were added to a solution of 5.0 g (0.038 mole) of 3-chloro-2-methyl-2-pentenal in 10 ml of ethanol with stirring, and subsequently 6 ml (0.043 mole) of triethylamine were added thereto and stirred at room temperature for 7 hours. After the precipitates deposited were filtered off, 5.35 g (0.048 mole) of potassium tert-butoxide were added to the filtrate by portions and the mixture was stirred for 30 minutes. The reaction mixture was poured into about 150 ml of a saturated aqueous solution of ammonium chloride and extracted with ethyl acetate (once with 100 ml and twice with 50 ml). The combined extracts were washed with a saturated aqueous solution of sodium chloride and dried over anhydrous sodium sulfate, and the solvent was distilled off. The residue was purified by column chromatography through silica gel using a 3:97 mixture of ethyl acetate and hexane as an eluent to give 1.53 g of ethyl 1-(2-butenyl)-5-ethyl-4-methylpyrrole-2-carboxylate (cis/trans=76/24) as an orange oil.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]2[C:20](=[CH:21][CH:22]=1)[O:19][C:7]1[C:8]([F:18])=[N:9][C:10]([O:12][CH2:13][C:14]([CH3:17])([CH3:16])[CH3:15])=[CH:11][C:6]=1[C:5]2=[CH2:23].O.II.C([O-])([O-])=[O:28].[K+].[K+]>C1COCC1.[Ag]=O>[Br:1][C:2]1[CH:3]=[C:4]2[C:5]3([CH2:23][O:28]3)[C:6]3[CH:11]=[C:10]([O:12][CH2:13][C:14]([CH3:17])([CH3:16])[CH3:15])[N:9]=[C:8]([F:18])[C:7]=3[O:19][C:20]2=[CH:21][CH:22]=1
Reactant: C=C1c2cc(Br)ccc2Oc2c1cc(OCC(C)(C)C)nc2F
Reactant: O=C([O-])[O-]
Agent: O=[Ag]
Agent: II
Agent: [K+]
Solvent: C1CCOC1
Solvent: O
Product: CC(C)(C)COc1cc2c(c(F)n1)Oc1ccc(Br)cc1C21CO1
Temperature: 25 °C
Reaction time: 0.33 h
Yield: 96.4 %

Procedure:
To a solution of 7-bromo-1-fluoro-5-methylene-3-(neopentyloxy)-5H-chromeno[2,3-c]pyridine (995 mg, 2.63 mmol) in THF (60 mL)/Water (10 mL) was added iodine (1335 mg, 5.26 mmol) and silver oxide (1219 mg, 5.26 mmol). The reaction mixture was allowed to stir at rt for 20 min. K2CO3 (545 mg, 3.95 mmol) was added in one portion and the reaction mixture was allowed to stir for 30 min. The reaction mixture was filtered through a pad of celite. The reaction mixture was partitioned between water and EtOAc. The organic phase was separated, dried over Na2SO4. The solvent was removed under reduced pressure to afford 7-bromo-1-fluoro-3-(neopentyloxy)spiro[chromeno[2,3-c]pyridine-5,2′-oxirane] as a yellow solid (1000 mg) which was taken onto the next step without further purification.
Reaction SMILES: [F:1][C:2]1[CH:10]=[CH:9][C:8]([F:11])=[CH:7][C:3]=1[C:4]([OH:6])=O.[NH2:12][C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1>>[NH2:12][C:13]1[CH:18]=[CH:17][C:16]([C:4](=[O:6])[C:3]2[CH:7]=[C:8]([F:11])[CH:9]=[CH:10][C:2]=2[F:1])=[CH:15][CH:14]=1
Reactant: O=C(O)c1cc(F)ccc1F
Reactant: Nc1ccccc1
Product: Nc1ccc(C(=O)c2cc(F)ccc2F)cc1
Reaction time: 1 h
Yield: 209.6 %

Procedure:
To stirred 90° C. polyphosphoric acid (125 g) was added 2,5-difluoro-benzoic acid (10.0 g, 6.32 mmol) and aniline (5.87 g 6.3 mmol) and the bath temperature raised to 180°-190° C. and held there for 1 hour. The heating bath was removed and the stirred mixture (sublimate above the solution) was treated cautiously with 50 mL of water. The mixture was stirred at 140°-155° C. for 1 hour, the heating bath removed, 45 mL of 3N HCl added, the mixture poured into 650 mL of water and filtered through a pad of Celite. The filtrate was basified with 15% sodium hydroxide and the mixture filtered through a pad of Celite. The Celite pad was washed well with methylene chloride, the methylene chloride dried (MgSO4), filtered and the solvent removed in vacuo. Purification by flash column chromatography (methylene chloride) followed by recrystallization twice from 50% ethanol (80 mL) yielded the aniline as a yellow solid (3.08 g, 21%); mp 101°-103° C. 1H-NHR (300 MHz, CDCl3): 4.27 (s, 2H, NH2) 6.63-6.67 (m, 2H, aromatic) 7.09-7.19 (m, 3H, aromatic) 7.68-7.71 (m, 2H, aromatic). MS (CI, CH4): 234 (M+1).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]2[NH:8][C:9](=[O:40])[C:10]3([CH:15]([C:16]4[CH:21]=[CH:20][CH:19]=[C:18]([Cl:22])[CH:17]=4)[CH2:14][C:13](=[O:23])[NH:12][CH:11]3[C:24]3[CH:29]=[C:28](I)[CH:27]=[CH:26][C:25]=3[O:31][C:32]3[C:33]([CH3:39])=[N:34][N:35]([CH3:38])[C:36]=3[CH3:37])[C:5]2=[CH:4][CH:3]=1.C[Si]([C:45]#[CH:46])(C)C.C(N(CC)CC)C.[OH-].[Na+]>CN(C)C=O.CO.[Cu]I.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>[Cl:1][C:2]1[CH:7]=[C:6]2[NH:8][C:9](=[O:40])[C:10]3([CH:15]([C:16]4[CH:21]=[CH:20][CH:19]=[C:18]([Cl:22])[CH:17]=4)[CH2:14][C:13](=[O:23])[NH:12][CH:11]3[C:24]3[CH:29]=[C:28]([C:45]#[CH:46])[CH:27]=[CH:26][C:25]=3[O:31][C:32]3[C:33]([CH3:39])=[N:34][N:35]([CH3:38])[C:36]=3[CH3:37])[C:5]2=[CH:4][CH:3]=1
Reactant: Cc1nn(C)c(C)c1Oc1ccc(I)cc1C1NC(=O)CC(c2cccc(Cl)c2)C12C(=O)Nc1cc(Cl)ccc12
Reactant: C#C[Si](C)(C)C
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Cu]I
Agent: [Na+]
Solvent: CCN(CC)CC
Solvent: CO
Solvent: CN(C)C=O
Product: C#Cc1ccc(Oc2c(C)nn(C)c2C)c(C2NC(=O)CC(c3cccc(Cl)c3)C23C(=O)Nc2cc(Cl)ccc23)c1
Yield: 89.2 %

Procedure:
In a manner similar to the method described in example 6a, racemic(2′R, 3R, 4′S)-6-chloro-4′-(3-chlorophenyl)-2′-[5-iodo-2-(1,3,5-trimethyl-1H-pyrazol-4-yloxy)-phenyl]spiro[3H-indole-3,3′-piperidine]-2,6′(1H)-dione (0.62 g, 0.9 mmol) was reacted with trimethylsilyl acetylene (0.88 g, 9 mmol), CuI (10 mg), triethylamine (2.71 g, 27 mmol), and dichlorobis(triphenylphosphine)palladium (0) (50.5 mg, 0.07 mmol) in anhydrous N,N-dimethylformamide, and then treated with aqueous NaOH in methanol to give racemic(2′R, 3R, 4′S)-6-chloro-4′-(3-chlorophenyl)-2′-[5-ethynyl-2-(1,3,5-trimethyl-1H-pyrazol-4-yloxy)-phenyl]spiro[3H-indole-3,3′-piperidine]-2,6′(1H)-dione as a white solid (Yield 0.47 g, 90%)