Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:27]=[CH:28][CH:29]=1)[CH2:5][N:6]1[C:18]2[CH2:17][CH2:16][C@@H:15]([NH:19][C:20]([CH:22]3[CH2:24][CH2:23]3)=[O:21])[CH2:14][C:13]=2[C:12]2[C:7]1=[CH:8][CH:9]=[C:10]([CH:25]=O)[CH:11]=2.Cl.[NH2:31][OH:32].[OH-].[Na+]>O>[F:1][C:2]1[CH:3]=[C:4]([CH:27]=[CH:28][CH:29]=1)[CH2:5][N:6]1[C:18]2[CH2:17][CH2:16][C@@H:15]([NH:19][C:20]([CH:22]3[CH2:24][CH2:23]3)=[O:21])[CH2:14][C:13]=2[C:12]2[C:7]1=[CH:8][CH:9]=[C:10]([CH:25]=[N:31][OH:32])[CH:11]=2
Reactant: O=Cc1ccc2c(c1)c1c(n2Cc2cccc(F)c2)CC[C@@H](NC(=O)C2CC2)C1
Reactant: NO
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: O=C(N[C@@H]1CCc2c(c3cc(C=NO)ccc3n2Cc2cccc(F)c2)C1)C1CC1
Yield: 82 %

Procedure:
Combine (R)-cyclopropanecarboxylic acid[9-(3-fluorobenzyl)-6-formyl-2,3,4,9-tetrahydro-1H-carbazol-3-yl]-amide (Preparation 71) (1.50 g, 3.82 mmol), hydroxylamine hydrochloride (0.801 g, 11.5 mmol), and sodium hydroxide (0.23 g, 5.76 mmol) and stir under nitrogen for 1.5 h. Dilute with water and extract with EtOAc. Pass the dark residue through a pad of silica eluting with 50% EtOAc/hexanes to give 1.27 g (82%) of the title compound. MS (ES): m/z 406 (M+1).
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=1[C:10](=[O:17])[C:11]#[C:12][Si:13]([CH3:16])([CH3:15])[CH3:14])([O-])=O.Cl>C1(C)C=CC=CC=1.C(OCC)(=O)C.[Pd]>[NH2:1][C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=1[C:10](=[O:17])[CH2:11][CH2:12][Si:13]([CH3:16])([CH3:15])[CH3:14]
Reactant: C[Si](C)(C)C#CC(=O)c1ccccc1[N+](=O)[O-]
Agent: [Pd]
Agent: Cl
Solvent: CCOC(C)=O
Solvent: Cc1ccccc1
Product: C[Si](C)(C)CCC(=O)c1ccccc1N
Reaction time: 72 h
Yield: 83.5 %

Procedure:
To the solution of 1-(2-nitrophenyl)-3-(trimethylsilyl)prop-2-yn-1-one (11) (294 g; 1.19 mole) in toluene (4.5 L) was added Pd/C (10% wt; 30 g) under N2. The resulting suspension was degassed under vacuum and back-filled 3-times with H2. The mixture was hydrogenated under 0.3 MPa of hydrogen at room temperature for 72 hours. The progress of the reaction was monitored by HPLC. When the HPLC analysis indicated the disappearance of compound (II), the catalyst was filtered off through a Celite pad. The filtrate was concentrated under vacuum to give the crude product as black liquid. HPLC analysis showed 90% purity. The crude product was dissolved in ethyl acetate (7.5 L) and treated with 4N hydrochloric acid (600 mL). After the phase separation, HPLC analysis showed the 92.8% purity. The organic phase was washed again with 4 N hydrochloric acid (600 mL). The organic phase was further washed with 4 N hydrochloric acid (500 mL) one additional time. The organic phase was dried over sodium sulfate (200 g), concentrated to give the crude product (3) (220 g; 84% yield).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8](=[O:15])[CH2:9][CH2:10][C:11](OC)=[O:12])=[CH:4][C:3]=1[S:16](=[O:20])(=[O:19])[NH:17][CH3:18].[CH3:21][NH2:22]>CO>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2([OH:15])[N:22]([CH3:21])[C:11](=[O:12])[CH2:10][CH2:9]2)=[CH:4][C:3]=1[S:16](=[O:20])(=[O:19])[NH:17][CH3:18]
Reactant: CNS(=O)(=O)c1cc(C(=O)CCC(=O)OC)ccc1Cl
Reactant: CN
Solvent: CO
Product: CNS(=O)(=O)c1cc(C2(O)CCC(=O)N2C)ccc1Cl

Procedure:
7.9 of methyl 4-(4-chloro-3-methylsulfamoylphenyl)-4-oxobutanoate are reacted with 6.9 g of methylamine in 100 ml of methanol and the mixture is worked up analogously to the instructions indicated in Example 2(b). 5-(4-Chloro-3-methylsulfamoylphenyl)-5-hydroxy-1-methyl-2-oxopyrrolidine of melting point 147°-150° C. is obtained.
Reaction SMILES: Cl([O-])=O.[Na+].P([O-])(O)(O)=[O:6].[Na+].CC(=CC)C.[F:16][C:17]1[CH:18]=[CH:19][C:20]([O:43][CH3:44])=[C:21]([C:23]2[N:27]=[C:26]([C:28]3[CH:29]=[C:30]([CH:41]=[O:42])[C:31]([C:34]4[CH:39]=[CH:38][CH:37]=[CH:36][C:35]=4[CH3:40])=[CH:32][CH:33]=3)[O:25][N:24]=2)[CH:22]=1>O.O1CCOCC1>[F:16][C:17]1[CH:18]=[CH:19][C:20]([O:43][CH3:44])=[C:21]([C:23]2[N:27]=[C:26]([C:28]3[CH:29]=[C:30]([C:41]([OH:6])=[O:42])[C:31]([C:34]4[CH:39]=[CH:38][CH:37]=[CH:36][C:35]=4[CH3:40])=[CH:32][CH:33]=3)[O:25][N:24]=2)[CH:22]=1
Reactant: COc1ccc(F)cc1-c1noc(-c2ccc(-c3ccccc3C)c(C=O)c2)n1
Reactant: O=P([O-])(O)O
Agent: CC=C(C)C
Agent: [Na+]
Agent: [O-][Cl+][O-]
Solvent: C1COCCO1
Solvent: O
Product: COc1ccc(F)cc1-c1noc(-c2ccc(-c3ccccc3C)c(C(=O)O)c2)n1
Temperature: 25 °C
Reaction time: 16 h
Yield: 88.6 %

Procedure:
A solution of sodium chlorite (59 mg; 0.65 mmol; 5.5 eq.) and sodium dihydrogenphosphate (51 mg; 0.43 mmol; 3.6 eq.) in water (1 mL) was added to a mixture of 2-methyl-2-butene (0.13 mL) and 4-[3-(5-fluoro-2-methoxyphenyl)-1,2,4-oxadiazol-5-yl]-2′-methylbiphenyl-2-carbaldehyde (46.2 mg; 0.12 mmol; 1 eq.) in dioxane (1 mL) and the reaction was stirred at room temperature for 16 hours. The suspension was partitioned between water and ethyl acetate. The aqueous phase was acidified to pH 3-4 with acetic acid and extracted with ethyl acetate. The combined organic phase was washed with brine, dried over magnesium sulfate and concentrated in vacuo to afford the title compound (43 mg; 89%) as a white solid.
Reaction SMILES: [CH3:1][O:2][C:3]1[C:15]2[C:10](=[CH:11][CH:12]=[C:13]([N+:16]([O-:18])=[O:17])[CH:14]=2)[N:9]=[C:5]([C:6]([OH:8])=O)[CH:4]=1.[NH2:19][C:20]1[NH:24][N:23]=[N:22][N:21]=1>CN(C)C=O>[CH3:1][O:2][C:3]1[C:15]2[C:10](=[CH:11][CH:12]=[C:13]([N+:16]([O-:18])=[O:17])[CH:14]=2)[N:9]=[C:5]([C:6]([NH:19][C:20]2[NH:24][N:23]=[N:22][N:21]=2)=[O:8])[CH:4]=1
Reactant: Nc1nnn[nH]1
Reactant: COc1cc(C(=O)O)nc2ccc([N+](=O)[O-])cc12
Solvent: CN(C)C=O
Product: COc1cc(C(=O)Nc2nnn[nH]2)nc2ccc([N+](=O)[O-])cc12

Procedure:
4-Methoxy-6-nitroquinaldic acid (1 g) and N,N'-carbonyldiimidazole (0.7 g) in dimethylformamide (25 ml) were heated on a steam bath for 1 hour. 5-Aminotetrazole (0.7 g) was added and the mixture was heated for 30 minutes on a steam bath. 4-Methoxy-6-nitro-N(1H-tetrazol- 5-yl) quinaldamide, m.p. 308° was filtered off.
Reaction SMILES: [OH:1][C@H:2]1[CH2:6][NH:5][C@H:4]([C:7]([OH:9])=[O:8])[CH2:3]1.[OH-].[Na+].[C:12](Cl)(=[O:17])[O:13][CH2:14][CH:15]=[CH2:16]>O.C(Cl)Cl>[CH2:14]([O:13][C:12]([N:5]1[CH2:6][C@H:2]([OH:1])[CH2:3][C@H:4]1[C:7]([OH:9])=[O:8])=[O:17])[CH:15]=[CH2:16]
Reactant: C=CCOC(=O)Cl
Reactant: O=C(O)[C@@H]1C[C@@H](O)CN1
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: ClCCl
Product: C=CCOC(=O)N1C[C@H](O)C[C@H]1C(=O)O
Reaction time: 2 h
Yield: 95.2 %

Procedure:
To a solution of trans-4-hydroxy-L-proline (35.9 g) and sodium hydroxide (23.9 g) in water (330 ml) was added dropwise a solution of allyl chlorocarbonate (36.3 g) in methylene chloride (250 ml) under ice-cooling, and stirring was continued for 2 hours. Aqueous layer was separated from the reaction mixture, washed twice each with methylene chloride (100 ml), and then acidified by adding concentrated sulfuric acid (25 g) dropwise at a temperature below 30° C. After adding table salt (120 g), the mixture was extracted twice each with ethyl acetate (220 ml). Extract was dried over magnesium sulfate. Distillation of the solvent gave crude crystalline trans-1-allyloxycarbonyl-4-hydroxy-L-proline (62 g). Purification of the crude crystals by repulping with toluene gave trans-1-allyloxycarbonyl-4-hydroxyl-L-proline (56.1 g) having m.p. 93-°94° C.
Reaction SMILES: [CH3:1][C:2]1[N:7]=[C:6]([CH3:8])[CH:5]=[C:4]([OH:9])[N:3]=1.[Cl:10][C:11]1[CH:12]=[C:13]([CH:16]=[CH:17][CH:18]=1)[CH:14]=O>C(OC(=O)C)(=O)C>[Cl:10][C:11]1[CH:12]=[C:13](/[CH:14]=[CH:1]/[C:2]2[N:3]=[C:4]([OH:9])[CH:5]=[C:6]([CH3:8])[N:7]=2)[CH:16]=[CH:17][CH:18]=1
Reactant: O=Cc1cccc(Cl)c1
Reactant: Cc1cc(O)nc(C)n1
Solvent: CC(=O)OC(C)=O
Product: Cc1cc(O)nc(/C=C/c2cccc(Cl)c2)n1
Temperature: 145 °C
Yield: 77.8 %

Procedure:
1.24 g (10 mmol) of 2,4-dimethyl-6-hydroxypyrimidine in acetic anhydride (2.8 ml) were treated at RT with 1.41 g (10 mmol) of 3-chlorobenzaldehyde and the mixture was heated for 5 hours at 145° C. until completion of the reaction according to TLC analysis. The reaction mixture was cooled to RT, the crystalline solid which had formed was filtered off by suction and washed with diethyl ether to give 1.92 g (78%) of the desired (E)-2-[2-(3-chloro-phenyl)-vinyl]-6-methyl-pyrimidin-4-ol as off-white crystals. EI mass spectrum, m/e: 246.1 (M calculated for C13H11ClN2O: 246).
Reaction SMILES: Cl[C:2]1[CH:3]=[C:4]2[CH:10]=[C:9]([C:11]3([CH3:14])[CH2:13][CH2:12]3)[NH:8][C:5]2=[CH:6][N:7]=1.[NH3:15]>CCO>[CH3:14][C:11]1([C:9]2[NH:8][C:5]3=[CH:6][N:7]=[C:2]([NH2:15])[CH:3]=[C:4]3[CH:10]=2)[CH2:13][CH2:12]1
Reactant: CC1(c2cc3cc(Cl)ncc3[nH]2)CC1
Reactant: N
Solvent: CCO
Product: CC1(c2cc3cc(N)ncc3[nH]2)CC1
Temperature: 25 °C
Reaction time: 8 h
Yield: 27 %

Procedure:
In a 100 mL autoclave, a solution of 5-chloro-2-(1-methylcyclopropyl)-1H-pyrrolo[2,3-c]pyridine (1.0 g, 4.9 mmol) and CuSO4′5H2O (100 mg, 0.4 mmol) in aqueous ammonia (60 mL) and EtOH (20 mL) was heated to 200° C. and stirred at this temperature for 8 hours. The mixture was allowed to cool down to room temperature. The alcohol was removed under vacuum. The resulting mixture was extracted with ethyl acetate (50 mL×3). The combined organic layer was dried over anhydrous Na2SO4 and purified by chromatography on silica gel (2% CH3OH in dichloromethane as eluant) to afford 2-(1-methylcyclopropyl)-1H-pyrrolo[2,3-c]pyridin-5-amine (250 mg, 27%). 1H-NMR (DMSO, 300 MHz) δ 7.96 (s, 1H), 6.37 (s, 1H), 5.88 (d, J=1.2, 1H), 5.01 (br s, 2H), 1.41 (s, 3H), 0.98 (t, J=2.1, 2H), 0.80 (t, J=2.1, 2H).
Reaction SMILES: Br[C:2]1[CH:11]=[C:10]2[C:5]([C:6]([CH3:16])([CH3:15])[CH2:7][C:8](=[O:14])[N:9]2[CH2:12][CH3:13])=[CH:4][C:3]=1[CH3:17].[CH3:18][O:19][C:20]1[CH:25]=[CH:24][C:23]([CH:26]=[O:27])=[CH:22][C:21]=1B(O)O.C1(C)C=CC=CC=1.C([O-])([O-])=O.[K+].[K+]>C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.C(O)C>[CH2:12]([N:9]1[C:10]2[C:5](=[CH:4][C:3]([CH3:17])=[C:2]([C:21]3[CH:22]=[C:23]([CH:24]=[CH:25][C:20]=3[O:19][CH3:18])[CH:26]=[O:27])[CH:11]=2)[C:6]([CH3:16])([CH3:15])[CH2:7][C:8]1=[O:14])[CH3:13]
Reactant: CCN1C(=O)CC(C)(C)c2cc(C)c(Br)cc21
Reactant: COc1ccc(C=O)cc1B(O)O
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCO
Solvent: Cc1ccccc1
Product: CCN1C(=O)CC(C)(C)c2cc(C)c(-c3cc(C=O)ccc3OC)cc21
Temperature: 80 °C
Yield: 98.8 %

Procedure:
A round bottom flask was charged with 6.0 g of Compound 1A (20.3 mmol), 5.5 g of 2-methoxy-5-formylphenylboronic acid (30.4 mmol) and tetrakis(triphenylphosphine)palladium(0), (1.17 g, 0.10 mmol). The flask was sealed and 100 mL of toluene and 30 mL of ethanol was added. The resulting solution was stirred to dissolve the reactants and then 21 mL of 2M K2CO3 was added via syringe. The reaction mixture was heated to 80° C. for 4 hours. After cooling, the reaction mixture was partitioned between ethyl acetate (200 mL) and water (75 mL). The water layer was further extracted (2×100 mL) and the combined organic layers were washed with water (50 mL) followed by brine (50 mL), dried over magnesium sulfate, filtered and excess solvent removed on the rotary evaporator. The crude product was purified by flash chromatography (EtOAc/Hexanes; gradient 20% to 40%) to give 7.05 g (99%) of product Compound 1B as a foamy solid. MS (electrospray): mass calculated for C22H25NO3, 351.18; m/z found 352.4, [M+H]+. 1HNMR (300 MHz, CDCl3): 9.94 (s, 1H), 7.93 (dd, J=2.1, 8.6 Hz, 1H), 7.73 (d, J=2.1 Hz, 1H), 7.18 (s, 1H), 7.12 (d, J=8.6 Hz, 1H), 6.85 (s, 1H), 4.01 (q, J=7.1 Hz, 2H), 3.90 (s, 3H), 2.52 (s, 2H), 2.10 (s, 3H), 1.33 (s, 6H), 1.23 (t, J=6.9 Hz, 3H).
Reaction SMILES: [N:1]1[CH:6]=[CH:5][N:4]=[CH:3][C:2]=1[NH:7][C:8]([NH2:10])=[S:9].Br[CH:12]([C:16]1[CH:21]=[CH:20][C:19]([S:22]([NH2:25])(=[O:24])=[O:23])=[C:18]([Cl:26])[CH:17]=1)[C:13](=O)[CH3:14]>C(O)C>[Cl:26][C:18]1[CH:17]=[C:16]([C:12]2[S:9][C:8]([NH:7][C:2]3[CH:3]=[N:4][CH:5]=[CH:6][N:1]=3)=[N:10][C:13]=2[CH3:14])[CH:21]=[CH:20][C:19]=1[S:22]([NH2:25])(=[O:24])=[O:23]
Reactant: CC(=O)C(Br)c1ccc(S(N)(=O)=O)c(Cl)c1
Reactant: NC(=S)Nc1cnccn1
Solvent: CCO
Product: Cc1nc(Nc2cnccn2)sc1-c1ccc(S(N)(=O)=O)c(Cl)c1
Temperature: 60 °C

Procedure:
Pyrazin-2-yl-thiourea (Example 1a) (0.047 g, 0.31 mmol) is added to a stirred solution of 4-(1-bromo-2-oxo-propyl)-2-chloro-benzenesulfonamide (0.10 g, 0.31 mmol) in ethanol (5 ml). The solution is heated at 60° C. for 3 hours. The mixture is filtered to remove the precipitate which is washed with methanol and dried. (0.055 g).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:38]=[C:39]([F:41])[CH:40]=1)[CH2:5][C:6]1[CH:7]=[C:8]2[C:12](=[CH:13][CH:14]=1)[NH:11][N:10]=[C:9]2[NH:15][C:16](=[O:37])[C:17]1[CH:22]=[CH:21][C:20]([NH2:23])=[CH:19][C:18]=1[N:24]([CH:31]1[CH2:36][CH2:35][O:34][CH2:33][CH2:32]1)[C:25](=[O:30])[C:26]([F:29])([F:28])[F:27].[CH:42]([CH:44]1[CH2:47][N:46]([C:48]([O:50][C:51]([CH3:54])([CH3:53])[CH3:52])=[O:49])[CH2:45]1)=O.FC(F)(F)C(O)=O.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.C[N+](C)(C)C>ClCCl>[F:41][C:39]1[CH:38]=[C:4]([CH:3]=[C:2]([F:1])[CH:40]=1)[CH2:5][C:6]1[CH:7]=[C:8]2[C:12](=[CH:13][CH:14]=1)[NH:11][N:10]=[C:9]2[NH:15][C:16]([C:17]1[CH:22]=[CH:21][C:20]([NH:23][CH2:42][CH:44]2[CH2:47][N:46]([C:48]([O:50][C:51]([CH3:52])([CH3:54])[CH3:53])=[O:49])[CH2:45]2)=[CH:19][C:18]=1[N:24]([CH:31]1[CH2:32][CH2:33][O:34][CH2:35][CH2:36]1)[C:25](=[O:30])[C:26]([F:29])([F:27])[F:28])=[O:37]
Reactant: CC(C)(C)OC(=O)N1CC(C=O)C1
Reactant: Nc1ccc(C(=O)Nc2n[nH]c3ccc(Cc4cc(F)cc(F)c4)cc23)c(N(C(=O)C(F)(F)F)C2CCOCC2)c1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: C[N+](C)(C)C
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CC(C)(C)OC(=O)N1CC(CNc2ccc(C(=O)Nc3n[nH]c4ccc(Cc5cc(F)cc(F)c5)cc34)c(N(C(=O)C(F)(F)F)C3CCOCC3)c2)C1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of N-[5-(3,5-difluorobenzyl)-1H-indazol-3-yl]-4-amino-2-[tetrahydro-2H-pyran-4-yl(trifluoroacetyl)amino]benzamide (240 mg, 0.42 mmol) in dichloromethane (20 mL) were added tert-butyl 3-formylazetidine-1-carboxylate (116 mg, 0.63 mmol), trifluoroacetic acid (0.32 mL) and tetramethylammonium triacetoxyborohydride (165 mg g, 0.63 mmol). The mixture was stirred at room temperature overnight, then diluted with dichloromethane, washed with NaHCO3 sat.sol. and brine, dried over sodium sulfate and evaporated to dryness.
Reaction SMILES: [CH2:1]([N:8]1[C:16]2[C:11](=[CH:12][CH:13]=[C:14]([Cl:17])[CH:15]=2)[C:10]([O:18][C:19]2[CH:20]=[C:21]([CH2:25]O)[CH:22]=[CH:23][CH:24]=2)=[C:9]1[CH3:27])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH:28]([N:31](CC)C(C)C)(C)C.CS(Cl)(=O)=O.[C-]#N.[Na+]>C(Cl)Cl.CN(C=O)C>[CH2:1]([N:8]1[C:16]2[C:11](=[CH:12][CH:13]=[C:14]([Cl:17])[CH:15]=2)[C:10]([O:18][C:19]2[CH:20]=[C:21]([CH2:25][C:28]#[N:31])[CH:22]=[CH:23][CH:24]=2)=[C:9]1[CH3:27])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CCN(C(C)C)C(C)C
Reactant: Cc1c(Oc2cccc(CO)c2)c2ccc(Cl)cc2n1Cc1ccccc1
Agent: CS(=O)(=O)Cl
Agent: [C-]#N
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: ClCCl
Product: Cc1c(Oc2cccc(CC#N)c2)c2ccc(Cl)cc2n1Cc1ccccc1
Temperature: 60 °C
Reaction time: 0.08 h

Procedure:
[3-(1-Benzyl-6-chloro-2-methyl-1H-indol-3-yloxy)-phenyl]-methanol (0.092 g, 0.243 mmol) and N,N-diisopropylethylamine (3 μL, 0.486 mmol) were dissolved in DCM at 0° C. Methanesulfonyl chloride (28 μL, 0.365 mmol) was added and the reaction stirred for 5 minutes then sodium cyanide (0.024 g, 0.486 mmol) and DMF (2 mL) were added. The reaction was then concentrated under vacuum and DMF (2 mL) was added. The reaction was heated to 60° C. for 20 minutes then submitted to aqueous workup to give the title compound.
Reaction SMILES: [OH:1][C@@H:2]([CH2:12]OS(C1C=CC(C)=CC=1)(=O)=O)[CH2:3][P:4]([CH3:11])(=[O:10])[O:5][CH2:6][CH:7]([CH3:9])[CH3:8].[N-:24]=[N+:25]=[N-:26].[Na+].O>CN(C)C=O>[N:24]([CH2:12][C@H:2]([OH:1])[CH2:3][P:4]([CH3:11])(=[O:10])[O:5][CH2:6][CH:7]([CH3:9])[CH3:8])=[N+:25]=[N-:26]
Reactant: [N-]=[N+]=[N-]
Reactant: Cc1ccc(S(=O)(=O)OC[C@H](O)CP(C)(=O)OCC(C)C)cc1
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: CC(C)COP(C)(=O)C[C@@H](O)CN=[N+]=[N-]
Temperature: 25 °C

Procedure:
A solution of 3.32 g of isobutyl P-[2(S)-hydroxy-3-tosyloxy-propyl]-P-methyl-phosphinate and 1.19 g of sodium azide in 25 ml of dry dimethylformamide is heated to a temperature of 120° for a period of 3 hours, under an inert gas atmosphere. The reaction mixture is allowed to cool to room temperature, poured onto 50 ml of water and extracted twice with 100 ml of ethyl acetate. The organic extract is dried over magnesium sulphate and the solvent removed under reduced pressure. The residue is chromatographed on silica gel using 5 parts of ethyl acetate to 1 part of ethanol as eluent. There is obtained isobutyl P-[3-azido-2(S)-hydroxy-propyl]-P-methyl-phosphinate as a viscous oil, 31P-NMR spectrum: δ=+54.8 and +53.7 ppm (CDCl3), [α]D25 =+18.6 (0.56% in ethanol).
Reaction SMILES: C[O:2][C:3]([CH:5]1[CH2:13][C:12]2[C:7](=[CH:8][CH:9]=[C:10]([O:14][CH3:15])[CH:11]=2)[NH:6]1)=O.[H-].[H-].[H-].[H-].[Li+].[Al+3].O>C1COCC1>[CH3:15][O:14][C:10]1[CH:11]=[C:12]2[C:7](=[CH:8][CH:9]=1)[NH:6][CH:5]([CH2:3][OH:2])[CH2:13]2
Reactant: COC(=O)C1Cc2cc(OC)ccc2N1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: C1CCOC1
Solvent: O
Product: COc1ccc2c(c1)CC(CO)N2
Temperature: 25 °C
Reaction time: 8 h
Yield: 65.2 %

Procedure:
(RS)-5-methoxy-2,3-dihydro-1H-indole-2-carboxylic acid methyl ester (2.5 g, 12.06 mmol) in THF (130 ml) was added dropwise to a suspension of LiAlH4 in THF (80 ml) at 4° C., and the mixture allowed to stir at RT overnight, and then heated at 65° C. for 4 hr. After cooling, H2O (20 ml) was added cautiously and the mixture stirred 20 min, then filtered and the filtrate extracted with EtOAc (3×50 ml), the extracts were washed with satd. NaCl solution (50 ml), dried (Na2SO4) filtered and evaporated. The crude oil was chromatographed over SiO2 (Merck 230-400 mesh) eluting with CH2Cl2—MeOH (9:1) affording (RS)-(5-methoxy-2,3-dihydro-1H-indol-2-yl)-methanol as a yellow oil (1.41 g, 7.86 mmol, 65%), MS: m/e=179.1 (M+).
Reaction SMILES: [C-:1]#[N:2].[Na+].[Cl:4][C:5]1[CH:42]=[CH:41][C:40]([F:43])=[CH:39][C:6]=1[CH2:7][N:8]1[C:16]2[C:15](=[O:17])[N:14]([CH3:18])[C:13](S(C)(=O)=O)=[N:12][C:11]=2[C:10]([C:23]#[N:24])=[C:9]1[N:25]1[CH2:30][CH2:29][CH2:28][C@@H:27]([NH:31][C:32](=[O:38])[O:33][C:34]([CH3:37])([CH3:36])[CH3:35])[CH2:26]1.O>O1CCCC1>[Cl:4][C:5]1[CH:42]=[CH:41][C:40]([F:43])=[CH:39][C:6]=1[CH2:7][N:8]1[C:16]2[C:15](=[O:17])[N:14]([CH3:18])[C:13]([C:1]#[N:2])=[N:12][C:11]=2[C:10]([C:23]#[N:24])=[C:9]1[N:25]1[CH2:30][CH2:29][CH2:28][C@@H:27]([NH:31][C:32](=[O:38])[O:33][C:34]([CH3:37])([CH3:36])[CH3:35])[CH2:26]1
Reactant: [C-]#N
Reactant: Cn1c(S(C)(=O)=O)nc2c(C#N)c(N3CCC[C@@H](NC(=O)OC(C)(C)C)C3)n(Cc3cc(F)ccc3Cl)c2c1=O
Agent: [Na+]
Solvent: O
Solvent: C1CCOC1
Product: Cn1c(C#N)nc2c(C#N)c(N3CCC[C@@H](NC(=O)OC(C)(C)C)C3)n(Cc3cc(F)ccc3Cl)c2c1=O
Temperature: 25 °C
Reaction time: 3 h
Yield: 93.5 %

Procedure:
An aqueous solution (2 ml) of sodium cyanide (338 mg) was added to a solution of tert-butyl {(3R)-1-[5-(2-chloro-5-fluorobenzyl)-7-cyano-3-methyl-2-(methylsulfonyl)-4-oxo-4,5-dihydro-3H-pyrrolo[3,2-d]pyrimidin-6-yl]piperidin-3-yl}carbamate (890 mg) in tetrahydrofuran (10 ml), and the resulting mixture was stirred at room temperature for 3 hours. Water was added to the reaction solution, followed by extraction with ethyl acetate (200 ml). The organic layer was washed with a 10% aqueous potassium carbonate solution and a saturated aqueous sodium chloride solution, dried over sodium sulfate and then filtered and the filtrate was concentrated under reduced pressure. The resulting residue was purified by a silica gel column chromatography (hexane/ethyl acetate=2/1) to obtain the title compound (758 mg).
Reaction SMILES: [H-].[Na+].[Cl:3][C:4]1[N:5]=[CH:6][CH:7]=[C:8]2[C:12]([CH3:13])=[C:11]([CH3:14])[NH:10][C:9]=12.I[CH2:16][CH:17]([CH3:19])[CH3:18].O>O1CCCC1>[Cl:3][C:4]1[N:5]=[CH:6][CH:7]=[C:8]2[C:12]([CH3:13])=[C:11]([CH3:14])[N:10]([CH2:16][CH:17]([CH3:19])[CH3:18])[C:9]=12
Reactant: CC(C)CI
Reactant: Cc1[nH]c2c(Cl)nccc2c1C
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: C1CCOC1
Product: Cc1c(C)n(CC(C)C)c2c(Cl)nccc12
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 86.1 %

Procedure:
Sodium hydride (60%, 33 mg, 0.83 mmol) was added to a solution of 7-chloro-2,3-dimethyl-1H-pyrrolo[2,3-c]pyridine (100 mg, 0.53 mmol) prepared in Step 1 in anhydrous tetrahydrofuran (2.8 ml). The reaction mixture was stirred for 30 minutes at room temperature. 1-Iodo-2-methylpropane (64 t, 0.67 mmol) was added to the reaction mixture, which was then stirred overnight at room temperature. Water was added to the reaction mixture, which was then extracted with dichloromethane. The organic layer was dried on anhydrous magnesium sulfate and then concentrated under reduced pressure. The resulting residue was purified with silica gel column chromatography (ethyl acetate/n-hexane=1/9, v/v) to give 108 mg of the titled compound as a white solid. (Yield: 86%)
Reaction SMILES: [NH2:1][CH:2](C1C2CCCCC=2C=CC=1)[CH2:3][N:4]1[C:13]([C:14]#[N:15])=[C:12]([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)[C:11]2[C:6](=[CH:7][CH:8]=[C:9]([O:22][CH3:23])[CH:10]=2)[C:5]1=[O:24].[C:35](=[O:38])([O-:37])N>>[C:6]([O:37][C:35](=[O:38])[NH:1][CH2:2][CH2:3][N:4]1[C:13]([C:14]#[N:15])=[C:12]([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)[C:11]2[C:6](=[CH:7][CH:8]=[C:9]([O:22][CH3:23])[CH:10]=2)[C:5]1=[O:24])([CH3:11])([CH3:7])[CH3:5]
Reactant: NC(=O)[O-]
Reactant: COc1ccc2c(=O)n(CC(N)c3cccc4c3CCCC4)c(C#N)c(-c3ccccc3)c2c1
Product: COc1ccc2c(=O)n(CCNC(=O)OC(C)(C)C)c(C#N)c(-c3ccccc3)c2c1

Procedure:
Compound 56a was prepared essentially according to the procedure described above in Example I for compound 8 by using tert-butyl-N-2-aminoethyl)-carbamate in place of aminoacetaldehyde diethyl acetal in Step D.
Reaction SMILES: Br[C:2]1[CH:11]=[CH:10][CH:9]=[C:8]2[C:3]=1[CH:4]=[CH:5][C:6]([CH3:12])=[N:7]2.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C(NCC)C.[CH3:37][Si:38]([C:41]#[CH:42])([CH3:40])[CH3:39]>[Cu](I)I.CN(C=O)C>[CH3:12][C:6]1[CH:5]=[CH:4][C:3]2[C:8](=[CH:9][CH:10]=[CH:11][C:2]=2[C:42]#[C:41][Si:38]([CH3:40])([CH3:39])[CH3:37])[N:7]=1
Reactant: C#C[Si](C)(C)C
Reactant: Cc1ccc2c(Br)cccc2n1
Agent: I[Cu]I
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CCNCC
Solvent: CN(C)C=O
Product: Cc1ccc2c(C#C[Si](C)(C)C)cccc2n1
Temperature: 110 °C
Yield: 90 %

Procedure:
In a sealed tube were introduced 5-bromo-2-methyl-quinoline (1.0 g, 4.5 mmol, 1.0 eq), PdCl2(PPh3)3 (154 mg, 0.22 mmol, 5% mol), copper iodide (42 mg, 0.22 mmol, 5% mol), and triphenylphosphine (236 mg, 0.9 mmol, 20% mol). Then, DMF (10 mL) was added followed by diethylamine (9.5 mL, 68 mmol, 15 eq) and trimethylsilylacetylene (700 μL, 5.0 mmol, 1.1 eq). The mixture was heated at 110° C. overnight. After cooling down the solvent was evaporated and the crude product was purified by column chromatography (Florisil, Cyclohexane-EtOAc 95:5) to afford 2-methyl-5-trimethylsilanylethynyl-quinoline as a white solid (970 mg, 90%).
Reaction SMILES: [CH2:1]([C:5]1[C:9]([CH2:10][N:11]2C(=O)C3C(=CC=CC=3)C2=O)=[C:8]([CH3:22])[O:7][N:6]=1)[CH2:2][CH2:3][CH3:4].O.NN>CO>[CH2:1]([C:5]1[C:9]([CH2:10][NH2:11])=[C:8]([CH3:22])[O:7][N:6]=1)[CH2:2][CH2:3][CH3:4]
Reactant: CCCCc1noc(C)c1CN1C(=O)c2ccccc2C1=O
Agent: NN
Solvent: CO
Solvent: O
Product: CCCCc1noc(C)c1CN
Temperature: 55 °C
Yield: 81.7 %

Procedure:
2-(3-Butyl-5-methyl-isoxazol-4-ylmethyl)-isoindole-1,3-dione (1.20 g, 4.0 mmol) was dissolved in MeOH (20 mL) then hydrazine hydrate (1.51 g, 30.1 mmol) was added and the reaction mixture heated at 55° C. After 2 h the reaction mixture was cooled and filtered. The filtrate was evaporated then purified by chromatography (silica, 2 to 10% methanol in dichloromethane) to give the title compound (550 mg, 81%) as a yellow liquid. MS: m/e=348.5 [M+H]+.