Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[C:7](=[O:24])[C:8]2[CH:9]=[C:10]3[CH:20]=[C:19]([F:21])[C:18](F)=[C:17]([F:23])[C:11]3=[N:12][C:13]=2[N:14]([CH3:16])[CH:15]=1)=[O:5])[CH3:2].[C:25]1([CH:31]2[CH2:36][NH:35][CH2:34][CH2:33][NH:32]2)[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1.O>CS(C)=O>[CH2:1]([O:3][C:4]([C:6]1[C:7](=[O:24])[C:8]2[CH:9]=[C:10]3[CH:20]=[C:19]([F:21])[C:18]([N:35]4[CH2:34][CH2:33][NH:32][CH:31]([C:25]5[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=5)[CH2:36]4)=[C:17]([F:23])[C:11]3=[N:12][C:13]=2[N:14]([CH3:16])[CH:15]=1)=[O:5])[CH3:2]
Reactant: CCOC(=O)c1cn(C)c2nc3c(F)c(F)c(F)cc3cc2c1=O
Reactant: c1ccc(C2CNCCN2)cc1
Solvent: O
Solvent: CS(C)=O
Product: CCOC(=O)c1cn(C)c2nc3c(F)c(N4CCNC(c5ccccc5)C4)c(F)cc3cc2c1=O
Temperature: 100 °C
Reaction time: 1 h
Yield: 78.1 %

Procedure:
A suspension of 3-ethoxycarbonyl-7,8,9-trifluoro-1-methyl-4-oxo-1,4-dihydrobenzo[b][1,8]naphthyridine (1.8 g) and (RS)-2-phenylpiperazine (3.2 g) in dimethyl sulphoxide (30 cc) is heated to a temperature in the region of 100° C. with stirring for 1 hour and a half. The solution obtained, at approximately 100° C., is poured with stirring into a mixture of water (150 cc) and ice (50 g). The suspension obtained is extracted at approximately 20° C. with trichloromethane (3×40 cc). The combined organic extracts are washed with water (2×50 cc), dried over magnesium sulphate, filtered and concentrated to dryness under reduced pressure (20 kPa) at approximately 50° C. The solid obtained is recrystallized in a mixture of dimethylformamide (40 cc) and ethanol (40 cc). (RS)-3-Ethoxycarbonyl-7,9-difluoro-1-methyl-4-oxo-8-(3-phenyl-1-piperazinyl)-1,4-dihydrobenzo[b][1,8]naphthyridine (2 g) is obtained in the form of a yellow solid, m.p. 216° C.
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[CH:33]=[CH:32][C:8]2[N:9]=[C:10]([C:12]([C:17]3[CH:22]=[CH:21][C:20]([O:23]CC4C=CC=CC=4)=[C:19]([CH3:31])[CH:18]=3)([CH2:15][CH3:16])[CH2:13][CH3:14])[O:11][C:7]=2[CH:6]=1)=[O:4]>CO.C1COCC1.[Pd]>[CH3:1][O:2][C:3]([C:5]1[CH:33]=[CH:32][C:8]2[N:9]=[C:10]([C:12]([CH2:13][CH3:14])([C:17]3[CH:22]=[CH:21][C:20]([OH:23])=[C:19]([CH3:31])[CH:18]=3)[CH2:15][CH3:16])[O:11][C:7]=2[CH:6]=1)=[O:4]
Reactant: CCC(CC)(c1ccc(OCc2ccccc2)c(C)c1)c1nc2ccc(C(=O)OC)cc2o1
Agent: [Pd]
Solvent: C1CCOC1
Solvent: CO
Product: CCC(CC)(c1ccc(O)c(C)c1)c1nc2ccc(C(=O)OC)cc2o1
Reaction time: 12 h
Yield: 100.5 %

Procedure:
A solution of 2-[1-(4-benzyloxy-3-methyl-phenyl)-1-ethyl-propyl]-benzooxazole-6-carboxylic acid methyl ester (1.50 g, 3.38 mmol) in MeOH (20 mL) is added a slurry of Pd—C (150 mg, 10%) in THF (20 mL) at RT. The resulting mixture is stirred under hydrogen balloon pressure for 12 h. The mixture is filtered through a pad of celite, and the filtrate is concentrated. The residue is purified with 20% EtOAc/Hex to afford the title compound (1.20 g, 100%). H-NMR (ppm, CDCl3) δ: 8.11 (1H, s), 8.03 (1H, dd, J=1.8, 8.4 Hz), 7.73 (1H, d, J=8.4 Hz), 6.97 (1H, d, J=2.2 Hz), 6.92 (1H, dd, J=2.2, 8.4 Hz), 6.70 (1H, d, J=8.4 Hz), 3.93 (3H, s), 2.40 (2H, q, J=7.5 Hz), 2.30 (2H, q, J=7.5 Hz), 2.20 (3H, s), 0.76 (6H, t, J=7.5 Hz).
Reaction SMILES: [CH:1]1[C:6]([CH:7]=O)=[CH:5][C:4]2[O:9][CH2:10][O:11][C:3]=2[CH:2]=1.[NH2:12][CH2:13][CH:14]1[O:19][CH2:18][CH2:17][N:16]([CH2:20][CH:21]([C:23]2[C:32]3[C:27](=[CH:28][CH:29]=[C:30]([O:33][CH3:34])[CH:31]=3)[N:26]=[CH:25][CH:24]=2)[OH:22])[CH2:15]1.[BH4-].[Na+]>C(Cl)Cl.CO>[O:11]1[C:3]2[CH:2]=[CH:1][C:6]([CH2:7][NH:12][CH2:13][CH:14]3[O:19][CH2:18][CH2:17][N:16]([CH2:20][CH:21]([C:23]4[C:32]5[C:27](=[CH:28][CH:29]=[C:30]([O:33][CH3:34])[CH:31]=5)[N:26]=[CH:25][CH:24]=4)[OH:22])[CH2:15]3)=[CH:5][C:4]=2[O:9][CH2:10]1
Reactant: O=Cc1ccc2c(c1)OCO2
Reactant: COc1ccc2nccc(C(O)CN3CCOC(CN)C3)c2c1
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Solvent: ClCCl
Product: COc1ccc2nccc(C(O)CN3CCOC(CNCc4ccc5c(c4)OCO5)C3)c2c1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
Activated 3A molecular sieve (3.485 g) and piperonal (0.172 g, 1.15 mmol) were added to a solution of 2-(2-aminomethyl-morpholin-4-yl)-1-(6-methoxy-quinolin-4-yl)-ethanol (0.365 g, 1.15 mmol) in DCM (10.5 ml) and methanol (3.5 ml). The mixture was stirred overnight at room temperature before sodium borohydride (0.112 g, 2.9 mmol) was added. The reaction mixture was stirred at room temperature for a further 2 hours, filtered over Hydromatrix (wetted with NaHCO3) and concentrated. The residue was purified by chromatography on silica gel (DCM:MeOH 9:1+1% NH4OH).
Reaction SMILES: [CH2:1]([NH2:3])[CH3:2].[C:4]([NH:6][C:7](=[N:10][CH2:11][CH2:12][S:13][CH2:14][C:15]1[N:16]=[N:17][CH:18]=[CH:19][CH:20]=1)SC)#[N:5]>>[C:4]([NH:6][C:7]([NH:3][CH2:1][CH3:2])=[N:10][CH2:11][CH2:12][S:13][CH2:14][C:15]1[N:16]=[N:17][CH:18]=[CH:19][CH:20]=1)#[N:5]
Reactant: CSC(=NCCSCc1cccnn1)NC#N
Reactant: CCN
Product: CCNC(=NCCSCc1cccnn1)NC#N

Procedure:
Anhydrous ethylamine is reacted with N-cyano-N'-[2-(3-pyridazinylmethylthio)ethyl]-S-methylisothiourea by the procedure of Example 4 to give N-cyano-N'-ethyl-N"-[2-(3-pyridazinylmethylthio)ethyl]guanidine.
Reaction SMILES: [OH-].[Na+].C1COCC1.[Cl:8][C:9]1[CH:14]=[C:13]([Cl:15])[CH:12]=[CH:11][C:10]=1[C:16]1[CH:21]=[CH:20][C:19]([NH:22][CH2:23][C:24]2[CH:29]=[CH:28][C:27]([C:30]([F:33])([F:32])[F:31])=[CH:26][C:25]=2[C:34]2[CH:35]=[CH:36][C:37]([C:40]([NH:42][CH2:43][CH2:44][C:45]([O:47]CC)=[O:46])=[O:41])=[N:38][CH:39]=2)=[CH:18][CH:17]=1>CO>[Cl:8][C:9]1[CH:14]=[C:13]([Cl:15])[CH:12]=[CH:11][C:10]=1[C:16]1[CH:21]=[CH:20][C:19]([NH:22][CH2:23][C:24]2[CH:29]=[CH:28][C:27]([C:30]([F:31])([F:33])[F:32])=[CH:26][C:25]=2[C:34]2[CH:35]=[CH:36][C:37]([C:40]([NH:42][CH2:43][CH2:44][C:45]([OH:47])=[O:46])=[O:41])=[N:38][CH:39]=2)=[CH:18][CH:17]=1
Reactant: CCOC(=O)CCNC(=O)c1ccc(-c2cc(C(F)(F)F)ccc2CNc2ccc(-c3ccc(Cl)cc3Cl)cc2)cn1
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CO
Product: O=C(O)CCNC(=O)c1ccc(-c2cc(C(F)(F)F)ccc2CNc2ccc(-c3ccc(Cl)cc3Cl)cc2)cn1
Temperature: 25 °C

Procedure:
A 3M aqueous solution of NaOH (0.63 mL, 1.9 mmol) was added to a THF (4 mL) and MeOH (2 mL) solution of ethyl 3-(5-(2-(((2′,4′-dichloro-[1,1-biphenyl]-4-yl)amino)methyl)-5-(trifluoromethyl)phenyl)picolinamido)propanoate (388 mg, 0.6 mmol) and the homogeneous mixture was stirred at room temperature. After 16 h the resulting mixture was concentrated in vacuo, suspended in water, and acidified with 2 M HCl. The resulting precipitate was filtered off and dried in vacuo to yield the title compound.
Reaction SMILES: [CH3:1][C:2]1[C:7]([B:8]2[O:16][C:13]([CH3:15])([CH3:14])[C:10]([CH3:12])([CH3:11])[O:9]2)=[CH:6][C:5]([C:17]([F:20])([F:19])[F:18])=[CH:4][CH:3]=1.C1C(=O)N([Br:28])C(=O)C1.C1(=O)NC(=O)CC1>CC(N=NC(C#N)(C)C)(C#N)C.C(Cl)(Cl)(Cl)Cl>[Br:28][CH2:1][C:2]1[C:7]([B:8]2[O:16][C:13]([CH3:15])([CH3:14])[C:10]([CH3:11])([CH3:12])[O:9]2)=[CH:6][C:5]([C:17]([F:19])([F:18])[F:20])=[CH:4][CH:3]=1
Reactant: O=C1CCC(=O)N1Br
Reactant: Cc1ccc(C(F)(F)F)cc1B1OC(C)(C)C(C)(C)O1
Agent: CC(C)(C#N)N=NC(C)(C)C#N
Agent: O=C1CCC(=O)N1
Solvent: ClC(Cl)(Cl)Cl
Product: CC1(C)OB(c2cc(C(F)(F)F)ccc2CBr)OC1(C)C
Temperature: 25 °C
Yield: 98.6 %

Procedure:
6-Methyl-3-(trifluoromethyl)phenylboronic acid pinacol ester (24b, 3.0 g, 10 mmol) and 60 ml CCl4 were placed in 500 ml round-bottom flask. NBS (1.9, 10.5 mmol, 1.05 eq) and AIBN (0.02 g, 0.14 mmol, 0.014 eq) were added and the reaction mixture was refluxed for 4.5 h in the presence of 75 W incandescent bulb. After 4.5 h the solution was cooled down to room temperature allowing the succinimide to precipitate out. The solid was filtered off. The solvent was removed and oily product was collected. The crude product was purified by triturating with hexane which resulted in 80% pure product (25b, 3.6 g, 95% yield).
Reaction SMILES: [C:1]([C:4]1[C:5](Cl)=[N:6][C:7]([NH:23][C:24]2[C:29]([O:30][CH:31]([CH3:33])[CH3:32])=[CH:28][C:27]([CH:34]3[CH2:39][CH2:38][N:37](C(OC(C)(C)C)=O)[CH2:36][CH2:35]3)=[C:26]([CH3:47])[CH:25]=2)=[N:8][C:9]=1[NH:10][C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=1[S:17]([CH:20]([CH3:22])[CH3:21])(=[O:19])=[O:18])(=O)[CH3:2].[Cl-].[Cl-].[NH2:51][NH2:52].C([O-])(=O)C.[Na+]>CCO>[CH:31]([O:30][C:29]1[CH:28]=[C:27]([CH:34]2[CH2:39][CH2:38][NH:37][CH2:36][CH2:35]2)[C:26]([CH3:47])=[CH:25][C:24]=1[NH:23][C:7]1[N:6]=[C:5]2[NH:51][N:52]=[C:1]([CH3:2])[C:4]2=[C:9]([NH:10][C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=2[S:17]([CH:20]([CH3:22])[CH3:21])(=[O:18])=[O:19])[N:8]=1)([CH3:32])[CH3:33]
Reactant: NN
Reactant: CC(=O)c1c(Cl)nc(Nc2cc(C)c(C3CCN(C(=O)OC(C)(C)C)CC3)cc2OC(C)C)nc1Nc1ccccc1S(=O)(=O)C(C)C
Agent: CC(=O)[O-]
Agent: [Cl-]
Agent: [Na+]
Solvent: CCO
Product: Cc1cc(Nc2nc(Nc3ccccc3S(=O)(=O)C(C)C)c3c(C)n[nH]c3n2)c(OC(C)C)cc1C1CCNCC1
Temperature: 80 °C
Reaction time: 0.5 h

Procedure:
To a solution of tert-butyl 4-(4-(5-acetyl-4-chloro-6-(2-(isopropylsulfonyl)phenylamino)pyrimidin-2-ylamino)-5-isopropoxy-2-methylphenyl)piperidine-1-carboxylate (81 mg, 0.12 mmol) in EtOH (2 mL) was added hydrazine dichloride (36 mg, 0.34 mmoL) and sodium acetate (47 mg, 0.57 mmol) sequentially, and the reaction mixture was heated at 80° C. overnight. The reaction was cooled to room temperature and concentrated in vacuo. The crude was dissolved in the solution of TFA (2 mL) in DCM (2 mL), and the reaction was stirred for 30 min, followed by concentration and purification by RP-HPLC to afford N6-(2-isopropoxy-5-methyl-4-(piperidin-4-yl)phenyl)-N4-(2-(isopropylsulfonyl)phenyl)-3-methyl-1H-pyrazolo[3,4-d]pyrimidine-4,6-diamine. MS (ES+): 578.3 (MH+).
Reaction SMILES: [Cl:1][C:2]1[C:3]([C:19]([N:21]2[CH2:25][CH2:24][C:23]([F:27])([F:26])[CH2:22]2)=[O:20])=[CH:4][C:5]([O:11][CH2:12][C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)=[C:6]([CH:10]=1)[C:7](O)=[O:8].C(N(C(C)C)CC)(C)C.CN(C(ON1N=[N:52][C:47]2[CH:48]=[CH:49][CH:50]=[N:51][C:46]1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.NC1C=NC=CC=1>CN(C)C=O>[Cl:1][C:2]1[C:3]([C:19]([N:21]2[CH2:25][CH2:24][C:23]([F:26])([F:27])[CH2:22]2)=[O:20])=[CH:4][C:5]([O:11][CH2:12][C:13]2[CH:14]=[CH:15][CH:16]=[CH:17][CH:18]=2)=[C:6]([CH:10]=1)[C:7]([NH:52][C:47]1[CH:46]=[N:51][CH:50]=[CH:49][CH:48]=1)=[O:8]
Reactant: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Reactant: O=C(O)c1cc(Cl)c(C(=O)N2CCC(F)(F)C2)cc1OCc1ccccc1
Agent: F[P-](F)(F)(F)(F)F
Agent: Nc1cccnc1
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: O=C(Nc1cccnc1)c1cc(Cl)c(C(=O)N2CCC(F)(F)C2)cc1OCc1ccccc1
Reaction time: 18 h

Procedure:
To a solution of 5-chloro-4-[(3,3-difluoro-1-pyrrolidinyl)carbonyl]-2-[(phenylmethyl)oxy]benzoic acid (may be prepared as described in Description 65; 90 mg, 0.23 mmol) in N,N-dimethylformamide (3 ml) was added diisopropylethylamine (0.08 ml, 0.46 mmol), HATU (156 mg, 0.41 mmol) and 3-aminopyridine (25.7 mg, 0.27 mmol). The solution was stirred for 18 hours. The solvent removed in vacuo to give a gum. Purification by MDAP gave the title compound as a white solid. 65 mg.
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[C:8]([NH:10][C:11](=[O:13])[CH3:12])[CH:7]=[CH:6][C:5]=1[O:14][CH3:15])([O-])=O.C(O)C.N.[H][H]>[Pd].O>[CH3:15][O:14][C:5]1[CH:6]=[CH:7][C:8]([NH:10][C:11](=[O:13])[CH3:12])=[CH:9][C:4]=1[NH2:1]
Reactant: COc1ccc(NC(C)=O)cc1[N+](=O)[O-]
Reactant: [H][H]
Agent: [Pd]
Agent: N
Solvent: O
Solvent: CCO
Product: COc1ccc(NC(C)=O)cc1N
Reaction time: 2 h

Procedure:
104 parts of 2-nitro-4-acetamidoanisole, 160 parts of ethanol, 12.5 parts of a 30% aqueous solution of ammonia and 1 part of a 50% suspension of palladium on charcoal, moist with water, in 2 parts of water are charged to an autoclave equipped with an aerating stirrer. The autoclave is pressurised with hydrogen and, at a pressure of 8 bar and a temperature of 100° C., hydrogenation is carried out for 2 hours. 2-Methoxy-5-acetamidoaniline is obtained in quantitative yield in a purity of >97% (analysis by liquid chromatography).
Reaction SMILES: [C:1](O)(=O)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[Br:10][C:11]1[CH:12]=[C:13]([CH:15]=[CH:16][CH:17]=1)[NH2:14].C(=O)C1C=CC=CC=1.N#N>Cl[Pd]Cl.C(N(CC)CC)C>[CH:1](=[N:14][C:13]1[CH:12]=[C:11]([Br:10])[CH:17]=[CH:16][CH:15]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=C(O)c1ccccc1
Reactant: Nc1cccc(Br)c1
Agent: Cl[Pd]Cl
Agent: N#N
Solvent: O=Cc1ccccc1
Solvent: CCN(CC)CC
Product: Brc1cccc(N=Cc2ccccc2)c1

Procedure:
To a nitrogen purged 250 mL three-neck flask equipped with a mechanical stirrer, reflux condenser and septum inlet was added benzoic acid (300 mg, 2.8 mmol) and PdCl2 (25 mg). Then 3-bromoaniline (25 g, 145 mmol), benzaldehyde (4.6 g, 44 mmol) and triethylamine (80 mL) were charged. The resulting mixture was vacuum deaerated (150 torr; N2 backfill; 5×) and heated under nitrogen at reflux for one hour to form the N-benzylidene 3-aminophenylbromide.
Reaction SMILES: Br[C:2]1[CH:11]=[C:10]2[C:5]([O:6][CH2:7][CH2:8][N:9]2[S:12]([C:15]2[CH:20]=[C:19]([Cl:21])[CH:18]=[CH:17][C:16]=2[O:22][CH3:23])(=[O:14])=[O:13])=[N:4][CH:3]=1.C(N(CC)CC)C.[C:31]([O:34][CH2:35][CH3:36])(=[O:33])C>C(O)C>[CH2:35]([O:34][C:31]([C:2]1[CH:11]=[C:10]2[C:5]([O:6][CH2:7][CH2:8][N:9]2[S:12]([C:15]2[CH:20]=[C:19]([Cl:21])[CH:18]=[CH:17][C:16]=2[O:22][CH3:23])(=[O:14])=[O:13])=[N:4][CH:3]=1)=[O:33])[CH3:36]
Reactant: CCOC(C)=O
Reactant: COc1ccc(Cl)cc1S(=O)(=O)N1CCOc2ncc(Br)cc21
Solvent: CCO
Solvent: CCN(CC)CC
Product: CCOC(=O)c1cnc2c(c1)N(S(=O)(=O)c1cc(Cl)ccc1OC)CCO2
Yield: 67 %

Procedure:
A solution of 7-bromo-1-(5-chloro-2-methoxy-benzenesulfonyl)-2,3-dihydro-1H-4-oxa-1,5-diaza-naphthalene (200 mg, 0.476 mmol), triethylamine (120 mg, 1.19 mmol), and dichloro[1,1′-bis(diphenylphosphino)ferrocene]palladium dichloromethane complex (19 mg, 29 μmol) in ethanol (2 mL) and ethyl acetate (2 mL) was heated at 110° C. under a carbon monoxide atmosphere (70 bar) for 20 h. The reaction mixture was evaporated and the residue chromatographed (SiO2, toluene-acetonitrile gradient) to produce 1-(5-chloro-2-methoxy-benzenesulfonyl)-2,3-dihydro-1H-4-oxa-1,5-diaza-naphthalene-7-carboxylic acid ethyl ester (132 mg, 67%). Off-white solid, MS (ISP)=413.2 (M+H)+.
Reaction SMILES: [CH:1]([O:4][CH2:5][CH2:6][CH2:7][NH2:8])([CH3:3])[CH3:2].C(N(CC)C(C)C)(C)C.C[C:19]1[C:27]([S:28](Cl)(=[O:30])=[O:29])=[CH:26][CH:25]=[CH:24][C:20]=1[C:21]([OH:23])=[O:22]>C1COCC1>[CH:1]([O:4][CH2:5][CH2:6][CH2:7][NH:8][S:28]([C:27]1[CH:19]=[C:20]([CH:24]=[CH:25][CH:26]=1)[C:21]([OH:23])=[O:22])(=[O:30])=[O:29])([CH3:3])[CH3:2]
Reactant: CC(C)OCCCN
Reactant: Cc1c(C(=O)O)cccc1S(=O)(=O)Cl
Solvent: C1CCOC1
Solvent: CCN(C(C)C)C(C)C
Product: CC(C)OCCCNS(=O)(=O)c1cccc(C(=O)O)c1
Temperature: 25 °C

Procedure:
3-Isopropoxypropylamine (1.1 eq.) is dissolved in THF with stirring at room temperature. N,N-diisopropylethylamine (1 eq.) is added followed by methyl 3-(chlorosulfonyl)benzoic acid (1 eq.). The reaction mixture is stirred at room temperature for 2 hours before the solvent is evaporated in vacuo to yield the crude titled product.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([OH:14])[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].F[C:16]1[CH:21]=[CH:20][C:19]([N+:22]([O-:24])=[O:23])=[CH:18][CH:17]=1.[H-].[Na+].O>CS(C)=O>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([O:14][C:16]2[CH:21]=[CH:20][C:19]([N+:22]([O-:24])=[O:23])=[CH:18][CH:17]=2)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)N1CCC(O)CC1
Reactant: O=[N+]([O-])c1ccc(F)cc1
Agent: [H-]
Agent: [Na+]
Solvent: CS(C)=O
Solvent: O
Product: CC(C)(C)OC(=O)N1CCC(Oc2ccc([N+](=O)[O-])cc2)CC1
Temperature: 25 °C
Reaction time: 1 h
Yield: 85.4 %

Procedure:
To a solution of 4-hydroxypiperidine-1-carboxylic acid tert-butyl ester (38.28 g) and 4-fluoronitrobenzene (26.84 g) in dimethyl sulfoxide (326 ml) was added 60% sodium hydride (7.99 g) under nitrogen atmosphere and with ice-cooling, and the mixture was stirred at room temperature for 1 hour. After completion of the reaction, water was added and the mixture was extracted with ethyl acetate and washed with water. The organic layer was dried over anhydrous sodium sulfate and the solvent was evaporated. The obtained residue was purified by silica gel column chromatography (hexane:ethyl acetate=10:1) to give the title compound (52.384 g).
Reaction SMILES: [N:1]1([C:8]([O:10][C:11]([CH3:14])([CH3:13])[CH3:12])=[O:9])[CH2:7][CH2:6][C@H:2]1[C:3]([OH:5])=O.CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.[B-](F)(F)(F)F.[NH2:37][CH2:38][C:39]1[CH:46]=[CH:45][C:42](C#N)=[C:41](F)[CH:40]=1>CN(C=O)C>[N:1]1([C:8]([O:10][C:11]([CH3:14])([CH3:13])[CH3:12])=[O:9])[CH2:7][CH2:6][C@H:2]1[C:3]([NH:37][CH2:38][C:39]1[CH:46]=[CH:45][CH:42]=[CH:41][CH:40]=1)=[O:5]
Reactant: CC(C)(C)OC(=O)N1CC[C@H]1C(=O)O
Reactant: N#Cc1ccc(CN)cc1F
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[B-](F)(F)F
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)N1CC[C@H]1C(=O)NCc1ccccc1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 100.8 %

Procedure:
To an ice cooled solution of Boc-Aze-OH (0.194 g, 0.96 mmol) in 5 mL of DMF was added TBTU (0.50 g, 9.6 mmol). After 30 min another solution, comprising 4-aminomethyl-2-fluorobenzonitrile (0.17 g, 0.81 mmol; see step (y) above) and diiisopropylethyl amine (0.326 g, 2.53 mmol) in 7 mL of DMF was added. The resulting solution was stirred overnight at room temperature. The solvent was evaporated and the product was purified by preparative RPLC using CH3CN:0.1M NH4OAc (50:50). Freeze-drying gave 0.237 g (74%) of the desired sub-title compound.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5](Br)=[CH:4][N:3]=1.O.[NH2:10][NH2:11]>O1CCOCC1>[Br:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([NH:10][NH2:11])[N:3]=1
Reactant: Brc1ccc(Br)nc1
Reactant: NN
Solvent: C1COCCO1
Solvent: O
Product: NNc1cccc(Br)n1
Temperature: 80 °C

Procedure:
2,5-Dibromopyridine (2.0 g, 8.4 mmol) was dissolved in 1,4-dioxane (2 mL) and a solution of hydrazine hydrate (500 mg, 8.4 mmol) in 1,4-dioxane (15 mL) was added dropwise by syringe pump. The reaction was heated to 80° C. for 16 h. The solvents were removed in vaccuo and the residue was chromatographed on silica gel eluting with hexanes:EtOAc (1:1) to afford 2-bromo-6-hydrazinopyridine as a brown solid. MS (ESI) 187.0 (M++H), 189.0 (M+H+2).
Reaction SMILES: [Cl:1][C:2]1[C:3]([C:14]2[CH:19]=[C:18]([Cl:20])[CH:17]=[CH:16][C:15]=2[C:21]#[N:22])=[CH:4][C:5](=[O:13])[N:6]([CH:8]([CH3:12])[C:9](O)=[O:10])[CH:7]=1.[NH2:23][C:24]1[CH:29]=[CH:28][C:27]([C:30]2[N:34]([C:35]([O:37][C:38]([CH3:41])([CH3:40])[CH3:39])=[O:36])[NH:33][C:32](=[O:42])[CH:31]=2)=[CH:26][CH:25]=1>>[Cl:1][C:2]1[C:3]([C:14]2[CH:19]=[C:18]([Cl:20])[CH:17]=[CH:16][C:15]=2[C:21]#[N:22])=[CH:4][C:5](=[O:13])[N:6]([CH:8]([CH3:12])[C:9]([NH:23][C:24]2[CH:29]=[CH:28][C:27]([C:30]3[N:34]([C:35]([O:37][C:38]([CH3:40])([CH3:39])[CH3:41])=[O:36])[NH:33][C:32](=[O:42])[CH:31]=3)=[CH:26][CH:25]=2)=[O:10])[CH:7]=1
Reactant: CC(C)(C)OC(=O)n1[nH]c(=O)cc1-c1ccc(N)cc1
Reactant: CC(C(=O)O)n1cc(Cl)c(-c2cc(Cl)ccc2C#N)cc1=O
Product: CC(C(=O)Nc1ccc(-c2cc(=O)[nH]n2C(=O)OC(C)(C)C)cc1)n1cc(Cl)c(-c2cc(Cl)ccc2C#N)cc1=O

Procedure:
150 mg (purity 82%, 0.37 mmol) of 2-[5-chloro-4-(5-chloro-2-cyanophenyl)-2-oxopyridin-1(2H)-yl]propanoic acid (racemate) and 1.2 eq. of tert-butyl 5-(4-aminophenyl)-3-oxo-2,3-dihydro-1H-pyrazole-1-carboxylate were reacted according to General Method 5A. Yield: 17.8 mg (purity 78%, 6% of theory)
Reaction SMILES: [F:1][C:2]([F:7])([F:6])[C:3]([OH:5])=[O:4].[F:8][C:9]([F:14])([F:13])[C:10]([OH:12])=[O:11].FC(F)(F)C(O)=O.[Cl:22][C:23]1[CH:24]=[N:25][C:26]2[NH:27][C:28]3[CH:29]=[N:30][CH:31]=[C:32]([CH:54]=3)[CH2:33][CH2:34][C:35]3[CH:43]=[C:39]([NH:40][C:41]=1[N:42]=2)[CH:38]=[CH:37][C:36]=3[NH:44][C:45](=[O:53])[CH2:46][CH:47]1[CH2:52][CH2:51][NH:50][CH2:49][CH2:48]1.[C:55]([C:57]1[CH:62]=[CH:61][CH:60]=[CH:59][C:58]=1[S:63](Cl)(=[O:65])=[O:64])#[N:56]>>[F:1][C:2]([F:7])([F:6])[C:3]([OH:5])=[O:4].[F:8][C:9]([F:14])([F:13])[C:10]([OH:12])=[O:11].[Cl:22][C:23]1[CH:24]=[N:25][C:26]2[NH:27][C:28]3[CH:29]=[N:30][CH:31]=[C:32]([CH:54]=3)[CH2:33][CH2:34][C:35]3[CH:43]=[C:39]([NH:40][C:41]=1[N:42]=2)[CH:38]=[CH:37][C:36]=3[NH:44][C:45](=[O:53])[CH2:46][CH:47]1[CH2:52][CH2:51][N:50]([S:63]([C:58]2[CH:59]=[CH:60][CH:61]=[CH:62][C:57]=2[C:55]#[N:56])(=[O:65])=[O:64])[CH2:49][CH2:48]1
Reactant: N#Cc1ccccc1S(=O)(=O)Cl
Reactant: O=C(CC1CCNCC1)Nc1ccc2cc1CCc1cncc(c1)Nc1ncc(Cl)c(n1)N2
Solvent: O=C(O)C(F)(F)F
Product: N#Cc1ccccc1S(=O)(=O)N1CCC(CC(=O)Nc2ccc3cc2CCc2cncc(c2)Nc2ncc(Cl)c(n2)N3)CC1
Yield: 20 %

Procedure:
The desired compound was prepared according to the procedure of Example A42 using N-[6-chloro-2,4,8,18,22-pentaazatetracyclo[14.3.1.1(3,7).1(9,13)]docosa-1(20),3(22),4,6,9(21),10,12,16,18-nonaen-12-yl]-2-piperidin-4-ylacetamide tris(trifluoroacetate) and 2-cyanobenzenesulfonyl chloride as starting materials in 20% yield. LCMS for C31H30ClN8O3S (M+H)+: m/z=629.2.
Reaction SMILES: [C:1]1([C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[N:7]1[C:16](=[O:17])[C:15]2[C:10](=[CH:11][CH:12]=[CH:13][C:14]=2[Cl:18])[N:9]=[C:8]1[CH2:19]Cl.[N:27]1[C:35]([NH2:36])=[C:34]2[C:30]([N:31]=[CH:32][NH:33]2)=[N:29][CH:28]=1.C([O-])([O-])=O.[K+].[K+]>CN(C=O)C>[NH2:36][C:35]1[N:27]=[CH:28][N:29]=[C:30]2[C:34]=1[N:33]=[CH:32][N:31]2[CH2:19][C:8]1[N:7]([C:2]2[CH:3]=[CH:4][CH:5]=[CH:6][C:1]=2[C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)[C:16](=[O:17])[C:15]2[C:10](=[CH:11][CH:12]=[CH:13][C:14]=2[Cl:18])[N:9]=1
Reactant: O=c1c2c(Cl)cccc2nc(CCl)n1-c1ccccc1-c1ccccc1
Reactant: Nc1ncnc2nc[nH]c12
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: Nc1ncnc2c1ncn2Cc1nc2cccc(Cl)c2c(=O)n1-c1ccccc1-c1ccccc1
Yield: 68.3 %

Procedure:
Prepared according to Procedure C using Intermediate 2i (400 mg, 1.05 mmol), adenine (155 mg, 1.15 mmol), K2CO3 (159 mg, 1.15 mmol), and DMF (5 mL). The crude product was recrystallized from EtOH to provide 344 mg of a white solid (68%), mp 299.9-300.1° C. (discolors). 1H NMR (DMSO-d6) δ: 8.08 (s, 1H); 7.89 (s, 1H); 7.58-7.73 (m, 5H); 7.51 (d, J=7.9 Hz, 1H); 7.46 (d, J=7.5 Hz, 2H); 7.27-7.41 (m, 3H); 7.14-7.27 (m, 3H); 5.14 (d, J=17 Hz, 1H); 4.82 (d, J=17 Hz, 1H). 13C NMR (DMSO-d6) ppm: 159.6, 156.2, 152.8, 152.5, 150.0, 149.0, 141.7, 140.2, 137.7, 135.0, 133.3, 133.2, 131.8, 130.7, 130.1, 129.8, 129.5, 128.8, 128.6, 128.4, 127.1, 118.4, 117.6, 45.3. MS (ES): m/z 480.1 (M+). Anal. calcd. for C26H18ClN7O: C, 65.07; H, 3.78; Cl, 7.39; N, 20.43. Found: C, 64.77; H, 3.75; Cl, 7.43; N, 20.35.
Reaction SMILES: [CH2:1](O)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.S(Cl)(Cl)=O.[C-:13]#[N:14].[K+]>ClCCl>[CH2:1]([C:13]#[N:14])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: [C-]#N
Reactant: OCc1ccccc1
Agent: [K+]
Solvent: ClCCl
Solvent: O=S(Cl)Cl
Product: N#CCc1ccccc1
Temperature: 52.5 °C
Yield: 195.4 %

Procedure:
To a solution of 40.00 g(180 mmoles) of benzyl alcohol in 530 ml of dichloromethane was added within 5 min 32.7 ml (450 mmoles) of thionyl chloride. The solution was evaporated in vacuo to dryness, which was repeated after toluene addition: 46.30 g (106.9%) of crude benzyl chloride, which was dissolved in 230 ml of dimethylformamide and treated with 23.50 g (360 mmoles) of potassium cyanide. The mixture was heated for 4 hours to 50-55° C. The salt was filtered off and the filtrate evaporated in vacuo to dryness, which was repeated after the addition of water, the residue was taken up in ether and extracted with 1N NaOH. The ether phase is evaporated to dryness to yield 41.20 g (99.0%) of crude benzyl cyanide.