Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([C:4]1[S:5][C:6](Br)=[CH:7][CH:8]=1)(=O)C.[Br:10][C:11]1[S:15][C:14]([C:16]([CH2:18][C:19]#[N:20])=[O:17])=[CH:13][CH:12]=1.C1(=O)CCCC1.N1CCOCC1.[S]>>[NH2:20][C:19]1[S:5][C:6]2[CH2:1][CH2:4][CH2:8][C:7]=2[C:18]=1[C:16]([C:14]1[S:15][C:11]([Br:10])=[CH:12][CH:13]=1)=[O:17]
Reactant: CC(=O)c1ccc(Br)s1
Reactant: N#CCC(=O)c1ccc(Br)s1
Agent: [S]
Solvent: C1COCCN1
Solvent: O=C1CCCC1
Product: Nc1sc2c(c1C(=O)c1ccc(Br)s1)CCC2
Yield: 73 %

Procedure:
The procedure of Example 1 was followed except that 2-acetyl-5-bromothiophene (Aldrich) was used in place of acetophenone to prepare the corresponding 2-(5-bromothiophene-2-carbonyl)acetonitrile (Steps A and B). Cyclopentanone (Aldrich), 2-(5-bromothiophene-2-carbonyl)acetonitrile, morpholine, and sulfur were reacted according to the procedure of Step C, Example 1, to afford the desired compound. Yield: 73%; IR (KBr) cm−1: 3349, 3236, 3130, 1590, 1549, 1431, 1414, 1269, 975; 1H NMR (CDCl3):δ2.285 (m, 2H), 2.51 (t, 2H, J=7.4 Hz), 2.70 (t, 2H, J=7.4 Hz), 6.64 (bs, 2H), 7.02 (d, 1H, J=4 Hz), 7.13 (d, 1H, J=4 Hz); red solid, mp: 154-156° C. (petroleum ether).
Reaction SMILES: [H-].[Al+3].[Li+].[H-].[H-].[H-].[CH2:7]([NH:14][C:15](=O)[C@H:16]1[CH2:20][CH2:19][C:18](=O)[NH:17]1)[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1.O.[OH-].[Na+]>O1CCCC1>[C:8]1([CH2:7][NH:14][CH2:15][C@H:16]2[CH2:20][CH2:19][CH2:18][NH:17]2)[CH:9]=[CH:10][CH:11]=[CH:12][CH:13]=1
Reactant: O=C1CC[C@H](C(=O)NCc2ccccc2)N1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: C1CCOC1
Solvent: O
Product: c1ccc(CNC[C@H]2CCCN2)cc1
Temperature: 60 °C
Yield: 93.3 %

Procedure:
To a suspension of lithium aluminum hydride (5.40 g) in tetrahydrofuran (150 mL) was added dropwise a suspension (350 mL) of N-benzyl-5-oxo-D-prolinamide (11.0 g) in tetrahydrofuran under ice-cooling, and the mixture was stirred with heating at 60° C. for 14 hr. The reaction mixture was cooled to 0° C., water (10.8 mL), 1M aqueous sodium hydroxide solution (5.4 mL) and water (5.4 mL) were added, and the resultant insoluble material was filtered off. The filtrate was concentrated under reduced pressure to give the title compound (8.95 g) as a pale-yellow oil. This compound was used for the next reaction without further purification.
Reaction SMILES: Br[C:2]1[CH:8]=[CH:7][C:5]([NH2:6])=[C:4]([N+:9]([O-:11])=[O:10])[CH:3]=1.[CH3:12][C:13]1[N:14]=[CH:15][NH:16][CH:17]=1.C([O-])([O-])=O.[K+].[K+].OC1C=CC=C2C=1N=CC=C2.N>CS(C)=O.[Cu]I.CCOC(C)=O.O>[CH3:12][C:13]1[N:14]=[CH:15][N:16]([C:2]2[CH:8]=[CH:7][C:5]([NH2:6])=[C:4]([N+:9]([O-:11])=[O:10])[CH:3]=2)[CH:17]=1
Reactant: Nc1ccc(Br)cc1[N+](=O)[O-]
Reactant: Cc1c[nH]cn1
Agent: [Cu]I
Agent: N
Agent: O=C([O-])[O-]
Solvent: CCOC(C)=O
Solvent: CS(C)=O
Solvent: O
Product: Cc1cn(-c2ccc(N)c([N+](=O)[O-])c2)cn1
Temperature: 120 °C
Reaction time: 29 h
Yield: 56.6 %

Procedure:
A suspension of 4-bromo-2-nitroaniline (4.34 g, 20 mmol), 4-methylimidazole (1.97 g, 24 mmol), K2CO3 (3.04 g, 22 mmol), CuI (0.57 g, 3 mmol) and 8-hydroxyquinoline (0.44 g, 3 mmol) in 20 mL DMSO was stirred at 120° C. in a sealed tube under Ar2 for 29 hrs. The mixture was cooled down to rt and 28% aqueous ammonia (10 mL) was added and then H2O and EtOAc were added. The aqueous layer was extracted with EtOAc (80 mL×3) and the organic layer was washed with brine, dried with Na2SO4, after filtration, the filtrate was evaporated in vacuo and the residue was washed with PE/EtOAc to give 2.47 g product as a red solid (56.6%). 1H NMR (300 MHz, DMSO-d6) δ: 8.03 (1 H, d, J=2.1 Hz), 7.64-7.68 (1 H, dd, J=2.1 and 9.0 Hz), 7.53 (2 H, brs), 7.10-7.13 (1 H, d, J=9.0 Hz), 2.12 (3 H, s). LCMS: m/z [M+H]+ 219.0895.
Reaction SMILES: [F:1][C:2]([F:14])([F:13])[C:3]1[CH:8]=[CH:7][C:6]([CH2:9][C:10]([OH:12])=O)=[CH:5][CH:4]=1.[CH3:15][NH:16][C@H:17]1[CH2:36][N:21]2[C:22]3[C:27]([C:28]([CH2:29][C:30]([O:32]CCC)=[O:31])=[C:20]2[CH2:19][CH2:18]1)=[CH:26][CH:25]=[CH:24][CH:23]=3>>[CH3:15][N:16]([C:10](=[O:12])[CH2:9][C:6]1[CH:5]=[CH:4][C:3]([C:2]([F:1])([F:14])[F:13])=[CH:8][CH:7]=1)[C@H:17]1[CH2:36][N:21]2[C:22]3[C:27]([C:28]([CH2:29][C:30]([OH:32])=[O:31])=[C:20]2[CH2:19][CH2:18]1)=[CH:26][CH:25]=[CH:24][CH:23]=3
Reactant: CCCOC(=O)Cc1c2n(c3ccccc13)C[C@H](NC)CC2
Reactant: O=C(O)Cc1ccc(C(F)(F)F)cc1
Product: CN(C(=O)Cc1ccc(C(F)(F)F)cc1)[C@@H]1CCc2c(CC(=O)O)c3ccccc3n2C1

Procedure:
The title compound was prepared using analogous procedures described in Example 1 (Method A) from [4-(trifluoromethyl)phenyl]acetic acid and propyl [(7R)-7-(methylamino)-6,7,8,9-tetrahydropyrido[1,2-a]indol-10-yl]acetate. MS (+ESI) m/z: 445.
Reaction SMILES: [NH2:1][CH2:2][C:3]([NH:5][S:6]([C:9]1[CH:14]=[CH:13][C:12]([C:15]2[C:16]([C:21]3[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=3)=[N:17][O:18][C:19]=2[CH3:20])=[CH:11][CH:10]=1)(=[O:8])=[O:7])=[O:4].C(N(CC)CC)C.[C:34](OC(=O)C)(=[O:36])[CH3:35]>C(#N)C>[C:34]([NH:1][CH2:2][C:3]([NH:5][S:6]([C:9]1[CH:10]=[CH:11][C:12]([C:15]2[C:16]([C:21]3[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=3)=[N:17][O:18][C:19]=2[CH3:20])=[CH:13][CH:14]=1)(=[O:8])=[O:7])=[O:4])(=[O:36])[CH3:35]
Reactant: CC(=O)OC(C)=O
Reactant: Cc1onc(-c2ccccc2)c1-c1ccc(S(=O)(=O)NC(=O)CN)cc1
Solvent: CCN(CC)CC
Solvent: CC#N
Product: CC(=O)NCC(=O)NS(=O)(=O)c1ccc(-c2c(-c3ccccc3)noc2C)cc1
Reaction time: 2 h
Yield: 72.1 %

Procedure:
The 2-amino-N-[[4-(5-methyl-3-phenylisoxazol-4-yl)phenyl]sulfonyl]acetamide (Example 79)(4.08 g, 10.9 mmol) was mixed in acetonitrile at room temperature. Triethylamine (3.03 g, 30.0 mmol) and acetic anhydride (1.23 g, 12.1 mmol) were added and the heterogeneous solution was stirred for 2 hours. The solution was vacuum filtered through a pad of diatomaceous earth and solvent was removed at reduced pressure. Water was added and the solution was stirred for 30 minutes. White crystals formed, were collected by vacuum filtration and dried to afford the desired product as a white solid (3.25 g, 78%): mp 218.2-219.3° C. 1H NMR (CD3OD/300 MHz) 8.01 (d, 2H, J=8.2 Hz), 7.42-7.36 (m, 7H), 3.85 (s, 2H), 2.50 (s, 3H), 1.95 (s, 3H). FABLRMS m/z 414 (M+H). Anal. Calc'd for C20H19N3O5S: C, 58.10; H, 4.63; N, 10.16. Found: C, 58.18; H, 4.66; N, 10.14.
Reaction SMILES: [F:1][C:2]1[CH:16]=[CH:15][CH:14]=[CH:13][C:3]=1[CH:4]([OH:12])[C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][C:6]=1[F:11]>[O-2].[Mn+2].C1C=CC=CC=1>[F:1][C:2]1[CH:16]=[CH:15][CH:14]=[CH:13][C:3]=1[C:4]([C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][C:6]=1[F:11])=[O:12]
Reactant: OC(c1ccccc1F)c1ccccc1F
Agent: [Mn+2]
Agent: [O-2]
Solvent: c1ccccc1
Product: O=C(c1ccccc1F)c1ccccc1F
Temperature: 25 °C
Yield: 82.5 %

Procedure:
To a mixture of 440.4 mg (2.0 mmol) of 2,2′-bisfluorobenzhydrol and 1.04 g (12.0 mmol) of activated manganese oxide was added 10 ml of benzene. The resultant was refluxed for 2 hours. The reaction mixture was cooled to room temperature, and filtrated with celite. The filtrate was concentrated and purified by column chromatography on silica gel (ethyl acetate:hexane=1:5) to give 360 mg (yield: 82%) of the title compound in the form of a yellow solution.
Reaction SMILES: [NH2:1][C:2]1[C:11]([C:12]#[N:13])=[C:10](O)[C:9]2[C:4](=[CH:5][CH:6]=[C:7]([N:15]([CH3:17])[CH3:16])[CH:8]=2)[N:3]=1.P(Cl)(Cl)([Cl:20])=O.[OH-].[Na+]>>[NH2:1][C:2]1[C:11]([C:12]#[N:13])=[C:10]([Cl:20])[C:9]2[C:4](=[CH:5][CH:6]=[C:7]([N:15]([CH3:17])[CH3:16])[CH:8]=2)[N:3]=1
Reactant: CN(C)c1ccc2nc(N)c(C#N)c(O)c2c1
Reactant: O=P(Cl)(Cl)Cl
Agent: [Na+]
Agent: [OH-]
Product: CN(C)c1ccc2nc(N)c(C#N)c(Cl)c2c1
Temperature: 120 °C
Reaction time: 4 h

Procedure:
The mixture of 1.7 g of 2-amino-3-cyano-4-hydroxy-6-dimethylaminoquinoline and 3.4 mL of phosphoryl chloride is stirred at 120° C. for 4 hours. The cooled reaction mixture is poured onto 30 g of ice, the pH of the mixture is adjusted to 8 with 10% NaOH solution and the precipitated material is filtered off. After drying 1.5 g of the title compound is obtained, m.p.: 285° C.
Reaction SMILES: [CH2:1]=[CH:2][CH2:3][CH2:4][CH2:5][CH3:6].B1C2CCCC1CCC2.[CH2:16]([O:23][C:24]1[C:33](=[O:34])[C:32]2[C:27](=[CH:28][C:29](I)=[CH:30][CH:31]=2)[O:26][C:25]=1[C:36]1[CH:41]=[C:40]([O:42][CH3:43])[C:39]([O:44][CH3:45])=[C:38]([O:46][CH3:47])[CH:37]=1)[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1.C(Cl)Cl>O1CCCC1.[OH-].[Na+].Cl[Pd]Cl>[CH2:16]([O:23][C:24]1[C:33](=[O:34])[C:32]2[C:27](=[CH:28][C:29]([CH2:1][CH2:2][CH2:3][CH2:4][CH2:5][CH3:6])=[CH:30][CH:31]=2)[O:26][C:25]=1[C:36]1[CH:41]=[C:40]([O:42][CH3:43])[C:39]([O:44][CH3:45])=[C:38]([O:46][CH3:47])[CH:37]=1)[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1
Reactant: COc1cc(-c2oc3cc(I)ccc3c(=O)c2OCc2ccccc2)cc(OC)c1OC
Reactant: C=CCCCC
Agent: Cl[Pd]Cl
Agent: B1C2CCCC1CCC2
Agent: [Na+]
Solvent: C1CCOC1
Solvent: ClCCl
Product: CCCCCCc1ccc2c(=O)c(OCc3ccccc3)c(-c3cc(OC)c(OC)c(OC)c3)oc2c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 24.8 %

Procedure:
To a stirring solution of 1-hexene (0.109 g, 1.3 mmol, 1.4 eq) in tetrahydrofuran (2 ml) under argon at 0° C. was added 9-BBN in tetrahydrofuran (0.5M, 2.7 ml, 1.4 mmol, 1.5 eq). The reaction was allowed to warm to room temperature and stirred for 8 hours then 34 (0.505 g, 0.9 mmol) (produced as described in Example 2) in tetrahydrofuran (5 ml), 3M NaOH solution (1.1 ml) and dichloropalladium (dppf) (0.032 g, 0.04 mmol, 0.04 eq) were added and the reaction heated to reflux for 15 hours. The reaction was then quenched with water and diethyl ether. The organic layer was collected and the aqueous layer extracted with dichloromethane. The combined organic layers were dried (MgSO4) and concentrated in vacuo to give a brown oil. Column chromatography (silica gel, DCM) yielded 39e (0.112 g, 24%) as a colourless oil.
Reaction SMILES: [Cl:1][C:2]1[N:3]([S:16]([C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)(=[O:18])=[O:17])[C:4]([C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)=[C:5]([F:9])[C:6]=1[CH2:7][OH:8].C[N+]1([O-])CCOCC1>C(#N)C.C(OCC)(=O)C.[Ru]([O-])(=O)(=O)=O.C([N+](CCC)(CCC)CCC)CC>[Cl:1][C:2]1[N:3]([S:16]([C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)(=[O:18])=[O:17])[C:4]([C:10]2[CH:11]=[CH:12][CH:13]=[CH:14][CH:15]=2)=[C:5]([F:9])[C:6]=1[CH:7]=[O:8]
Reactant: O=S(=O)(c1ccccc1)n1c(Cl)c(CO)c(F)c1-c1ccccc1
Agent: O=[Ru](=O)(=O)[O-]
Agent: CCC[N+](CCC)(CCC)CCC
Agent: C[N+]1([O-])CCOCC1
Solvent: CC#N
Solvent: CCOC(C)=O
Product: O=Cc1c(F)c(-c2ccccc2)n(S(=O)(=O)c2ccccc2)c1Cl
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 67 %

Procedure:
To a solution (15 mL) of [2-chloro-4-fluoro-5-phenyl-1-(phenylsulfonyl)-1H-pyrrol-3-yl]methanol (210 mg) in acetonitrile were added tetra-n-propylammonium perruthenate (31 mg), N-methylmorpholine N-oxide (156 mg) and molecular sieves 4A powder (500 mg), and the mixture was stirred at room temperature for 1.5 hr. The reaction mixture was diluted with ethyl acetate, filtered through celite, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluent: hexane-ethyl acetate=90:10→85:15) to give the title compound as a colorless oil (yield 140 mg, 67%).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:12]([C:13]3[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=3)[N:11]=[C:10]([CH2:19][CH2:20][CH:21]=O)[CH:9]=2)=[CH:4][CH:3]=1.[CH3:23][C:24]1[C:29]([CH3:30])=[CH:28][CH:27]=[CH:26][C:25]=1[N:31]1[CH2:36][CH2:35][NH:34][CH2:33][CH2:32]1.CCN(C(C)C)C(C)C.[BH-](OC(C)=O)(OC(C)=O)OC(C)=O.[Na+]>>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:12]([C:13]3[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=3)[N:11]=[C:10]([CH2:19][CH2:20][CH2:21][N:34]3[CH2:35][CH2:36][N:31]([C:25]4[CH:26]=[CH:27][CH:28]=[C:29]([CH3:30])[C:24]=4[CH3:23])[CH2:32][CH2:33]3)[CH:9]=2)=[CH:4][CH:3]=1
Reactant: Cc1cccc(N2CCNCC2)c1C
Reactant: O=CCCc1cc(-c2ccc(Cl)cc2)n(-c2ccccc2)n1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: CCN(C(C)C)C(C)C
Product: Cc1cccc(N2CCN(CCCc3cc(-c4ccc(Cl)cc4)n(-c4ccccc4)n3)CC2)c1C

Procedure:
89 mg (67%) of target compound was obtained by using a method same as in Example 1 by using 3-(5-(4-chlorophenyl)-1-phenyl-1H-pyrazol-3-yl)-propanal (80 mg, 0.257 mmol), 1-(2,3-dimethylphenyl)piperazine (49 mg, 0.257 mmol), DIPEA (0.070 mL, 0.386 mmol) and NaBH(OAc)3 (163 mg, 0.771 mmol).
Reaction SMILES: [CH:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][C:2]=1[C:11]1[C:12]2[N:13]([CH:25]=[N:26][N:27]=2)[C:14](SC)=[N:15][C:16]=1[C:17]1[CH:22]=[CH:21][N:20]=[CH:19][CH:18]=1.[C:28]1([CH2:34][C@H:35]([NH2:38])[CH2:36][NH2:37])[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1.O>CN(C=O)C>[NH2:38][C@@H:35]([CH2:34][C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1)[CH2:36][NH:37][C:14]1[N:13]2[CH:25]=[N:26][N:27]=[C:12]2[C:11]([C:2]2[CH:3]=[CH:4][C:5]3[C:10](=[CH:9][CH:8]=[CH:7][CH:6]=3)[CH:1]=2)=[C:16]([C:17]2[CH:22]=[CH:21][N:20]=[CH:19][CH:18]=2)[N:15]=1
Reactant: NC[C@@H](N)Cc1ccccc1
Reactant: CSc1nc(-c2ccncc2)c(-c2ccc3ccccc3c2)c2nncn12
Solvent: O
Solvent: CN(C)C=O
Product: N[C@H](CNc1nc(-c2ccncc2)c(-c2ccc3ccccc3c2)c2nncn12)Cc1ccccc1
Temperature: 25 °C
Reaction time: 48 h

Procedure:
8-(2-naphthyl)-5-methylthio-7-(4-pyridyl)-1,2,4-triazolo[4,3-c]pyrimidine (350 mg, 1 mmol), K3CO3 (100 mg) and (2S)-3-phenylpropane-1,2-diamine (150 mg, 1 mmol) were combined in dry DMF (ca. 5 mL) and the mixture was stirred at room temperature for 48 h. To the reaction solution was added water (ca. 10 mL) at RT and a precipitate formed. The suspension was stirred at RT for 1 h. The solid was filtered off and washed with water (3×10 ml) and dried under vacuum at 50° C. overnight; MS (m/z) 472.3 (M+H)+; C29H25N7 requir. 471.56.
Reaction SMILES: N(C(OC(C)C)=O)=NC(OC(C)C)=O.[OH:15][C:16]1[CH:25]=[C:24]2[C:19]([C:20]([O:26][C:27]3[CH:28]=[C:29]4[C:33](=[CH:34][CH:35]=3)[NH:32][C:31]([CH3:36])=[CH:30]4)=[N:21][CH:22]=[N:23]2)=[CH:18][CH:17]=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[N:56]1([CH2:61][CH2:62][CH2:63]O)[CH2:60][CH2:59][CH2:58][CH2:57]1>C(Cl)Cl>[CH3:36][C:31]1[NH:32][C:33]2[C:29]([CH:30]=1)=[CH:28][C:27]([O:26][C:20]1[C:19]3[C:24](=[CH:25][C:16]([O:15][CH2:63][CH2:62][CH2:61][N:56]4[CH2:60][CH2:59][CH2:58][CH2:57]4)=[CH:17][CH:18]=3)[N:23]=[CH:22][N:21]=1)=[CH:35][CH:34]=2
Reactant: OCCCN1CCCC1
Reactant: Cc1cc2cc(Oc3ncnc4cc(O)ccc34)ccc2[nH]1
Agent: CC(C)OC(=O)N=NC(=O)OC(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: ClCCl
Product: Cc1cc2cc(Oc3ncnc4cc(OCCCN5CCCC5)ccc34)ccc2[nH]1
Temperature: 25 °C
Reaction time: 8 h
Yield: 35.8 %

Procedure:
Diisopropyl azodicarboxylate (146 mg, 0.72 mmol) was added to a solution of 7-hydroxy-4-(2-methylindol-5-yloxy)quinazoline (100 mg, 0.34 mmol), triphenyl phosphine (189 mg, 0.72 mol), and 3-pyrrolidinopropan-1-ol (89 mg, 0.686 mmol), (J. Org. Chem. 1988, 53, 3164), in methylene chloride (2.5 ml). After stirring overnight at ambient temperature, the solid was filtered. The filtrate was purified by column chromatography eluting with ethyl acetate/methylene chloride (1/1) followed by ethyl acetate/methylene chloride/methanol (4/5/1), methylene chloride/methanol (9/1) and 3N ammonia in methanol/methylene chloride (1/9). After removal of the solvent, the residue was triturated with ether, filtered, and dried under vacuum to give 4-(2-methylindol-5-yloxy)-7-(3-(pyrrolidin-yl)propoxy)quinazoline (49 mg, 35%).
Reaction SMILES: [NH2:1][C:2]1[N:7]=[CH:6][N:5]=[C:4]2[N:8]([CH:32]3[CH2:37][CH2:36][NH:35][CH2:34][CH2:33]3)[N:9]=[C:10]([C:11]3[CH:16]=[CH:15][C:14]([NH:17][C:18]([C:20]4[N:21]([CH3:29])[C:22]5[C:27]([CH:28]=4)=[CH:26][CH:25]=[CH:24][CH:23]=5)=[O:19])=[C:13]([O:30][CH3:31])[CH:12]=3)[C:3]=12.[CH3:38][C:39]1[NH:40][CH:41]=[C:42]([CH:44]=O)[N:43]=1.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].C(O)(=O)C.C(=O)(O)[O-].[Na+]>ClCCCl>[NH2:1][C:2]1[N:7]=[CH:6][N:5]=[C:4]2[N:8]([CH:32]3[CH2:37][CH2:36][N:35]([CH2:44][C:42]4[N:43]=[C:39]([CH3:38])[NH:40][CH:41]=4)[CH2:34][CH2:33]3)[N:9]=[C:10]([C:11]3[CH:16]=[CH:15][C:14]([NH:17][C:18]([C:20]4[N:21]([CH3:29])[C:22]5[C:27]([CH:28]=4)=[CH:26][CH:25]=[CH:24][CH:23]=5)=[O:19])=[C:13]([O:30][CH3:31])[CH:12]=3)[C:3]=12
Reactant: Cc1nc(C=O)c[nH]1
Reactant: COc1cc(-c2nn(C3CCNCC3)c3ncnc(N)c23)ccc1NC(=O)c1cc2ccccc2n1C
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCCl
Solvent: CC(=O)O
Product: COc1cc(-c2nn(C3CCN(Cc4c[nH]c(C)n4)CC3)c3ncnc(N)c23)ccc1NC(=O)c1cc2ccccc2n1C
Temperature: 25 °C
Reaction time: 8 h
Yield: 72.4 %

Procedure:
N2-{4-[4-amino-1-(4-piperidyl)-1H-pyrazolo[3,4-d]pyrimidin-3-yl]-2-methoxyphenyl}-1-methyl-1H-2-indolecarboxamide (250 mg, 0.503 mmol), 2-methyl-1H-4-imidazolecarbaldehyde (83 mg, 0.755 mmol), sodium triacetoxyborohydride (159 mg, 0.755 mmol) and glacial acetic acid (30 mg, 0.554 mmol) were mixed in 1,2-dichloroethane (6 mL). The reaction mixture was stirred at room temperature overnight. Saturated sodium bicarbonate solution was added to adjust the pH to about 8. The layers were separated and the aqueous layer was extracted with dichloromethane. The combined organic layer was washed with brine, dried over MgSO4, filtered and evaporated. The residue was purified by flash column chromatography using dichloromethane/methanol/ammonium hydroxide (95:5:0.5 to 80:20:05) as mobile phase to give N2-[4-(4-amino-1-{1-[(2-methyl-1H-4-imidazolyl)methyl]-4-piperidyl}-1H-pyrazolo[3,4-d]pyrimidin-3-yl)-2-methoxyphenyl]-1-methyl-1H-2-indolecarboxamide (215 mg, 72%). 1H NMR (DMSO-d6) δ 1.91 (m, 2H), 2.23 (m, 7H), 3.00 (m, 2H), 3.41 (s, 2H), 3.96 (s, 3H), 4.04 (s, 3H), 4.78 (m, 1H), 6.72 (s, 1H), 7.15 (m, 1H), 7.32 (m, 4H), 7.78 (d, J=8.43 Hz, 1H), 7.70 (d, J=7.92 Hz, 1H), 8.11 (d, J=7.92 Hz, 1H), 8.24 (s, 1H), 9.44 (s, 1H). LCMS (Thermoquest AQA single Quad MS, Finnigan HPLC-Column: Genesis, C18, 3 um, 33×4.6 mm. Eluents: 30% B/A to 95% B/A in 4.5 min. (B: acetonitrile, A: 50 mM ammonia acetate buffer, PH 4.5), 0.8 mL/min.): RT=2.00 min. MH+=591.3.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[CH2:7][CH2:8][N:9]1[CH2:14][CH2:13][N:12]([C:15]2[C:23]3[O:22][C:21]([C:24]([O-])=[O:25])=[CH:20][C:19]=3[CH:18]=[CH:17][CH:16]=2)[CH2:11][CH2:10]1.[Li+].[CH:28]1([NH2:31])[CH2:30][CH2:29]1>>[CH:28]1([NH:31][C:24]([C:21]2[O:22][C:23]3[C:15]([N:12]4[CH2:11][CH2:10][N:9]([CH2:8][CH2:7][C:2]5[CH:3]=[CH:4][CH:5]=[CH:6][N:1]=5)[CH2:14][CH2:13]4)=[CH:16][CH:17]=[CH:18][C:19]=3[CH:20]=2)=[O:25])[CH2:30][CH2:29]1
Reactant: O=C([O-])c1cc2cccc(N3CCN(CCc4ccccn4)CC3)c2o1
Reactant: NC1CC1
Agent: [Li+]
Product: O=C(NC1CC1)c1cc2cccc(N3CCN(CCc4ccccn4)CC3)c2o1

Procedure:
The compound was prepared according to the procedure disclosed in Example 1 starting from lithium 7-(4-(2-(pyridin-2-yl)ethyl)piperazin-1-yl)benzofuran-2-carboxylate (80 mg, 0.21 mmol) and cyclopropylamine (64 mg, 1.1 mmol). Yield: 50 mg (57%).
Reaction SMILES: C(OC(N1CCC(N[C:14]([C:16]2[S:17][CH:18]=[CH:19][C:20]=2[NH:21][C:22]2[CH:27]=[CH:26][N:25]=[C:24]3[NH:28][CH:29]=[CH:30][C:23]=23)=[O:15])C1)=O)(C)(C)C.[CH3:31][O:32][C:33](=[O:38])[CH:34]([NH2:37])[CH2:35][OH:36]>>[CH3:31][O:32][C:33](=[O:38])[CH:34]([NH:37][C:14]([C:16]1[S:17][CH:18]=[CH:19][C:20]=1[NH:21][C:22]1[CH:27]=[CH:26][N:25]=[C:24]2[NH:28][CH:29]=[CH:30][C:23]=12)=[O:15])[CH2:35][OH:36]
Reactant: COC(=O)C(N)CO
Reactant: CC(C)(C)OC(=O)N1CCC(NC(=O)c2sccc2Nc2ccnc3[nH]ccc23)C1
Product: COC(=O)C(CO)NC(=O)c1sccc1Nc1ccnc2[nH]ccc12

Procedure:
This compound was prepared in an analogous manner as 3-{[3-(1H-Pyrrolo[2,3-b]pyridin-4-ylamino)-thiophene-2-carbonyl]-amino}-pyrrolidine-1-carboxylic acid tert-butyl ester using 2-amino-3-hydroxy-propionic acid methyl ester instead of 1-BOC-3-aminopyrrolidine. LCMS (ESI) 361 (M+H) 1H NMR (400 MHz, DMSO-d6) δ ppm 11.60 (1H, br. s.) 10.09 (1H, s) 8.13 (1H, d, J=7.57 Hz) 8.03 (1H, d, J=5.56 Hz) 7.85 (1H, d, J=5.42 Hz) 7.46 (1H, d, J=5.42 Hz) 7.32 (1H, dd, J=3.22, 2.64 Hz) 6.80 (1H, d, J=5.56 Hz) 6.43 (1H, dd, J=3.39, 1.78 Hz) 5.06 (1H, t, J=6.05 Hz) 4.56 (1H, dt, J=7.53, 5.02 Hz) 3.72-3.83 (2H, m) 3.63 (3H, s)
Reaction SMILES: [C:1]1(OC2C=CC=CC=2)C=CC=C[CH:2]=1.C([C:16]1[C:21]([NH:22]/[C:23](=[CH:27]\[C:28]([O-:30])=O)/[C:24]([O-:26])=[O:25])=[C:20](CC)[C:19]([Cl:33])=[CH:18][C:17]=1[Cl:34])C>>[Cl:33][C:19]1[CH:18]=[C:17]([Cl:34])[CH:16]=[C:21]2[C:20]=1[C:28](=[O:30])[CH:27]=[C:23]([C:24]([O:26][CH2:1][CH3:2])=[O:25])[NH:22]2
Reactant: c1ccc(Oc2ccccc2)cc1
Reactant: CCc1c(Cl)cc(Cl)c(CC)c1N/C(=C\C(=O)[O-])C(=O)[O-]
Product: CCOC(=O)c1cc(=O)c2c(Cl)cc(Cl)cc2[nH]1
Temperature: 244 °C

Procedure:
A 5-L three-neck flask equipped with a thermocouple, an addition funnel, and a distillation apparatus was charged with diphenyl ether (about 2.8 L), which was heated to about 244° C. The concentrated reaction mixture containing Compound 3 (about 1.1 mole) from Reaction 1, above, was added from the dropping funnel into the hot diphenyl ether over about 10 minutes with a nitrogen purge. The funnel was rinsed with about 200 mL of diphenyl ether, which was also added to the flask. The resulting mixture was heated at about 244° C. for about 1 hour to cyclize Compound 3 to form Compound 4. The reaction mixture then was cooled to room temperature, at which point Compound 4 crystallized out. The crystallized product was isolated and slurried with ethyl acetate (EtOAc; about 1 L). The crystals were collected and rinsed with EtOAc (3×500 mL), and then dried under high vacuum at room temperature to afford about 269.95 g of Compound 4 (85.8% yield over two steps).
Reaction SMILES: [Cl:1][C:2]1[C:11]2[NH:10][C:9](=[O:12])[O:8][C:7]([CH3:14])([CH3:13])[C:6]=2[CH:5]=[C:4]([O:15][CH2:16][CH2:17][CH2:18][CH2:19][S:20][C:21]2[CH:26]=[CH:25][C:24]([CH3:27])=[CH:23][CH:22]=2)[CH:3]=1.[OH:28]O>>[Cl:1][C:2]1[C:11]2[NH:10][C:9](=[O:12])[O:8][C:7]([CH3:14])([CH3:13])[C:6]=2[CH:5]=[C:4]([O:15][CH2:16][CH2:17][CH2:18][CH2:19][S:20]([C:21]2[CH:26]=[CH:25][C:24]([CH3:27])=[CH:23][CH:22]=2)=[O:28])[CH:3]=1
Reactant: Cc1ccc(SCCCCOc2cc(Cl)c3c(c2)C(C)(C)OC(=O)N3)cc1
Reactant: OO
Product: Cc1ccc(S(=O)CCCCOc2cc(Cl)c3c(c2)C(C)(C)OC(=O)N3)cc1

Procedure:
Prepared analogously to Example 2 from 8-chloro-6-[4-(4-methyl-phenylmercapto)-butoxy]-4,4-dimethyl-4H-3,1-benzoxazin-2-one and hydrogen peroxide.
Reaction SMILES: [CH2:1]([O:3][C:4]1[CH:9]=[CH:8][C:7]([NH:10][CH:11]=[C:12]([C:18]([O:20]CC)=O)[C:13]([O:15][CH2:16][CH3:17])=[O:14])=[CH:6][N:5]=1)[CH3:2]>C1(OC2C=CC=CC=2)C=CC=CC=1>[CH2:1]([O:3][C:4]1[N:5]=[C:6]2[C:7](=[CH:8][CH:9]=1)[NH:10][CH:11]=[C:12]([C:13]([O:15][CH2:16][CH3:17])=[O:14])[C:18]2=[O:20])[CH3:2]
Reactant: CCOC(=O)C(=CNc1ccc(OCC)nc1)C(=O)OCC
Solvent: c1ccc(Oc2ccccc2)cc1
Product: CCOC(=O)c1c[nH]c2ccc(OCC)nc2c1=O
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 58 %

Procedure:
Diethyl (2-ethoxy-5-pyridylaminomethylene)malonate (6.04 g) was added to diphenyl ether (20 mL) preheated to 230° C. Heating was continued for 0.5 h, the reaction flask removed from the oil bath, and the mixture allowed to cool to ambient temperature. The product was triturated with 1:1 ether:hexanes, collected, rinsed with ether, and dried to give 2.98 g of ethyl 6-ethoxy-4-oxo-1,4-dihydro-1,5-naphthyridine-3-carboxylate as a tan solid.
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]([CH:13]=[CH:14][CH:15]=1)[C:7]([O:9][CH2:10][C:11]#[CH:12])=[O:8])([O-])=O.[H][H]>C(C(C)=O)C>[NH2:1][C:4]1[CH:5]=[C:6]([CH:13]=[CH:14][CH:15]=1)[C:7]([O:9][CH2:10][C:11]#[CH:12])=[O:8]
Reactant: [H][H]
Reactant: C#CCOC(=O)c1cccc([N+](=O)[O-])c1
Solvent: CCC(C)=O
Product: C#CCOC(=O)c1cccc(N)c1
Reaction time: 14 h
Yield: 65.3 %

Procedure:
In a stirred autoclave, 0.5 g of a catalyst prepared according to Example H1 and containing 0.182 g of Pb(OAc)2 3H2O (corresponding to 2% Pb), and 50 mg (0.5mol %) of FeCl2 4H2O are added to a solution of 10.4 g of propargyl 3-nitrobenzoate in 100 ml of methyl ethyl ketone. The mixture is then hydrogenated for 14 hours at a temperature of 140° C. and at a hydrogen pressure of 20 bar. The catalyst is filtered off, the solvent is distilled off and the remaining mixture is purified by column chromatography to give 5.8 g of propargyl 3-aminobenzoate. The content of allyl 3-aminobenzoate according to 1H--NMR is 18%.