Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:21])[C:5](Cl)=[N:6][NH:7][C:8]1[CH:13]=[C:12]([Br:14])[CH:11]=[CH:10][C:9]=1[O:15][CH2:16][CH2:17][C:18]#[CH:19])[CH3:2].C(N(CC)CC)C>C1(C)C=CC=CC=1>[CH2:1]([O:3][C:4]([C:5]1[CH:19]=[C:18]2[N:7]([N:6]=1)[C:8]1[CH:13]=[C:12]([Br:14])[CH:11]=[CH:10][C:9]=1[O:15][CH2:16][CH2:17]2)=[O:21])[CH3:2]
Reactant: C#CCCOc1ccc(Br)cc1NN=C(Cl)C(=O)OCC
Solvent: CCN(CC)CC
Solvent: Cc1ccccc1
Product: CCOC(=O)c1cc2n(n1)-c1cc(Br)ccc1OCC2
Temperature: 120 °C
Yield: 85.1 %

Procedure:
A mixture of chloro-(5-bromo-2-but-3-ynyloxyphenylhydrazono)acetic acid ethyl ester (3.28 g, 8.78 mmol) and triethylamine (12.2 mL, 88 mmol) in dry toluene (900 mL) was heated at gentle reflux (120° C.) for 54 h. The cooled mixture was filtered, the residue washed with ethyl acetate and the filtrate concentrated in vacuo. The resultant residue was subjected to flash chromatography (SiO2, gradient 10 to 15% ethyl acetate in cyclohexane) to give 9-Bromo-4,5-dihydro-6-oxa-1,10b-diaza-benzo[e]azulene-2-carboxylic acid ethyl ester as a yellow solid (2.52 g, 85%). LCMS: RT=4.52 min, M+H+=337/339, [M+Na]+=359/361.
Reaction SMILES: [C:1]([O:5][C:6](=[O:17])[NH:7][CH2:8][C:9]1[C:14]([Br:15])=[CH:13][N:12]=[C:11]([NH2:16])[CH:10]=1)([CH3:4])([CH3:3])[CH3:2].N1([CH:27](N(CCOC)C)[CH:28](N2C3C=CC=CC=3N=N2)[N:29]([CH2:31][CH2:32][O:33][CH3:34])[CH3:30])C2C=CC=CC=2N=N1>>[C:1]([O:5][C:6](=[O:17])[NH:7][CH2:8][C:9]1[C:14]([Br:15])=[CH:13][N:12]2[C:28]([N:29]([CH2:31][CH2:32][O:33][CH3:34])[CH3:30])=[CH:27][N:16]=[C:11]2[CH:10]=1)([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)NCc1cc(N)ncc1Br
Reactant: COCCN(C)C(C(N(C)CCOC)n1nnc2ccccc21)n1nnc2ccccc21
Product: COCCN(C)c1cnc2cc(CNC(=O)OC(C)(C)C)c(Br)cn12
Yield: 66 %

Procedure:
The cyclization was carried out as described for Example 6 from (2-amino-5-bromo-pyridin-4-ylmethyl)-carbamic acid tert-butyl ester (600 mg, 2.0 mmol, prepared according to Example 1, Step 1.3) and 1,2-bis-benzotriazol-1-yl-N,N′-bis-(2-methoxy-ethyl)-N,N′-dimethyl-ethane-1,2-diamine (871 mg, 2.0 mmol, prepared according to Example 6, Step 3.1). After the work-up, the crude was purified by Combi-Flash Companion™ (Isco Inc.) column chromatography (SiO2; gradient elution, [hexane/DCM 1:1]/TBME (containing 0.5% of a 7.0 M solution of NH3 in MeOH) 1:0→0:1) to yield the title compound (546 mg, 1.32 mmol, 67%) as a brownish oil. MS: 414 [M−1]+; HPLC: AtRet=1.40; TLC—RF 0.15 (hexane/DCM/TBME (containing 0.5% of a 7.0 M solution of NH3 in MeOH) 1:1:2).
Reaction SMILES: Cl.[NH2:2][C@@H:3]1[CH2:8][CH2:7][C@H:6]([NH:9][C:10]([C:12]2[C:16]3[N:17]=[CH:18][N:19]=[C:20]([C:21]4[C:29]5[O:28][CH2:27][O:26][C:25]=5[CH:24]=[CH:23][C:22]=4[O:30][CH2:31][CH:32]4[CH2:34][CH2:33]4)[C:15]=3[NH:14][C:13]=2[CH3:35])=[O:11])[CH2:5][CH2:4]1.Cl[C:37]([O:39][CH2:40][CH3:41])=[O:38]>>[CH:32]1([CH2:31][O:30][C:22]2[CH:23]=[CH:24][C:25]3[O:26][CH2:27][O:28][C:29]=3[C:21]=2[C:20]2[C:15]3[NH:14][C:13]([CH3:35])=[C:12]([C:10]([NH:9][C@@H:6]4[CH2:7][CH2:8][C@H:3]([NH:2][C:37](=[O:38])[O:39][CH2:40][CH3:41])[CH2:4][CH2:5]4)=[O:11])[C:16]=3[N:17]=[CH:18][N:19]=2)[CH2:34][CH2:33]1
Reactant: CCOC(=O)Cl
Reactant: Cc1[nH]c2c(-c3c(OCC4CC4)ccc4c3OCO4)ncnc2c1C(=O)N[C@H]1CC[C@@H](N)CC1
Agent: Cl
Product: CCOC(=O)N[C@H]1CC[C@@H](NC(=O)c2c(C)[nH]c3c(-c4c(OCC5CC5)ccc5c4OCO5)ncnc23)CC1

Procedure:
Starting from N-(cis-4-aminocyclohexyl)-4-[5-(cyclopropylmethoxy)-1,3-benzodioxol-4-yl]-6-methyl-5H-pyrrolo[3,2-d]pyrimidine-7-carboxamide hydrochloride (example D.f3) and commercially available ethyl chloroformate the title compound is obtained as colorless solid.
Reaction SMILES: [F:1][C:2]1[CH:30]=[CH:29][CH:28]=[C:27]([F:31])[C:3]=1[O:4][C:5]1[CH:10]=[CH:9][C:8]([C:11]2[C:19]3[C:14](=[N:15][CH:16]=[N:17][C:18]=3[NH2:20])[N:13]([CH2:21][C@H:22]3[CH2:26][CH2:25][CH2:24][NH:23]3)[N:12]=2)=[CH:7][CH:6]=1.[C:32]([CH2:34][C:35](O)=[O:36])#[N:33]>ClCCl>[NH2:20][C:18]1[N:17]=[CH:16][N:15]=[C:14]2[N:13]([CH2:21][C@H:22]3[CH2:26][CH2:25][CH2:24][N:23]3[C:35](=[O:36])[CH2:34][C:32]#[N:33])[N:12]=[C:11]([C:8]3[CH:7]=[CH:6][C:5]([O:4][C:3]4[C:27]([F:31])=[CH:28][CH:29]=[CH:30][C:2]=4[F:1])=[CH:10][CH:9]=3)[C:19]=12
Reactant: N#CCC(=O)O
Reactant: Nc1ncnc2c1c(-c1ccc(Oc3c(F)cccc3F)cc1)nn2C[C@H]1CCCN1
Solvent: ClCCl
Product: N#CCC(=O)N1CCC[C@@H]1Cn1nc(-c2ccc(Oc3c(F)cccc3F)cc2)c2c(N)ncnc21
Temperature: 25 °C
Reaction time: 12 h
Yield: 48.7 %

Procedure:
Into a 100 mL round-bottom flask, was placed a solution of 3-[4-(2,6-difluoro-phenoxy)phenyl]-1-[(2R)-pyrrolidin-2-ylmethyl]-1H-pyrazolo[3,4-d]pyrimidin-4-amine (200 mg, 0.47 mmol, 1.00 equiv) in dichloromethane (10 mL), 2-cyanoacetic acid (121 mg, 1.42 mmol, 3.00 equiv), and 1,1-carbonyldiimidazole (230 mg, 1.42 mmol, 3.00 equiv). The resulting solution was stirred for 12 h at 25° C. and then washed with water and brine. The mixture was dried over anhydrous sodium sulfate and concentrated under vacuum. The residue was loaded onto a silica gel column and eluted with dichloromethane/methanol (50/1) to give 112 mg (48%) of 3-[(2R)-2-([4-amino-3-[4-(2,6-difluorophenoxy)phenyl]-1H-pyrazolo[3,4-d]pyrimidin-1-yl]methyl)pyrrolidin-1-yl]-3-oxopropanenitrile as a white solid.
Reaction SMILES: C(=O)C.[OH:4][C:5]1[CH:10]=[C:9]([O:11][CH3:12])[CH:8]=[CH:7][C:6]=1[C:13](=[O:15])[CH3:14].Br[CH2:17][C:18]([O:20][CH2:21][CH3:22])=[O:19].C(=O)([O-])[O-].[K+].[K+].CN(C)C=O>>[CH2:21]([O:20][C:18](=[O:19])[CH2:17][O:4][C:5]1[CH:10]=[C:9]([O:11][CH3:12])[CH:8]=[CH:7][C:6]=1[C:13](=[O:15])[CH3:14])[CH3:22]
Reactant: CCOC(=O)CBr
Reactant: COc1ccc(C(C)=O)c(O)c1
Agent: CC=O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CCOC(=O)COc1cc(OC)ccc1C(C)=O
Temperature: 90 °C

Procedure:
Into a Round bottom flask was added Ethanone, 1-(2-hydroxy-4-methoxyphenyl)-ethanone (40.01 g, 0.241 mol), ethyl bromoacetate (28.17 mL, 0.2540 mol), potassium carbonate (69.6 g, 0.504 mol), and N,N-Dimethylformamide (200 mL, 2 mol). The reaction was heated at 90° C. for 6 h before cooling to RT overnight. The reaction was poured into ice/water and extracted with ethyl ether (twice). The combined ether extracts were dried, filtered and concentrated. The resulting solid was triturated in hexanes, filtered and dried. The product was used in the next reaction step without further purification.
Reaction SMILES: [Br-].[C:2]([CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][P+](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)([OH:4])=[O:3].[OH:30][CH2:31][CH2:32][CH:33]([CH3:40])[CH2:34][CH2:35][CH2:36][C:37](=O)[CH3:38]>O1CCCC1>[OH:30][CH2:31][CH2:32][CH:33]([CH3:40])[CH2:34][CH2:35][CH2:36][C:37]([CH3:38])=[CH:10][CH2:9][CH2:8][CH2:7][CH2:6][CH2:5][C:2]([OH:4])=[O:3]
Reactant: O=C(O)CCCCCC[P+](c1ccccc1)(c1ccccc1)c1ccccc1
Reactant: CC(=O)CCCC(C)CCO
Agent: [Br-]
Solvent: C1CCOC1
Product: CC(=CCCCCCC(=O)O)CCCC(C)CCO
Yield: 53.4 %

Procedure:
95 g (0.2 mol) of (6-carboxyhexyl)triphenylphosphonium bromide in 600 ml of tetrahydrofuran were added to 48 g (0.42 mol) of potassium t-butylate in 200 ml of tetrahydrofuran. Thereafter, 29 g (0.18 mol) of 8-hydroxy-6-methyl-2-octanone were added. After work up and chromatography 26 g (48%) of 14-hydroxy-8,12-dimethyltetradec-7-enoic acid were obtained having the following characteristics: Z/E=58/42;
Reaction SMILES: [Br:1][C:2]1[CH:10]=[C:9]2[C:5]([C:6]([C:16](=O)[C:17]3[CH:22]=[CH:21][CH:20]=[C:19]([N+:23]([O-:25])=[O:24])[C:18]=3[CH3:26])=[C:7]([C:11](OCC)=[O:12])[NH:8]2)=[CH:4][CH:3]=1.O.[NH2:29][NH2:30]>C(O)C>[Br:1][C:2]1[CH:3]=[CH:4][C:5]2[C:6]3[C:16]([C:17]4[CH:22]=[CH:21][CH:20]=[C:19]([N+:23]([O-:25])=[O:24])[C:18]=4[CH3:26])=[N:30][NH:29][C:11](=[O:12])[C:7]=3[NH:8][C:9]=2[CH:10]=1
Reactant: NN
Reactant: CCOC(=O)c1[nH]c2cc(Br)ccc2c1C(=O)c1cccc([N+](=O)[O-])c1C
Solvent: O
Solvent: CCO
Product: Cc1c(-c2n[nH]c(=O)c3[nH]c4cc(Br)ccc4c23)cccc1[N+](=O)[O-]
Yield: 81.8 %

Procedure:
A solution of ethyl 6-bromo-3-(2-methyl-3-nitrobenzoyl)-1H-indole-2-carboxylate (6.02 g, 13.96 mmol) and hydrazine hydrate (2.446 g, 48.9 mmol) in ethanol (200 mL) was heated at reflux for 16 hr. The mixture was concentrated under vacuum to a volume of approximate 30 mL. The insoluble product (4.56 g, 11.42 mmol, 82% yield) was collected by suction filtration and dried under vacuum at 50° C.
Reaction SMILES: [O:1]=[C:2]1[CH2:9][C:6]([CH3:8])([CH3:7])[CH2:5][C:4]([CH3:10])=[CH:3]1.[Br:11]N1C(=O)CCC1=O.N(C(C)(C)C#N)=NC(C)(C)C#N>C(Cl)(Cl)(Cl)Cl>[CH3:10][C:4]1[CH:5]([Br:11])[C:6]([CH3:8])([CH3:7])[CH2:9][C:2](=[O:1])[CH:3]=1
Reactant: O=C1CCC(=O)N1Br
Reactant: CC1=CC(=O)CC(C)(C)C1
Agent: CC(C)(C#N)N=NC(C)(C)C#N
Solvent: ClC(Cl)(Cl)Cl
Product: CC1=CC(=O)CC(C)(C)C1Br

Procedure:
A mixture of isophorone (13.82 g; 0.1 Mole) and N-bromo-succinimide (17.80 g; 0.1 Mole) in the presence of traces of α,α'-azodiisobutyronitrile was refluxed in 500 ml of CCl4 during 15 minutes. 500 ml of petrol-ether (30°-50° C) were then added to the cool reaction mixture and the succinimide thus precipitated was filtered off. By evaporating the volatile components of the clear filtrate, crude 3,5,5-trimethyl-4-bromo-cyclohex-2-en-1-one was obtained.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([C:8](=[O:12])[N:9]([CH3:11])[CH3:10])[CH:5]=[CH:4][C:3]=1[N:13]([CH3:33])[C:14]([C:16]1[S:32][C:19]2[C:20]3[CH:28]=[CH:27][C:26]([C:29](O)=[O:30])=[CH:25][C:21]=3[O:22][CH2:23][CH2:24][C:18]=2[CH:17]=1)=[O:15].[CH3:34][C:35]([NH2:39])([CH3:38])[CH2:36][NH2:37].CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C>C1COCC1>[NH2:39][C:35]([CH3:38])([CH3:34])[CH2:36][NH:37][C:29]([C:26]1[CH:27]=[CH:28][C:20]2[C:19]3[S:32][C:16]([C:14]([N:13]([C:3]4[CH:4]=[CH:5][C:6]([C:8](=[O:12])[N:9]([CH3:10])[CH3:11])=[CH:7][C:2]=4[Cl:1])[CH3:33])=[O:15])=[CH:17][C:18]=3[CH2:24][CH2:23][O:22][C:21]=2[CH:25]=1)=[O:30]
Reactant: CC(C)(N)CN
Reactant: CN(C)C(=O)c1ccc(N(C)C(=O)c2cc3c(s2)-c2ccc(C(=O)O)cc2OCC3)c(Cl)c1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: C1CCOC1
Product: CN(C)C(=O)c1ccc(N(C)C(=O)c2cc3c(s2)-c2ccc(C(=O)NCC(C)(C)N)cc2OCC3)c(Cl)c1

Procedure:
Following the procedures in Examples 47 and 235, 2-((2-chloro-4-(dimethylcarbamoyl)phenyl)(methyl)carbamoyl)-4,5-dihydrobenzo[b]thieno[2,3-d]oxepine-8-carboxylic acid was reacted with 2-methylpropane-1,2-diamine, HATU and DIPEA in THF to give 340 as a colorless solid after reverse phase HPLC. MS: (ESI+) 555.3
Reaction SMILES: [C:1]1(=[CH:7][C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=2[N+:14]([O-])=O)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1>C(O)(=O)C.[Fe]>[C:1]1(=[CH:7][C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=2[NH2:14])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6]1
Reactant: O=[N+]([O-])c1ccccc1C=C1CCCCC1
Agent: [Fe]
Solvent: CC(=O)O
Product: Nc1ccccc1C=C1CCCCC1

Procedure:
To 1-(cyclohexylidenemethyl)-2-nitrobenzene (1.6 g) in glacial acetic acid (50 mL), at 85° C., was added iron powder (2.07 g). The mixture was refluxed for 15 min. The mixture was cooled and filtered through clay. The filtrate was partitioned between EtOAc and ice water. The ethyl acetate layer was washed well with a saturated NaHCO3 solution, dried (MgSO4), and concentrated in vacuo. The residue was chromatographed on silica gel eluting with hexanes to give 2-(cyclohexylidenemethyl)aniline.
Reaction SMILES: C1CO[C:8]23OCC[O:12][C:3]2([C@:4]2([CH2:27][CH2:26][C@H:25]4[C@@H:15]([CH2:16][C:17](=[C:28]([F:30])[F:29])[CH:18]5[C@:23]4([CH3:24])[CH2:22][CH2:21][CH2:20][CH2:19]5)[C@@H:6]2[CH2:7]3)[CH3:5])O1.C=C1C2[C@](C)(CCC(=[O:50])C2)[C@@H]2[C@H]([C@H]3[C@@](CC2)(C)C(=O)CC3)C1>>[F:29][C:28]([F:30])=[C:17]1[CH:18]2[C@:23]([CH3:24])([CH2:22][CH2:21][C:20](=[O:50])[CH2:19]2)[C@@H:25]2[C@H:15]([C@H:6]3[C@@:4]([CH2:27][CH2:26]2)([CH3:5])[C:3](=[O:12])[CH2:8][CH2:7]3)[CH2:16]1
Reactant: C=C1C[C@@H]2[C@H](CC[C@]3(C)C(=O)CC[C@@H]23)[C@@]2(C)CCC(=O)CC12
Reactant: C[C@]12CCCCC1C(=C(F)F)C[C@@H]1[C@@H]2CC[C@@]2(C)[C@H]1CC13OCCOC12OCCO3
Product: C[C@]12CCC(=O)CC1C(=C(F)F)C[C@@H]1[C@@H]2CC[C@]2(C)C(=O)CC[C@@H]12
Yield: 99 %

Procedure:
The title compound II-ak was prepared in 99% yield from 3,3:17,17-bis(ethylendioxy)-6-difluoromethyleneandrostane by the procedure described above for the preparation of 6-methyleneandrostane-3,17-dione (II-ac, Prepn. 13). The combined organic extracts were washed with H2O, dried over Na2SO4 and evaporated to dryness. 1H-NMR (300 MHz, acetone-d6, ppm from TMS): δ 2.85-0.95 (20H, m), 1.12 (3H, s), 0.88 (3H, s).
Reaction SMILES: [F:1][C:2]([S:5]([C:8]1[CH:13]=[CH:12][C:11]([NH2:14])=[CH:10][CH:9]=1)(=[O:7])=[O:6])([F:4])[F:3].[C:15]1([CH2:25][C:26]([OH:28])=O)[CH:20]=[CH:19][CH:18]=[C:17]([CH2:21][C:22]([OH:24])=O)[CH:16]=1>>[F:1][C:2]([F:4])([F:3])[S:5]([C:8]1[CH:13]=[CH:12][C:11]([NH:14][C:22](=[O:24])[CH2:21][C:17]2[CH:18]=[CH:19][CH:20]=[C:15]([CH2:25][C:26](=[O:28])[NH:14][C:11]3[CH:12]=[CH:13][C:8]([S:5]([C:2]([F:4])([F:1])[F:3])(=[O:7])=[O:6])=[CH:9][CH:10]=3)[CH:16]=2)=[CH:10][CH:9]=1)(=[O:6])=[O:7]
Reactant: O=C(O)Cc1cccc(CC(=O)O)c1
Reactant: Nc1ccc(S(=O)(=O)C(F)(F)F)cc1
Product: O=C(Cc1cccc(CC(=O)Nc2ccc(S(=O)(=O)C(F)(F)F)cc2)c1)Nc1ccc(S(=O)(=O)C(F)(F)F)cc1

Procedure:
Same procedure as example 20 except 4-aminophenyl trifluoromethyl sulfone and 1,3-phenylenediacetic acid were used. 1H NMR (300 MHz, DMSO-d6) δ 10.91 (s, 2H, 2×NH), 8.05 (d, J=9.1 Hz, 4H), 7.99 (d, J=9.1 Hz, 4H), 7.21-7.29 (m, 4H), 3.73 (s, 4H, 2×CH2). MS 609 [M++1].
Reaction SMILES: [NH2:1][C:2]1[C:3]([F:27])=[CH:4][C:5]([F:26])=[C:6]([N:8]2[C:17]3[C:12](=[CH:13][C:14]([N+:19]([O-:21])=[O:20])=[C:15](F)[CH:16]=3)[C:11](=[O:22])[C:10]([C:23]([OH:25])=[O:24])=[CH:9]2)[CH:7]=1.[CH3:28][NH:29][NH2:30].N1C=CC=CC=1>O>[NH2:1][C:2]1[C:3]([F:27])=[CH:4][C:5]([F:26])=[C:6]([N:8]2[C:17]3[C:12](=[CH:13][C:14]([N+:19]([O-:21])=[O:20])=[C:15]([N:29]([CH3:28])[NH2:30])[CH:16]=3)[C:11](=[O:22])[C:10]([C:23]([OH:25])=[O:24])=[CH:9]2)[CH:7]=1
Reactant: Nc1cc(-n2cc(C(=O)O)c(=O)c3cc([N+](=O)[O-])c(F)cc32)c(F)cc1F
Reactant: CNN
Solvent: c1ccncc1
Solvent: O
Product: CN(N)c1cc2c(cc1[N+](=O)[O-])c(=O)c(C(=O)O)cn2-c1cc(N)c(F)cc1F
Temperature: 25 °C
Reaction time: 3 h
Yield: 93.6 %

Procedure:
1-(5-Amino-2,4-difluorophenyl)-7-fluoro-6-nitro-4-oxo-1,4-dihydroquinoline-3-carboxylic acid (60 mg) was added to a mixed liquid of methylhydrazine (32 mg) and pyridine (0.5 ml), and the mixture was stirred at room temperature for 3 hours. Water (5 ml) was added. At this time, the pH of the reaction mixture was about 5. Solids formed were collected by filtration and subjected to azeotropic distillation with ethanol and toluene. Hexane was added to the resultant residue to conduct filtration, thereby obtaining the title compound (60 mg) as a brown powder.
Reaction SMILES: [CH2:1]([N:3]=[C:4]=[O:5])[CH3:2].[NH2:6][CH2:7][C:8]1[C:9]([CH3:53])=[N:10][C:11]([CH3:52])=[CH:12][C:13]=1[O:14][CH2:15][C:16]1[CH:21]=[CH:20][C:19]([C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][C:23]=2[C:28]2[N:29]=[N:30][N:31]([C:33]([C:46]3[CH:51]=[CH:50][CH:49]=[CH:48][CH:47]=3)([C:40]3[CH:45]=[CH:44][CH:43]=[CH:42][CH:41]=3)[C:34]3[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=3)[N:32]=2)=[CH:18][CH:17]=1>ClCCl>[CH3:53][C:9]1[C:8]([CH2:7][NH:6][C:4]([NH:3][CH2:1][CH3:2])=[O:5])=[C:13]([O:14][CH2:15][C:16]2[CH:17]=[CH:18][C:19]([C:22]3[CH:27]=[CH:26][CH:25]=[CH:24][C:23]=3[C:28]3[N:29]=[N:30][N:31]([C:33]([C:40]4[CH:41]=[CH:42][CH:43]=[CH:44][CH:45]=4)([C:46]4[CH:51]=[CH:50][CH:49]=[CH:48][CH:47]=4)[C:34]4[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=4)[N:32]=3)=[CH:20][CH:21]=2)[CH:12]=[C:11]([CH3:52])[N:10]=1
Reactant: CCN=C=O
Reactant: Cc1cc(OCc2ccc(-c3ccccc3-c3nnn(C(c4ccccc4)(c4ccccc4)c4ccccc4)n3)cc2)c(CN)c(C)n1
Solvent: ClCCl
Product: CCNC(=O)NCc1c(OCc2ccc(-c3ccccc3-c3nnn(C(c4ccccc4)(c4ccccc4)c4ccccc4)n3)cc2)cc(C)nc1C
Reaction time: 2 h
Yield: 86.1 %

Procedure:
(Example 51A): A solution of ethyl isocyanate (71 mg) and 3-aminomethyl-2,6-dimethyl-4-[(2'-(2-triphenylmethyl-2H-tetrazol-5-yl)biphenyl-4-yl)methoxy]pyridine (628 mg) in dichloromethane (15 ml) was left to stand for 2 hours. The solvent was removed by evaporation and the residue was purified by flash chromatography, eluting with methanol/dichloromethane (7:93 v/v), to give 2,6-dimethyl-3-(ethylaminocarbonylamino)methyl-4-[(2'-(2-triphenylmethyl-2H-tetrazol-5-yl)biphenyl-4-yl)methoxy]pyridine (602 mg), as a foam: NMR (CDCl3): 1.0(t,3H), 2.5(s,3H), 2.65(s,3H), 3.0-3.1(m,2H), 4.1(br t, 1H), 4.4(d,2H), 4.5(br d, 1H), 5.0(s,2H), 6.6(s,1H), 6.8-7.0(m,6H), 7.1-7.55 (complex m,16H), 7.9(dd,1H).
Reaction SMILES: [CH2:1]([N:8]1[C:16]2[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=2)[C:10]2[CH2:17][CH2:18][NH:19][CH2:20][C:9]1=2)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH3:21][C:22]1[CH:23]=[C:24]([N:28]=[C:29]=[O:30])[CH:25]=[CH:26][CH:27]=1>O1CCOCC1>[CH2:1]([N:8]1[C:16]2[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=2)[C:10]2[CH2:17][CH2:18][N:19]([C:29](=[O:30])[NH:28][C:24]3[CH:25]=[CH:26][CH:27]=[C:22]([CH3:21])[CH:23]=3)[CH2:20][C:9]1=2)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: c1ccc(Cn2c3c(c4ccccc42)CCNC3)cc1
Reactant: Cc1cccc(N=C=O)c1
Solvent: C1COCCO1
Product: Cc1cccc(NC(=O)N2CCc3c(n(Cc4ccccc4)c4ccccc34)C2)c1

Procedure:
A solution of 9-benzyl-1,2,3,4-tetrahydro-9H-pyrido[3,4-b]indole(2.66 g, 10.1 mmol) and 3-methylphenylisocyanate (1.42 ml, 11.0 mmol) was stirred in dioxan (40 ml) at room temperature for 4 hours. Evaporation of the solvent and chromatography on silica gel with ethyl acetate-hexane (2:3) as eluant gave the product. (3.04 g, 76%).
Reaction SMILES: [Br:1][C:2]1[C:6]([N+:7]([O-:9])=[O:8])=[C:5](Br)[N:4]([CH3:11])[N:3]=1.[CH3:12][NH2:13].O>C(O)C>[Br:1][C:2]1[C:6]([N+:7]([O-:9])=[O:8])=[C:5]([NH:13][CH3:12])[N:4]([CH3:11])[N:3]=1
Reactant: Cn1nc(Br)c([N+](=O)[O-])c1Br
Reactant: CN
Solvent: O
Solvent: CCO
Product: CNc1c([N+](=O)[O-])c(Br)nn1C
Yield: 88 %

Procedure:
2 g (7.02 mmoles) of 3,5-dibromo-1-methyl-4-nitropyrazole are heated in 50 ml of a 40-percent solution of methylamine in ethanol for 4 hours at boiling temperature. After cooling, 100 ml water are added to the reaction mixture, the separated product is filtered out and washed with a small amount of water (20 ml). After vacuum drying, 1.45 g (88 percent of theory) of 3-bromo-1-methyl-5-methylamino-4-nitropyrazole are obtained in the form of yellow crystals with a melting point of 185° C.
Reaction SMILES: [CH2:1]([C:8]([N:25]([CH3:27])[CH3:26])([CH2:23][CH3:24])[C:9]([C:11]1[CH:16]=[CH:15][C:14]([N:17]2[CH2:22][CH2:21][O:20][CH2:19][CH2:18]2)=[CH:13][CH:12]=1)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH:28]([Si:30]([O:37][CH2:38][CH3:39])([O:34][CH2:35][CH3:36])[O:31][CH2:32][CH3:33])=[CH2:29]>C1(C)C=CC=CC=1>[CH2:1]([C:8]([N:25]([CH3:27])[CH3:26])([CH2:23][CH3:24])[C:9]([C:11]1[CH:16]=[CH:15][C:14]([N:17]2[CH2:18][CH2:19][O:20][CH2:21][CH2:22]2)=[CH:13][C:12]=1[CH2:29][CH2:28][Si:30]([O:31][CH2:32][CH3:33])([O:34][CH2:35][CH3:36])[O:37][CH2:38][CH3:39])=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: C=C[Si](OCC)(OCC)OCC
Reactant: CCC(Cc1ccccc1)(C(=O)c1ccc(N2CCOCC2)cc1)N(C)C
Solvent: Cc1ccccc1
Product: CCO[Si](CCc1cc(N2CCOCC2)ccc1C(=O)C(CC)(Cc1ccccc1)N(C)C)(OCC)OCC
Yield: 98.8 %

Procedure:
14.6 g (40 mmol) of 2-benzyl-2-dimethylamino-1-(4-morpholinophenyl) -1-butanone, 750 mg (0.8 mmol) of RuH2 (CO) (PPh3)3 and 18.4 ml (88 mmol) of vinyltriethoxysilane were dissolved in 50 ml of toluene and degased using argon. After heating for 29 hours with stirring at reflux, the solvent was distilled off and the product was chromatographed (silica gel, heptane/CH2Cl2 /ethyl acetate). 22 g (100%) of a brown oil were obtained which were purified by boiling in heptane with active charcoal followed by filtration to give a yellow, viscous oil in a quantity of 20.6 g (95%). 1H-NMR (CDCl3): 0.64 ppm (3H, t, Bu-H4, 3JH,H =7.0 Hz); 1.10 ppm (2H, mc, Et-H2); 1.26 ppm (9H, t, CH3 of Si(OEt)3, 3JH,H =6.8 Hz); 1.88 ppm (2H, mc, Bu-H3); 2.36 ppm (6H, s, N(CH3)2); 2.72 ppm (2H, mc, Et-H1); 3.15 ppm (2H, mc, CH2 -Ph); 3.24 ppm (4H, mc, morpholine-N-CH2); 3.85 ppm (4H, mc, morpholine-o--CH2); 3.88 ppm (6H, q, SiOCH2); 6.60 ppm (1H, dd, Ph-H5, 3JH5,H6 =8.6 Hz, 4 JH3,H5 =2.6 Hz); 6.77 ppm (1H, d, Ph-H3); 7.12-7.28 ppm (5H, m, Ph'-H); 8.38 ppm (1H, d, Ph-H6).
Reaction SMILES: ClC1C=CC(CN2C3C(=CC([O:16][CH2:17][C:18]4[N:23]=[C:22]5[C:24]([Cl:28])=[C:25]([Cl:27])[S:26][C:21]5=[CH:20][CH:19]=4)=CC=3)C(CC(C)(C)C)=C2CC(C)(C)C(O)=O)=CC=1.[H-].C([Al+]CC(C)C)C(C)C>C1COCC1>[Cl:27][C:25]1[S:26][C:21]2[C:22](=[N:23][C:18]([CH2:17][OH:16])=[CH:19][CH:20]=2)[C:24]=1[Cl:28]
Reactant: CC(C)(C)Cc1c(CC(C)(C)C(=O)O)n(Cc2ccc(Cl)cc2)c2ccc(OCc3ccc4sc(Cl)c(Cl)c4n3)cc12
Agent: CC(C)C[Al+]CC(C)C
Agent: [H-]
Solvent: C1CCOC1
Product: OCc1ccc2sc(Cl)c(Cl)c2n1
Reaction time: 0.17 h
Yield: 78 %

Procedure:
To a -30° C. solution of the methyl ester (60 g, 230 mmol) of Step 1 in 2.2 L of THF was added diisobutylaluminum hydride (570 mmol) over 1 hr. The reaction mixture was brought to -25° C. and allowed to proceed for another 10 min. The reaction was quenched with an aqueous solution of sodium potassium tartrate (1750 mL of 30% w/v) and extracted with EtOAc. The organic phase was dried over Na2SO4, and the solvent evaporated. The crude product was swished in CH2Cl2 (100 mL) to give 42 g (78%) of the title alcohol as a light yellow solid.
Reaction SMILES: C([O:5][C:6](=[O:17])/[CH:7]=[CH:8]/[C:9]1[CH:14]=[CH:13][C:12]([CH:15]=[O:16])=[CH:11][N:10]=1)(C)(C)C.C(O)(C(F)(F)F)=O>C(Cl)Cl>[CH:15]([C:12]1[CH:13]=[CH:14][C:9](/[CH:8]=[CH:7]/[C:6]([OH:17])=[O:5])=[N:10][CH:11]=1)=[O:16]
Reactant: CC(C)(C)OC(=O)/C=C/c1ccc(C=O)cn1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: O=Cc1ccc(/C=C/C(=O)O)nc1
Temperature: 25 °C
Reaction time: 6 h
Yield: 143.5 %

Procedure:
A mixture of (E)-3-(5-formyl-pyridin-2-yl)-acrylic acid tert-butyl ester (described in Example 11 STEP A-D, 250 mg, 1.07 mmol) and TFA (1 ml) in DCM (4 ml) was stirred at room temperature for 6 h. The solvent was then removed in vacuo and the solid was triturated with Et2O to give 272 mg of (E)-3-(5-formyl-pyridin-2-yl)-acrylic acid as its trifluoroacetate salt.
Reaction SMILES: Br[CH2:2][CH2:3][CH2:4][N:5]1[C:17]2[CH:16]=[C:15]([C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=3)[C:14]3[C:24](=[O:28])[NH:25][C:26](=[O:27])[C:13]=3[C:12]=2[C:11]2[CH:10]=[C:9]([OH:29])[CH:8]=[CH:7][C:6]1=2.[NH:30]1[CH2:35][CH2:34][O:33][CH2:32][CH2:31]1>>[OH:29][C:9]1[CH:8]=[CH:7][C:6]2[N:5]([CH2:4][CH2:3][CH2:2][N:30]3[CH2:35][CH2:34][O:33][CH2:32][CH2:31]3)[C:17]3[CH:16]=[C:15]([C:18]4[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=4)[C:14]4[C:24](=[O:28])[NH:25][C:26](=[O:27])[C:13]=4[C:12]=3[C:11]=2[CH:10]=1
Reactant: C1COCCN1
Reactant: O=C1NC(=O)c2c1c(-c1ccccc1)cc1c2c2cc(O)ccc2n1CCCBr
Product: O=C1NC(=O)c2c1c(-c1ccccc1)cc1c2c2cc(O)ccc2n1CCCN1CCOCC1
Yield: 72 %

Procedure:
Bromide (204) (0.01 g, 0.22 mmol) prepared as described in example 173 was reacted with morpholine according to the procedure described in example 179 to give amine (210) (73 mg, 72%) as a yellow powder, mp 252–255° C. 1H NMR δ [(CD3)2SO] 11.04 (br s, 1H), 9.33 (s, 1H), 8.41 (d, J=2.5 Hz, 1H), 7.81 (s, 1H), 7.62 (m, 2H), 7.57 (d, J=8.9 Hz, 1H), 7.47 (m, 3H), 7.12 (dd, J=8.9, 2.5 Hz, 1H), 4.51 (t, J=6.3 Hz, 2H), 3.38 (t, J=4.0 Hz, 4H), 2.18 (br s, 4H), 2.14 (t, J=6.3 Hz, 2H), 1.93 (m, 2H). Found: C, 71.11; H, 5.46; N, 9.29. C27H25N3O4 requires: C, 71.19; H, 5.53; N, 9.22.