Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]1([NH:7]/[N:8]=[CH:9]/[C:10]([O:12][CH2:13][CH3:14])=[O:11])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[N+]([C:18]([CH3:45])=[CH:19][C:20]1[CH:32]=[CH:31][C:23]([C:24]([O:26][C:27]([CH3:30])([CH3:29])[CH3:28])=[O:25])=[CH:22][C:21]=1[C:33]([N:35]1[CH2:44][CH2:43][C:42]2[C:37](=[CH:38][CH:39]=[CH:40][CH:41]=2)[CH2:36]1)=[O:34])([O-])=O>>[C:27]([O:26][C:24]([C:23]1[CH:31]=[CH:32][C:20]([C:19]2[C:9]([C:10]([O:12][CH2:13][CH3:14])=[O:11])=[N:8][N:7]([C:1]3[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=3)[C:18]=2[CH3:45])=[C:21]([C:33]([N:35]2[CH2:44][CH2:43][C:42]3[C:37](=[CH:38][CH:39]=[CH:40][CH:41]=3)[CH2:36]2)=[O:34])[CH:22]=1)=[O:25])([CH3:28])([CH3:29])[CH3:30]
Reactant: CCOC(=O)/C=N/Nc1ccccc1
Reactant: CC(=Cc1ccc(C(=O)OC(C)(C)C)cc1C(=O)N1CCc2ccccc2C1)[N+](=O)[O-]
Product: CCOC(=O)c1nn(-c2ccccc2)c(C)c1-c1ccc(C(=O)OC(C)(C)C)cc1C(=O)N1CCc2ccccc2C1
Yield: 67.5 %

Procedure:
Following a procedure analogous to that for the synthesis of Intermediate 224E, (E)-ethyl 2-(2-phenylhydrazono)acetate (22 mg, 0.11 mmol) and tert-butyl 4-(2-nitroprop-1-enyl)-3-(1,2,3,4-tetrahydroisoquinoline-2-carbonyl)benzoate (48 mg, 0.11 mmol) were converted to the title compound (42 mg, 65%) as a colorless oil. 1H NMR (CDCl3, 1:1 mixture of amide rotamers) δ 8.10 (dd, J=8, 2 Hz, 1H), 8.06-8.04 (m, 1H), 7.49-7.40 (m, 6H), 7.21-6.81 (m, 4H), 5.02-4.96 (m, 1H), 4.49-4.28 (m, 3H), 4.17-4.03 (m, 1H), 3.54-3.33 (m, 1H), 2.82-2.43 (m, 2H), 2.19 (s, 3H), 1.61 (s, 9H), 1.28 (t, J=8 Hz, 1.5H), 1.23 (t, J=8 Hz, 1.5H); MS(ESI+) m/z 566.3 (M+H)+.
Reaction SMILES: [Si]([O:8][CH2:9][CH2:10][CH:11]1[CH2:16][CH2:15][N:14]([C:17]2[CH:18]=[CH:19][C:20]([NH:23][C:24]3[N:25]=[CH:26][C:27]4[C:32]5[CH:33]=[CH:34][N:35]=[C:36]([F:37])[C:31]=5[N:30]([CH:38]5[CH2:42][CH2:41][CH2:40][CH2:39]5)[C:28]=4[N:29]=3)=[N:21][CH:22]=2)[CH2:13][CH2:12]1)(C(C)(C)C)(C)C.[F-].C([N+](CCCC)(CCCC)CCCC)CCC>C1COCC1>[CH:38]1([N:30]2[C:28]3[N:29]=[C:24]([NH:23][C:20]4[N:21]=[CH:22][C:17]([N:14]5[CH2:13][CH2:12][CH:11]([CH2:10][CH2:9][OH:8])[CH2:16][CH2:15]5)=[CH:18][CH:19]=4)[N:25]=[CH:26][C:27]=3[C:32]3[CH:33]=[CH:34][N:35]=[C:36]([F:37])[C:31]2=3)[CH2:42][CH2:41][CH2:40][CH2:39]1
Reactant: CC(C)(C)[Si](C)(C)OCCC1CCN(c2ccc(Nc3ncc4c5ccnc(F)c5n(C5CCCC5)c4n3)nc2)CC1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: C1CCOC1
Product: OCCC1CCN(c2ccc(Nc3ncc4c5ccnc(F)c5n(C5CCCC5)c4n3)nc2)CC1
Temperature: 25 °C
Reaction time: 4 h
Yield: 70 %

Procedure:
Compound 294 (78 mg, 132 mop was dissolved in dry THF (3 mL). Tetrabutylammonium fluoride, 1.0M in THF (1.00 mL, 1.00 mmol) was added and the reaction stirred at room temperature for 4 hours. The solvent was removed in vacuo and silica gel chromatography (gradient elution hexanes+2.5%/0-100% ethyl acetate+2.5% TEA) afforded compound 291 as a beige solid (44 mg, 70%). 1H NMR (500 MHz, DMSO-d6) δ 11.60-11.85 (m, 2 H) 9.49 (s, 2 H) 8.19-8.24 (m, 2 H) 8.13-8.19 (m, 2 H) 8.05-8.10 (m, 2 H) 7.96-8.04 (m, 2 H) 7.61-7.71 (m, 2 H) 5.48 (s, 1 H) 3.64 (d, J=11.98 Hz, 2 H) 3.44 (t, J=6.48 Hz, 2 H) 2.71-2.90 (m, 2 H) 2.20 (br. s., 2 H) 2.09 (br. s., 2 H) 2.00 (br. s., 2 H) 1.66-1.82 (m, 4 H) 1.52-1.66 (m, 1 H) 1.37 (d, J=6.60 Hz, 2 H) 1.28 (none, 2 H) ppm.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([N:9]2[C:18](=[O:19])[C:17]3[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=3)[N:11]=[C:10]2[CH:20]([NH:22][C:23]2[N:31]=[CH:30][N:29]=[C:28]3[C:24]=2[N:25]=[CH:26][NH:27]3)[CH3:21])[CH:5]=[C:6]([F:8])[CH:7]=1.[NH2:32]C1N=C2C(NC=N2)=C(Br)N=1.BrC1N=CN=C2C=1NC=N2.BrC1C2C(NC(C3N(C4C=CC=C(F)C=4)C(=O)C4C(=CC=CC=4C)N=3)C)=NC=NC=2NC=1>>[NH2:32][C:30]1[N:29]=[C:28]2[C:24]([N:25]=[CH:26][NH:27]2)=[C:23]([NH:22][CH:20]([C:10]2[N:9]([C:4]3[CH:3]=[C:2]([F:1])[CH:7]=[C:6]([F:8])[CH:5]=3)[C:18](=[O:19])[C:17]3[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=3)[N:11]=2)[CH3:21])[N:31]=1
Reactant: Nc1nc(Br)c2[nH]cnc2n1
Reactant: CC(Nc1ncnc2[nH]cnc12)c1nc2ccccc2c(=O)n1-c1cc(F)cc(F)c1
Agent: Brc1ncnc2nc[nH]c12
Agent: Cc1cccc2nc(C(C)Nc3ncnc4[nH]cc(Br)c34)n(-c3cccc(F)c3)c(=O)c12
Product: CC(Nc1nc(N)nc2[nH]cnc12)c1nc2ccccc2c(=O)n1-c1cc(F)cc(F)c1

Procedure:
Compound 99 was prepared using the general procedure described above with respect to compound 95, but 2-amino-6-bromopurine was substituted for 6-bromopurine in step D. ESI-MS m/z 435 (MH+). Compound 96 is shown below.
Reaction SMILES: C[O:2][C:3]1[CH:4]=[C:5]2[C:9](=[CH:10][C:11]=1[O:12][CH3:13])[C:8](=[O:14])[CH2:7][CH2:6]2.[Cl-].[Li+].CN(C=O)C>O>[OH:2][C:3]1[CH:4]=[C:5]2[C:9](=[CH:10][C:11]=1[O:12][CH3:13])[C:8](=[O:14])[CH2:7][CH2:6]2
Reactant: COc1cc2c(cc1OC)C(=O)CC2
Agent: [Cl-]
Agent: [Li+]
Solvent: O
Solvent: CN(C)C=O
Product: COc1cc2c(cc1O)CCC2=O
Temperature: 160 °C
Reaction time: 60 h

Procedure:
A mixture of 5,6 dimethoxyindan-1-one (25.0 g, 0.13 mole), lithium chloride (20.0 g, 0.47 mole) and DMF (200.0 mL) was stirred at 160° C. for 60 hrs. Water (400.0 mL) was added and the mixture washed with ethyl acetate. The aqueous layer was acidified with 2N HCl and extracted with ethyl acetate (2×300.0 mL). The organic layer was washed with brine and the solvent removed in vacuo. The crude material was purified on a silica gel column using DCM/MeOH(97/3) as the eluent. The solvent was removed in vacuo to yield 5-hydroxy-6-methoxy-indan-1-one (Intermediate H) as a light yellow solid. MS m/z 179 (M+H)+: 179 m/z. The title compound (Intermediate H) is a known compound and may also be prepared by demethylation of 5,6 dimethyoxyindan-1-one using KCN/DMSO at 100° C. (J. M. Saa et al., J. Org. Chem. 1992, 57, 589).
Reaction SMILES: [Cl:1][C:2]1[C:6]([Cl:7])=[C:5]([CH3:8])[NH:4][C:3]=1[C:9]([NH:11][C@@H:12]1[CH2:17][CH2:16][N:15]([C:18]2[S:19][C:20]([C:25]([O:27][CH2:28][CH3:29])=[O:26])=[C:21]([CH2:23]O)[N:22]=2)[CH2:14][C@@H:13]1[O:30][CH3:31])=[O:10].C1(P([N:46]=[N+:47]=[N-:48])(C2C=CC=CC=2)=O)C=CC=CC=1.C1CCN2C(=NCCC2)CC1>C1(C)C=CC=CC=1>[N:46]([CH2:23][C:21]1[N:22]=[C:18]([N:15]2[CH2:16][CH2:17][C@@H:12]([NH:11][C:9]([C:3]3[NH:4][C:5]([CH3:8])=[C:6]([Cl:7])[C:2]=3[Cl:1])=[O:10])[C@@H:13]([O:30][CH3:31])[CH2:14]2)[S:19][C:20]=1[C:25]([O:27][CH2:28][CH3:29])=[O:26])=[N+:47]=[N-:48]
Reactant: [N-]=[N+]=NP(=O)(c1ccccc1)c1ccccc1
Reactant: CCOC(=O)c1sc(N2CC[C@@H](NC(=O)c3[nH]c(C)c(Cl)c3Cl)[C@@H](OC)C2)nc1CO
Solvent: C1CCC2=NCCCN2CC1
Solvent: Cc1ccccc1
Product: CCOC(=O)c1sc(N2CC[C@@H](NC(=O)c3[nH]c(C)c(Cl)c3Cl)[C@@H](OC)C2)nc1CN=[N+]=[N-]
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
To a suspension of ethyl 2-((3S,4R)-4-{[(3,4-dichloro-5-methyl-1H-pyrrol-2-yl)carbonyl]amino}-3-methoxypiperidin-1-yl)-4-(hydroxymethyl)-1,3-thiazole-5-carboxylate (0.10 g, 0.2 mmol, Example 143) in anhydrous toluene was added diphenylphosphorylazide (0.053 mL, 0.24 mmol). The reaction was cooled to 0 deg and DBU was added slowly. After stirring at 0 deg for 30 min the reaction was warmed to room temperature and stirred overnight. The biphasic reaction mixture was washed with water (×3), 1NHCl (×1), brine (×1), dried with MgSO4 and concentrated (0.048 g). MS (ES) M+H: 516 for C19H23Cl2N7O4S.
Reaction SMILES: Cl.Cl.[NH2:3][C@@H:4]1[C:10](=[O:11])[N:9]([CH2:12][C:13]2[C:22]3[C:17](=[CH:18][CH:19]=[CH:20][CH:21]=3)[N:16]=[CH:15][C:14]=2[CH:23]2[CH2:25][CH2:24]2)[C:8]2[CH:26]=[CH:27][C:28]([C:30]#[N:31])=[CH:29][C:7]=2[NH:6][C@H:5]1[CH3:32].[C:33]([N:40]([CH3:46])[C@H:41]([C:43](O)=[O:44])[CH3:42])([O:35][C:36]([CH3:39])([CH3:38])[CH3:37])=[O:34].C(N(CC)C(C)C)(C)C.CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F>CN(C=O)C.CCOC(C)=O>[C:30]([C:28]1[CH:27]=[CH:26][C:8]2[N:9]([CH2:12][C:13]3[C:22]4[C:17](=[CH:18][CH:19]=[CH:20][CH:21]=4)[N:16]=[CH:15][C:14]=3[CH:23]3[CH2:25][CH2:24]3)[C:10](=[O:11])[C@@H:4]([NH:3][C:43](=[O:44])[C@@H:41]([N:40]([CH3:46])[C:33](=[O:34])[O:35][C:36]([CH3:37])([CH3:39])[CH3:38])[CH3:42])[C@H:5]([CH3:32])[NH:6][C:7]=2[CH:29]=1)#[N:31]
Reactant: C[C@@H]1Nc2cc(C#N)ccc2N(Cc2c(C3CC3)cnc3ccccc23)C(=O)[C@H]1N
Reactant: C[C@@H](C(=O)O)N(C)C(=O)OC(C)(C)C
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: C[C@@H]1Nc2cc(C#N)ccc2N(Cc2c(C3CC3)cnc3ccccc23)C(=O)[C@H]1NC(=O)[C@H](C)N(C)C(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 1 h
Yield: 92.2 %

Procedure:
To a rt solution of (3S,4S)-3-amino-1-((3-cyclopropylquinolin-4-yl)methyl)-4-methyl-2-oxo-2,3,4,5-tetrahydro-1H-benzo[b][1,4]diazepine-7-carbonitrile dihydrochloride (126 mg, 268 μmol) in DMF (893 μl) was added Boc-N-methyl-L-alanine (59.9 mg, 295 μmol), N,N-diisopropylethylamine (232 μl, 1.34 mmol), and HBTU (112 mg, 295 μmol). The reaction was stirred at rt for 1 h, then diluted with EtOAc, washed with H2O, sat. aq. NaHCO3, and sat. aq. NaCl, dried over Na2SO4, filtered, and concentrated. The crude material was purified by flash chromatography to provide tert-butyl(S)-1-((3S,4S)-7-cyano-1-((3-cyclopropylquinolin-4-yl)methyl)-4-methyl-2-oxo-2,3,4,5-tetrahydro-1H-benzo[b][1,4]diazepin-3-ylamino)-1-oxopropan-2-yl(methyl)carbamate (144 mg, 92%) as a white solid. MS m/z 583 (MH)+.
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:14]=[CH:13][C:12](/[CH:15]=[CH:16]/[N+:17]([O-:19])=[O:18])=[CH:11][CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(O)(=O)C.CS(C)=O.[BH4-].[Na+]>O>[CH2:1]([O:8][C:9]1[CH:14]=[CH:13][C:12]([CH2:15][CH2:16][N+:17]([O-:19])=[O:18])=[CH:11][CH:10]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: O=[N+]([O-])/C=C/c1ccc(OCc2ccccc2)cc1
Agent: [BH4-]
Agent: [Na+]
Solvent: CC(=O)O
Solvent: CS(C)=O
Solvent: O
Product: O=[N+]([O-])CCc1ccc(OCc2ccccc2)cc1
Temperature: 25 °C
Reaction time: 0.67 h
Yield: 70.8 %

Procedure:
To a mixture of 1-benzyloxy-4-((E)-2-nitro-vinyl)-benzene (1.0 g, 3.9 mmol) described in Manufacturing Example 1-1-1, acetic acid (1 mL) and dimethyl sulfoxide (17 mL) was added sodium borohydride (250 mg, 6.3 mmol) at room temperature while cooling appropriately, and the reaction mixture was stirred for 40 minutes at room temperature. Water was added to the reaction mixture. The reaction mixture was partitioned into ethyl acetate and water. The organic layer was washed with water and saturated aqueous sodium chloride, and dried over anhydrous magnesium sulfate, and the solvent was evaporated under a reduced pressure. The residue was purified by NH silica gel column chromatography (ethyl acetate:heptane=1:3) to obtain the title compound (710 mg, 70%).
Reaction SMILES: [CH2:1]([C@H:8]1[CH2:13][C@H:12]([NH:14][CH2:15][C:16]2[C:25]3[C:20](=[CH:21][CH:22]=[CH:23][CH:24]=3)[N:19]=[CH:18][CH:17]=2)[CH2:11][CH2:10][N:9]1[C:26](=[O:35])[C:27]1[CH:32]=[C:31]([Cl:33])[CH:30]=[C:29]([Cl:34])[CH:28]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH:36]1([N:42]=[C:43]=[O:44])[CH2:41][CH2:40][CH2:39][CH2:38][CH2:37]1>>[CH2:1]([C@@H:8]1[CH2:13][C@@H:12]([N:14]([CH2:15][C:16]2[C:25]3[C:20](=[CH:21][CH:22]=[CH:23][CH:24]=3)[N:19]=[CH:18][CH:17]=2)[C:43](=[O:44])[NH:42][CH:36]2[CH2:41][CH2:40][CH2:39][CH2:38][CH2:37]2)[CH2:11][CH2:10][N:9]1[C:26](=[O:35])[C:27]1[CH:28]=[C:29]([Cl:34])[CH:30]=[C:31]([Cl:33])[CH:32]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=C(c1cc(Cl)cc(Cl)c1)N1CC[C@@H](NCc2ccnc3ccccc23)C[C@@H]1Cc1ccccc1
Reactant: O=C=NC1CCCCC1
Product: O=C(NC1CCCCC1)N(Cc1ccnc2ccccc12)[C@H]1CCN(C(=O)c2cc(Cl)cc(Cl)c2)[C@H](Cc2ccccc2)C1

Procedure:
200 mg (0.396 mmol) of (2S*,4R*)-2-benzyl-1-(3,5-dichlorobenzoyl)-N-(4-quinolylmethyl)-4-piperidinamine are reacted with 66 μl (0.5 15 mmol) of cyclohexyl isocyanate in analogy to Example 16a. The title compound ##STR79## is obtained as white crystals (165 mg, 66% ) of melting point 229° C. (decomposition). TLC: methylene chloride/methanol/conc. ammonia (700:50:1) Rf =0.44, FD-MS: M+ =628, 630.
Reaction SMILES: [CH3:1][C:2]1[C:3]([C:11]#N)=[N:4][CH:5]=[C:6]([CH3:10])[C:7]=1[O:8][CH3:9].CC1C(CN)=NC=C(C)C=1[O:20]C.N([O-])=O.[Na+]>>[CH3:1][C:2]1[C:3]([CH2:11][OH:20])=[N:4][CH:5]=[C:6]([CH3:10])[C:7]=1[O:8][CH3:9]
Reactant: COc1c(C)cnc(C#N)c1C
Reactant: COc1c(C)cnc(CN)c1C
Agent: O=N[O-]
Agent: [Na+]
Product: COc1c(C)cnc(CO)c1C

Procedure:
L. Pharma's U.S. Pat. No. 5,066,810 teaches a process to manufacture ##STR6## where X is OH or Cl by catalytic hydrogenation of 3,5-dimethyl-4-methoxy-2-cyanopyridine as depicted below ##STR7## in the presence of an inert diluent, the resulting 3,5-dimethyl-4-methoxy-2-aminomethylpyridine as depicted below ##STR8## which is then reacted with sodium nitrite in aqueous-acidic solution to give 3,5-dimethyl-4-methoxy-2-hydroxymethylpyridine and ultimately reacting the latter with thionyl chloride to give 3,5-dimethyl-4-methoxy-2-chloromethylpyridine.
Reaction SMILES: [CH:1]1([CH2:4][NH:5][C:6](=[O:17])[NH:7][C:8]2[CH:16]=[CH:15][C:11]([C:12]([OH:14])=O)=[CH:10][CH:9]=2)[CH2:3][CH2:2]1.[F:18][C:19]([F:42])([F:41])[C:20]([C:26]1[CH:31]=[CH:30][C:29]([CH2:32][N:33]2[CH2:38][CH2:37][CH:36]([NH:39][CH3:40])[CH2:35][CH2:34]2)=[CH:28][CH:27]=1)([OH:25])[C:21]([F:24])([F:23])[F:22].C(N(CC)CC)C.Cl.C(N=C=NCCCN(C)C)C>ClCCl.ClCCl.CO>[CH:1]1([CH2:4][NH:5][C:6](=[O:17])[NH:7][C:8]2[CH:9]=[CH:10][C:11]([C:12]([N:39]([CH:36]3[CH2:37][CH2:38][N:33]([CH2:32][C:29]4[CH:28]=[CH:27][C:26]([C:20]([OH:25])([C:19]([F:42])([F:18])[F:41])[C:21]([F:22])([F:23])[F:24])=[CH:31][CH:30]=4)[CH2:34][CH2:35]3)[CH3:40])=[O:14])=[CH:15][CH:16]=2)[CH2:2][CH2:3]1
Reactant: CNC1CCN(Cc2ccc(C(O)(C(F)(F)F)C(F)(F)F)cc2)CC1
Reactant: O=C(NCC1CC1)Nc1ccc(C(=O)O)cc1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Solvent: CO
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CN(C(=O)c1ccc(NC(=O)NCC2CC2)cc1)C1CCN(Cc2ccc(C(O)(C(F)(F)F)C(F)(F)F)cc2)CC1
Reaction time: 24 h
Yield: 77.9 %

Procedure:
To a mixture of 4-(3-(cyclopropylmethyl)ureido)benzoic acid (0.810 mmol, 190 mg), 1,1,1,3,3,3-hexafluoro-2-(4-((4-(methylamino)piperidin-1-yl)methyl)phenyl)propan-2-ol (0.810 mmol, 300 mg) and triethylamine (1.944 mmol, 0.271 mL, 197 mg) in dichloromethane (50 mL) was added N1-((ethylimino)methylene)-N3,N3-dimethylpropane-1,3-diamine hydrochloride (0.972 mmol, 186 mg). The reaction was stirred for 24 hours. Chromatography on silica eluting with dichloromethane to dichloromethane/methanol (10%) gave the title compound (370 mg).
Reaction SMILES: [CH2:1]([NH:4][C:5]([NH2:7])=[O:6])[CH:2]=[CH2:3].[C:8](OCC)(=[O:13])[CH2:9][C:10]([CH3:12])=O.[OH-].[K+]>C(O)C.Cl.CO>[CH2:1]([N:4]1[C:8](=[O:13])[CH:9]=[C:10]([CH3:12])[NH:7][C:5]1=[O:6])[CH:2]=[CH2:3]
Reactant: C=CCNC(N)=O
Reactant: CCOC(=O)CC(C)=O
Agent: Cl
Agent: [K+]
Agent: [OH-]
Solvent: CO
Solvent: CCO
Product: C=CCn1c(=O)cc(C)[nH]c1=O
Reaction time: 288 h

Procedure:
To allylurea (25 g, 0.25 mol) in ethanol (10 mL) was added ethyl acetoacetate (31.86 mL, 0.25 mol) and 10 drops conc. HCl. After 12 days at room temperature, concentration gave an oil which was dissolved in MeOH. KOH (22.5 g, 0.34 mol) was added and the solution refluxed for 1 hour. After neutralization, the resulting solid 1 was collected. Yield 2.7 g (7%). NMR (CDCl3) δ: 2.16 (3H, s), 4.52 (2H, d), 5.18 (1H, d), 5.23 (1H, d), 5.60 (1H, s), 5.82-5.93 (1H, m), 10.3 (1H, s).
Reaction SMILES: I[CH2:2][CH2:3][CH3:4].[CH2:5]([O:9][C:10]1[N:18]=[C:17]2[C:13]([N:14]=[C:15]([O:27]C)[N:16]2[CH2:19][CH2:20][CH:21]2[CH2:26][CH2:25][NH:24][CH2:23][CH2:22]2)=[C:12]([NH2:29])[N:11]=1)[CH2:6][CH2:7][CH3:8].CCN(C(C)C)C(C)C.CS(C)=O>CN(C=O)C>[NH2:29][C:12]1[N:11]=[C:10]([O:9][CH2:5][CH2:6][CH2:7][CH3:8])[N:18]=[C:17]2[C:13]=1[NH:14][C:15](=[O:27])[N:16]2[CH2:19][CH2:20][CH:21]1[CH2:26][CH2:25][N:24]([CH2:2][CH2:3][CH3:4])[CH2:23][CH2:22]1
Reactant: CCCI
Reactant: CCCCOc1nc(N)c2nc(OC)n(CCC3CCNCC3)c2n1
Solvent: CS(C)=O
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: CCCCOc1nc(N)c2[nH]c(=O)n(CCC3CCN(CCC)CC3)c2n1
Temperature: 50 °C
Reaction time: 18 h
Yield: 13.5 %

Procedure:
1-Iodopropane (0.1 mmol) was weighed into a vial and an aliquot (0.4 ml, 0.12 mmol) of a solution of 2-(butyloxy)-8-(methyloxy)-9-[2-(4-piperidinyl)ethyl]-9H-purin-6-amine (0.418 g mg, 1.2 mmol) suspended in DMF (4.8 ml) was added to each tube. DIPEA 40 μl, 0.229 mmol) was added finally to each tube, the tube was heated at 50° C. for 18 hours. An additional portion of 1-iodopropane (15 μl) and DIPEA (20 μl) was added to each tube and heating continued for a further 18 hours. DMSO (200 uL) was added and the solution and the mixture purified by Mass Directed AutoPrep (Method A). The solvent was evaporated in vacuo using the Genevac. The residue was redissolved in 4M HCl/dioxane (0.2 ml), capped and stood at room temperature for 18 hours. The solvent was dried under a stream of nitrogen in the Radleys blowdown apparatus. The material was redissolved in methanol (0.5 ml), and applied to top of 0.1 g aminopropyl SPE (preconditioned with methanol, 1.5 ml). The cartridge was eluted with methanol (1.5 ml) and the solvent was removed to give the title compound (5.1 mg).
Reaction SMILES: [Cl:1][C:2]1[C:6]([C:7]#[N:8])=[C:5](Cl)[S:4][N:3]=1.[C:10]([O:14][C:15]([NH:17][C:18]1[CH:23]=[CH:22][C:21](B(O)O)=[CH:20][CH:19]=1)=[O:16])([CH3:13])([CH3:12])[CH3:11].[F-].[K+].C1OCCOCCOCCOCCOCCOC1>C1(C)C=CC=CC=1.O.CCOC(C)=O.C([O-])(=O)C.[Pd+2].C([O-])(=O)C>[Cl:1][C:2]1[C:6]([C:7]#[N:8])=[C:5]([C:21]2[CH:20]=[CH:19][C:18]([NH:17][C:15](=[O:16])[O:14][C:10]([CH3:12])([CH3:11])[CH3:13])=[CH:23][CH:22]=2)[S:4][N:3]=1
Reactant: N#Cc1c(Cl)nsc1Cl
Reactant: CC(C)(C)OC(=O)Nc1ccc(B(O)O)cc1
Agent: [Pd+2]
Agent: C1COCCOCCOCCOCCOCCO1
Agent: CC(=O)[O-]
Solvent: Cc1ccccc1
Solvent: O
Solvent: CCOC(C)=O
Product: CC(C)(C)OC(=O)Nc1ccc(-c2snc(Cl)c2C#N)cc1
Temperature: 25 °C
Yield: 84.9 %

Procedure:
A mixture of 3,5-dichloroisothiazole-4-carbonitrile (5.37 g, 30 mmol), 4-(tertbutoxycarbonylamino)phenylboronic acid (14.22 g, 60 mmol), potassium fluoride (6.11 g, 105 mmol), 18-crown-6 (3.96 g, 15 mmol), and palladium acetate (337 mg, 1.5 mmol) in toluene (250 ml) was heated at reflux for 6 hours. The reaction was cooled to RT and the mixture was diluted with water and EtOAc. Layers were separated and the aqueous layer was extracted with EtOAc×3. The combined organics was washed with brine and dried with MgSO4, filtered, and concentrated. The crude product was purified by flash silica gel column eluted with 5-15% EtOAc in hexanes to obtain the above compound as a white crystalline solid (8.55 g, 85%). NMR and MS spectra are consistent with the structure. HPLC purity 97.6%.
Reaction SMILES: C[O:2][C:3](=O)[CH2:4][C:5]1[CH:10]=[CH:9][CH:8]=[C:7]([O:11][CH:12]([CH3:14])[CH3:13])[CH:6]=1.[H-].[Al+3].[Li+].[H-].[H-].[H-].O.O.O.O.O.O.O.O.O.O.S([O-])([O-])(=O)=O.[Na+].[Na+]>>[CH:12]([O:11][C:7]1[CH:6]=[C:5]([CH2:4][CH2:3][OH:2])[CH:10]=[CH:9][CH:8]=1)([CH3:14])[CH3:13]
Reactant: COC(=O)Cc1cccc(OC(C)C)c1
Agent: O=S(=O)([O-])[O-]
Agent: [Al+3]
Agent: [H-]
Solvent: O
Product: CC(C)Oc1cccc(CCO)c1
Reaction time: 0.42 h

Procedure:
To a solution of methyl(3-isopropoxyphenyl)acetate (280 mg) in tetrahedron (5 ml), 52 mg of lithium aluminum hydride was added under ice-cooling, and the reaction solution was stirred at the same temperature for 25 minutes. To the reaction solution was added sodium sulfate decahydrate, and the mixture was stirred at room temperature for 2 hours. The reaction solution was filtered, and then the filtrate was distilled off under reduced pressure. The residue obtained was purified by silica gel column chromatography (eluent: ethyl acetate/hexane (0:100-50:50) to afford the title compound as a colorless oil.
Reaction SMILES: [NH2:1][C:2]1[C:3]([C:7]2[NH:23][C:10]3=[CH:11][C:12]4[C:13]([CH3:22])([CH3:21])[C:14](=[O:20])[N:15]([CH2:18][CH3:19])[C:16]=4[CH:17]=[C:9]3[N:8]=2)=[N:4][NH:5][CH:6]=1.[C:24]1([CH:30]([CH2:34][CH3:35])[C:31](Cl)=[O:32])[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1>>[CH2:18]([N:15]1[C:16]2[CH:17]=[C:9]3[N:8]=[C:7]([C:3]4[C:2]([NH:1][C:31](=[O:32])[CH:30]([C:24]5[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=5)[CH2:34][CH3:35])=[CH:6][NH:5][N:4]=4)[NH:23][C:10]3=[CH:11][C:12]=2[C:13]([CH3:22])([CH3:21])[C:14]1=[O:20])[CH3:19]
Reactant: CCC(C(=O)Cl)c1ccccc1
Reactant: CCN1C(=O)C(C)(C)c2cc3[nH]c(-c4n[nH]cc4N)nc3cc21
Product: CCC(C(=O)Nc1c[nH]nc1-c1nc2cc3c(cc2[nH]1)C(C)(C)C(=O)N3CC)c1ccccc1

Procedure:
N-[3-(5-Ethyl-7,7-dimethyl-6-oxo-1,5,6,7-tetrahydro-imidazo[4,5-f]indol-2-yl)-1H-pyrazol-4-yl]-2-phenyl-butyramide was prepared using 2-(4-amino-1H-pyrazol-3-yl)-5-ethyl-7,7-dimethyl-5,7-dihydro-1H-imidazo[4,5-f]indol-6-one (250 mg, 0.81 mmol) and 2-phenylbutyryl chloride (148 μl, 0.88 mmol). The title compound was obtained as yellow powder (69 mg, 19%).
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[C:4]([CH2:9][CH2:10][C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][N:12]=2)[C:3]=1[OH:17].[S:18]1[C:22]([C:23](Cl)=O)=[CH:21][C:20]2[CH:26]=[CH:27][CH:28]=[CH:29][C:19]1=2.CS(O)(=O)=O.O>O1CCOCC1.C1(C)C=CC=CC=1>[S:18]1[C:22]([C:23]2[O:17][C:3]3[C:4]([CH2:9][CH2:10][C:11]4[CH:16]=[CH:15][CH:14]=[CH:13][N:12]=4)=[CH:5][C:6]([Cl:8])=[CH:7][C:2]=3[N:1]=2)=[CH:21][C:20]2[CH:26]=[CH:27][CH:28]=[CH:29][C:19]1=2
Reactant: Nc1cc(Cl)cc(CCc2ccccn2)c1O
Reactant: O=C(Cl)c1cc2ccccc2s1
Agent: CS(=O)(=O)O
Solvent: O
Solvent: Cc1ccccc1
Solvent: C1COCCO1
Product: Clc1cc(CCc2ccccn2)c2oc(-c3cc4ccccc4s3)nc2c1
Yield: 41 %

Procedure:
This compound is prepared from 2-amino-4-chloro-6-[2-(pyridin-2-yl)ethyl]-phenol and benzo[b]thiophene-2-carbonyl chloride using method A with 1,4-dioxan as solvent to give the crude amide (73%). This is treated with methanesulphonic acid in toluene at reflux with azeotropic removal of water to give the title compound, (41%) as a white crystalline solid m.p.=183-184° C. TLC (SiO2, EtOAc:hexanes 1:1, Rf=0.56). CI Mass Spectrum (methane) m/z=391 [M+H]+.
Reaction SMILES: [Br:1][C:2]1[C:3]([F:12])=[C:4]2[C:10]([NH2:11])=[CH:9][NH:8][C:5]2=[N:6][CH:7]=1.[C:13](O)(=[O:20])[C:14]1[CH:19]=[CH:18][CH:17]=[N:16][CH:15]=1.C1N(P(Cl)(N2C(=O)OCC2)=O)C(=O)OC1.C(N(CC)CC)C.C([O-])([O-])=O.[Na+].[Na+]>CN(C=O)C.[Li+].[OH-]>[Br:1][C:2]1[C:3]([F:12])=[C:4]2[C:10]([NH:11][C:13](=[O:20])[C:14]3[CH:19]=[CH:18][CH:17]=[N:16][CH:15]=3)=[CH:9][NH:8][C:5]2=[N:6][CH:7]=1
Reactant: O=C(O)c1cccnc1
Reactant: Nc1c[nH]c2ncc(Br)c(F)c12
Agent: O=C([O-])[O-]
Agent: O=C1OCCN1P(=O)(Cl)N1CCOC1=O
Agent: [Li+]
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: O=C(Nc1c[nH]c2ncc(Br)c(F)c12)c1cccnc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 55 %

Procedure:
5-Bromo-4-fluoro-1H-pyrrolo[2,3-b]pyridin-3-amine (0.044 g, 0.19 mmol), nicotinic acid (0.0283 g, 0.230 mmol), and BOP-Cl (0.0584 g, 0.230 mmol) were placed in DMF (3 mL) at room temperature. Triethylamine (0.133 mL, 0.956 mmol) was then added, and the reaction was stirred for 1 hour at room temperature. The reaction was then diluted with 3M LiOH (aq., 0.5 mL) and stirred for 10 minutes. The reaction was then poured into saturated Na2CO3, extracted into DCM, and the organic fractions were combined, dried, filtered and concentrated to give a crude residue. The crude residue was triturated with 1:2 MeOH/DCM to give N-(5-bromo-4-fluoro-1H-pyrrolo[2,3-b]pyridin-3-yl)nicotinamide (0.035 g, 54.6% yield) as a solid.
Reaction SMILES: Cl[CH2:2][CH2:3][CH2:4][CH:5]1[O:9][CH2:8][CH2:7][O:6]1.[C-]#[N:11].[K+]>CS(C)=O.O>[O:6]1[CH2:7][CH2:8][O:9][CH:5]1[CH2:4][CH2:3][C:2]#[N:11]
Reactant: [C-]#N
Reactant: ClCCCC1OCCO1
Agent: [K+]
Solvent: CS(C)=O
Solvent: O
Product: N#CCCC1OCCO1
Temperature: 100 °C
Yield: 43.7 %

Procedure:
A mixture of 2-(3-chloropropyl)-1,3-dioxolane (5.7 g, 37.8 mmol) and potassium cyanide (3.8 g, 58.4 mmol) in dimethylsulfoxide (12 mL) was heated at 100° C. for 48 hours. The reaction mixture was diluted with water (80 mL) and extracted with ether (3×60 mL). The combined ether layer was washed with water (3×60 mL), dried (magnesium sulfate), concentrated in vacuo and purified by silica gel chromatography (ethyl acetate in hexane, 1:2) to afford the title compound (2.1 g, 40%) as a pale yellow liquid;
Reaction SMILES: [CH3:1][S:2]([CH2:5][C:6](=O)[CH3:7])(=[O:4])=[O:3].O.[NH2:10][NH2:11]>C(O)C>[CH3:1][S:2]([CH2:5][C:6](=[N:10][NH2:11])[CH3:7])(=[O:4])=[O:3]
Reactant: NN
Reactant: CC(=O)CS(C)(=O)=O
Solvent: CCO
Solvent: O
Product: CC(CS(C)(=O)=O)=NN
Temperature: 0 °C
Reaction time: 23.5 h

Procedure:
To a 200 ml volume four-necked flask, 1-methylsulfonyl-2-propanone (7-2-1) (10.21 g) and ethanol (50 ml) were added under a nitrogen atmosphere and cooled to 0° C. Hydrazine monohydrate (14-b) (3.9 ml) was added dropwise. After stirring at room temperature for 23.5 hours, the mixture was concentrated under reduced pressure to give 10.69 g of (1-methylsulfonyl-2-propylidene)hydrazine (5-2-2).