Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[C:9]2[C:5]([C:6]([C:11]([N:13]3[CH2:18][CH2:17][CH:16]([N:19]4[C:23]5[CH:24]=[CH:25][CH:26]=[CH:27][C:22]=5[NH:21][C:20]4=[O:28])[CH2:15][CH2:14]3)=[O:12])=[CH:7][NH:8]2)=[CH:4][CH:3]=1.[H-].[Na+].Cl[CH2:32][C:33]#[N:34]>CN(C=O)C>[Cl:1][C:2]1[CH:10]=[C:9]2[C:5]([C:6]([C:11]([N:13]3[CH2:18][CH2:17][CH:16]([N:19]4[C:23]5[CH:24]=[CH:25][CH:26]=[CH:27][C:22]=5[NH:21][C:20]4=[O:28])[CH2:15][CH2:14]3)=[O:12])=[CH:7][N:8]2[CH2:32][C:33]#[N:34])=[CH:4][CH:3]=1
Reactant: O=C(c1c[nH]c2cc(Cl)ccc12)N1CCC(n2c(=O)[nH]c3ccccc32)CC1
Reactant: N#CCCl
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: N#CCn1cc(C(=O)N2CCC(n3c(=O)[nH]c4ccccc43)CC2)c2ccc(Cl)cc21
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 13.7 %

Procedure:
To a stirred solution of 40 mg (0.101 mmol) of 1-[1-(6-Chloro-1H-indole-3-carbonyl)-piperidin-4-yl]-1,3-dihydro-benzoimidazol-2-one (the preparation of which has been described in example 18) in 5 ml DMF was added 4.2 mg (0.105 mmol) NaH (60% in oil). The mixture was stirred at RT for 30 min. and then 8.3 mg (0.11 mmol) of chloro-acetonitrile was added. The mixture was stirred an additional hour and then poured onto water and extracted with ethyl acetate. The combined organic phases were dried over Na2SO4 and concentrated in vacuo. Preparative HPLC afforded 6 mg (14%) of {6-Chloro-3-[4-(2-oxo-2,3-dihydro-benzoimidazol-1-yl)-piperidine-1-carbonyl]-indol-1-yl}-acetonitrile as a white solid.
Reaction SMILES: [C:1]1([C:7]2[N:12]=[C:11]3[CH2:13][CH2:14][CH2:15][NH:16][C:10]3=[N:9][C:8]=2[C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.Br[CH2:24][CH2:25][CH2:26][CH2:27][C:28]([O:30]CC)=[O:29]>>[C:1]1([C:7]2[N:12]=[C:11]3[CH2:13][CH2:14][CH2:15][N:16]([CH2:24][CH2:25][CH2:26][CH2:27][C:28]([OH:30])=[O:29])[C:10]3=[N:9][C:8]=2[C:17]2[CH:18]=[CH:19][CH:20]=[CH:21][CH:22]=2)[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: c1ccc(-c2nc3c(nc2-c2ccccc2)NCCC3)cc1
Reactant: CCOC(=O)CCCCBr
Product: O=C(O)CCCCN1CCCc2nc(-c3ccccc3)c(-c3ccccc3)nc21

Procedure:
This compound was prepared from 2,3-diphenyl-5,6,7,8-tetrahydropyrido[3,2-b]pyrazine (Example 4.1 step 1) and ethyl 5-bromovalerate analogously to 7-(6,7-diphenyl-3,4-dihydro-1,8-naphthyridin-1(2H)-yl)heptanoic acid (Example 1 step 1 and step 2. Step 1 was carried out using microwave radiation).
Reaction SMILES: [Cl:1][C:2]([Cl:9])([Cl:8])[C:3]([N:5]=[C:6]=[O:7])=[O:4].[OH:10][CH2:11][C:12]1[CH2:13][S:14][C@@H:15]2[C@H:35]([NH:36][C:37](=[O:44])[CH2:38][C:39]3[S:40][CH:41]=[CH:42][CH:43]=3)[C:34](=[O:45])[N:16]2[C:17]=1[C:18]([O:20][CH:21]([C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1)[C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1)=[O:19]>CC(C)=O>[S:40]1[CH:41]=[CH:42][CH:43]=[C:39]1[CH2:38][C:37]([NH:36][C@@H:35]1[C:34](=[O:45])[N:16]2[C:17]([C:18]([O:20][CH:21]([C:28]3[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=3)[C:22]3[CH:23]=[CH:24][CH:25]=[CH:26][CH:27]=3)=[O:19])=[C:12]([CH2:11][O:10][C:6](=[O:7])[NH:5][C:3](=[O:4])[C:2]([Cl:9])([Cl:8])[Cl:1])[CH2:13][S:14][C@H:15]12)=[O:44]
Reactant: O=C=NC(=O)C(Cl)(Cl)Cl
Reactant: O=C(Cc1cccs1)N[C@@H]1C(=O)N2C(C(=O)OC(c3ccccc3)c3ccccc3)=C(CO)CS[C@H]12
Solvent: CC(C)=O
Product: O=C(Cc1cccs1)N[C@@H]1C(=O)N2C(C(=O)OC(c3ccccc3)c3ccccc3)=C(COC(=O)NC(=O)C(Cl)(Cl)Cl)CS[C@H]12
Reaction time: 1 h
Yield: 93.4 %

Procedure:
Trichloroacetyl isocyanate (13.2 g, 70 mmole) was added to a stirred suspension of diphenylmethyl (6R,7R)-3-hydroxymethyl-7-(thien-2-ylacetamido)ceph-3-em-4 carboxylate (26.0 g, 50 mmole) in anhydrous acetone (600 ml) at 20°. The solid soon dissolved and after the mixture had been stirred at 20° for 1 hour it was chilled for 1 hour and the resulting solid was filtered off and washed with ether to give the title compound (33.1 g, 93%), m.p. 183° to 184°; [α]D21 + 24° (c 0.95 in DMSO); λinf.EtOH 235 nm (ε 14,500) and λinf.EtOH 256 nm (ε 8,820).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[N:10]=[C:9]([CH2:11][OH:12])[N:8]([CH3:13])[C:5]2=[N:6][CH:7]=1.O[C:15]1[CH:47]=[CH:46][C:18]([CH2:19][CH:20]2[S:24][C:23](=[O:25])[N:22]([C:26]([C:39]3[CH:44]=[CH:43][CH:42]=[CH:41][CH:40]=3)([C:33]3[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=3)[C:27]3[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=3)[C:21]2=[O:45])=[CH:17][CH:16]=1.C(P(CCCC)CCCC)CCC.N(C(N1CCCCC1)=O)=NC(N1CCCCC1)=O>C1(C)C=CC=CC=1>[Cl:1][C:2]1[CH:3]=[C:4]2[N:10]=[C:9]([CH2:11][O:12][C:15]3[CH:47]=[CH:46][C:18]([CH2:19][CH:20]4[S:24][C:23](=[O:25])[N:22]([C:26]([C:39]5[CH:44]=[CH:43][CH:42]=[CH:41][CH:40]=5)([C:33]5[CH:34]=[CH:35][CH:36]=[CH:37][CH:38]=5)[C:27]5[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=5)[C:21]4=[O:45])=[CH:17][CH:16]=3)[N:8]([CH3:13])[C:5]2=[N:6][CH:7]=1
Reactant: Cn1c(CO)nc2cc(Cl)cnc21
Reactant: O=C1SC(Cc2ccc(O)cc2)C(=O)N1C(c1ccccc1)(c1ccccc1)c1ccccc1
Agent: CCCCP(CCCC)CCCC
Agent: O=C(N=NC(=O)N1CCCCC1)N1CCCCC1
Solvent: Cc1ccccc1
Product: Cn1c(COc2ccc(CC3SC(=O)N(C(c4ccccc4)(c4ccccc4)c4ccccc4)C3=O)cc2)nc2cc(Cl)cnc21

Procedure:
A procedure similar to that described in Preparation 4 was repeated, except that 0.52 g of 6-chloro-2-hydroxymethyl-3-methylimidazo[5,4-b]pyridine (prepared as described in Preparation 64), 1.23 g of 5-(4-hydroxy-benzyl)-3-triphenylmethylthiazolidine-2,4-dione, 0.66 ml of tributylphosphine, 0.67 g of 1,1'-(azodicarbonyl)di-piperidine and 20 ml of toluene were used, to give the title compound as a crude product. This crude product was purified by column chromatography through silica gel, using a 1:1 by volume mixture of hexane and ethyl acetate as the eluent, to give 1.51 g of the title compound, melting at 82°-84° C. (softening).
Reaction SMILES: C[O:2][C:3](=[O:41])[C@@H:4]([NH:9][C:10]([C:12]1[N:13]=[C:14]([CH2:35][CH:36]2[CH2:40][CH2:39][CH2:38][CH2:37]2)[C:15]2[C:20]([CH:21]=1)=[CH:19][CH:18]=[C:17]([C:22](=[O:34])[NH:23][CH:24]1[CH2:29][CH2:28][CH:27]([C:30]([CH3:33])([CH3:32])[CH3:31])[CH2:26][CH2:25]1)[CH:16]=2)=[O:11])[C:5]([CH3:8])([CH3:7])[CH3:6].[Li+].[OH-]>C1COCC1.CO>[C:30]([CH:27]1[CH2:28][CH2:29][CH:24]([NH:23][C:22]([C:17]2[CH:16]=[C:15]3[C:20]([CH:21]=[C:12]([C:10]([NH:9][C@@H:4]([C:5]([CH3:8])([CH3:7])[CH3:6])[C:3]([OH:41])=[O:2])=[O:11])[N:13]=[C:14]3[CH2:35][CH:36]3[CH2:37][CH2:38][CH2:39][CH2:40]3)=[CH:19][CH:18]=2)=[O:34])[CH2:25][CH2:26]1)([CH3:33])([CH3:32])[CH3:31]
Reactant: COC(=O)[C@@H](NC(=O)c1cc2ccc(C(=O)NC3CCC(C(C)(C)C)CC3)cc2c(CC2CCCC2)n1)C(C)(C)C
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CO
Product: CC(C)(C)C1CCC(NC(=O)c2ccc3cc(C(=O)N[C@H](C(=O)O)C(C)(C)C)nc(CC4CCCC4)c3c2)CC1
Yield: 85.3 %

Procedure:
A solution of (2S)-{[7-(4-tert-butyl-cyclohexylcarbamoyl)-1-cyclopentylmethyl-isoquinoline-3-carbonyl]-amino}3,3-dimethylbutyric acid methyl ester (18 mg, 0.032 mmol) in THF:MeOH(4:1, 2.0 mL) was treated with a solution of LiOH (2.0 M, 0.240 mL) by the general procedure I to give 15 mg of 2(S)-{[7-(4-tert-butyl-cyclohexylcarbamoyl)-1-cyclopentylmethyl-isoquinoline-3-carbonyl]amino}3,3-dimethylbutyric acid as a white solid.
Reaction SMILES: C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[CH3:20][O:21][C:22](=[O:34])[C:23]1[CH:32]=[C:31]([OH:33])[CH:30]=[C:25]([C:26]([O:28][CH3:29])=[O:27])[CH:24]=1.CCOC(/N=N/C(OCC)=O)=O.[Cl:47][C:48]1[CH:53]=[C:52]([Cl:54])[CH:51]=[CH:50][C:49]=1[CH2:55][CH2:56]O>C1COCC1>[CH3:29][O:28][C:26](=[O:27])[C:25]1[CH:30]=[C:31]([O:33][CH2:56][CH2:55][C:49]2[CH:50]=[CH:51][C:52]([Cl:54])=[CH:53][C:48]=2[Cl:47])[CH:32]=[C:23]([C:22]([O:21][CH3:20])=[O:34])[CH:24]=1
Reactant: OCCc1ccc(Cl)cc1Cl
Reactant: COC(=O)c1cc(O)cc(C(=O)OC)c1
Agent: CCOC(=O)/N=N/C(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: COC(=O)c1cc(OCCc2ccc(Cl)cc2Cl)cc(C(=O)OC)c1
Temperature: 25 °C
Reaction time: 0.75 h

Procedure:
1.75 g of triphenylphosphine and 1 g of 5-Hydroxy-isophthalic acid dimethyl ester were dissolved in 17 ml of anhydrous THF. The solution was cooled to 0–10° C. and a solution of 1 ml DEAD in 1 ml anhydrous THF was added dropwise over 20 min. The reaction was warmed to RT and stirred for 45 min. A solution of 11.3 ml 2-(2,4-Dichlorophenyl)-ethanol in 1 ml anhydrous THF was added with cooling. The reaction was stirred at RT for 16 h, then the solvents were removed under reduced pressure. The residue was treated with n-heptane:ethyl acetate/1:1. The filtrate was dried under reduced pressure and the product was purified by silica gel chromatography, eluting with n-heptane:ethyl acetate/4:1 to n-heptane:ethyl acetate/3:1.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:18])[CH2:5][C:6]([CH3:17])([CH3:16])[C:7]([C:9]1[CH:14]=[CH:13][C:12]([OH:15])=[CH:11][CH:10]=1)=[O:8])[CH3:2].Br[CH2:20][CH2:21][CH2:22][Cl:23].C([O-])([O-])=O.[K+].[K+]>C(#N)C>[CH2:1]([O:3][C:4](=[O:18])[CH2:5][C:6]([CH3:17])([CH3:16])[C:7]([C:9]1[CH:10]=[CH:11][C:12]([O:15][CH2:20][CH2:21][CH2:22][Cl:23])=[CH:13][CH:14]=1)=[O:8])[CH3:2]
Reactant: CCOC(=O)CC(C)(C)C(=O)c1ccc(O)cc1
Reactant: ClCCCBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: CCOC(=O)CC(C)(C)C(=O)c1ccc(OCCCCl)cc1

Procedure:
The product from step 2 (1.0 g, 4.2 mmol), 1-bromo-3-chloropropane (1.0 g, 8 mmol) and K2CO3 in acetonitrile (20 mL) was heated to reflux for 24 h. The reaction was cooled, filtered, concentrated to an oil and purified by ISCO silica gel chromatography (10% EtOAc/hexanes) to give 0.7 g.
Reaction SMILES: [CH:1]1([CH2:4][O:5][C:6]2[CH:25]=[CH:24][C:9]([C:10]([O:12][CH2:13][C:14]([O:16]CC3C=CC=CC=3)=[O:15])=[O:11])=[CH:8][C:7]=2[O:26][S:27]([CH3:30])(=[O:29])=[O:28])[CH2:3][CH2:2]1>CO.CCOC(C)=O.[Pd]>[CH:1]1([CH2:4][O:5][C:6]2[CH:25]=[CH:24][C:9]([C:10]([O:12][CH2:13][C:14]([OH:16])=[O:15])=[O:11])=[CH:8][C:7]=2[O:26][S:27]([CH3:30])(=[O:29])=[O:28])[CH2:3][CH2:2]1
Reactant: CS(=O)(=O)Oc1cc(C(=O)OCC(=O)OCc2ccccc2)ccc1OCC1CC1
Agent: [Pd]
Solvent: CCOC(C)=O
Solvent: CO
Product: CS(=O)(=O)Oc1cc(C(=O)OCC(=O)O)ccc1OCC1CC1
Reaction time: 2 h
Yield: 94.3 %

Procedure:
A mixture of 2-(benzyloxy)-2-oxoethyl 4-(cyclopropylmethoxy)-3-(methylsulfonyloxy)benzoate (0.238 g, 0.548 mmol) and 10% w/w Pd/C (0.030 g, 0.028 mmol) in MeOH (17 ml) and EtOAc (3 ml) was hydrogenated at 20 psi for 2 hours. The catalyst was filtered off, and the solvent was removed under vacuum affording 2-(4-(cyclopropylmethoxy)-3-(methylsulfonyloxy)benzoyloxy)acetic acid (0.178 g, 0.517 mmol, 94% yield, MS/ESI+ 344.9 [MH]+). The product was used without any further purification.
Reaction SMILES: Cl.C([NH:4][C:5]1[S:6][CH:7]=[C:8]([C:10](=[N:26][O:27][CH2:28][CH2:29][CH2:30][NH:31]C(OC(C)(C)C)=O)[C:11]([NH:13][CH:14]2[C:24](=[O:25])[N:16]3[C:17]([C:21]([OH:23])=[O:22])=[CH:18][CH2:19][S:20][C@H:15]23)=[O:12])[N:9]=1)=O>CO>[NH2:4][C:5]1[S:6][CH:7]=[C:8]([C:10](=[N:26][O:27][CH2:28][CH2:29][CH2:30][NH2:31])[C:11]([NH:13][CH:14]2[C:24](=[O:25])[N:16]3[C:17]([C:21]([OH:23])=[O:22])=[CH:18][CH2:19][S:20][C@H:15]23)=[O:12])[N:9]=1
Reactant: CC(C)(C)OC(=O)NCCCON=C(C(=O)NC1C(=O)N2C(C(=O)O)=CCS[C@H]12)c1csc(NC=O)n1
Agent: Cl
Solvent: CO
Product: NCCCON=C(C(=O)NC1C(=O)N2C(C(=O)O)=CCS[C@H]12)c1csc(N)n1
Temperature: 25 °C
Reaction time: 3.5 h
Yield: 61.9 %

Procedure:
Conc.hydrochloric acid (1.6 ml.) was added to a solution of 7-[2-(2-formamidothiazol-4-yl)-2-(3-tert-butoxycarbonylaminopropoxyimino)acetamido]-3-cephem-4-carboxylic acid (syn isomer, 2.1 g.) in methanol (30 ml.), and stirred at room temperature for 3.5 hours. After evaporating the solvent in vacuo, methanol was added to the residue and the mixture was evaporated in vacuo again. The residue was dissolved in water (30 ml.) and adjusted to pH 3.5 with a sodium bicarbonate saturated aqueous solution under ice-cooling. The solution was subjected to column chromatography on macroporous non-ionic adsorption resin "Diaion HP-20" (trademark, manufactured by Mitsubishi Chemical Industries Ltd.) and eluted with 30% aqueous isopropyl alcohol. The eluate was concentrated in vacuo and lyophilized to give 7-[2-(2-aminothiazol-4-yl)-2-(3-aminopropoxyimino)-acetamido]-3-cephem-4-carboxylic acid (syn isomer, 1.0 g.).
Reaction SMILES: C([C:4]1[CH:9]=[C:8]([O:10][C:11]2[CH:16]=[CH:15][C:14]([NH:17][C:18](=[O:25])[CH2:19][C:20]([O:22][CH2:23][CH3:24])=[O:21])=[CH:13][C:12]=2[F:26])[CH:7]=[CH:6][N:5]=1)(=O)N.C[N:28](C=O)C>>[NH2:28][C:4]1[CH:9]=[C:8]([O:10][C:11]2[CH:16]=[CH:15][C:14]([NH:17][C:18](=[O:25])[CH2:19][C:20]([O:22][CH2:23][CH3:24])=[O:21])=[CH:13][C:12]=2[F:26])[CH:7]=[CH:6][N:5]=1
Reactant: CN(C)C=O
Reactant: CCOC(=O)CC(=O)Nc1ccc(Oc2ccnc(C(N)=O)c2)c(F)c1
Product: CCOC(=O)CC(=O)Nc1ccc(Oc2ccnc(N)c2)c(F)c1
Yield: 86 %

Procedure:
Prepared in a manner similar to that which is described in Step A of Example 91. Ethyl 3-(4-(2-carbamoylpyridin-4-yloxy)-3-fluorophenylamino)-3-oxopropanoate (900 mg, 2.5 mmol) in DMF (10.0 mL) was converted to ethyl 3-(4-(2-aminopyridin-4-yloxy)-3-fluorophenylamino)-3-oxopropanoate (710 mg, 86% yield). MS (ESI+) m/z 334.26 (M+H)+.
Reaction SMILES: [CH3:1][N:2]1[CH2:6][CH2:5][CH2:4][C@H:3]1[CH2:7][OH:8].CC(C)([O-])C.[K+].[CH2:15]([N:19]1[CH:23]=[C:22]([C:24]([CH3:27])([CH3:26])[CH3:25])[S:21]/[C:20]/1=[N:28]\[C:29](=[O:41])[C:30]1[CH:35]=[C:34]([C:36]([F:39])([F:38])[F:37])[CH:33]=[CH:32][C:31]=1F)[CH2:16][CH2:17][CH3:18]>C1COCC1>[CH2:15]([N:19]1[CH:23]=[C:22]([C:24]([CH3:26])([CH3:27])[CH3:25])[S:21]/[C:20]/1=[N:28]\[C:29](=[O:41])[C:30]1[CH:35]=[C:34]([C:36]([F:39])([F:37])[F:38])[CH:33]=[CH:32][C:31]=1[O:8][CH2:7][C@@H:3]1[CH2:4][CH2:5][CH2:6][N:2]1[CH3:1])[CH2:16][CH2:17][CH3:18]
Reactant: CCCCn1cc(C(C)(C)C)s/c1=N\C(=O)c1cc(C(F)(F)F)ccc1F
Reactant: CN1CCC[C@H]1CO
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: C1CCOC1
Product: CCCCn1cc(C(C)(C)C)s/c1=N\C(=O)c1cc(C(F)(F)F)ccc1OC[C@@H]1CCCN1C
Reaction time: 0.25 h
Yield: 74.8 %

Procedure:
A solution of (S)-(1-methylpyrrolidin-2-yl)methanol (109 mg, 0.94 mmol) in THF (5 mL) was treated with 1 M solution of potassium t-butoxide (0.95 mL, 0.944 mmol) and stirred for 15 min. A solution of Example 9B (190 mg, 0.47 mmol) was added to the reaction mixture and stirred for 6 hours. The reaction mixture was quenched with saturated NH4Cl solution, concentrated in vacuo, partitioned between EtOAc and brine, dried (MgSO4), filtered, and concentrated. The residue was purified using an Analogix® Intelliflash280™ (SiO2, 0-15% methanol in dichloromethane) to afford the title compound (175 mg, 75% yield). 1H NMR (300 MHz, DMSO-d6) δ ppm 0.91 (t, J=7.3 Hz, 3H), 1.17-1.42 (m, 11H), 1.49-1.83 (m, 5H), 1.82-2.03 (m, 1H), 2.17 (q, J=8.7 Hz, 1H), 2.32 (s, 3H), 2.54-2.67 (m, 1H), 2.83-3.01 (m, 1H), 3.92-4.10 (m, 2H), 4.14 (t, J=7.3 Hz, 2H), 7.28 (d, J=8.8 Hz, 1H), 7.32 (s, 1H), 7.72 (dd, J=9.0, 2.2 Hz, 1H), 7.95 (d, J=2.0 Hz, 1H). MS (DCI/NH3) m/z 498 (M+H)+. Anal. calcd for C25H34F3N3O2S: C, 60.34; H, 6.99; N, 8.44. Found: C, 60.27; H, 7.09; N, 8.40.
Reaction SMILES: [NH2:1][C:2]1[C:3]([CH3:24])=[C:4]([CH:21]=[CH:22][CH:23]=1)[O:5][C:6]1[CH:7]=[CH:8][C:9]2[N:10]([CH:12]=[C:13]([NH:15][C:16]([CH:18]3[CH2:20][CH2:19]3)=[O:17])[N:14]=2)[N:11]=1.[CH3:25][N:26]1[C:30]([C:31](Cl)=[O:32])=[CH:29][C:28]([CH3:34])=[N:27]1.C(N(CC)CC)C>O1CCCC1>[CH:18]1([C:16]([NH:15][C:13]2[N:14]=[C:9]3[CH:8]=[CH:7][C:6]([O:5][C:4]4[C:3]([CH3:24])=[C:2]([NH:1][C:31]([C:30]5[N:26]([CH3:25])[N:27]=[C:28]([CH3:34])[CH:29]=5)=[O:32])[CH:23]=[CH:22][CH:21]=4)=[N:11][N:10]3[CH:12]=2)=[O:17])[CH2:20][CH2:19]1
Reactant: Cc1c(N)cccc1Oc1ccc2nc(NC(=O)C3CC3)cn2n1
Reactant: Cc1cc(C(=O)Cl)n(C)n1
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: Cc1cc(C(=O)Nc2cccc(Oc3ccc4nc(NC(=O)C5CC5)cn4n3)c2C)n(C)n1
Yield: 81.5 %

Procedure:
Using N-[6-(3-amino-2-methylphenoxy)imidazo[1,2-b]pyridazin-2-yl]cyclopropanecarboxamide (130 mg, 0.402 mmol), 1,3-dimethyl-1H-pyrazole-5-carbonyl chloride (83 mg, 0.523 mmol), triethylamine (122 mg, 1.21 mmol) and tetrahydrofuran (5.0 mL) as starting materials and in the same manner as in Example 96, the title compound (146 mg, 82%) was obtained as a white powder.
Reaction SMILES: [Si]([O:8][C@@H:9]1[C@@:36]2([CH3:37])[C:13](=[CH:14][CH:15]=[C:16]3[C@@H:35]2[CH2:34][CH2:33][C@@:32]2([CH3:38])[C@H:17]3[CH2:18][CH:19]=[C:20]2[C@@H:21]([S:23][CH2:24][CH2:25][C:26]([CH2:30][CH3:31])([OH:29])[CH2:27][CH3:28])[CH3:22])[CH2:12][C@@H:11]([OH:39])[CH2:10]1)(C(C)(C)C)(C)C.[F-].C([N+](CCCC)(CCCC)CCCC)CCC>O1CCCC1>[OH:8][C@@H:9]1[C@@:36]2([CH3:37])[C:13](=[CH:14][CH:15]=[C:16]3[C@@H:35]2[CH2:34][CH2:33][C@@:32]2([CH3:38])[C@H:17]3[CH2:18][CH:19]=[C:20]2[C@@H:21]([S:23][CH2:24][CH2:25][C:26]([CH2:30][CH3:31])([OH:29])[CH2:27][CH3:28])[CH3:22])[CH2:12][C@@H:11]([OH:39])[CH2:10]1
Reactant: CCC(O)(CC)CCS[C@@H](C)C1=CC[C@H]2C3=CC=C4C[C@@H](O)C[C@H](O[Si](C)(C)C(C)(C)C)[C@]4(C)[C@H]3CC[C@]12C
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: C1CCOC1
Product: CCC(O)(CC)CCS[C@@H](C)C1=CC[C@H]2C3=CC=C4C[C@@H](O)C[C@H](O)[C@]4(C)[C@H]3CC[C@]12C
Yield: 64 %

Procedure:
Under the same conditions as in Example 9, the crude 1α-(tert-butyldimethylsilyloxy)-3β-hydroxy-20(S)-(3-ethyl-3-hydroxypentylthio)pregna-5,7,16-triene obtained in Example 7, tetrahydrofuran (2 ml) and 1M tetra-n-butylammonium fluoride solution in tetrahydrofuran (2 ml) were reacted and worked up, and then the residue was purified by preparative thin layer chromatography (0.5 mm×2, dichloromethane:ethanol=7:1, developed once) to give the title compound as a colorless oil (42.0 mg, 64%, 2 steps).
Reaction SMILES: [NH:1]1[CH:5]=[N:4][C:3]([C:6]2[C:7]([NH2:12])=[N:8][CH:9]=[CH:10][CH:11]=2)=[N:2]1.[CH2:13]([O:20][C:21]1[CH:28]=[CH:27][C:24]([CH2:25]Cl)=[CH:23][CH:22]=1)[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1.C(=O)([O-])[O-].[K+].[K+].CN(C=O)C>O>[CH2:13]([O:20][C:21]1[CH:22]=[CH:23][C:24]([CH2:25][N:1]2[CH:5]=[N:4][C:3]([C:6]3[C:7]([NH2:12])=[N:8][CH:9]=[CH:10][CH:11]=3)=[N:2]2)=[CH:27][CH:28]=1)[C:14]1[CH:15]=[CH:16][CH:17]=[CH:18][CH:19]=1
Reactant: Nc1ncccc1-c1nc[nH]n1
Reactant: ClCc1ccc(OCc2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: Nc1ncccc1-c1ncn(Cc2ccc(OCc3ccccc3)cc2)n1
Temperature: 60 °C
Reaction time: 0.5 h
Yield: 60.9 %

Procedure:
3-(1H-[1,2,4]triazol-3-yl)-pyridin-2-ylamine (20 mg) described in Manufacturing Example 14-3, 4-benzyloxybenzyl chloride (32 mg), potassium carbonate (86 mg, and DMF (3.0 mL) were stirred for 0.5 hour at 60° C. Water was added to the reaction solution, which was extracted with ethyl acetate. The organic layer was concentrated and purified by NH silica gel column chromatography (heptane:ethyl acetate=2:1, then 1:1) to obtain the titled compound (27 mg).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([SH:9])[CH:6]=[CH:7][CH:8]=1.[OH-].[K+].Br[CH2:13][C:14]([C:16]1[CH:21]=[CH:20][C:19]([O:22][CH3:23])=[CH:18][CH:17]=1)=[O:15]>C(O)C>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([S:9][CH2:13][C:14]([C:16]2[CH:21]=[CH:20][C:19]([O:22][CH3:23])=[CH:18][CH:17]=2)=[O:15])[CH:6]=[CH:7][CH:8]=1
Reactant: COc1cccc(S)c1
Reactant: COc1ccc(C(=O)CBr)cc1
Agent: [K+]
Agent: [OH-]
Solvent: CCO
Product: COc1ccc(C(=O)CSc2cccc(OC)c2)cc1
Reaction time: 3 h
Yield: 76.5 %

Procedure:
3-Methoxythiophenol (50.0 g, 0.356 mol) was dissolved in 700 mL of ethanol. To this mixture was added (20 g, 0.36 mol) of potassium hydroxide pellets. A total of (82.5 g, 0.36 mol) of 2-bromo-4'-methoxyacetophenone was added in small portions to keep the temperature of the reaction at approximately 25° C. The reaction was allowed to proceed at ambient temperature for three hours. The reaction was terminated by evaporation of the alcohol, which resulted in obtaining a brown oil. The oil was partitioned between 2 L of water and 1.5 L of diethylether. The ether layer was separated and washed with water, dried with anhydrous magnesium sulfate, and evaporated to a solid. The solid was crystallized from a mixture of diethylether-petroleum ether (3:1) to yield 78.5 g of the title compound as a pink crystalline solid. mp 53° C.-54° C. EA calculated for C16H16O3S: C, 66.64; H, 5.59; O, 16.64; S, 11.12. Found: C, 66.55; H, 5.87; O, 16.82; S, 10.86.
Reaction SMILES: [NH2:1][C:2]1[C:3]([NH2:12])=[N:4][CH:5]=[C:6]([CH:11]=1)[C:7]([O:9][CH3:10])=[O:8].[CH2:13](OC(OCC)OCC)C>C(O)=O>[N:1]1[C:2]2[C:3](=[N:4][CH:5]=[C:6]([C:7]([O:9][CH3:10])=[O:8])[CH:11]=2)[NH:12][CH:13]=1
Reactant: COC(=O)c1cnc(N)c(N)c1
Reactant: CCOC(OCC)OCC
Solvent: O=CO
Product: COC(=O)c1cnc2[nH]cnc2c1
Temperature: 90 °C
Yield: 33 %

Procedure:
A stirred mixture of methyl 5,6-diaminonicotinate (1.69 g, 10.12 mmol) from Step 1 of this Example, formic acid (0.5 mL), and triethylorthoformate (25 mL) was heated at 90° C. for 2.5 h. The reaction mixture was cooled to rt and then the precipitated solid was collected by filtration and dried to afford methyl 3H-imidazo[4,5-b]pyridine-6-carboxylate (588 mg, 33%) as a cream solid which did not require further purification. The filtrate was concentrated under reduced pressure, and the residue purified by silica gel flash chromatography eluting with 100% DCM to 10% MeOH in DCM to afford additional methyl 3H-imidazo[4,5-b]pyridine-6-carboxylate (550 mg, 31%) as a cream solid. 1H NMR (300 MHz, DMSO-d6) δ 13.33 (br s, 1H), 8.95 (d, J=1.5 Hz, 1H), 8.64 (s, 1H), 8.50 (d, J=1.5 Hz, 1H), 3.91 (s, 3H). LCMS (ESI) m/z 178 (M+H)+.
Reaction SMILES: [CH2:1]([N:3]([CH:11]1[CH2:16][CH2:15][CH2:14][CH:13]([C:17]2[C:25]3[C:20](=[CH:21][CH:22]=[C:23]([N+:26]([O-])=O)[CH:24]=3)[NH:19][CH:18]=2)[CH2:12]1)[C:4](=[O:10])[O:5][C:6]([CH3:9])([CH3:8])[CH3:7])[CH3:2].O.NN>CO.O.[Ni]>[NH2:26][C:23]1[CH:24]=[C:25]2[C:20](=[CH:21][CH:22]=1)[NH:19][CH:18]=[C:17]2[CH:13]1[CH2:14][CH2:15][CH2:16][CH:11]([N:3]([CH2:1][CH3:2])[C:4](=[O:10])[O:5][C:6]([CH3:7])([CH3:8])[CH3:9])[CH2:12]1
Reactant: CCN(C(=O)OC(C)(C)C)C1CCCC(c2c[nH]c3ccc([N+](=O)[O-])cc23)C1
Agent: [Ni]
Agent: NN
Solvent: O
Solvent: CO
Product: CCN(C(=O)OC(C)(C)C)C1CCCC(c2c[nH]c3ccc(N)cc23)C1
Yield: 94.7 %

Procedure:
To a solution of tert-butyl ethyl(3-(5-nitro-1H-indol-3-yl)cyclohexyl)carbamate (0.24 g, 0.62 mmol) in dry MeOH (10 mL) was added Raney-Ni (0.1 g as a slurry in water) and hydrazine hydrate (0.30 mL, 6.20 mmol). The resulting mixture was immersed in a preheated oil bath and refluxed for 15 min. or until the solution became clear. The reaction was cooled and filtered trough celite, washed with MeOH (20 mL) and the solvent evaporated. The crude material was purified on column chromatography (2 M NH3 in MeOH:CH2Cl2, 2:98) to give the title compound as a brownish solid (0.21 g, 96%). 1H-NMR (CDCl3) δ1.09 (t, 3H, J=6.9 Hz), 1.30-1.66 (m, 3H), 1.48 (s, 9H), 1.80-1.83 (m, 1H), 1.90-1.94 (m, 1H), 1.98-2.04 (m, 1H), 2.11-2.15 (m, 1H), 2.80-2.90 (m, 1H), 3.05-3.22 (m, 2H), 4.12-4.19 (m, 1H), 6.65 (dd, 1H, J=2.1, 8.7 Hz), 6.87 (d, 1H, J=2.1 Hz), 6.96 (s, 1H), 7.15 (d, 1H, J=8.7 Hz), 7.725 (s, 1H); EI-MS (m/z, %) 357 (M+, 100).
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][C:6]([O:10][C:11]3[C:20]4[C:15](=[CH:16][C:17]([O:23][CH2:24][C@@H:25]5[CH2:27][O:26]5)=[C:18]([O:21][CH3:22])[CH:19]=4)[N:14]=[CH:13][N:12]=3)=[CH:7][CH:8]=2)[CH:3]=[CH:2]1.[CH:28]([NH2:31])([CH3:30])[CH3:29]>C1COCC1>[OH:26][C@@H:25]([CH2:27][NH:31][CH:28]([CH3:30])[CH3:29])[CH2:24][O:23][C:17]1[CH:16]=[C:15]2[C:20]([C:11]([O:10][C:6]3[CH:5]=[C:4]4[C:9](=[CH:8][CH:7]=3)[NH:1][CH:2]=[CH:3]4)=[N:12][CH:13]=[N:14]2)=[CH:19][C:18]=1[O:21][CH3:22]
Reactant: COc1cc2c(Oc3ccc4[nH]ccc4c3)ncnc2cc1OC[C@@H]1CO1
Reactant: CC(C)N
Solvent: C1CCOC1
Product: COc1cc2c(Oc3ccc4[nH]ccc4c3)ncnc2cc1OC[C@@H](O)CNC(C)C
Temperature: 75 °C
Reaction time: 18 h
Yield: 56 %

Procedure:
A mixture of (2S)-4-(indol-5-yloxy)-6-methoxy-7-(oxiran-2-ylmethoxy)quinazoline (100 mg, 0.28 mmol), (prepared as described for the starting material in Example 297), and isopropylamine (1.0 ml) in THF (10 ml) was stirred at 75° C. for 18 hours under an atmosphere of nitrogen and then allowed to cool to ambient temperature. The mixture was filtered and the filtrate evaporated in vacuo. The residue was purified by silica gel chromatography using gradient elution with dichloromethane/methanolic ammonia (7M) (100/0 to 90/10) to give (2S)-7-(2-hydroxy-3-(isopropylamino)propoxy)-4-(indol-5-yloxy)-6-methoxyquinazoline (66 mg, 56%).