Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl.FC1C=C(C=CC=1)CN1C=C(C2C3C(=NC=C(C4C=CC(C5CCNCC5)=CC=4)C=3)N(S(C3C=CC(C)=CC=3)(=O)=O)C=2)C=N1.[F:46][C:47]1[CH:48]=[C:49]([CH:87]=[C:88]([F:90])[CH:89]=1)[CH2:50][N:51]1[CH:55]=[C:54]([C:56]2[C:64]3[C:59](=[N:60][CH:61]=[C:62]([C:65]4[CH:66]=[N:67][C:68]([N:71]5[CH2:76][CH2:75][NH:74][CH2:73][CH2:72]5)=[CH:69][CH:70]=4)[CH:63]=3)[N:58](S(C3C=CC(C)=CC=3)(=O)=O)[CH:57]=2)[CH:53]=[N:52]1.FC1C=C(C=C(F)C=1)CN1C=C(C2C3C(=NC=C(C4C=NC(N5CCN(C)CC5)=CC=4)C=3)NC=2)C=N1.[OH-].[Li+]>C1COCC1.CO.O>[F:46][C:47]1[CH:48]=[C:49]([CH:87]=[C:88]([F:90])[CH:89]=1)[CH2:50][N:51]1[CH:55]=[C:54]([C:56]2[C:64]3[C:59](=[N:60][CH:61]=[C:62]([C:65]4[CH:66]=[N:67][C:68]([N:71]5[CH2:72][CH2:73][NH:74][CH2:75][CH2:76]5)=[CH:69][CH:70]=4)[CH:63]=3)[NH:58][CH:57]=2)[CH:53]=[N:52]1
Reactant: Cc1ccc(S(=O)(=O)n2cc(-c3cnn(Cc4cc(F)cc(F)c4)c3)c3cc(-c4ccc(N5CCNCC5)nc4)cnc32)cc1
Agent: CN1CCN(c2ccc(-c3cnc4[nH]cc(-c5cnn(Cc6cc(F)cc(F)c6)c5)c4c3)cn2)CC1
Agent: Cc1ccc(S(=O)(=O)n2cc(-c3cnn(Cc4cccc(F)c4)c3)c3cc(-c4ccc(C5CCNCC5)cc4)cnc32)cc1
Agent: Cl
Solvent: CO
Solvent: O
Solvent: C1CCOC1
Product: Fc1cc(F)cc(Cn2cc(-c3c[nH]c4ncc(-c5ccc(N6CCNCC6)nc5)cc34)cn2)c1
Yield: 123.5 %

Procedure:
Using similar reaction conditions as described in step-iii of example-1, 3-(1-(3,5-difluorobenzyl)-1H-pyrazol-4-yl)-5-(6-(piperazin-1-yl)pyridin-3-yl)-1-tosyl-1H-pyrrolo[2,3-b]pyridine (step 2 compound of example 133) (50 mg, 0.079 mmol) was hydrolyzed with lithium hydroxide (32 mg, 0.743 mmol) in THF/methanol/water (2/2/1 mL) to yield 46 mg (63.8% yield) of the titled compound. 1H NMR (CD3OD, 300 MHz): δ 8.58 (s, 1H), 8.537-8.530 (d, 2H), 8.28 (s, 1H), 8.19-8.16 (dd, 1H), 8.00 (s, 1H), 7.77 (s, 1H), 7.22-7.19 (d, 1H), 6.88-6.85 (m, 3H), 5.43 (s, 2H), 3.94-3.90 (t, 4H), 3.41-3.37 (t, 4H). MS: m/z=472.3 (M+1), HPLC: 95.01% in method A.
Reaction SMILES: [N:1]([C:4]1[CH:9]=[CH:8][C:7]([N:10]2[CH2:15][CH2:14][N:13]([C:16]3[CH:21]=[CH:20][C:19]([O:22][CH3:23])=[CH:18][CH:17]=3)[CH2:12][CH2:11]2)=[CH:6][CH:5]=1)=[C:2]=[S:3].[CH3:24][O:25][CH:26]([O:30][CH3:31])[CH2:27][NH:28][CH3:29]>ClCCl>[CH3:24][O:25][CH:26]([O:30][CH3:31])[CH2:27][N:28]([CH3:29])[C:2]([NH:1][C:4]1[CH:9]=[CH:8][C:7]([N:10]2[CH2:15][CH2:14][N:13]([C:16]3[CH:21]=[CH:20][C:19]([O:22][CH3:23])=[CH:18][CH:17]=3)[CH2:12][CH2:11]2)=[CH:6][CH:5]=1)=[S:3]
Reactant: CNCC(OC)OC
Reactant: COc1ccc(N2CCN(c3ccc(N=C=S)cc3)CC2)cc1
Solvent: ClCCl
Product: COc1ccc(N2CCN(c3ccc(NC(=S)N(C)CC(OC)OC)cc3)CC2)cc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 95 %

Procedure:
A mixture of 15 parts of 1-(4-isothiocyanatophenyl)-4-(4-methoxyphenyl)piperazine, 6.5 parts of 2,2-dimethoxy-N-methylethanamine and 195 parts of dichloromethane was stirred for 1 hour at room temperature. The reaction mixture was evaporated and the residue was triturated in 4-methyl-2-pentanone. The product was filtered off and dried, yielding 19.4 parts (95%) of N-(2,2-dimethoxyethyl)-N'-[4-[4-(4-methoxyphenyl)-1-piperazinyl]phenyl]-N-methylthiourea; mp. 155.0° C. (40).
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:29])[CH2:5][C:6]1[CH:11]=[CH:10][C:9]([O:12][CH3:13])=[C:8]([O:14][C:15]2[CH:20]=[CH:19][C:18]([NH2:21])=[CH:17][C:16]=2[CH2:22][N:23]2[CH2:27][CH2:26][O:25][C:24]2=[O:28])[CH:7]=1)[CH3:2].[Cl:30][C:31]1[CH:36]=[CH:35][C:34]([S:37](Cl)(=[O:39])=[O:38])=[CH:33][CH:32]=1>>[CH2:1]([O:3][C:4](=[O:29])[CH2:5][C:6]1[CH:11]=[CH:10][C:9]([O:12][CH3:13])=[C:8]([O:14][C:15]2[CH:20]=[CH:19][C:18]([NH:21][S:37]([C:34]3[CH:35]=[CH:36][C:31]([Cl:30])=[CH:32][CH:33]=3)(=[O:39])=[O:38])=[CH:17][C:16]=2[CH2:22][N:23]2[CH2:27][CH2:26][O:25][C:24]2=[O:28])[CH:7]=1)[CH3:2]
Reactant: CCOC(=O)Cc1ccc(OC)c(Oc2ccc(N)cc2CN2CCOC2=O)c1
Reactant: O=S(=O)(Cl)c1ccc(Cl)cc1
Product: CCOC(=O)Cc1ccc(OC)c(Oc2ccc(NS(=O)(=O)c3ccc(Cl)cc3)cc2CN2CCOC2=O)c1

Procedure:
Prepared according to the procedure described in Example 91, Step 3, using the following starting materials: {3-[4-amino-2-(2-oxo-oxazolidin-3-ylmethyl)-phenoxy]-4-methoxy-phenyl}-acetic acid ethyl ester and 4-chlorobenzenesulfonyl chloride.
Reaction SMILES: [P:1]([O:35]C(C)(C)C)([O:30]C(C)(C)C)([O:3][CH2:4][C:5]1[CH:6]=[CH:7][C:8]2[C:14]3[C:15]([O:23][CH3:24])=[C:16]([O:21][CH3:22])[C:17]([O:19][CH3:20])=[CH:18][C:13]=3[CH2:12][CH2:11][C@H:10]([NH:25][C:26](=[O:28])[CH3:27])[C:9]=2[CH:29]=1)=[O:2].Cl>O1CCOCC1>[P:1]([OH:30])([OH:35])([O:3][CH2:4][C:5]1[CH:6]=[CH:7][C:8]2[C:14]3[C:15]([O:23][CH3:24])=[C:16]([O:21][CH3:22])[C:17]([O:19][CH3:20])=[CH:18][C:13]=3[CH2:12][CH2:11][C@H:10]([NH:25][C:26](=[O:28])[CH3:27])[C:9]=2[CH:29]=1)=[O:2]
Reactant: COc1cc2c(c(OC)c1OC)-c1ccc(COP(=O)(OC(C)(C)C)OC(C)(C)C)cc1[C@@H](NC(C)=O)CC2
Agent: Cl
Solvent: C1COCCO1
Product: COc1cc2c(c(OC)c1OC)-c1ccc(COP(=O)(O)O)cc1[C@@H](NC(C)=O)CC2
Yield: 95 %

Procedure:
Using an analogous procedure to that described for Example 27 [(5S)-5-(acetylamino)-9,10,11-trimethoxy-6,7-dihydro-5H-dibenzo[a,c]cyclohepten-3-yl]methyl ditertbutyl phosphate was treated with 1M hydrogen chloride in 1,4-dioxane to give [(5S)-5-(acetylamino)-9,10,11-trimethoxy-6,7-dihydro-5H-dibenzo[a,c]cyclohepten-3-yl]methyl dihydrogen phosphate.
Reaction SMILES: C([O:4][CH2:5][C:6]1[C:7]([N:27]2[CH2:39][CH2:38][N:30]3[C:31]4[CH2:32][CH2:33][CH2:34][CH2:35][C:36]=4[CH:37]=[C:29]3[C:28]2=[O:40])=[N:8][CH:9]=[CH:10][C:11]=1[C:12]1[CH:17]=[C:16]([NH:18][C:19]2[CH:24]=[CH:23][N:22]=[CH:21][N:20]=2)[C:15](=[O:25])[N:14]([CH3:26])[CH:13]=1)(=O)C.[Li+].[OH-]>CC(O)C.C1COCC1.O>[OH:4][CH2:5][C:6]1[C:7]([N:27]2[CH2:39][CH2:38][N:30]3[C:31]4[CH2:32][CH2:33][CH2:34][CH2:35][C:36]=4[CH:37]=[C:29]3[C:28]2=[O:40])=[N:8][CH:9]=[CH:10][C:11]=1[C:12]1[CH:17]=[C:16]([NH:18][C:19]2[CH:24]=[CH:23][N:22]=[CH:21][N:20]=2)[C:15](=[O:25])[N:14]([CH3:26])[CH:13]=1
Reactant: CC(=O)OCc1c(-c2cc(Nc3ccncn3)c(=O)n(C)c2)ccnc1N1CCn2c(cc3c2CCCC3)C1=O
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Solvent: CC(C)O
Product: Cn1cc(-c2ccnc(N3CCn4c(cc5c4CCCC5)C3=O)c2CO)cc(Nc2ccncn2)c1=O
Temperature: 35 °C
Reaction time: 0.5 h
Yield: 48.2 %

Procedure:
A mixture of 142b (121.6 mg, 0.225 mmol) and LiOH (100 mg, 4.2 mmol) in iPrOH/THF (1:1, 4 mL) and H2O (1 mL) was stirred at 35° C. for 0.5 h. The mixture was evaporated in vacuo and the residue was extracted with EtOAc (20 mL×3). The combined EtOAc extract was concentrated under reduced pressure and the residue was purified by reverse-phase prep-HPLC to afford 142 (54 mg, 48.2%) as a pale yellow solid. LCMS: [M+H]+ 498.1. 1H NMR (500 MHz, DMSO-d6) δ 9.23 (s, 1H), 8.76 (d, J=2.5, 1H), 8.65 (s, 1H), 8.50 (d, J=5.0, 1H), 8.31 (d, J=6.0, 1H), 7.69 (d, J=2.5, 1H), 7.37 (d, J=5.0, 1H), 7.31-7.33 (m, 1H), 6.58 (s, 1H), 4.97 (t, J=4.5, 1H), 4.39-4.43 (m, 2H), 4.10-4.24 (m, 3H), 3.87 (d, J=12.0, 1H), 3.61 (s, 3H), 2.57-2.64 (m, 2H), 2.47 (d, J=6, 2H), 1.79 (d, J=4.0, 2H), 1.69 (d, J=6.0, 2H)
Reaction SMILES: [CH2:1]([O:8]C1C=C2C(C=CN2)=CC=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(O[C:22]1[CH:23]=[C:24]2[C:28](=[CH:29][CH:30]=1)[N:27]([C:31]([NH2:33])=[O:32])[CH:26]=[C:25]2[N:34]=[C:35]=[O:36])C=C>>[CH2:1]([O:8][C:30]1[CH:29]=[C:28]2[C:24]([C:25]([N:34]=[C:35]=[O:36])=[CH:26][N:27]2[C:31]([NH2:33])=[O:32])=[CH:23][CH:22]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: c1ccc(COc2ccc3cc[nH]c3c2)cc1
Reactant: C=CCOc1ccc2c(c1)c(N=C=O)cn2C(N)=O
Product: NC(=O)n1cc(N=C=O)c2ccc(OCc3ccccc3)cc21

Procedure:
was prepared from 6-benzyloxyindole using the protocol described for steps B-E in scheme A4 for the preparation of 5-allyloxy-3-isocyanato-indole-1-carboxylic acid amide.
Reaction SMILES: [C:1]([C:5]1[CH:10]=[C:9]([Cl:11])[CH:8]=[CH:7][C:6]=1[N:12]1[CH2:17][CH2:16][N:15]([C:18](=[O:24])[C:19]([O:21]CC)=[O:20])[CH2:14][CH2:13]1)([CH3:4])([CH3:3])[CH3:2].[Li+].[OH-].Cl>CCO>[C:1]([C:5]1[CH:10]=[C:9]([Cl:11])[CH:8]=[CH:7][C:6]=1[N:12]1[CH2:13][CH2:14][N:15]([C:18](=[O:24])[C:19]([OH:21])=[O:20])[CH2:16][CH2:17]1)([CH3:4])([CH3:2])[CH3:3]
Reactant: CCOC(=O)C(=O)N1CCN(c2ccc(Cl)cc2C(C)(C)C)CC1
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: CCO
Product: CC(C)(C)c1cc(Cl)ccc1N1CCN(C(=O)C(=O)O)CC1
Temperature: 25 °C
Reaction time: 1 h
Yield: 69.8 %

Procedure:
A mixture of ethyl [4-(2-tert-butyl-4-chlorophenyl)piperazin-1-yl](oxo)acetate (Example 179, 0.45 g, 1.28 mmol) and 1 M LiOH (3.8 mL) in EtOH (15 mL) was stirred at room temperature for 1 h. The reaction mixture was acidified with 1 M HCl, concentrated under reduced pressure, and partitioned between ethyl acetate and water. The organic layer was washed with saturated brine, dried over anhydrous magnesium sulfate, filtered and concentrated under reduced pressure. The resulting white solid was triturated with diisopropyl ether to give the title compound (0.29 g) as a white solid: mp 154-155° C.
Reaction SMILES: O=P(Cl)(Cl)Cl.CN([CH:9]=[O:10])C.[Cl:11][C:12]1[CH:13]=[C:14]([C:18]([O:20][CH2:21][CH3:22])=[O:19])[NH:15][C:16]=1[CH3:17].C([O-])(=O)C.[Na+]>ClCCCl.O>[Cl:11][C:12]1[C:13]([CH:9]=[O:10])=[C:14]([C:18]([O:20][CH2:21][CH3:22])=[O:19])[NH:15][C:16]=1[CH3:17]
Reactant: CCOC(=O)c1cc(Cl)c(C)[nH]1
Reactant: CN(C)C=O
Agent: CC(=O)[O-]
Agent: [Na+]
Solvent: O=P(Cl)(Cl)Cl
Solvent: ClCCCl
Solvent: O
Product: CCOC(=O)c1[nH]c(C)c(Cl)c1C=O
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 30.7 %

Procedure:
POCl3 in 1,2-dichloroethane (14 mL) was slowly added to a solution of DMF (4.37 mL, 59.79 mmol) in 1,2-dichloroethane (10 mL). The reaction mixture was stirred for 15 min and then Intermediate 7 (2.04 g, 10.87 mmol) was added. The reaction mixture was heated at reflux for 3 h and then cooled to room temperature. The reaction mixture was treated with sodium acetate (10 g) in water (25 mL) and stirred for 1 h. The mixture was extracted with methylene chloride, washed with water, dried over sodium sulfate, filtered, and concentrated under reduced pressure. Purification by flash column chromatography (silica, 2:1 hexanes/ethyl acetate) gave the desired compound (720 mg).
Reaction SMILES: C[O:2][C:3]([C:5]1([CH2:11][S:12](=[O:19])(=[O:18])[N:13]([CH:15]2[CH2:17][CH2:16]2)[CH3:14])[CH2:10][CH2:9][CH2:8][CH2:7][CH2:6]1)=[O:4].[OH-].[K+]>CO>[CH:15]1([N:13]([CH3:14])[S:12]([CH2:11][C:5]2([C:3]([OH:4])=[O:2])[CH2:6][CH2:7][CH2:8][CH2:9][CH2:10]2)(=[O:18])=[O:19])[CH2:16][CH2:17]1
Reactant: COC(=O)C1(CS(=O)(=O)N(C)C2CC2)CCCCC1
Agent: [K+]
Agent: [OH-]
Solvent: CO
Product: CN(C1CC1)S(=O)(=O)CC1(C(=O)O)CCCCC1
Reaction time: 18 h
Yield: 99 %

Procedure:
To a RT solution of MeOH (30 mL) containing ester 1261-E (4 mmol, 1.1 g) was added aqueous KOH (17.6 mL, 61.7 mmol) and the reaction was brought to 55° C. for 18 hours. Volatile were removed under vacuum and residue was acidified to pH 4 with HCl 1.0N. Diluted with EtOAc and washed with water (2×20 mL) and brine. Organic layer was dried over MgSO4, filtered and concentrated down to give acid 1261-F (1.09 g, 96%).
Reaction SMILES: Br[C:2]1[CH:12]=[CH:11][C:5]2[O:6][C:7]([F:10])([F:9])[O:8][C:4]=2[CH:3]=1.[Li]CCCC.CN([CH:21]=[O:22])C>C1COCC1>[F:9][C:7]1([F:10])[O:6][C:5]2[CH:11]=[CH:12][C:2]([CH:21]=[O:22])=[CH:3][C:4]=2[O:8]1
Reactant: FC1(F)Oc2ccc(Br)cc2O1
Reactant: CN(C)C=O
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: O=Cc1ccc2c(c1)OC(F)(F)O2
Reaction time: 0.17 h

Procedure:
A solution of 127 mmol of 5-bromo-2,2-difluorobenzo[d][1,3]dioxole in 200 mL of THF is cooled under argon in a CO2/acetone bath and treated with 1.05 equivalents of n-BuLi in THF. The mixture is stirred for about 10 min in the cold, then treated with 1.2 equivalents of DMF. The mixture is stirred for 30 min in the cold, then the cold bath is removed and the reaction is stirred for 1.5 h at ambient temperature and then quenched with 150 mL of saturated ammonium chloride solution. The organic layer is separated and the aqueous layer is washed 2× with ether. The combined organics are washed with brine, dried over MgSO4 and concentrated in vacuo. Silica gel chromatography (EtOAc/hexanes eluant) yields the title compound.
Reaction SMILES: C[O:2][C:3](=[O:35])[CH2:4][CH2:5][C:6]1[CH:7]=[C:8]([C:12]2[CH:17]=[CH:16][CH:15]=[C:14]([C:18]3[CH:19]=[C:20]([C:28]([S:31]([CH3:34])(=[O:33])=[O:32])([CH3:30])[CH3:29])[CH:21]=[C:22]4[C:27]=3[N:26]=[CH:25][CH:24]=[CH:23]4)[CH:13]=2)[CH:9]=[CH:10][CH:11]=1.[Li+].[OH-].CC(O)=O>>[CH3:34][S:31]([C:28]([C:20]1[CH:21]=[C:22]2[C:27](=[C:18]([C:14]3[CH:13]=[C:12]([C:8]4[CH:9]=[CH:10][CH:11]=[C:6]([CH2:5][CH2:4][C:3]([OH:35])=[O:2])[CH:7]=4)[CH:17]=[CH:16][CH:15]=3)[CH:19]=1)[N:26]=[CH:25][CH:24]=[CH:23]2)([CH3:30])[CH3:29])(=[O:33])=[O:32]
Reactant: COC(=O)CCc1cccc(-c2cccc(-c3cc(C(C)(C)S(C)(=O)=O)cc4cccnc34)c2)c1
Agent: [Li+]
Agent: [OH-]
Solvent: CC(=O)O
Product: CC(C)(c1cc(-c2cccc(-c3cccc(CCC(=O)O)c3)c2)c2ncccc2c1)S(C)(=O)=O
Temperature: 25 °C
Reaction time: 12 h

Procedure:
To a solution of 3-{3′-[6-(1-methanesulfonyl-1-methyl-ethyl)-quinolin-8-yl]-biphenyl-3-yl}-propionic acid methyl ester (1.0 eq.) from step 1, in TBF:MeOH (2:1; 0.2M) was added aqueous LiOH (2M; 4.0 eq.). The mixture was stirred for 12 h at rt, quenched with AcOH (20 eq.), poured in saturated aqueous NH4OAc and extracted with EtOAc (2×). The combined organic extracts were washed with brine, dried over Na2SO4, filtered and concentrated. Crystallization in Hex:CH2Cl2 afforded the title compound as a white solid.
Reaction SMILES: [N+:1]([C:4]1[C:5]([NH:10][C:11]2[CH:20]=[C:19]3[C:14]([CH:15]=[CH:16][CH:17]=[C:18]3[CH:21]3[CH2:26][CH2:25][N:24]([CH3:27])[CH2:23][CH2:22]3)=[CH:13][CH:12]=2)=[N:6][CH:7]=[CH:8][CH:9]=1)([O-])=O>[Pd].C(O)C.C(OCC)(=O)C>[NH2:1][C:4]1[C:5]([NH:10][C:11]2[CH:20]=[C:19]3[C:14]([CH:15]=[CH:16][CH:17]=[C:18]3[CH:21]3[CH2:26][CH2:25][N:24]([CH3:27])[CH2:23][CH2:22]3)=[CH:13][CH:12]=2)=[N:6][CH:7]=[CH:8][CH:9]=1
Reactant: CN1CCC(c2cccc3ccc(Nc4ncccc4[N+](=O)[O-])cc23)CC1
Agent: [Pd]
Solvent: CCO
Solvent: CCOC(C)=O
Product: CN1CCC(c2cccc3ccc(Nc4ncccc4N)cc23)CC1
Reaction time: 4 h

Procedure:
A mixture of the product from Example 58 (0.18 g, 0.5 mmol) and 10% palladium on carbon (0.04 g)in ethanol (35 mL) and ethyl acetate (15 mL) was hydrogenated at 45 psi for 4 hours. The mixture was filtered through celite and concentrated to give 7-(3-amino-2-pyridylamino)-1-(1-methyl-4-piperidinyl)-naphthalene which was suitable for further reaction; 1H NMR δ 8.07 (d, J=2 Hz, 1 H), 7.89 (dd, J=1.5, 5 Hz, 1 H), 7.79 (d, J=9 Hz, 1 H), 7.64 (d, J=7.5 Hz, 1 H), 7.45 (dd, J=2, 9 Hz, 1 H), 7.36-7.26 (m, 2H with CHCl3 from NMR solvent overlapping), 7.07 (dd, J=1.5, 7.5 Hz, 1 H), 6.82 (dd, J=5, 7.5 Hz, 1 H), 6.51 (br s, 1 H), 3.49 (br s, 2 H), 3.18 (tt, J=4, 12 Hz, 1H), 3.03 (long range coupled d, J=13.5 Hz, 2 H), 2.39 (s, 3 H), 2.23 (dt, J=2.5, 11.5 Hz, 2H), 2.08-1.87 (m, 4 H). HRMS m/e calculated for C21H24N4 : 332.1996. Observed m/e 332.2003.
Reaction SMILES: [CH3:1][C:2]1[CH:11]=[C:10]2[C:5]([O:6][CH2:7][C:8]3[N:14]=[C:13]([NH:15][C:16](=[O:18])C)[S:12][C:9]=32)=[CH:4][N:3]=1.C(C1N=CC2CCC3N=C(NC([N:39]4[CH:43]=[CH:42][N:41]=[CH:40]4)=O)SC=3C=2N=1)(C)(C)C>>[CH3:1][C:2]1[CH:11]=[C:10]2[C:5]([O:6][CH2:7][C:8]3[N:14]=[C:13]([NH:15][C:16]([N:39]4[CH:43]=[CH:42][N:41]=[CH:40]4)=[O:18])[S:12][C:9]=32)=[CH:4][N:3]=1
Reactant: CC(C)(C)c1ncc2c(n1)-c1sc(NC(=O)n3ccnc3)nc1CC2
Reactant: CC(=O)Nc1nc2c(s1)-c1cc(C)ncc1OC2
Product: Cc1cc2c(cn1)OCc1nc(NC(=O)n3ccnc3)sc1-2

Procedure:
Imidazole-1-carboxylic acid (8-methyl-4H-5-oxa-1-thia-3,7-diaza-cyclopenta[a]naphthalen-2-yl)-amide was prepared from N-(8-methyl-4H-5-oxa-1-thia-3,7-diaza-cyclopenta[a]naphthalen-2-yl)-acetamide (Stage 40.2) using synthetic methodology as described for the preparation of intermediate A.
Reaction SMILES: [Br:1][C:2]1[CH:9]=[CH:8][C:5]([CH2:6]O)=[C:4]([Cl:10])[CH:3]=1.C1(C)C=CC=CC=1.[BrH:18].O>C(OCC)(=O)C>[Br:1][C:2]1[CH:9]=[CH:8][C:5]([CH2:6][Br:18])=[C:4]([Cl:10])[CH:3]=1
Reactant: OCc1ccc(Br)cc1Cl
Reactant: Br
Solvent: CCOC(C)=O
Solvent: O
Solvent: Cc1ccccc1
Product: Clc1cc(Br)ccc1CBr
Reaction time: 2 h

Procedure:
To 4-bromo-2-chlorobenzyl alcohol (399 g) of Reference Example 12 were added toluene (2452 mL) and 48% aqueous hydrogen bromide solution (2453 mL), and the mixture was refluxed with stirring for 2 hr. After cooling, water and ethyl acetate were added to the reaction mixture. After partitioning and extraction, the organic layer was washed with water, 1M aqueous sodium hydroxide solution and 25% brine, and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure to give the title compound (535 g) as a pale-yellow oil.
Reaction SMILES: FC(F)(F)C(O)=O.C(OC([N:15]([O:37][CH2:38][C:39]1[CH:44]=[CH:43][CH:42]=[CH:41][CH:40]=1)[CH2:16][CH2:17][CH2:18][CH2:19][C:20](=[O:36])[N:21]([O:28][CH2:29][C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1)[CH2:22][CH2:23][CH2:24][CH2:25][C:26]#[N:27])=O)(C)(C)C>C(Cl)Cl>[CH2:29]([O:28][N:21]([C:20](=[O:36])[CH2:19][CH2:18][CH2:17][CH2:16][NH:15][O:37][CH2:38][C:39]1[CH:40]=[CH:41][CH:42]=[CH:43][CH:44]=1)[CH2:22][CH2:23][CH2:24][CH2:25][C:26]#[N:27])[C:30]1[CH:31]=[CH:32][CH:33]=[CH:34][CH:35]=1
Reactant: CC(C)(C)OC(=O)N(CCCCC(=O)N(CCCCC#N)OCc1ccccc1)OCc1ccccc1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: N#CCCCCN(OCc1ccccc1)C(=O)CCCCNOCc1ccccc1
Temperature: 0 °C
Reaction time: 0.25 h

Procedure:
Trifluoroacetic acid (25 mL) was slowly dripped into a solution of (4) (7.10 g, 13.93 mmol) in CH2Cl2 (150 mL) which had been cooled to 0° C. The solution was stirred at 0° C. for 30 minutes and at room temperature for 15 minutes. Solvent and excess TFA were removed by rotary evaporation, and the concentrate was cooled to 0° C., treated with saturated NaHCO3 (150 mL) and extracted with CH2Cl2 (4×80 mL). After solvent removal, the crude oil was purified by silica gel column chromatography with 1:1 hexane/EtOAc as the eluant, generating 4.6 g (81%) of (5) as an oil: NMR δ 1.40-190 (m, 8 H), 2.30 (t, 2 H, J=6), 2.40 (t, 2 H, J=6), 2.90 (t, 2 H, J=6), 3.63 (t, 2 H, J=6), 4.63 (s, 2 H), 4.75 (s, 2 H), 4.93 (br s, 1 H), 7.27 (s, 5 H), 7.33 (s, 5 H). Anal. (C24H31N3O3) C, H, N.
Reaction SMILES: [NH2:1][C:2]1[CH:11]=[CH:10][C:5]([C:6]([O:8]C)=[O:7])=[CH:4][N:3]=1.Cl[CH2:13][C:14](=O)[CH3:15]>C(O)C>[CH3:15][C:14]1[N:1]=[C:2]2[CH:11]=[CH:10][C:5]([C:6]([OH:8])=[O:7])=[CH:4][N:3]2[CH:13]=1
Reactant: CC(=O)CCl
Reactant: COC(=O)c1ccc(N)nc1
Solvent: CCO
Product: Cc1cn2cc(C(=O)O)ccc2n1
Temperature: 25 °C
Reaction time: 1 h
Yield: 71.1 %

Procedure:
A mixture of methyl 6-aminonicotinate (510 mg), chloroacetone (620 mg) and ethanol (10 ml) was refluxed for 10 hours. After the solvent was removed, ethanol (5 ml) and water (5 ml) was added to the residue. To the solution containing methyl 2-methylimidazo[1,2-a]pyridine-6-carboxylate was added sodium hydroxide (536 mg) and the mixture was stirred for 1 hour at ambient temperature. Ethanol was evaporated and the resulting crystal was collected. A suspension of the obtained crystal in water (3 ml) was adjusted to pH 3.5 with hydrochloric acid, and the residual crystal was collected and dried to give 2-methylimidazo[1,2-a]pyridine-6-carboxylic acid (0.42 g).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([OH:15])[CH:5]=[C:6]([NH:8][C:9]2[CH:10]=[N:11][CH:12]=[CH:13][CH:14]=2)[CH:7]=1.[H-].[Na+].[Si:18](Cl)([C:31]([CH3:34])([CH3:33])[CH3:32])([C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1)[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1>CN(C=O)C.C(OC)(C)(C)C>[Br:1][C:2]1[CH:7]=[C:6]([NH:8][C:9]2[CH:10]=[N:11][CH:12]=[CH:13][CH:14]=2)[CH:5]=[C:4]([O:15][Si:18]([C:31]([CH3:34])([CH3:33])[CH3:32])([C:25]2[CH:26]=[CH:27][CH:28]=[CH:29][CH:30]=2)[C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)[CH:3]=1
Reactant: CC(C)(C)[Si](Cl)(c1ccccc1)c1ccccc1
Reactant: Oc1cc(Br)cc(Nc2cccnc2)c1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: COC(C)(C)C
Product: CC(C)(C)[Si](Oc1cc(Br)cc(Nc2cccnc2)c1)(c1ccccc1)c1ccccc1
Temperature: 0 °C
Reaction time: 0.25 h
Yield: 96.1 %

Procedure:
3-Bromo-5-(pyridin-3-ylamino)-phenol (11.62 g, 43.83 mmol) was dissolved in DMF (115 mL) under dry argon and cooled to 0° C. Then 60% NaH (1.93 g, 48.21 mmol) was added in small portions over a period of 45 min. Stirring was continued for 15 min, followed by drop wise addition of TBDPS-chloride (11.2 mL, 43.83 mmol). The mixture was warmed to room temperature and stirred for 20 h. The reaction mixture was diluted with tert-butylmethyl ether (200 mL) and washed with water and brine (2×50 mL each). The organic layer was dried (MgSO4) and concentrated to give the crude product which was purified by flash chromatography on silica gel (600 g, AcOEt/heptane 1:2→1:1). [3-Bromo-5-(tert-butyl-diphenyl-silanyloxy)-phenyl]-pyridin-3-yl-amine (21.2 g, 96%) was obtained as a yellow resin.
Reaction SMILES: [N+:1]([C:4]1[CH:24]=[CH:23][CH:22]=[CH:21][C:5]=1[NH:6][C:7]1[S:11][C:10]2[CH:12]=[CH:13][C:14]([CH3:16])=[CH:15][C:9]=2[C:8]=1[C:17]([O:19][CH3:20])=[O:18])([O-])=O.[H][H]>C(OCC)(=O)C>[NH2:1][C:4]1[CH:24]=[CH:23][CH:22]=[CH:21][C:5]=1[NH:6][C:7]1[S:11][C:10]2[CH:12]=[CH:13][C:14]([CH3:16])=[CH:15][C:9]=2[C:8]=1[C:17]([O:19][CH3:20])=[O:18]
Reactant: COC(=O)c1c(Nc2ccccc2[N+](=O)[O-])sc2ccc(C)cc12
Reactant: [H][H]
Solvent: CCOC(C)=O
Product: COC(=O)c1c(Nc2ccccc2N)sc2ccc(C)cc12

Procedure:
In the same manner as in Starting Material Synthesis Example 19 and using methyl 2-(2-nitroanilino)-5-methylbenzo[b]thiophene-3-carboxylate, ethyl acetate, 10%/opalladium-carbon and hydrogen (60 atm kg/cm2), methyl 2-(2-aminoanilino)-5-methylbenzo[b]thiophene-3-carboxylate is obtained.
Reaction SMILES: Cl[CH2:2][C:3]1[N:4]([C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=2[Cl:23])[C:5](=[O:16])[C:6]2[C:11]3[CH2:12][CH2:13][CH2:14][CH2:15][C:10]=3[S:9][C:7]=2[N:8]=1.C(=O)([O-])[O-].[K+].[K+].[CH2:30]([N:32]1[CH2:37][CH2:36][NH:35][CH2:34][CH2:33]1)[CH3:31]>C(Cl)(Cl)Cl>[Cl:23][C:18]1[CH:19]=[CH:20][CH:21]=[CH:22][C:17]=1[N:4]1[C:5](=[O:16])[C:6]2[C:11]3[CH2:12][CH2:13][CH2:14][CH2:15][C:10]=3[S:9][C:7]=2[N:8]=[C:3]1[CH2:2][N:35]1[CH2:36][CH2:37][N:32]([CH2:30][CH3:31])[CH2:33][CH2:34]1
Reactant: CCN1CCNCC1
Reactant: O=c1c2c3c(sc2nc(CCl)n1-c1ccccc1Cl)CCCC3
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: ClC(Cl)Cl
Product: CCN1CCN(Cc2nc3sc4c(c3c(=O)n2-c2ccccc2Cl)CCCC4)CC1
Yield: 68.4 %

Procedure:
In 40 ml of chloroform was dissolved 820 mg of 3,4,5,6,7,8-hexahydro-2-chloromethyl-3-(2-chlorophenyl)-4-oxo(1)-benzothieno[2,3-d]pyrimidine, and 300 mg of potassium carbonate was added. Further, 310 mg of 1-ethylpiperazine was added dropwise. The mixture was heated under reflux for 5 hours. The reaction mixture was filtered, and the filtrate was concentrated under reduced pressure to give an oily substance, which was purified by silica gel chromatography. The obtained white crystals were recrystallized from ethanol to give 680 mg of the title compound, m.p. 140°-142° C.
Reaction SMILES: [O:1]=[C:2]1[NH:7][C:6]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=2[O:14][CH2:15][CH3:16])=[N:5][CH:4]=[C:3]1[C:17]#[N:18].[N-:19]=[N+:20]=[N-:21].[Na+].[Cl-].[NH4+]>>[CH2:15]([O:14][C:9]1[CH:10]=[CH:11][CH:12]=[CH:13][C:8]=1[C:6]1[NH:7][C:2](=[O:1])[C:3]([C:17]2[NH:21][N:20]=[N:19][N:18]=2)=[CH:4][N:5]=1)[CH3:16]
Reactant: [N-]=[N+]=[N-]
Reactant: CCOc1ccccc1-c1ncc(C#N)c(=O)[nH]1
Agent: [Cl-]
Agent: [NH4+]
Agent: [Na+]
Product: CCOc1ccccc1-c1ncc(-c2nnn[nH]2)c(=O)[nH]1
Reaction time: 16 h
Yield: 50 %

Procedure:
A mixture of 1,6-dihydro-6-oxo-2-(2-ethoxyphenyl) pyrimidine-5-carbonitrile (2.17 g., 9.0 mmole), sodium azide (0.645 g., 9.9 mmole), and ammonium chloride (0.53 g., 9.9 mmole) in dry, N,N-dimethylformamide (18 ml.) was stirred at 125° for 16 hours. The solvent was removed under reduced pressure. The residue was treated with water and the resulting slurry acidified with 1N hydrochloric acid. The mixture was filtered. The collected solid was washed with water, dried, and recrystallized from glacial acetic acid to give the title compound (1.28 g., 50% yield). An analytical sample had m.p. 289°-290° with decomposition.