Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][N:2]1[C:14]2[C:13]3[N:12]=[C:11]([NH:15][C:16]4[CH:21]=[CH:20][C:19]([Br:22])=[CH:18][C:17]=4[O:23][C:24]([F:27])([F:26])[F:25])[N:10]=[CH:9][C:8]=3[CH2:7][CH2:6][C:5]=2[C:4]([C:28]([O:30]CC)=O)=[N:3]1.[Cl-].[NH4+].[Li][N:36]([Si](C)(C)C)[Si](C)(C)C>O1CCCC1>[CH3:1][N:2]1[C:14]2[C:13]3[N:12]=[C:11]([NH:15][C:16]4[CH:21]=[CH:20][C:19]([Br:22])=[CH:18][C:17]=4[O:23][C:24]([F:25])([F:26])[F:27])[N:10]=[CH:9][C:8]=3[CH2:7][CH2:6][C:5]=2[C:4]([C:28]([NH2:36])=[O:30])=[N:3]1
Reactant: CCOC(=O)c1nn(C)c2c1CCc1cnc(Nc3ccc(Br)cc3OC(F)(F)F)nc1-2
Reactant: [Li]N([Si](C)(C)C)[Si](C)(C)C
Agent: [Cl-]
Agent: [NH4+]
Solvent: C1CCOC1
Product: Cn1nc(C(N)=O)c2c1-c1nc(Nc3ccc(Br)cc3OC(F)(F)F)ncc1CC2
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 93 %

Procedure:
Ethyl 1-methyl-8-(2-trifluoromethoxy-4-bromophenylamino]-4,5-dihydro-1H-pyrazolo[4,3-h]quinazoline-3-carboxylate (330 mg, 0.64 mmol) was suspended in 10 mL of tetrahydrofuran. Ammonium chloride (106 mg 2.0 mmol) and LiN(TMS)2 1 N in THF (4.0 mL, 4.0 mmol) were added. The mixture was stirred at room temperature for 0.5 h. The solvent was then evaporated to dryness, the residue suspended in water and filtered to afford 288 mg (93% yield) of the title compound.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][C:9]2[CH:18]=[C:17]3[C:12]([C:13]([OH:29])=[C:14]([C:24]([O:26]CC)=O)[C:15](=[O:23])[N:16]3[CH2:19][CH2:20][O:21][CH3:22])=[N:11][CH:10]=2)=[CH:4][CH:3]=1.[NH2:30][CH2:31][CH2:32][N:33]([CH3:38])[S:34]([CH3:37])(=[O:36])=[O:35]>>[F:1][C:2]1[CH:3]=[CH:4][C:5]([CH2:8][C:9]2[CH:18]=[C:17]3[C:12]([C:13]([OH:29])=[C:14]([C:24]([NH:30][CH2:31][CH2:32][N:33]([CH3:38])[S:34]([CH3:37])(=[O:36])=[O:35])=[O:26])[C:15](=[O:23])[N:16]3[CH2:19][CH2:20][O:21][CH3:22])=[N:11][CH:10]=2)=[CH:6][CH:7]=1
Reactant: CCOC(=O)c1c(O)c2ncc(Cc3ccc(F)cc3)cc2n(CCOC)c1=O
Reactant: CN(CCN)S(C)(=O)=O
Product: COCCn1c(=O)c(C(=O)NCCN(C)S(C)(=O)=O)c(O)c2ncc(Cc3ccc(F)cc3)cc21
Yield: 63.2 %

Procedure:
In a manner similar to that described in example 316, from ethyl 7-[(4-fluorophenyl)methyl]-4-hydroxy-1-[2-(methyloxy)ethyl]-2-oxo-1,2-dihydro-1,5-naphthyridine-3-carboxylate (10 mg, 0.025 mmol) and N-(2-aminoethyl)-N-methylmethanesulfonamide (50 mg, 0.329 mmol) was prepared 7-[(4-fluorophenyl)methyl]-4-hydroxy-N-{2-[methyl(methylsulfonyl)amino]ethyl}-1-[2-(methyloxy)ethyl]-2-oxo-1,2-dihydro-1,5-naphthyridine-3-carboxamide (8 mg, 62% yield) as a white solid after purification by reverse phase HPLC. 1H NMR (CDCl3) δ 10.36 (br s, 1 H), 8.53 (s, 1 H), 7.69 (s, 1 H), 7.16-7.13 (m, 2 H), 7.02-6.98 (m, 2 H), 4.33 (m, 2 H), 4.10 (s, 2 H), 3.68-3.61 (m, 4 H), 3.39 (m, 2 H), 3.18 (s, 3 H), 2.95 (s, 3 H), 2.82 (s, 3 H); MS m/z 507 M+1).
Reaction SMILES: [Br:1][C:2]1[C:3]([CH3:13])=[C:4]([C:8]([O:10][CH2:11][CH3:12])=[O:9])[NH:5][C:6]=1[CH3:7].[H-].[Na+].[CH3:16]I>C1COCC1>[Br:1][C:2]1[C:3]([CH3:13])=[C:4]([C:8]([O:10][CH2:11][CH3:12])=[O:9])[N:5]([CH3:16])[C:6]=1[CH3:7]
Reactant: CI
Reactant: CCOC(=O)c1[nH]c(C)c(Br)c1C
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: CCOC(=O)c1c(C)c(Br)c(C)n1C
Reaction time: 0.17 h

Procedure:
To a solution of ethyl 4-bromo-3,5-dimethyl-1H-pyrrole-2-carboxylate (0.050 mL, 0.610 mmol) in THF (3 mL), was added NaH (36.6 mg, 0.914 mmol). The mixture was stirred for 10 min and then MeI (0.046 mL, 0.731 mmol) was added dropwise. The resulting mixture was stirred overnight. The reaction was quenched with sat. NH4Cl. The aqueous layer was extracted with EtOAc (3×). The combined organic layers were washed with brine (1×), dried (Na2SO4) and concentrated in vacuo. The residue was purified by flash chromatography (Biotage Horizon, 12M, Si, ˜10 mL/min, 100% hexanes for 36 mL, gradient to 20% EtOAc in hexanes over 1032 mL) to afford ethyl 4-bromo-1,3,5-trimethyl-1H-pyrrole-2-carboxylate. 1H NMR (500 MHz, CDCl3): δ 4.31 (q, J=7.1 Hz, 2H); 3.82 (s, 3H); 2.31 (s, 3H); 2.26 (s, 3H); 1.38 (t, J=7.1 Hz, 3H).
Reaction SMILES: C(NC(C)C)(C)C.C([Li])CCC.[CH2:13]([N:20]1[CH:25]([C:26]#[N:27])[CH2:24][CH2:23][CH2:22][CH:21]1[C:28]#[N:29])[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1.CN(C)P(=O)(N(C)C)N(C)C.Br[CH2:42][C:43]([O:45][C:46]([CH3:49])([CH3:48])[CH3:47])=[O:44]>O1CCCC1>[CH2:13]([N:20]1[CH:25]([C:26]#[N:27])[CH2:24][CH2:23][CH2:22][C:21]1([CH2:42][C:43]([O:45][C:46]([CH3:49])([CH3:48])[CH3:47])=[O:44])[C:28]#[N:29])[C:14]1[CH:15]=[CH:16][CH:17]=[CH:18][CH:19]=1
Reactant: N#CC1CCCC(C#N)N1Cc1ccccc1
Reactant: CC(C)(C)OC(=O)CBr
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: CN(C)P(=O)(N(C)C)N(C)C
Solvent: CC(C)NC(C)C
Product: CC(C)(C)OC(=O)CC1(C#N)CCCC(C#N)N1Cc1ccccc1
Temperature: -20 °C
Reaction time: 0.5 h

Procedure:
A solution of 378.000 mmol of diisopropylamine in 180 ml of tetrahydrofuran is admixed dropwise at −78° C. with 179.000 mmol of n-butyllithium (1.6M in hexane). The yellowish solution is stirred at −20° C. for 30 minutes then cooled again to −78° C. This solution is admixed dropwise at −78° C. with a solution of 126.000 mmol of 1-benzylpiperidine-2,6-dicarbonitrile [98195-08-5] and 138.600 mmol of hexamethylphosphorictriamide in 50 ml of tetrahydrofuran. The mixture is subsequently stirred at this temperature for 30 minutes. Then a solution of 130.000 mmol of tert-butyl bromoacetate in 50 ml of tetrahydrofuran is added dropwise. The mixture is subsequently stirred at −78° C. for an hour, the cold bath is removed, and the temperature is allowed to increase slowly overnight to room temperature. The reaction mixture is admixed with aqueous saturated ammonium chloride solution, the organic phase is separated off and the aqueous phase is extracted repeatedly with diethyl ether. The combined organic phases are washed with water and brine, dried with sodium sulphate and evaporated. From the residue the title compound is obtained by means of flash chromatography (SiO2 60 F) and identified on the basis of the Rf value.
Reaction SMILES: [Br:1][C:2]1[C:3]([N:12]2[CH2:17][CH2:16][N:15]([CH2:18][C:19]3[CH:20]=[N:21][CH:22]=[CH:23][CH:24]=3)[CH2:14][CH2:13]2)=[C:4]([N+:9]([O-])=O)[C:5]([NH2:8])=[N:6][CH:7]=1.[CH3:25][O:26][C:27]1[CH:34]=[CH:33][C:30]([CH:31]=O)=[CH:29][CH:28]=1.[O-]S(S([O-])=O)=O.[Na+].[Na+]>C(O)C>[Br:1][C:2]1[C:3]([N:12]2[CH2:17][CH2:16][N:15]([CH2:18][C:19]3[CH:20]=[N:21][CH:22]=[CH:23][CH:24]=3)[CH2:14][CH2:13]2)=[C:4]2[N:9]=[C:31]([C:30]3[CH:33]=[CH:34][C:27]([O:26][CH3:25])=[CH:28][CH:29]=3)[NH:8][C:5]2=[N:6][CH:7]=1
Reactant: COc1ccc(C=O)cc1
Reactant: Nc1ncc(Br)c(N2CCN(Cc3cccnc3)CC2)c1[N+](=O)[O-]
Agent: O=S([O-])S(=O)[O-]
Agent: [Na+]
Solvent: CCO
Product: COc1ccc(-c2nc3c(N4CCN(Cc5cccnc5)CC4)c(Br)cnc3[nH]2)cc1
Temperature: 70 °C

Procedure:
To a mixture of 5-bromo-3-nitro-4-(4-(pyridin-3-ylmethyl)piperazin-1-yl)pyridin-2-amine (0.043 g, 0.11 mmol) and ethanol (2.4 ml) was added 4-methoxybenzaldehyde (0.024 g, 0.18 mmol) with the aid of ethanol (1 ml) followed by a freshly prepared aqueous solution of Na2S2O4 (1M; 0.44 ml, 0.44 mmol). The reaction mixture was heated at 70° C. for 4.5 h, then allowed to cool to room temperature and the solvents were removed in vacuo. The residue was absorbed on silica gel and the free running powder was placed on a 10 g isolute silica column which was eluted with 50% ethyl acetate in dichloromethane, and then 3% to 6% methanol in ethyl acetate/dichloromethane (v/v; 1:1). The title compound was obtained as a yellow solid after trituration with diethyl ether (0.015 g, 28%); 1H-NMR (500 MHz, DMSO-d6) 2.62 (br s, 4H, piperazine N(CH2)2), 3.62 (s, 2H, NCH2CO), 3.66 (br s, 4H, piperazine N(CH2)2), 3.84 (s, 3H, OCH3), 7.10 (d, J=8.89 Hz, 2H) and 8.14 (d, J=8.57 Hz, 2H) (3,5-C6H4OMe and 2,6-C6H4—OMe), 7.39 (dd, J=7.91, 5.08 Hz, 1H, pyridyl 5-H), 7.76 (d, J=7.80 Hz, 1H, pyridyl 4-H), 8.20 (s, 1H, imidazo[4,5-b]pyridine 5-H), 8.50 (dd, J=4.76, 1.58 Hz, 1H, pyridyl 6-H), 8.56 (d, J=1.62 Hz, 1H, pyridyl 2-H), 13.37 (s, 1H, imidazo[4,5-b]pyridine N—H);
Reaction SMILES: [O:1]1[C:5]2[CH:6]=[CH:7][C:8]([S:10]([N:13]([CH2:38][CH:39]([CH3:41])[CH3:40])[CH2:14][C@@H:15]([OH:37])[C@@H:16]([NH:25][C:26](=[O:36])[O:27][C@@H:28]3[C@H:35]4[C@H:31]([O:32][CH2:33][CH2:34]4)[O:30][CH2:29]3)[CH2:17][C:18]3[CH:23]=[CH:22][C:21]([OH:24])=[CH:20][CH:19]=3)(=[O:12])=[O:11])=[CH:9][C:4]=2[O:3][CH2:2]1.[Si:42]([O:49][CH2:50][CH2:51][CH2:52]O)([C:45]([CH3:48])([CH3:47])[CH3:46])([CH3:44])[CH3:43].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.N(C(OC(C)C)=O)=NC(OC(C)C)=O>>[O:1]1[C:5]2[CH:6]=[CH:7][C:8]([S:10]([N:13]([CH2:38][CH:39]([CH3:41])[CH3:40])[CH2:14][C@@H:15]([OH:37])[C@@H:16]([NH:25][C:26](=[O:36])[O:27][C@@H:28]3[C@H:35]4[C@H:31]([O:32][CH2:33][CH2:34]4)[O:30][CH2:29]3)[CH2:17][C:18]3[CH:23]=[CH:22][C:21]([O:24][CH2:52][CH2:51][CH2:50][O:49][Si:42]([C:45]([CH3:46])([CH3:48])[CH3:47])([CH3:43])[CH3:44])=[CH:20][CH:19]=3)(=[O:12])=[O:11])=[CH:9][C:4]=2[O:3][CH2:2]1
Reactant: CC(C)CN(C[C@@H](O)[C@H](Cc1ccc(O)cc1)NC(=O)O[C@H]1CO[C@H]2OCC[C@H]21)S(=O)(=O)c1ccc2c(c1)OCO2
Reactant: CC(C)(C)[Si](C)(C)OCCCO
Agent: CC(C)OC(=O)N=NC(=O)OC(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Product: CC(C)CN(C[C@@H](O)[C@H](Cc1ccc(OCCCO[Si](C)(C)C(C)(C)C)cc1)NC(=O)O[C@H]1CO[C@H]2OCC[C@H]21)S(=O)(=O)c1ccc2c(c1)OCO2

Procedure:
(3R,3aS,6aR)-Hexahydrofuro[2,3-b]furan-3-yl (1S,2R)-3-[(1,3-benzodioxol-5-ylsulfonyl)(isobutyl)amino]-2-hydroxy-1-(4-hydroxybenzyl)propylcarbamate was treated with 3-{[tert-butyl(dimethyl)silyl]oxy}-1-propanol (J. Org. Chem. 1986, 51, 3388-3390)/triphenyl phosphine/diisopropyl azodicarboxylate as described in step a (Example 213) to provide the title compound as solid foam. 1H NMR (DMSO-d6): δ 0.0 (6H, s), 0.78 (3H, d), 0.8 (9H, s), 0.82 (3H, d), 1.2 (1H, dd), 1.4 (1H, quintuplet), 1.8 (2H, quintuplet), 1.9-2.0 (1H, m), 2.38 (1H, dd), 2.6-2.8 (3H, m), 2.9 (1H, d), 2.98 (1H, dd), 3.2-3.3 (2H, m), 3.35-3.45 (1H, m), 3.5-3.6 (3H, m), 3.7 (2H, t), 3.8 (1H, dd), 3.9 (2H, t), 4.8 (1H, dt), 5.0 (1H, d), 5.5 (1H, d), 6.18 (2H, s), 6.75 (2H, d), 7.0-7.1 (3H, m), 7.18 (1H, d), 7.2 (1H, s), 7.28 (1H, d); MS: 765 (MH+)
Reaction SMILES: [CH3:1][NH:2][NH2:3].[CH3:4][O:5][C:6](=[O:12])/[CH:7]=[CH:8]\[C:9]([OH:11])=[O:10].[CH2:13]([N:15]([CH2:18][CH3:19])[CH2:16][CH3:17])[CH3:14].[CH:20](=O)[CH3:21]>C1COCC1>[CH2:13]([N:15]([CH2:18][CH3:19])[CH2:16][CH3:17])[CH3:14].[C:9]([CH:8]([N:2]([CH3:1])[N:3]=[CH:20][CH3:21])[CH2:7][C:6]([O:5][CH3:4])=[O:12])([OH:11])=[O:10]
Reactant: CC=O
Reactant: CNN
Reactant: COC(=O)/C=C\C(=O)O
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: CC=NN(C)C(CC(=O)OC)C(=O)O
Reaction time: 2 h

Procedure:
A solution of 88.5 g methylhydrazine (1.92 moles) in 340 ml THF is added at +25° C. to a solution of 250 g maleic acid monomethyl ester (1.92 moles) and 194.5 g triethylamine (1.92 moles) in 1850 ml THF. During the addition a precipitation of the triethylamine salt of the intermediate methyl 3-carboxy-3-(1-methyl-hydrazino)-propionate is formed. After stirring for 2 hours at +25° C., a solution of 101.6 g acetaldehyde (2.3 moles) in 370 ml THF is added at +25° C. The precipitation dissolves during the addition. After stirring for 1 hour at +25° C. the solution is evaporated completely. To remove traces of water or methanol, the residue is mixed with 750 ml toluene and evaporated again completely (10 mbar, 60° C.). Yield: 429.6 g of methyl 3-carboxy-3-(2-ethylidene-1-methylhydrazine)-propionate triethylamine salt as viscous yellow oil (83%).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:11][CH:10]([NH:12][C@H:13]2[CH2:17][CH2:16][NH:15][CH2:14]2)[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[C:18](O)(=[O:25])[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1.CCN(CC)CC.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F>C(Cl)Cl>[C:1]([O:5][C:6]([N:8]1[CH2:9][CH:10]([NH:12][C@H:13]2[CH2:17][CH2:16][N:15]([C:18](=[O:25])[C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=3)[CH2:14]2)[CH2:11]1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: O=C(O)c1ccccc1
Reactant: CC(C)(C)OC(=O)N1CC(N[C@H]2CCNC2)C1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CC(C)(C)OC(=O)N1CC(N[C@H]2CCN(C(=O)c3ccccc3)C2)C1
Temperature: 25 °C
Reaction time: 18 h
Yield: 67.1 %

Procedure:
To a solution of compound 5c (1 g, 4.14 mmol), compound 4a (0.557 g, 4.56 mmol), and Et3N (1.27 mL, 8.28 mmol) in CH2Cl2 (20 mL) was added HATU (2.05 g, 5.38 mmol). The reaction mixture was stirred at room temperature for 18 h. The resultant mixture was diluted with CH2Cl2 and washed with aq. NaHCO3. The organic phase was dried over Na2SO4, filtered, and concentrated under reduced pressure. Purification of the residue by flash column chromatography (silica gel, 5% MeOH/EtOAc+0.5 TEA %) gave compound 5d (0.96 g). MS m/z (M+Na+) 368.0.
Reaction SMILES: [Cl:1][C:2]1[CH:23]=[CH:22][C:5]([O:6][C:7]2[CH:12]=[CH:11][C:10]([C:13]3[C:18](=[O:19])[CH:17]=[C:16]([CH3:20])O[C:14]=3[CH3:21])=[CH:9][CH:8]=2)=[CH:4][CH:3]=1.Cl.[NH2:25][OH:26].C([O-])(=O)C.[Na+]>C(O)C.O>[Cl:1][C:2]1[CH:23]=[CH:22][C:5]([O:6][C:7]2[CH:12]=[CH:11][C:10]([C:13]3[C:18](=[O:19])[CH:17]=[C:16]([CH3:20])[N:25]([OH:26])[C:14]=3[CH3:21])=[CH:9][CH:8]=2)=[CH:4][CH:3]=1
Reactant: Cc1cc(=O)c(-c2ccc(Oc3ccc(Cl)cc3)cc2)c(C)o1
Reactant: NO
Agent: CC(=O)[O-]
Agent: Cl
Agent: [Na+]
Solvent: CCO
Solvent: O
Product: Cc1cc(=O)c(-c2ccc(Oc3ccc(Cl)cc3)cc2)c(C)n1O
Temperature: 25 °C
Yield: 19.1 %

Procedure:
A mixture of 3-(4-(4-chlorophenoxy)phenyl)-2,6-dimethylpyran-4-one (1.0 g), hydroxylamine hydrochloride (1.06 g), sodium acetate (1.25 g) and water (5 ml) in ethanol (10 ml) was heated at reflux for 3 days. After cooling to rt the mixture was diluted with water (20 ml) and the precipitate filtered off and washed with ethyl acetate. Recrystallisation from DMF afforded the title compound (0.2 g), m.p. 232°-236°, NMR δH (d6-DMSO)7.5-7.4 (2H, d, a 8 Hz), 7.3-7.2 (2H, d, J 8 Hz), 7.15-7.0 (4H, m), 6.75 (1H, s), 2.35 (3H, s), 2.15 (3H, s).
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[C:7]2[S:14][CH:13]=[C:12]([CH2:15][O:16][C:17]3[CH:22]=[C:21]([NH2:23])[CH:20]=[CH:19][C:18]=3[CH3:24])[C:8]=2[CH:9]=[N:10][CH:11]=1)=[O:5])[CH3:2].C(N(C(C)C)CC)(C)C.[Cl:34][C:35]1[CH:36]=[C:37]([CH:41]=[CH:42][CH:43]=1)[C:38](Cl)=[O:39]>C1COCC1>[CH2:1]([O:3][C:4]([C:6]1[C:7]2[S:14][CH:13]=[C:12]([CH2:15][O:16][C:17]3[CH:22]=[C:21]([NH:23][C:38](=[O:39])[C:37]4[CH:41]=[CH:42][CH:43]=[C:35]([Cl:34])[CH:36]=4)[CH:20]=[CH:19][C:18]=3[CH3:24])[C:8]=2[CH:9]=[N:10][CH:11]=1)=[O:5])[CH3:2]
Reactant: O=C(Cl)c1cccc(Cl)c1
Reactant: CCOC(=O)c1cncc2c(COc3cc(N)ccc3C)csc12
Solvent: CCN(C(C)C)C(C)C
Solvent: C1CCOC1
Product: CCOC(=O)c1cncc2c(COc3cc(NC(=O)c4cccc(Cl)c4)ccc3C)csc12
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
To a solution of 3-(5-amino-2-methyl-phenoxymethyl)-thieno[3,2-c]pyridine-7-carboxylic acid ethyl ester (346.7 mg, 1.01 mmol) (from Example 23 supra) in THF (20 mL) were added diisopropylethylamine (258 mg, 2.03 mmol) (Aldrich) and then 3-chlorobenzoyl chloride (265 mg, 1.51 mmol) (Aldrich). The reaction was stirred at room temperature for 30 minutes before it was concentrated to remove the solvent. The residue was diluted with EtOAc (200 mL), washed with aqueous 1N NaOH (15 mL), brine (2×15 mL), dried (Na2SO4) and concentrated. The residue was purified by column chromatography (CH2Cl2/MeOH, 99/1 to 95/5) to give 3-[5-(3-chloro-benzoylamino)-2-methyl-phenoxymethyl]-thieno[3,2-c]pyridine-7-carboxylic acid ethyl ester as a white solid. (Yield 468 mg, 97%).
Reaction SMILES: [NH2:1]C1C2C(=CC(S(O)(=O)=O)=CC=2O)C=C(S(O)(=O)=O)C=1.C([O-])(=O)C.[Na+].ClCC[S:29]([C:32]1[CH:40]=[CH:39][C:35](C(Cl)=O)=[C:34](C)[CH:33]=1)(=[O:31])=[O:30].[OH2:42]>>[S:29]([C:32]1[CH:40]=[CH:39][CH:35]=[CH:34][C:33]=1[NH2:1])([OH:31])(=[O:30])=[O:42]
Reactant: Cc1cc(S(=O)(=O)CCCl)ccc1C(=O)Cl
Reactant: Nc1cc(S(=O)(=O)O)cc2cc(S(=O)(=O)O)cc(O)c12
Reactant: O
Agent: CC(=O)[O-]
Agent: [Na+]
Product: Nc1ccccc1S(=O)(=O)O

Procedure:
A neutral solution of 31.9 parts of 1-amino-8-hydroxynaphthalene-3,6-disulfonic acid in 300 parts of water is prepared, 30 parts of crystalline sodium acetate are added and the mixture is cooled to 5° to 10° C. 31 parts of finely ground 4-(β-chloroethylsulfonyl)-methyl-benzoyl chloride are added in the course of 1 to 2 hours, with stirring, and stirring is then continued for several hours. A diazonium salt solution obtained from 14.1 parts of 2-sulfo-aniline are then allowed to run in, and the coupling reaction is carried out at a pH value of 6 to 7. The coupling solution is then clarified and the azo compound prepared is isolated from the filtrate in the customary manner, for example by evaporation, spray-drying or salting out.
Reaction SMILES: [C:1]1(=[O:8])[CH:6]=[CH:5][C:4](=[O:7])[CH:3]=[CH:2]1.Br[CH:10](Br)[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=1[CH:17](Br)Br.[I-].[Na+]>CN(C)C=O>[C:1]1(=[O:8])[C:6]2[C:5](=[CH:10][C:11]3[C:12]([CH:17]=2)=[CH:13][CH:14]=[CH:15][CH:16]=3)[C:4](=[O:7])[CH:3]=[CH:2]1
Reactant: O=C1C=CC(=O)C=C1
Reactant: BrC(Br)c1ccccc1C(Br)Br
Agent: [I-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: O=C1C=CC(=O)c2cc3ccccc3cc21
Temperature: 70 °C
Reaction time: 8 h
Yield: 47 %

Procedure:
In an atmosphere of argon, 60 g (550 mmole) of 1,4-benzoquinone, 100 g (240 mmole) of 1,2-bis(dibromomethyl)benzene and 235 g (1.6 mole) of sodium iodide were dissolved into 850 ml of dry dimethylformamide. After the exothermic reaction was completed, the reaction solution was heated to 70° C. and stirred for 8 hours. After the reaction was completed, the formed crystals were separated by filtration and washed with methanol and water and 23 g (the yield: 47%) of light yellow needle crystals of 1,4-anthraquinone were obtained.
Reaction SMILES: [CH3:1][N:2]1[CH:7]=[C:6]([C:8](OCC)=[O:9])[C:5](=[O:13])[C:4]2[CH:14]=[C:15]([CH2:17][N:18]3[CH2:23][CH2:22][O:21][CH2:20][CH2:19]3)[S:16][C:3]1=2.[F:24][C:25]1[CH:32]=[CH:31][C:28]([CH2:29][NH2:30])=[CH:27][CH:26]=1>C1(C)C=CC=CC=1>[F:24][C:25]1[CH:32]=[CH:31][C:28]([CH2:29][NH:30][C:8]([C:6]2[C:5](=[O:13])[C:4]3[CH:14]=[C:15]([CH2:17][N:18]4[CH2:19][CH2:20][O:21][CH2:22][CH2:23]4)[S:16][C:3]=3[N:2]([CH3:1])[CH:7]=2)=[O:9])=[CH:27][CH:26]=1
Reactant: NCc1ccc(F)cc1
Reactant: CCOC(=O)c1cn(C)c2sc(CN3CCOCC3)cc2c1=O
Solvent: Cc1ccccc1
Product: Cn1cc(C(=O)NCc2ccc(F)cc2)c(=O)c2cc(CN3CCOCC3)sc21
Yield: 50 %

Procedure:
A mixture of ethyl 7-methyl-2-(4-morpholinylmethyl)-4-oxo-4,7-dihydro-thieno[2,3-b]pyridine-5-carboxylate (0.300 g) from Preparation No. 4 and 4-fluorobenzylamine (1.02 mL) is stirred at 175° C. for 3 h. The reaction mixture is allowed to cool for several minutes and is then diluted with toluene (15 mL). The resulting off-white precipitate is filtered off and recrystallized from acetonitrile then ethanol to yield 0.184 g (50%) of the title compound as a white, crystalline solid.
Reaction SMILES: C([O:3][C:4]([C:6]1[N:7]([CH3:15])[N:8]=[C:9]([C:11]([CH3:14])([CH3:13])[CH3:12])[CH:10]=1)=[O:5])C.O.[OH-].[Na+]>CO>[C:11]([C:9]1[CH:10]=[C:6]([C:4]([OH:5])=[O:3])[N:7]([CH3:15])[N:8]=1)([CH3:14])([CH3:12])[CH3:13]
Reactant: CCOC(=O)c1cc(C(C)(C)C)nn1C
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CO
Product: Cn1nc(C(C)(C)C)cc1C(=O)O
Temperature: 25 °C
Reaction time: 72 h

Procedure:
5-tert-Butyl-2-methyl-2H-pyrazole-3-carboxylic acid ethyl ester (1.08 g, 5.14 mmol, prepared as described in the previous step) was dissolved in MeOH (15 mL), and H2O (15 mL) and 2.5 M aqueous NaOH (5.00 mL, 12.5 mmol) was added. The resulting mixture was stirred at room temperature for 72 h, and then extracted with Et2O (2×10 mL). The aqueous layer was acidified to ca. pH 2 using 3 M aqueous HCl and extracted with DCM (3×20 mL). The combined organic extracts were dried over anhydrous MgSO4 and filtered, and the solvent was removed under reduced pressure to yield the title compound as a white solid. 1H-NMR (400 MHz, CDCl3) δ: 6.80 (s, 1H), 4.15 (s, 3H), 1.32 (s, 9H).
Reaction SMILES: [C:1](Cl)(=[O:6])/[C:2](=[CH:4]/[CH3:5])/[CH3:3].[CH3:8][C:9]1[CH:10]=[CH:11][C:12]([CH3:15])=[CH:13][CH:14]=1.Cl>C(=S)=S>[CH3:3][CH:2]1[CH:4]([CH3:5])[C:11]2[C:10](=[C:9]([CH3:8])[CH:14]=[CH:13][C:12]=2[CH3:15])[C:1]1=[O:6]
Reactant: C/C=C(\C)C(=O)Cl
Reactant: Cc1ccc(C)cc1
Agent: Cl
Solvent: S=C=S
Product: Cc1ccc(C)c2c1C(=O)C(C)C2C
Temperature: -10 °C
Reaction time: 2 h
Yield: 51.6 %

Procedure:
Under an argon atmosphere A1Cl3 (64 g, 0.48 mol) and CS2 (250 ml) were placed in a 1 liter three necked round bottomed flask fitted with a magnetic stirring apparatus, an addition funnel, an inner thermometer and a reflux condenser. A mixture of tigloyl chloride (33) (42 g, 0.35 mol) and p-xylene (42.8 ml, 0.35 mol) was added over a period of 1 h at −10° C. under vigorous stirring. After 2 h stirring at −10° C. the mixture was allowed to come to ambient temperature and was stirred at that temperature overnight. The brown reaction mixture was then refluxed for 3 h, after cooling to ambient temperature the reaction mixture was poured carefully onto a mixture of concentrated HCl (300 ml) and ice (500 g). Then the mixture was transferred into a separation funnel, the lower CS2 layer was separated and the aqueous layer extracted with diethyl ether (3×100 ml). The combined organic layers were dried over magnesium sulfate, filtered, and the solvents removed in a rotary evaporator to give a red brown liquid. This residue was rectified using a 35 cm Vigreux column to afford 2,3,4,7-tetramethyl-1-indanone (35) (34 g, 52%, 95-100° C., 1.5-1.2 mbar) as a pale yellow liquid. (35) was found to be a mixture of the two isomers of 2,3,4,7-tetramethyl-1-indanone (35a to 35b approximately 3:1). The 1H NMR spectrum was identical with the literature (S. Barlow, D. R. Cary, M. J. Drewitt, D. O'Hare, J. Chem. Soc. Dalton Trans. 1997 3867-3878).
Reaction SMILES: [CH2:1]([NH:3][C:4]1[CH:11]=[CH:10][CH:9]=[CH:8][C:5]=1[CH2:6]O)[CH3:2].S(Cl)([Cl:14])=O>C1C=CC=CC=1>[ClH:14].[CH2:1]([NH:3][C:4]1[CH:11]=[CH:10][CH:9]=[CH:8][C:5]=1[CH2:6][Cl:14])[CH3:2]
Reactant: CCNc1ccccc1CO
Reactant: O=S(Cl)Cl
Solvent: c1ccccc1
Product: CCNc1ccccc1CCl
Product: Cl
Temperature: 0 °C
Reaction time: 1 h

Procedure:
To a solution of 6.4 g (42 mmol) of 2-ethylaminobenzyl alcohol (prepared by reducing methyl 2-acetamidobenzoate with lithium aluminum hydride) in 90 ml of dry benzene was dropwise added under chilling with ice 4.6 ml (62 mmol) of thionyl chloride in 90 ml of dry benzene for 20 min. The mixture was stirred for 1 hr. at room temperature and subsequently 20 min. at 50° C. The solvent was distilled off under reduced pressure at a temperature below 50° C. to leave 7.7 g of 2-ethylaminobenzyl chloride hydrochloride as a brown oil. The obtained hydrochloride (7.7 g, 35 mmol) was portionwise added to a solution of 3.7 g (37 mmol) of 2-mercaptoimidazole in 60 ml of ethanol. The mixture was then stirred for 1 hr. Ethanol was distilled off under reduced pressure at a temperature below 40° C. The residue was shaken with saturated aqueous sodium hydrogencarbonate and chloroform. The chloroform portion was taken out and dried over anhydrous sodium sulfate. The solvent was distilled off under reduced pressure. The residue was crystallized by addition of ether to give 4.78 g of the desired compound as a pale yellow crystalline powder.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][CH2:6][CH2:5]2.CCN(C(C)C)C(C)C.[CH3:20][N:21]=[C:22]=[O:23]>C1COCC1>[Br:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[N:7]([C:22]([NH:21][CH3:20])=[O:23])[CH2:6][CH2:5]2
Reactant: Brc1ccc2c(c1)CCN2
Reactant: CN=C=O
Solvent: C1CCOC1
Solvent: CCN(C(C)C)C(C)C
Product: CNC(=O)N1CCc2cc(Br)ccc21
Temperature: 25 °C
Yield: 72.6 %

Procedure:
To a solution of 5-bromoindoline (1.0 g, 5.05 mmol) and DIEA (1.9 mL, 11.11 mmol) in THF (40 mL) was added methylisocyanate (346 mg, 6.06 mmol). The reaction was maintained at room temperature for 4 h. The resulting precipitate was filtered and dried under vacuum to afford 5-bromo-N-methylindoline-1-carboxamide (935 mg, 72% yield) as a white solid. 1H NMR (400 MHz, DMSO-d6) δ ppm 7.75 (d, J=8.78 Hz, 1H), 7.17-7.31 (m, 2 H), 6.60 (d, J=4.27 Hz, 1H), 3.85 (t, J=8.78 Hz, 2H), 3.10 (t, J=8.66 Hz, 2H), 2.65 (d, J=4.27 Hz, 3H); MS (EI) m/z=255.1[M+1]+.