Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [H-].[Na+].C[O:4][C:5]([C:7]1[S:8][C:9]([C:29]#[C:30][C:31]([CH3:41])([CH3:40])[CH2:32][O:33][CH:34]2[CH2:39][CH2:38][CH2:37][CH2:36][O:35]2)=[CH:10][C:11]=1[N:12]([CH:22]1[CH2:27][CH2:26][CH:25]([OH:28])[CH2:24][CH2:23]1)[C:13]([CH:15]1[CH2:20][CH2:19][CH:18]([CH3:21])[CH2:17][CH2:16]1)=[O:14])=[O:6].F[C:43]1[CH:48]=[CH:47][CH:46]=[CH:45][N:44]=1.O>CN(C=O)C>[CH3:41][C:31]([CH3:40])([CH2:32][O:33][CH:34]1[CH2:39][CH2:38][CH2:37][CH2:36][O:35]1)[C:30]#[C:29][C:9]1[S:8][C:7]([C:5]([OH:4])=[O:6])=[C:11]([N:12]([C:13]([CH:15]2[CH2:20][CH2:19][CH:18]([CH3:21])[CH2:17][CH2:16]2)=[O:14])[CH:22]2[CH2:23][CH2:24][CH:25]([O:28][C:43]3[CH:48]=[CH:47][CH:46]=[CH:45][N:44]=3)[CH2:26][CH2:27]2)[CH:10]=1
Reactant: Fc1ccccn1
Reactant: COC(=O)c1sc(C#CC(C)(C)COC2CCCCO2)cc1N(C(=O)C1CCC(C)CC1)C1CCC(O)CC1
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: CC1CCC(C(=O)N(c2cc(C#CC(C)(C)COC3CCCCO3)sc2C(=O)O)C2CCC(Oc3ccccn3)CC2)CC1
Yield: 43.6 %

Procedure:
NaH (45 mg of a 60% oil dispersion, 1.12 mmol) was added in one portion to a solution of 5-[3,3-dimethyl-4-(tetrahydro-pyran-2-yloxy)-but-1-ynyl]-3-[(4-hydroxy-cyclohexyl)-(4-methyl-cyclohexanecarbonyl)-amino]-thiophene-2-carboxylic acid methyl ester (124 mg, 0.221 mmol) and 2-fluoropyridine (0.095 mL, 1.1 mmol) in dry DMF (2.0 mL). After several minutes, the reaction was placed in a 85° C. oil bath and heated for 4 h. The reaction was cooled, water (0.50 mL) was added and the reaction mixture evaporated to dryness to provide a solid residue. The solid was washed with ethyl ether/hexanes then water, collected by centrifugation and washed with ethyl ether followed by water. The solid was collected and dried under vacuum to provide 5-[3,3-dimethyl-4-(tetrahydro-pyran-2-yloxy)-but-1-ynyl]-3-{(4-methyl-cyclohexanecarbonyl)-[4-(pyridin-2-yloxy)-cyclohexyl]-amino}-thiophene-2-carboxylic acid (Compound 311) (60 mg, 42%) as an off-white solid. MS (m/z): 528.3 [M+H-(2-hydroxypyridine)]+; HPLC retention time: 4.61 min (2-98% acetonitrile:water with 0.05% trifluoroacetic acid).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH:12]=[CH:11][CH:10]=[C:9]1B(O)O)=[O:7])([CH3:4])([CH3:3])[CH3:2].[N+:16]([C:19]1[CH:20]=[C:21](Br)[CH:22]=[CH:23][CH:24]=1)([O-:18])=[O:17]>COCCOC.C([O-])([O-])=O.[Na+].[Na+].C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[N+:16]([C:19]1[CH:24]=[C:23]([C:9]2[N:8]([C:6]([O:5][C:1]([CH3:4])([CH3:3])[CH3:2])=[O:7])[CH:12]=[CH:11][CH:10]=2)[CH:22]=[CH:21][CH:20]=1)([O-:18])=[O:17]
Reactant: O=[N+]([O-])c1cccc(Br)c1
Reactant: CC(C)(C)OC(=O)n1cccc1B(O)O
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: COCCOC
Product: CC(C)(C)OC(=O)n1cccc1-c1cccc([N+](=O)[O-])c1
Temperature: 90 °C
Yield: 76.3 %

Procedure:
A mixture of 3A (1.46 g, 6.9 mmol) and 3-nitrobromobenzene (0.81 g, 4.0 mmol) in DME (40 mL) and 2.0 M Na2CO3 (8.0 mL) was degassed by bubbling argon for 5 min. To this solution, Pd(PPh3)4 (280 mg, 0.25 mmol) was added. The mixture was heated at 90° C. for 5 h. After cooling to rt, it was extracted with EtOAc and dried over Na2SO4. The product was purified by silica gel chromatography (CH2Cl2/hexanes=1/5) to give 4A (880 mg, 75% yield) as viscous oil. 1H NMR (400 MHz, Methanol-d4) δ ppm 1.37 (s, 9H) 6.28 (t, J=3.52 Hz, 1H) 6.33 (dd, J=3.52, 1.76 Hz, 1H) 7.41 (dd, J=3.52, 1.76 Hz, 1H) 7.59 (m, 1H) 7.73 (d, J=7.91 Hz, 1H) 8.16 (m, 2H).
Reaction SMILES: [OH:1][CH2:2][C:3]1[S:4][CH:5]=[C:6]2[C:11]=1[C:10](=[O:12])[N:9]([C:13]1[CH:18]=[C:17]([S:19]([N:22]3[C:31]4[C:26](=[CH:27][CH:28]=[CH:29][CH:30]=4)[CH2:25][CH2:24][CH2:23]3)(=[O:21])=[O:20])[CH:16]=[CH:15][C:14]=1[Cl:32])[C:8](=[O:33])[NH:7]2>CN(C)C=O.C(OCC)(=O)C.[O-2].[O-2].[Mn+4]>[CH:2]([C:3]1[S:4][CH:5]=[C:6]2[C:11]=1[C:10](=[O:12])[N:9]([C:13]1[CH:18]=[C:17]([S:19]([N:22]3[C:31]4[C:26](=[CH:27][CH:28]=[CH:29][CH:30]=4)[CH2:25][CH2:24][CH2:23]3)(=[O:20])=[O:21])[CH:16]=[CH:15][C:14]=1[Cl:32])[C:8](=[O:33])[NH:7]2)=[O:1]
Reactant: O=c1[nH]c2csc(CO)c2c(=O)n1-c1cc(S(=O)(=O)N2CCCc3ccccc32)ccc1Cl
Agent: [Mn+4]
Agent: [O-2]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: O=Cc1scc2[nH]c(=O)n(-c3cc(S(=O)(=O)N4CCCc5ccccc54)ccc3Cl)c(=O)c12
Temperature: 25 °C
Reaction time: 8 h
Yield: 41.7 %

Procedure:
To a solution of 5-hydroxymethyl-3-[2-chloro-5-(3,4-dihydroquinolin-1(2H)-ylsulfonyl)phenyl]thieno[3,4-d]-pyrimidine-2,4(1H,3H)-dione (77 mg) in N,N-dimethylformamide (2.1 mL) was added manganese (IV) dioxide (0.77 g), and the mixture was stirred at room temperature overnight. The reaction mixture was diluted with ethyl acetate, and the insoluble material was removed by filtration. The filtrate was washed with water and brine successively, and dried over anhydrous magnesium sulfate. The solvent was removed under reduced pressure, and the residue was purified by column chromatography on silica gel (eluent: n-hexane/ethyl acetate=1/1) to give the title compound (32 mg).
Reaction SMILES: [OH:1][CH:2]1[CH2:6][N:5]([C:7]([O:9][CH2:10][C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)=[O:8])[CH2:4][CH:3]1[C:17]([OH:19])=O.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.[NH:44]1[C:52]2[C:47](=[C:48]([C:53]3[CH:54]=[C:55]([NH2:62])[C:56]4[CH:57]=[N:58][NH:59][C:60]=4[CH:61]=3)[CH:49]=[CH:50][CH:51]=2)[CH:46]=[CH:45]1.CCN(C(C)C)C(C)C>CN(C=O)C>[OH:1][CH:2]1[CH:3]([C:17]([NH:62][C:55]2[CH:54]=[C:53]([C:48]3[CH:49]=[CH:50][CH:51]=[C:52]4[C:47]=3[CH:46]=[CH:45][NH:44]4)[CH:61]=[C:60]3[C:56]=2[CH:57]=[N:58][NH:59]3)=[O:19])[CH2:4][N:5]([C:7]([O:9][CH2:10][C:11]2[CH:12]=[CH:13][CH:14]=[CH:15][CH:16]=2)=[O:8])[CH2:6]1
Reactant: O=C(O)C1CN(C(=O)OCc2ccccc2)CC1O
Reactant: Nc1cc(-c2cccc3[nH]ccc23)cc2[nH]ncc12
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: O=C(Nc1cc(-c2cccc3[nH]ccc23)cc2[nH]ncc12)C1CN(C(=O)OCc2ccccc2)CC1O
Reaction time: 0.17 h
Yield: 6.4 %

Procedure:
To a solution of 4-hydroxy-1-{[(phenylmethyl)oxy]carbonyl}-3-pyrrolidinecarboxylic acid (available from Fluorochem, 59 mg, 0.22 mmol) in DMF (1 ml) was added HATU (85 mg, 0.22 mmol) and the mixture stirred for 10 mins. Then 6-(1H-indol-4-yl)-1H-indazol-4-amine (46 mg, 0.19 mmol) and DIPEA (0.065 ml, 0.37 mmol) were added and the mixture allowed to stand for 18 h at 20° C. The solvent was removed under a stream of nitrogen and the residue purified by Mass Directed Automated Preparative HPLC (Method E), to give the title compound (6 mg) as a brown solid.
Reaction SMILES: [NH2:1][C:2]1[N:7]=[C:6]([C:8]2[CH:16]=[C:15]3[C:11]([C:12]([NH2:17])=[N:13][NH:14]3)=[CH:10][CH:9]=2)[CH:5]=[C:4](S(C)(=O)=O)[N:3]=1.[CH3:22][C:23]1[CH:24]=[C:25]([CH2:29][CH2:30][NH2:31])[CH:26]=[CH:27][CH:28]=1.CCN(C(C)C)C(C)C>CN1C(=O)CCC1>[NH2:17][C:12]1[C:11]2[C:15](=[CH:16][C:8]([C:6]3[N:7]=[C:2]([NH2:1])[N:3]=[C:4]([NH:31][CH2:30][CH2:29][C:25]4[CH:26]=[CH:27][CH:28]=[C:23]([CH3:22])[CH:24]=4)[CH:5]=3)=[CH:9][CH:10]=2)[NH:14][N:13]=1
Reactant: CS(=O)(=O)c1cc(-c2ccc3c(N)n[nH]c3c2)nc(N)n1
Reactant: Cc1cccc(CCN)c1
Solvent: CN1CCCC1=O
Solvent: CCN(C(C)C)C(C)C
Product: Cc1cccc(CCNc2cc(-c3ccc4c(N)n[nH]c4c3)nc(N)n2)c1
Temperature: 160 °C
Yield: 35.1 %

Procedure:
A mixture of 6-[2-amino-6-(methylsulfonyl)-4-pyrimidinyl]-1H-indazol-3-amine (300 mg, 0.99 mmol), 2-(3-methylphenyl)ethanamine (300 mg, 2.22 mmol), and Hunig's base (2 mL) in NMP (3 mL) was heated for 2 hours at 160° C. in a BiotageInitiator® microwave synthesizer. Upon cooling, the mixture was decanted to remove the solids, and the resulting solution was concentrated to dryness. The crude material was purified by RPHPLC to afford the title compound (125 mg) as a yellow solid. 1H NMR (400 MHz, DMSO-d6): δ 2.03 (s, 3H), 2.79-2.82 (m, 2H), 3.49-3.51 (m, 2H), 5.35 (s, 2H), 5.99 (s, 2H), 6.28 (s, 1H), 6.92-7.10 (m, 4H), 7.41 (d, J=7.6 Hz, 1H), 7.69 (d, J=8.8 Hz, 1H), 7.84 (s, 1H), 11.49 (s, 1H).
Reaction SMILES: C[O:2][C:3](=[O:48])[CH2:4][N:5]([CH2:43][C:44]([O:46]C)=[O:45])[C:6]1[CH:11]=[C:10]([O:12][CH2:13][CH2:14][O:15][CH2:16][CH2:17][O:18][CH2:19][CH2:20][O:21][CH2:22][CH3:23])[CH:9]=[C:8]([O:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][CH2:36][CH2:37][CH2:38][CH2:39][CH2:40][CH2:41][CH3:42])[CH:7]=1.[OH-].[Na+]>CO>[C:44]([CH2:43][N:5]([C:6]1[CH:7]=[C:8]([O:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][CH2:36][CH2:37][CH2:38][CH2:39][CH2:40][CH2:41][CH3:42])[CH:9]=[C:10]([O:12][CH2:13][CH2:14][O:15][CH2:16][CH2:17][O:18][CH2:19][CH2:20][O:21][CH2:22][CH3:23])[CH:11]=1)[CH2:4][C:3]([OH:48])=[O:2])([OH:46])=[O:45]
Reactant: CCCCCCCCCCCCCCCCCCOc1cc(OCCOCCOCCOCC)cc(N(CC(=O)OC)CC(=O)OC)c1
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: CCCCCCCCCCCCCCCCCCOc1cc(OCCOCCOCCOCC)cc(N(CC(=O)O)CC(=O)O)c1
Yield: 96 %

Procedure:
A solution of 1.76 g (2.58 mmol) of N-(2-methoxy-2-oxoethyl)-N-[3-octadecyloxy-5-(3,6,9-trioxaundec-1-yloxy)phenyl]glycine methyl ester and 2.2 ml (12.9 mmol) of 6N NaOH in 75 ml of methanol was kept at room temperature for 70 hours. The solvent was removed at reduced pressure and the residue was acidified to pH 2. The product was extracted with ethyl acetate and the dried extract was concentrated at reduced pressure to a solid which was triturated with hexane and filtered to give 1.62 g (96% yield, mp 76°-78°) of N-[(Carboxymethyl)-N-[3-[2-[2-(2-ethoxyethoxy)ethoxy]ethoxy]-5-(octadecyloxy) phenyl]glycine.
Reaction SMILES: [OH-].[Na+:2].[CH3:3][N:4]1[C:9](=[O:10])[CH:8]=[C:7]([N:11]2[CH2:16][CH2:15][O:14][CH2:13][CH2:12]2)[N:6]=[C:5]1[CH2:17][C:18]([O:20]CC)=[O:19]>O1CCCC1>[CH3:3][N:4]1[C:9](=[O:10])[CH:8]=[C:7]([N:11]2[CH2:12][CH2:13][O:14][CH2:15][CH2:16]2)[N:6]=[C:5]1[CH2:17][C:18]([O-:20])=[O:19].[Na+:2]
Reactant: CCOC(=O)Cc1nc(N2CCOCC2)cc(=O)n1C
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Product: Cn1c(CC(=O)[O-])nc(N2CCOCC2)cc1=O
Temperature: 25 °C
Reaction time: 48 h

Procedure:
2.88 ml of 2M sodium hydroxide are added to a solution of 1.62 g of ethyl [1-methyl-4-(morpholin-4-yl)-6-oxo-1,6-dihydropyrimidin-2-yl]acetate in 20 ml of tetrahydrofuran. The reaction mixture is stirred for 48 hours at ambient temperature. The precipitate formed is filtered off through sintered glass, washed with ethyl acetate and rinsed several times with ethyl ether. The solid obtained is then dried in a rotary evaporator. 730 mg of sodium [1-methyl-4-(morpholin-4-yl)-6-oxo-1,6-dihydropyrimidin-2-yl]acetate are obtained in the form of a white solid, the characteristics of which are the following:
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([N:8]2[CH:12]=[C:11]([CH3:13])[CH:10]=[N:9]2)[N:3]=1.C([Li])CCC.[Br:19]N1C(=O)CCC1=O.[Cl-].[NH4+]>C1COCC1.C(OCC)(=O)C>[Br:19][C:12]1[N:8]([C:4]2[CH:5]=[CH:6][CH:7]=[C:2]([CH3:1])[N:3]=2)[N:9]=[CH:10][C:11]=1[CH3:13]
Reactant: O=C1CCC(=O)N1Br
Reactant: Cc1cnn(-c2cccc(C)n2)c1
Agent: [Cl-]
Agent: [Li]CCCC
Agent: [NH4+]
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: Cc1cccc(-n2ncc(C)c2Br)n1
Temperature: -60 °C
Reaction time: 1 h

Procedure:
To a cold (−60° C.) solution of 2-methyl-6-(4-methyl-pyrazol-1-yl)-pyridine (0.52 g) (prepared by Reaction Condition 1 in Step i) in 14 mL of anhydrous THF was added 1.33 mL of a 2.5M solution of n-butyllithium (0.21 g) in hexanes. The reaction mixture was stirred at −60° C. for one hour. A 10 mL solution of N-bromosuccinimide (0.59 g) in THF was added and then the final solution was stirred at −60° C. for 2 hours. Saturated ammonium chloride (20 mL) was added and then the reaction mixture was allowed to warm to 24° C. The reaction mixture was diluted with 300 mL of ethyl acetate and then the aqueous phase was separated. The organic phase was washed with additional saturated ammonium chloride (50 mL) and then with brine (50 mL). The organic layer was separated, dried (sodium sulfate), filtered, and then the filtrate was evaporated to give a crude red oil. Purification by flash chromatography (silica gel, 20% ethyl acetate in heptane) provided, after drying, 0.377 g of the title compound as a yellow oil; 1H-NMR (400 MHz; DMSO-d6) δ 7.88 (t, 1H), 7.69 (s, 1H), 7.44 (s, 1H), 7.32 (s, 1H), 2.50 (s, 3H), 2.02 (s, 3H); MS (APCI+) m/z 254 (MH+).
Reaction SMILES: [CH2:1]([O:8][CH2:9][C@H:10]([NH:13][C:14]1[C:23]2[C:18](=[CH:19][CH:20]=[CH:21][CH:22]=2)[N:17]=[CH:16][C:15]=1[N+:24]([O-])=O)[CH2:11][OH:12])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1>C(#N)C.C(O)(C)C.[Pt]>[NH2:24][C:15]1[CH:16]=[N:17][C:18]2[C:23]([C:14]=1[NH:13][C@@H:10]([CH2:9][O:8][CH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1)[CH2:11][OH:12])=[CH:22][CH:21]=[CH:20][CH:19]=2
Reactant: O=[N+]([O-])c1cnc2ccccc2c1N[C@H](CO)COCc1ccccc1
Agent: [Pt]
Solvent: CC(C)O
Solvent: CC#N
Product: Nc1cnc2ccccc2c1N[C@H](CO)COCc1ccccc1
Reaction time: 2 h
Yield: 99.5 %

Procedure:
(2R)-3-(benzyloxy)-2-[(3-nitroquinolin-4-yl)amino]propan-1-ol (31 g, 87 mmol) was dissolved in a mixture of acetonitrile (810 mL) and isopropyl alcohol (90 mL) and the solution was placed in a pressure bottle. Platinum on carbon (5%, 3.1 g) was then added and the reaction mixture was shaken under H2 at 48 PSI (3.3×105 Pa). After 2 hours, the reaction mixture was filtered through a pad of CELITE filter agent. The pad was rinsed with acetonitrile and the combined filtrates were concentrated under reduced pressure to give (2R)-2-[(3-aminoquinolin-4-yl)amino]-3-(benzyloxy)propan-1-ol (28 g) as an orange oil.
Reaction SMILES: [C:1]([C:5]1[O:9][C:8]([CH3:10])=[C:7]([C:11](Cl)=[O:12])[CH:6]=1)([CH3:4])([CH3:3])[CH3:2].[OH-:14].[Li+]>C1COCC1.O>[C:1]([C:5]1[O:9][C:8]([CH3:10])=[C:7]([C:11]([OH:12])=[O:14])[CH:6]=1)([CH3:4])([CH3:3])[CH3:2]
Reactant: Cc1oc(C(C)(C)C)cc1C(=O)Cl
Reactant: [OH-]
Agent: [Li+]
Solvent: C1CCOC1
Solvent: O
Product: Cc1oc(C(C)(C)C)cc1C(=O)O
Temperature: 25 °C
Reaction time: 2 h
Yield: 93.7 %

Procedure:
To a solution of 5-tert-butyl-2-methylfuran-3-carbonyl chloride (0.341 g, 1.699 mmol) in THF (2 ml) added lithium hydroxide (0.107 g, 2.55 mmol) in water (1 mL) and the mixture was stirred for 2 h at RT. Solvent was removed in vacuo and the residue was acidified with 2N HCl to afford solid which was filtered and air dried to afford 5-tert-butyl-2-methylfuran-3-carboxylic acid (0.29 g, 94% yield) as a white solid. MS (ESI) m/z: 183.1 (M+H+).
Reaction SMILES: [CH2:1]([C:3]1[O:4][C:5]([C:23]2[CH:28]=[CH:27][C:26]([C:29]([F:32])([F:31])[F:30])=[CH:25][CH:24]=2)=[CH:6][C:7]=1[CH:8]([O:13][C:14]1[CH:22]=[CH:21][C:17]([C:18]([OH:20])=O)=[CH:16][CH:15]=1)[CH2:9][CH:10]([CH3:12])[CH3:11])[CH3:2].[CH3:33][NH:34][CH2:35][CH2:36][C:37]([O:39]CC)=[O:38]>>[CH2:1]([C:3]1[O:4][C:5]([C:23]2[CH:28]=[CH:27][C:26]([C:29]([F:32])([F:30])[F:31])=[CH:25][CH:24]=2)=[CH:6][C:7]=1[CH:8]([O:13][C:14]1[CH:22]=[CH:21][C:17]([C:18]([N:34]([CH3:33])[CH2:35][CH2:36][C:37]([OH:39])=[O:38])=[O:20])=[CH:16][CH:15]=1)[CH2:9][CH:10]([CH3:11])[CH3:12])[CH3:2]
Reactant: CCOC(=O)CCNC
Reactant: CCc1oc(-c2ccc(C(F)(F)F)cc2)cc1C(CC(C)C)Oc1ccc(C(=O)O)cc1
Product: CCc1oc(-c2ccc(C(F)(F)F)cc2)cc1C(CC(C)C)Oc1ccc(C(=O)N(C)CCC(=O)O)cc1
Yield: 95.3 %

Procedure:
An operation similar to that in Example 1 (4) was performed using 4-(1-{2-ethyl-5-[4-(trifluoromethyl)phenyl]-3-furyl}-3-methylbutoxy)benzoic acid (179 mg) as well as ethyl 3-(methylamino)propanoate (67 mg) to give the title compound (203 mg, 99%) as an oil.
Reaction SMILES: Br[CH2:2][CH2:3][CH2:4][NH:5][C:6](=[O:16])[C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][C:8]=1[N+:13]([O-:15])=[O:14].[NH:17]1[CH:21]=[N:20][N:19]=[N:18]1>CN(C)C=O>[NH:20]1[CH:21]=[N:17][NH:18][N:19]1[CH2:2][CH2:3][CH2:4][NH:5][C:6](=[O:16])[C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][C:8]=1[N+:13]([O-:15])=[O:14]
Reactant: c1nnn[nH]1
Reactant: O=C(NCCCBr)c1ccccc1[N+](=O)[O-]
Solvent: CN(C)C=O
Product: O=C(NCCCN1NC=NN1)c1ccccc1[N+](=O)[O-]
Temperature: 50 °C
Yield: 18.2 %

Procedure:
A solution of 24.5 g (0.085 mol) of N-(3-bromopropyl)-2-nitrobenzamide in 75 ml of dimethylformamide was slowly added to a solution of 7.00 g (0.10 mol) of tetrazole. The resulting solution was heated to 50° C. and allowed to react overnight. When the reaction was complete, as determined by thin layer chromatography, most of the dimethylformamide was removed under reduced pressure. The resultant residue was diluted with water, causing a precipitate to form. The precipitate was isolated by filtration and dried under vacuum. Thin layer chromatography and nuclear magnetic resonance spectroscopy indicated the presence of two isomers; namely, the N-1 and N-2 alkylated tetrazoles (75:25 ). The N-2 alkylated compound was isolated by column chromatography to provide 4.3 g of the desired subtitled intermediate. The N-1 alkylated compound was isolated by twice crystallizing the precipitate from cyanomethane to provide 3.72 g of that compound. (m.p. 148°-150° C.).
Reaction SMILES: [NH2:1][C:2]1[C:3]([F:17])=[C:4](/[CH:8]=[CH:9]/[C:10]([O:12][C:13]([CH3:16])([CH3:15])[CH3:14])=[O:11])[CH:5]=[CH:6][CH:7]=1>[Pd].C(O)C.C1COCC1>[NH2:1][C:2]1[C:3]([F:17])=[C:4]([CH2:8][CH2:9][C:10]([O:12][C:13]([CH3:15])([CH3:14])[CH3:16])=[O:11])[CH:5]=[CH:6][CH:7]=1
Reactant: CC(C)(C)OC(=O)/C=C/c1cccc(N)c1F
Agent: [Pd]
Solvent: C1CCOC1
Solvent: CCO
Product: CC(C)(C)OC(=O)CCc1cccc(N)c1F
Reaction time: 8 h

Procedure:
Palladium on carbon (10%) was added to a solution of 1660 mg (7.0 mmol) of tert-butyl (2E)-3-(3-amino-2-fluorophenyl)acrylate in a mixture of 5 ml of ethanol and 3 ml of THF, and the mixture was stirred vigorously at atmospheric pressure under an atmosphere of hydrogen overnight. The reaction mixture was then filtered through kieselguhr and the filter residue was washed repeatedly with ethanol/THF. The combined filtrates were concentrated under reduced pressure and the residue was purified by chromatography on silica gel (mobile phase cyclohexane/ethyl acetate 20:1→10:1). This gave 1350 mg of the target product (80.6% of theory).
Reaction SMILES: [NH2:1][C@@H:2]1[CH2:7][CH2:6][C@H:5]([NH:8][C:9]([C:11]2[C:15]3[N:16]=[CH:17][N:18]=[C:19]([C:20]4[CH:25]=[CH:24][C:23]([O:26][CH3:27])=[CH:22][C:21]=4[O:28][CH2:29][CH:30]4[CH2:32][CH2:31]4)[C:14]=3[NH:13][CH:12]=2)=[O:10])[CH2:4][CH2:3]1.Cl[C:34]([C@@H:36]([O:38]C(=O)C)[CH3:37])=[O:35]>>[OH:38][C@@H:36]([CH3:37])[C:34]([NH:1][C@@H:2]1[CH2:7][CH2:6][C@H:5]([NH:8][C:9]([C:11]2[C:15]3[N:16]=[CH:17][N:18]=[C:19]([C:20]4[CH:25]=[CH:24][C:23]([O:26][CH3:27])=[CH:22][C:21]=4[O:28][CH2:29][CH:30]4[CH2:31][CH2:32]4)[C:14]=3[NH:13][CH:12]=2)=[O:10])[CH2:4][CH2:3]1)=[O:35]
Reactant: CC(=O)O[C@@H](C)C(=O)Cl
Reactant: COc1ccc(-c2ncnc3c(C(=O)N[C@H]4CC[C@@H](N)CC4)c[nH]c23)c(OCC2CC2)c1
Product: COc1ccc(-c2ncnc3c(C(=O)N[C@H]4CC[C@@H](NC(=O)[C@H](C)O)CC4)c[nH]c23)c(OCC2CC2)c1

Procedure:
Starting from cis-4-(2-cyclopropylmethoxy-4-methoxy-phenyl)-5H-pyrrolo[3,2-d]pyrimidine-7-carboxylic acid (4-amino-cyclohexyl)-amide (example A151) and acetic acid (S)-1-chlorocarbonyl-ethyl ester the title compound is obtained as colorless solid.
Reaction SMILES: [CH2:1]([N:7]1[C:20]2[CH:19]=[CH:18][C:17]([O:21][CH3:22])=[CH:16][C:15]=2[S:14][C:13]2[C:8]1=[CH:9][CH:10]=[C:11]([O:23][CH3:24])[CH:12]=2)[CH2:2][CH2:3][CH2:4][CH2:5][CH3:6].C([Li])CCC.[CH:30](N1CCCCC1)=[O:31]>C(OCC)C.O1CCCC1>[CH2:1]([N:7]1[C:8]2[CH:9]=[CH:10][C:11]([O:23][CH3:24])=[C:12]([CH:30]=[O:31])[C:13]=2[S:14][C:15]2[C:20]1=[CH:19][CH:18]=[C:17]([O:21][CH3:22])[CH:16]=2)[CH2:2][CH2:3][CH2:4][CH2:5][CH3:6]
Reactant: O=CN1CCCCC1
Reactant: CCCCCCN1c2ccc(OC)cc2Sc2cc(OC)ccc21
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: CCOCC
Product: CCCCCCN1c2ccc(OC)cc2Sc2c1ccc(OC)c2C=O
Yield: 64.3 %

Procedure:
A solution of 3.42 g (10.0 mmol) of 10-hexyl-3,7-dimethoxy-phenothiazine in 50 ml of diethyl ether/tetrahydrofuran (4:1) was reacted with 8.12 ml of n-butyllithium solution (1.6M in hexane) and 3.35 g (29.6 mmol) of N-formylpiperidine analogously to that described in Example 4.1.1.c. The product was chromatographed on silica gel with ethyl acetate/hexane (1:4), whereupon 2.39 g (64.4%) of 10-hexyl-3,7-dimethoxy-phenothiazine-4-carbaldehyde were obtained as a red oil.
Reaction SMILES: CS(O[CH2:6][CH2:7][N:8]1[C:16]2[CH2:15][CH2:14][C:13]3[C:17]4[C:23]([NH:24][C:25]5[CH:26]=[C:27]6[C:31](=[CH:32][CH:33]=5)[N:30]([CH2:34][C:35]5[CH:40]=[CH:39][CH:38]=[C:37]([F:41])[CH:36]=5)[N:29]=[CH:28]6)=[N:22][CH:21]=[N:20][C:18]=4[S:19][C:12]=3[C:11]=2[CH:10]=[N:9]1)(=O)=O.[NH:42]1[CH:46]=[CH:45][N:44]=[CH:43]1.C(N(C(C)C)CC)(C)C>>[F:41][C:37]1[CH:36]=[C:35]([CH:40]=[CH:39][CH:38]=1)[CH2:34][N:30]1[C:31]2[C:27](=[CH:26][C:25]([NH:24][C:23]3[N:22]=[CH:21][N:20]=[C:18]4[S:19][C:12]5[C:11]6[CH:10]=[N:9][N:8]([CH2:7][CH2:6][N:42]7[CH:46]=[CH:45][N:44]=[CH:43]7)[C:16]=6[CH2:15][CH2:14][C:13]=5[C:17]=34)=[CH:33][CH:32]=2)[CH:28]=[N:29]1
Reactant: c1c[nH]cn1
Reactant: CS(=O)(=O)OCCn1ncc2c1CCc1c-2sc2ncnc(Nc3ccc4c(cnn4Cc4cccc(F)c4)c3)c12
Solvent: CCN(C(C)C)C(C)C
Product: Fc1cccc(Cn2ncc3cc(Nc4ncnc5sc6c(c45)CCc4c-6cnn4CCn4ccnc4)ccc32)c1

Procedure:
The title compound was prepared following the procedure described for example 277, utilizing 2-(6-{[1-(3-fluorobenzyl)-1H-indazol-5-yl]amino}-4,5-dihydro-3H-pyrimido[5′,4′:4,5]thieno[2,3-e]indazol-3-yl)ethyl methanesulfonate (1.53 g, 3.0 mmol), imidazole (17 mg, 0.25 mmol), and diisopropylethylamine (0.06 mL, 0.34 mmol). The desired product was collected as a white solid (37 mg, 39%). 1H-NMR (CD2Cl2-d2) δ 8.26 (s, 1H), 8.04 (s, 1H), 7.98 (s, 1H), 7.65 (s, 1H), 7.50 (d, 1H), 7.40 (d, 1H), 7.21-7.38 (m, 2H), 6.90-7.00 (m, 3H), 6.82 (dd, 1H), 6.72 (s, 1H), 5.60 (s, 2H), 4.42 (t, 2H), 4.35 (t, 2H), 3.17 (t, 2H), 2.40 (t, 2H); LCMS RT=2.58 min; [M+H]+=562.4
Reaction SMILES: [Cl:1][C:2]1[N:10]=[C:9]([O:11][CH3:12])[CH:8]=[CH:7][C:3]=1[C:4](Cl)=[O:5].[CH3:13][OH:14]>>[CH3:13][O:14][C:4](=[O:5])[C:3]1[CH:7]=[CH:8][C:9]([O:11][CH3:12])=[N:10][C:2]=1[Cl:1]
Reactant: CO
Reactant: COc1ccc(C(=O)Cl)c(Cl)n1
Product: COC(=O)c1ccc(OC)nc1Cl
Temperature: 25 °C
Reaction time: 1 h
Yield: 90 %

Procedure:
A mixture of 2-chloro-6-methoxy-nicotinoyl chloride (340 g, 1650 mmol) in MeOH (4500 mL) was stirred at RT for 1 h. The solvent was evaporated in vacuo. The mixture was basified with a saturated solution of NaHCO3 and extracted with EtOAc. The organic layer was separated, dried (Na2SO4), filtered and the solvents evaporated in vacuo. The crude product was purified by flash column chromatography (silica; petroleum ether/EtOAc 10/1). The desired fractions were collected and the solvents evaporated in vacuo to yield 2-chloro-6-methoxy-nicotinic acid methyl ester (280 g, 90%) as a solid.
Reaction SMILES: [CH3:1][C:2]1[N:6]([C:7]2[CH:12]=[CH:11][CH:10]=[C:9]([O:13][C:14]3[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=3)[CH:8]=2)[CH:5]=[N:4][C:3]=1[CH:20]=[N:21][OH:22].Cl.BrN1C(=O)CCC1=O.[CH2:32]([O:35][CH3:36])[C:33]#[CH:34]>CN(C)C=O.C(N(CC)CC)C>[CH3:36][O:35][CH2:32][C:33]1[O:22][N:21]=[C:20]([C:3]2[N:4]=[CH:5][N:6]([C:7]3[CH:12]=[CH:11][CH:10]=[C:9]([O:13][C:14]4[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=4)[CH:8]=3)[C:2]=2[CH3:1])[CH:34]=1
Reactant: Cc1c(C=NO)ncn1-c1cccc(Oc2ccccc2)c1
Reactant: C#CCOC
Agent: Cl
Agent: O=C1CCC(=O)N1Br
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: COCc1cc(-c2ncn(-c3cccc(Oc4ccccc4)c3)c2C)no1
Temperature: 25 °C
Reaction time: 14 h

Procedure:
660 mg of 5-methyl-1-(3-phenoxyphenyl)-imidazole-4-carbaldehydoxime, hydrochloride is dissolved in 4 ml of dimethylformamide. At 0° C., 0.28 ml of triethylamine is added and a solution of 360 mg of N-bromosuccinimide in 2 ml of dimethylformamide is instilled within one hour. Then, 1.7 ml of methyl propargyl ether and 0.28 ml of triethylamine are added, and the mixture is stirred for 14 hours at room temperature. 360 mg of N-bromosuccinimide in 2 ml of dimethylformamide and 0.28 ml of triethylamine are again added and the mixture is stirred for 18 hours at room temperature. After the concentration by evaporation, it is mixed with water and extracted with ethyl acetate. The extract that has been concentrated by evaporation is mixed with diethyl ether and filtered. The filtrate is purified by column chromatography. 230 mg (32% of theory) of the title compound is obtained as oil.