Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH:1]1([CH2:7][C:8](=[O:21])[CH:9]([C:14]2[CH:19]=[CH:18][C:17]([NH2:20])=[CH:16][CH:15]=2)[C:10](F)(F)F)[CH2:6][CH2:5][CH2:4][CH2:3]C1.C1(CC(=O)C(C2C=CC(N)=CC=2)C(F)(F)[F:31])CCCC1>>[CH:1]1([CH2:7][C:8](=[O:21])[C:9]([F:31])([C:14]2[CH:15]=[CH:16][C:17]([NH2:20])=[CH:18][CH:19]=2)[CH3:10])[CH2:3][CH2:4][CH2:5][CH2:6]1
Reactant: Nc1ccc(C(C(=O)CC2CCCCC2)C(F)(F)F)cc1
Reactant: Nc1ccc(C(C(=O)CC2CCCC2)C(F)(F)F)cc1
Product: CC(F)(C(=O)CC1CCCC1)c1ccc(N)cc1

Procedure:
1-cyclohexyl-3-(4'-aminophenyl)-4,4,4-trifluoro-2-butanone, and 1-cyclopentyl-3-(4'-aminophenyl)-4,4,4-trifluoro-2-butanone.
Reaction SMILES: [ClH:1].[CH2:2]([N:6]([CH2:41][CH:42]([CH3:44])[CH3:43])[C:7]([C:9]1[CH:40]=[CH:39][C:12]2[N:13]([CH2:29][CH2:30][NH:31]C(=O)OC(C)(C)C)[C:14]([NH:16][C:17]3[CH:22]=[C:21]([O:23][CH3:24])[C:20]([O:25][CH3:26])=[C:19]([O:27][CH3:28])[CH:18]=3)=[N:15][C:11]=2[CH:10]=1)=[O:8])[CH:3]([CH3:5])[CH3:4]>C(OCC)(=O)C>[ClH:1].[NH2:31][CH2:30][CH2:29][N:13]1[C:12]2[CH:39]=[CH:40][C:9]([C:7]([N:6]([CH2:2][CH:3]([CH3:4])[CH3:5])[CH2:41][CH:42]([CH3:44])[CH3:43])=[O:8])=[CH:10][C:11]=2[N:15]=[C:14]1[NH:16][C:17]1[CH:22]=[C:21]([O:23][CH3:24])[C:20]([O:25][CH3:26])=[C:19]([O:27][CH3:28])[CH:18]=1
Reactant: COc1cc(Nc2nc3cc(C(=O)N(CC(C)C)CC(C)C)ccc3n2CCNC(=O)OC(C)(C)C)cc(OC)c1OC
Agent: Cl
Solvent: CCOC(C)=O
Product: COc1cc(Nc2nc3cc(C(=O)N(CC(C)C)CC(C)C)ccc3n2CCN)cc(OC)c1OC

Procedure:
A stream of dry HCl is passed through a solution of tert-butyl 2-{5-[(diisobutylamino)carbonyl]-2-[(3,4,5-trimethoxy phenyl)amino]-1H-benzimidazol-1-yl}ethylcarbamate (2.56 g, prepared according to the procedure described in Example A1, reaction diagram A) in ethyl acetate (100 ml), (100% ethyl acetate) cooled down to 0° C. until the TLC shows complete disappearance of the starting product. The resulting mixture is then evaporated under reduced pressure. The solid obtained is triturated in diethylether and filtered in order to produce the expected compound in the form of white crystals (2.25 g, 97% yield).
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([C:8](Cl)=[O:9])[C:3]=1[N+:11]([O-:13])=[O:12].C(Cl)Cl.[CH3:17][OH:18].C(N(CC)CC)C>C(OCC)C>[CH3:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([C:8]([O:18][CH3:17])=[O:9])[C:3]=1[N+:11]([O-:13])=[O:12]
Reactant: Cc1cccc(C(=O)Cl)c1[N+](=O)[O-]
Reactant: CO
Solvent: CCN(CC)CC
Solvent: ClCCl
Solvent: CCOCC
Product: COC(=O)c1cccc(C)c1[N+](=O)[O-]
Reaction time: 1 h
Yield: 93.7 %

Procedure:
In this example a solution containing 1.002 mole of 2-methyl-6-chlorocarbonyl-nitrobenzene in 200 ml of ethyl ether and a small amount of methylene chloride was added to mixture containing 1.5 mole (60.8 ml) of methanol 1.002 mole (139.7 ml) of triethylamine and 200 ml of ethyl ether at about 0° C. The resulting mixture was stirred for one hour and then allowed to stand overnight. The mixture was then filtered and the filtrate washed with dilute aqueous acid and then washed with an aqueous sodium bicarbonate solution. The washed filtrate was dried and evaporated affording 183.3 g of the title product.
Reaction SMILES: BrC1C=CC=C2C=1C(C1C(O)=CC3OCOC=3C=1)[C:5](=[O:16])N2CCCCC.[CH2:27]([O:29][C:30](=[O:53])[CH2:31][N:32]1[C:40]2[C:35](=[CH:36][CH:37]=[CH:38][CH:39]=2)[CH:34]([C:41]2[C:50]([OH:51])=[CH:49][C:48]3[CH2:47][CH2:46][CH2:45][CH2:44][C:43]=3[CH:42]=2)[C:33]1=[O:52])[CH3:28]>>[CH2:27]([O:29][C:30](=[O:53])[CH2:31][N:32]1[C:40]2[C:35](=[CH:36][CH:37]=[CH:38][CH:39]=2)[C:34]([CH2:5][OH:16])([C:41]2[C:50]([OH:51])=[CH:49][C:48]3[CH2:47][CH2:46][CH2:45][CH2:44][C:43]=3[CH:42]=2)[C:33]1=[O:52])[CH3:28]
Reactant: CCCCCN1C(=O)C(c2cc3c(cc2O)OCO3)c2c(Br)cccc21
Reactant: CCOC(=O)CN1C(=O)C(c2cc3c(cc2O)CCCC3)c2ccccc21
Product: CCOC(=O)CN1C(=O)C(CO)(c2cc3c(cc2O)CCCC3)c2ccccc21

Procedure:
Following the procedure as described in PREPARATION 1E, and making non-critical variations to replace 4-bromo-3-(6-hydroxy-1,3-benzodioxol-5-yl)-1-pentyl-1,3-dihydro-2H-indol-2-one with ethyl[3-(3-hydroxy-5,6,7,8-tetrahydronaphthalen-2-yl)-2-oxo-2,3-dihydro-1H-indol-1-yl]acetate, the title compound was obtained: MS (ES+) m/z 378 (M−17), 418 (M+23).
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([CH:18]=[CH:19][CH:20]=1)[C:5]([C:7]1[N:8]=[CH:9][N:10]([S:12]([N:15]([CH3:17])[CH3:16])(=[O:14])=[O:13])[CH:11]=1)=[O:6].[CH2:21]([S:23](Cl)(=[O:25])=[O:24])[CH3:22]>N1C=CC=CC=1>[CH2:21]([S:23]([NH:1][C:2]1[CH:3]=[C:4]([CH:18]=[CH:19][CH:20]=1)[C:5]([C:7]1[N:8]=[CH:9][N:10]([S:12]([N:15]([CH3:17])[CH3:16])(=[O:13])=[O:14])[CH:11]=1)=[O:6])(=[O:25])=[O:24])[CH3:22]
Reactant: CN(C)S(=O)(=O)n1cnc(C(=O)c2cccc(N)c2)c1
Reactant: CCS(=O)(=O)Cl
Solvent: c1ccncc1
Product: CCS(=O)(=O)Nc1cccc(C(=O)c2cn(S(=O)(=O)N(C)C)cn2)c1
Temperature: 25 °C
Reaction time: 16 h
Yield: 57 %

Procedure:
A solution of Example 55C in pyridine (30 mL) was treated with ethanesulfonyl chloride (0.11 mL, 11 mmol) at 0° C. The mixture was stirred at room temperature for the next 16 hours and then concentrated under vacuum. The residue was purified by column chromatography (silica gel, ethyl acetate)to provide 2.31 g (57%) of the title compound.
Reaction SMILES: [NH2:1][C:2]1[S:3][CH:4]=[C:5]([C:7](=[N:11][O:12][CH:13]([F:15])[F:14])[C:8]([OH:10])=O)[N:6]=1.C(N(C(C)C)CC)(C)C.S(Cl)(C)(=O)=O.[NH2:30][CH:31]1[C:43](=[O:44])[N:33]2[C:34]([C:40]([OH:42])=[O:41])=[C:35]([CH2:38][OH:39])[CH2:36][S:37][C@H:32]12.C[Si](C)(C)NC(=O)C.C(=O)(O)[O-].[Na+:57]>CN(C)C=O.O.O1CCCC1>[NH2:1][C:2]1[S:3][CH:4]=[C:5]([C:7](=[N:11][O:12][CH:13]([F:15])[F:14])[C:8]([NH:30][CH:31]2[C:43](=[O:44])[N:33]3[C:34]([C:40]([O-:42])=[O:41])=[C:35]([CH2:38][OH:39])[CH2:36][S:37][C@H:32]23)=[O:10])[N:6]=1.[Na+:57]
Reactant: NC1C(=O)N2C(C(=O)O)=C(CO)CS[C@H]12
Reactant: Nc1nc(C(=NOC(F)F)C(=O)O)cs1
Agent: CC(=O)N[Si](C)(C)C
Agent: CS(=O)(=O)Cl
Agent: O=C([O-])O
Solvent: C1CCOC1
Solvent: CCN(C(C)C)C(C)C
Solvent: O
Product: Nc1nc(C(=NOC(F)F)C(=O)NC2C(=O)N3C(C(=O)[O-])=C(CO)CS[C@H]23)cs1
Temperature: -45 °C
Reaction time: 0.5 h
Yield: 38.7 %

Procedure:
To a solution of 2-(2-aminothiazol-4-yl)-2-difluoromethoxyiminoacetic acid (syn isomer) (948 mg) in N,N-dimethylformamide (20 ml) were added diisopropylethylamine (1.04 g) and mesyl chloride (920 mg) at -50° C., and the mixture was stirred for 30 minutes at the same temperature. On the other hand, a mixture of 7-amino-3-hydroxymethyl-3-cephem-4-carboxylic acid (1.0 g), N-trimethylsilylacetamide (16 g) and tetrahydrofuran (32 ml) was stirred for one hour at room temperature, cooled to -45° C. and added all at once to the above obtained activated acid solution, and the mixture was stirred for 2 hours at -40° to -30° C. The reaction mixture was poured into a solution of sodium bicarbonate (1.68 g) in water (100 ml) and the mixture was washed with ethyl acetate (50 ml). The aqueous solution was adjusted to pH 3-4 with 10% hydrogen chloride, salted out and extracted twice with a mixture of tetrahydrofuran (50 ml) and ethyl acetate (50 ml). The extract was washed three times with an aqueous solution of sodium chloride and dried over magnesium sulfate. To the extract was added a solution of sodium 2-ethylhexanoate (0.66 g) in ether (25 ml) and the resulting precipitates were collected by filtration to give sodium 7-[2-(2-aminothiazol-4-yl)-2-difluoromethoxyiminoacetamido]-3-hydroxymethyl-3-cephem-4-carboxylate (syn isomer) (0.73 g).
Reaction SMILES: [CH3:1][N:2]1[C:10]2[C:5](=[CH:6][CH:7]=[C:8]([C:11](OC)=[O:12])[CH:9]=2)[CH:4]=[N:3]1.[H-].[H-].[H-].[H-].[Li+].[Al+3].O>C1COCC1>[CH3:1][N:2]1[C:10]2[C:5](=[CH:6][CH:7]=[C:8]([CH2:11][OH:12])[CH:9]=2)[CH:4]=[N:3]1
Reactant: COC(=O)c1ccc2cnn(C)c2c1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: O
Solvent: C1CCOC1
Product: Cn1ncc2ccc(CO)cc21
Temperature: 0 °C
Reaction time: 1.5 h
Yield: 97.8 %

Procedure:
A solution of methyl 1-methyl-1H-indazole-6-carboxylate (230 mg, 1.21 mmol, PREPARATION 4) in anhydrous THF (4 mL) was cooled to 0° C., LiAlH4 (92 mg, 2.42 mmol) was added in portions below 0° C., and the mixture was then stirred at 0° C. for 1.5 h, added water:10% NaOH: water=0.2 mL: 0.2 mL: 0.6 mL carefully, filtered, and the filtrate was concentrated and purified by silica gel flash column to give 192 mg of crude product which was used directly for next step (98%). [M+H] Calc'd for C9H10N2O, 163; Found, 163.
Reaction SMILES: [CH3:1][C:2]12[CH2:15][C:6]1([C:7]([O:9]CC(Cl)(Cl)Cl)=[O:8])[N:5]1[C:16](=[O:33])[CH:17]([NH:18][C:19](=[O:32])[C:20](=[N:27][NH:28][C:29](=[O:31])[NH2:30])[C:21]3[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=3)[C@H:4]1[S:3]2.C(O)(=O)C>CN(C)C=O.[Zn]>[CH3:1][C:2]12[CH2:15][C:6]1([C:7]([OH:9])=[O:8])[N:5]1[C:16](=[O:33])[CH:17]([NH:18][C:19](=[O:32])[C:20](=[N:27][NH:28][C:29](=[O:31])[NH2:30])[C:21]3[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=3)[C@H:4]1[S:3]2
Reactant: CC12CC1(C(=O)OCC(Cl)(Cl)Cl)N1C(=O)C(NC(=O)C(=NNC(N)=O)c3ccccc3)[C@H]1S2
Agent: [Zn]
Solvent: CC(=O)O
Solvent: CN(C)C=O
Product: CC12CC1(C(=O)O)N1C(=O)C(NC(=O)C(=NNC(N)=O)c3ccccc3)[C@H]1S2
Reaction time: 1.5 h
Yield: 63.9 %

Procedure:
To a solution of 2,2,2-trichloroethyl 2-methyl-2,3-methylene-6-(2-phenyl-2-carbamoylhydrazonoacetamido)penam-3-carboxylate (560 mg.) in dimethylformamide (3 ml.) were added acetic acid (0.8 ml.) and zinc powder (0.75 g.) under ice-cooling, and the mixture was stirred for 1.5 hours. Zinc powder was filtered off, washed with dimethylformamide and the filtrate and the washings were combined, after which the combined solution was poured into ice-water. The solution was adjusted to pH 2 with 10% hydrochloric acid and precipitated crystals were filtered, washed with ethyl acetate and dissolved in a sodium bicarbonated aqueous solution. Insoluble material was filtered off and the filtrate was acidified with 10% hydrochloric acid to give 2-methyl-2,3-methylene-6-(2-phenyl-2-carbamoylhydrazonoacetamido)penam-3-carboxylic acid (270 mg.), mp 198° to 199°C (dec.).
Reaction SMILES: [C:1]1([CH:7](Cl)[C:8]2[S:9][CH:10]=[CH:11][CH:12]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[OH:14][CH:15]1[CH2:20][CH2:19][N:18]([CH2:21]/[CH:22]=[CH:23]\[CH2:24][O:25][C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][C:27]=2[N+:32]([O-:34])=[O:33])[CH2:17][CH2:16]1.OC1CCN(C/C=C/COC2C=CC=CC=2[N+]([O-])=O)CC1>>[C:1]1([CH:7]([C:8]2[S:9][CH:10]=[CH:11][CH:12]=2)[O:14][CH:15]2[CH2:16][CH2:17][N:18]([CH2:21]/[CH:22]=[CH:23]\[CH2:24][O:25][C:26]3[CH:31]=[CH:30][CH:29]=[CH:28][C:27]=3[N+:32]([O-:34])=[O:33])[CH2:19][CH2:20]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: O=[N+]([O-])c1ccccc1OC/C=C\CN1CCC(O)CC1
Reactant: ClC(c1ccccc1)c1cccs1
Agent: O=[N+]([O-])c1ccccc1OC/C=C/CN1CCC(O)CC1
Product: O=[N+]([O-])c1ccccc1OC/C=C\CN1CCC(OC(c2ccccc2)c2cccs2)CC1

Procedure:
The procedure of Example 39 (a) was repeated except for using phenyl-2-thienylmethyl chloride and 4-hydroxy-1-[4-(2-nitrophenoxy)-2(Z)-butenyl]piperidine instead of phenyl-2-thienylmethyl chloride and 4-hydroxy-1-[4-(2-nitrophenoxy)-2(E)-butenyl]piperidine to give oily 4-(phenyl-2-thienylmethoxy)-1-[4-(2-nitrophenoxy)-2(Z)-butenyl]piperidine.
Reaction SMILES: FC(F)(F)C([N:5]([CH2:15][CH:16]1[CH2:21][CH2:20][N:19]([CH2:22][CH2:23][CH2:24][C:25]2[CH:26]=[C:27]([CH:32]=[CH:33][CH:34]=2)[C:28]([O:30]C)=[O:29])[CH2:18][CH2:17]1)[C@@H:6]1[CH2:8][C@H:7]1[C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1)=O.[OH-].[Na+]>CO>[C:9]1([C@@H:7]2[CH2:8][C@H:6]2[NH:5][CH2:15][CH:16]2[CH2:21][CH2:20][N:19]([CH2:22][CH2:23][CH2:24][C:25]3[CH:26]=[C:27]([CH:32]=[CH:33][CH:34]=3)[C:28]([OH:30])=[O:29])[CH2:18][CH2:17]2)[CH:10]=[CH:11][CH:12]=[CH:13][CH:14]=1
Reactant: COC(=O)c1cccc(CCCN2CCC(CN(C(=O)C(F)(F)F)[C@@H]3C[C@H]3c3ccccc3)CC2)c1
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: O=C(O)c1cccc(CCCN2CCC(CN[C@@H]3C[C@H]3c3ccccc3)CC2)c1
Temperature: 25 °C
Reaction time: 18 h
Yield: 59.8 %

Procedure:
To a solution of methyl 3-(3-(4-((2,2,2-trifluoro-N-(trans-2-phenylcyclopropyl)acetamido) methyl)piperidin-1-yl)propyl)benzoate (90 mg, 0.179 mmol) in methanol (2 mL) was added sodium hydroxide (6M, 0.5 mL, 3.00 mmol), and the mixture was stirred at room temperature for 18 h. The mixture was purified using reverse-phase HPLC under the acidic conditions. The fractions containing the product were combined, treated with 1N HCl and concentrated. The residue was dried under vacuum to give 42 mg of product (HCl salt) as white solid. MS: (M+H)+=393.3. 1H NMR (400 MHz, DMSO-d6) δ ppm 1.20-1.34 (m, 1H), 1.49-1.65 (m, 3H), 1.91-2.14 (m, 6H), 2.58 (br. s., 1H), 2.65-2.78 (m, 2H), 2.81-3.06 (m, 5H), 3.49 (br. s., 2H), 7.11-7.35 (m, 5H), 7.42-7.58 (m, 2H), 7.74-7.92 (m, 2H).
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[N:9]1[C:13]([C:14]2[S:23][C:22]3[C:21]4[N:24]=[C:25]([C:28]5[CH:29]=[N:30][C:31](F)=[CH:32][CH:33]=5)[CH:26]=[CH:27][C:20]=4[O:19][CH2:18][CH2:17][C:16]=3[CH:15]=2)=[N:12][CH:11]=[N:10]1.[NH:35]1[CH2:40][CH2:39][CH2:38][CH2:37][CH2:36]1>CN1C(=O)CCC1>[F:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[N:9]1[C:13]([C:14]2[S:23][C:22]3[C:21]4[N:24]=[C:25]([C:28]5[CH:33]=[CH:32][C:31]([N:35]6[CH2:40][CH2:39][CH2:38][CH2:37][CH2:36]6)=[N:30][CH:29]=5)[CH:26]=[CH:27][C:20]=4[O:19][CH2:18][CH2:17][C:16]=3[CH:15]=2)=[N:12][CH:11]=[N:10]1
Reactant: C1CCNCC1
Reactant: Fc1ccc(-n2ncnc2-c2cc3c(s2)-c2nc(-c4ccc(F)nc4)ccc2OCC3)c(F)c1
Solvent: CN1CCCC1=O
Product: Fc1ccc(-n2ncnc2-c2cc3c(s2)-c2nc(-c4ccc(N5CCCCC5)nc4)ccc2OCC3)c(F)c1
Temperature: 150 °C
Yield: 8.5 %

Procedure:
2-[2-(2,4-Difluoro-phenyl)-2H-[1,2,4]triazol-3-yl]-9-(6-fluoro-pyridin-3-yl)-4,5-dihydro-6-oxa-1-thia-10-aza-benzo[e]azulene, from the procedure for 249, (470 mg, 1.0 mmol) Piperidine (102 mg, 1.2 mmol) DIPEA (340 mg, 3 mmol) and NMP (4 mL) were added in a 10 mL of sealed tube, and the mixture was heated by microwave at 150° C. for 120 min under N2. The reaction mixture was filtered to gather the solution and water was added. The mixture was extracted by DCM (20 mL×3). The combined organic layers were dried over Na2SO4, concentrated in vacuo, and purified by preparative HPLC to give 232 (46.2 mg, yield: 8.5%). 1HNMR (DMSO-d6, 400 MHz): δ8.74 (s, 1H), 8.31 (s, 1H), 8.10 (d, J=4.8 Hz, 1H), 7.91-7.87 (m, 1H), 7.78-7.77 (m, 2H), 7.50-7.40 (m, 1H), 7.18 (d, J=4.4 Hz, 1H), 7.19 (d, J=8.8 Hz, 1H), 6.93 (d, J=8.8 Hz, 1H), 4.31 (s, 2H), 3.64 (s, 4H), 3.16 (s, 2H), 1.63-1.57 (m, 4H) ESI-MS: m/z=543 [M+H+]
Reaction SMILES: [CH3:1][N:2]1[C:6]([SH:7])=[N:5][N:4]=[N:3]1.[C:8]1([S:14][CH2:15][CH2:16][CH2:17]Br)[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1.C(=O)([O-])[O-].[K+].[K+]>CC(C)=O>[CH3:1][N:2]1[C:6]([S:7][CH2:17][CH2:16][CH2:15][S:14][C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)=[N:5][N:4]=[N:3]1
Reactant: BrCCCSc1ccccc1
Reactant: Cn1nnnc1S
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: Cn1nnnc1SCCCSc1ccccc1
Yield: 65.4 %

Procedure:
1-Methyl-5-mercapto-1,2,3,4-tetrazole (1.2 g) is dissolved in acetone (50 ml). To the solution are added 3-bromopropyl phenyl sulfide (2.5 g) and potassium carbonate (1.5 g) and the mixture is refluxed for 4 hours. Acetone is distilled off and water is added to the residue. The mixture is extracted with chloroform. The chloroform solution is washed with saturated aqueous sodium chloride and dried over magnesium sulfate. Chloroform is distilled off and the residue is purified by column chromatography (Kieselgel 60). The column is eluted with benzenechloroform (3:2) to obtain 1-methyl-5-(3-phenylthiopropyl)thio-1,2,3,4-tetrazole (1.8 g) as colorless liquid, nD18 =1.6008.
Reaction SMILES: [CH2:1]([C:3]1([CH2:8][C:9](OC)=[O:10])[O:7][CH2:6][CH2:5][O:4]1)[CH3:2].[H-].[H-].[H-].[H-].[Li+].[Al+3].C(OCC)(=O)C>C1COCC1>[CH2:1]([C:3]1([CH2:8][CH2:9][OH:10])[O:7][CH2:6][CH2:5][O:4]1)[CH3:2]
Reactant: CCC1(CC(=O)OC)OCCO1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: CCC1(CCO)OCCO1
Temperature: 90 °C
Reaction time: 8 h
Yield: 27.7 %

Procedure:
To a solution of methyl 2-(2-ethyl-1,3-dioxolan-2-yl)acetate (1 g, 5.75 mmol) in anhydrous THF (40 mL) was added LAH (900 mg, 23.7 mmol) at 0° C. under nitrogen atmosphere, the resulting mixture was stirred at 90° C. overnight. The mixture was cooled to room temperature, and ethyl acetate was added to the mixture. The resulting slurry was filtered and the filtrate was concentrated to dryness. The crude product was purified by silica gel chromatography eluting with DCM/methanol (100:1 to 20:1) to give 2-(2-ethyl-1,3-dioxolan-2-yl)ethanol (233 mg, 27.4%) as yellow oil that was used without purification.
Reaction SMILES: C(OC([N:8]1[CH2:11][C:10]([CH3:34])([C@H:12]([C:14]2[CH:15]=[C:16]3[C:25](=[CH:26][C:27]=2[C:28]([F:31])([F:30])[F:29])[O:24][CH2:23][C:22]2[N:17]3[C@H:18]([CH3:33])[C:19](=[O:32])[NH:20][N:21]=2)[CH3:13])[CH2:9]1)=O)(C)(C)C.[C:35]([OH:41])([C:37]([F:40])([F:39])[F:38])=[O:36]>C(Cl)Cl>[F:38][C:37]([F:40])([F:39])[C:35]([OH:41])=[O:36].[CH3:33][C@H:18]1[N:17]2[C:22]([CH2:23][O:24][C:25]3[C:16]2=[CH:15][C:14]([C@H:12]([C:10]2([CH3:34])[CH2:9][NH:8][CH2:11]2)[CH3:13])=[C:27]([C:28]([F:29])([F:31])[F:30])[CH:26]=3)=[N:21][NH:20][C:19]1=[O:32]
Reactant: C[C@@H]1C(=O)NN=C2COc3cc(C(F)(F)F)c([C@H](C)C4(C)CN(C(=O)OC(C)(C)C)C4)cc3N21
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: C[C@@H]1C(=O)NN=C2COc3cc(C(F)(F)F)c([C@@H](C)C4(C)CNC4)cc3N21
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 84 %

Procedure:
To a solution of 3-methyl-3-[(S)-1-((R)-4-methyl-3-oxo-7-trifluoromethyl-2,3,4,10-tetrahydro-9-oxa-1,2,4a-triaza-phenanthren-6-yl)-ethyl]-azetidine-1-carboxylic acid tert-butyl ester (diastereomer 2, 0.009 g, 0.019 mmol) in DCM (2 mL) was added TFA (0.5 mL) and the reaction mixture was stirred at ambient temperature for 1.5 h. The solvent was removed in vacuo and the residue was purified by prep-HPLC (Table 3, Method 28) to give (R)-4-methyl-6-[(S)-1-(3-methyl-azetidin-3-yl)-ethyl]-7-trifluoromethyl-2,10-dihydro-9-oxa-1,2,4a-triaza-phenanthren-3-one trifluoroacetic acid (Example #147-2, Enantiomer 2, 0.006 g, 84%) as a solid. 1H NMR (CD3OD-d4, 400 MHz): δ 7.35 (s, 1H), 6.9 (s, 1H), 4.95 (m, 1H), 4.7 (d, J=12.0 Hz, 2H), 4.4 (d, J=11.2 Hz, 1H), 4.2 (d, J=11.2 Hz, 1H), 3.65 (t, J=8.4 Hz, 2H), 3.26 (m, 1H), 1.5 (m, 6H), 1.45 (m, 3H). LC/MS (Table 1, Method 5) Rt=2.310 min; MS m/z: 383 [M+H]+. SFC (Table 1, Method 36) Rt=4.712 min.
Reaction SMILES: [NH:1]([C:13]([O:15][C:16]([CH3:19])([CH3:18])[CH3:17])=[O:14])[C@H:2]([C:10]([OH:12])=O)[CH2:3][C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1.[CH3:20][NH:21][C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1.C1C=CC2N(O)N=NC=2C=1.CCN=C=NCCCN(C)C.Cl>CN(C=O)C>[NH:1]([C:13]([O:15][C:16]([CH3:19])([CH3:18])[CH3:17])=[O:14])[C@H:2]([C:10]([N:21]([C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1)[CH3:20])=[O:12])[CH2:3][C:4]1[CH:5]=[CH:6][CH:7]=[CH:8][CH:9]=1
Reactant: CC(C)(C)OC(=O)N[C@@H](Cc1ccccc1)C(=O)O
Reactant: CNc1ccccc1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Product: CN(C(=O)[C@H](Cc1ccccc1)NC(=O)OC(C)(C)C)c1ccccc1
Temperature: 25 °C
Reaction time: 5 h
Yield: 61.3 %

Procedure:
To a solution of Boc-Phe-OH (2.65 g), N-methylaniline (1.09 g) and HOBT (1.35 g) in DMF (25 ml) was added WSC.HCl (1.92 g) under ice-cooling. The mixture was stirred for 5 hours at room temperature. After evaporation and extraction with ethyl acetate, the organic layer was washed successively with 2% hydrochloric acid, water, 2% sodium hydrogencarbonate, water and saturated sodium chloride solution, and dried over magnesium sulfate. The evaporated residue was subjected to column chromatography on silica gel (100 g) and eluted with a mixture of chloroform and methanol (100:1). The fractions containing the object compound were combined and evaporated to give Boc-Phe-NMePh (2.17 g).
Reaction SMILES: Br[C:2]1[CH:3]=[N:4][CH:5]=[C:6]([CH:9]=1)[C:7]#[N:8].[C:10]([C:12]1[CH:17]=[CH:16][CH:15]=[C:14]([N+:18]([O-:20])=[O:19])[CH:13]=1)#[CH:11]>>[N+:18]([C:14]1[CH:13]=[C:12]([C:10]#[C:11][C:2]2[CH:3]=[N:4][CH:5]=[C:6]([CH:9]=2)[C:7]#[N:8])[CH:17]=[CH:16][CH:15]=1)([O-:20])=[O:19]
Reactant: N#Cc1cncc(Br)c1
Reactant: C#Cc1cccc([N+](=O)[O-])c1
Product: N#Cc1cncc(C#Cc2cccc([N+](=O)[O-])c2)c1
Yield: 21.6 %

Procedure:
Prepare essentially as described in PREPARATION 10 using 5-bromonicotinonitrile (400 mg, 2.19 mmol) and 1-ethynyl-3-nitrobenzene, (prepared as described in PREPARATION 11), (644 mg, 4.38 mmol) to give the title compound (118 mg, 65%).
Reaction SMILES: Br[CH:2]1[C:7]2=[N:8][CH:9]=[C:10]([C:13]([OH:15])=[O:14])[C:11](=[O:12])[N:6]2[CH:5]([CH3:16])[CH2:4][CH2:3]1.C(#N)C.[NH2:20][C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1>O>[NH:20]([CH:2]1[C:7]2=[N:8][CH:9]=[C:10]([C:13]([OH:15])=[O:14])[C:11](=[O:12])[N:6]2[CH:5]([CH3:16])[CH2:4][CH2:3]1)[C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1
Reactant: Nc1ccccc1
Reactant: CC1CCC(Br)c2ncc(C(=O)O)c(=O)n21
Solvent: CC#N
Solvent: O
Product: CC1CCC(Nc2ccccc2)c2ncc(C(=O)O)c(=O)n21
Temperature: 25 °C
Reaction time: 48 h
Yield: 86.11 %

Procedure:
148.7 g. (0.50 mole) of 9-bromo-6-methyl-4-oxo-6,7,8,9-tetrahydro-4H-pyrido[1,2-a]pyrimidine-3-carboxylic acid are dissolved in 250 ml. of acetonitrile and 100 ml. of aniline are further added. The solution is stirred for 2 days in a nitrogen gas atmosphere at room temperature. 1000 ml. of water is added and the mixture is stirred for a further half an hour. The crystals are filtered and washed with water and finally reboiled in 1400 ml. of methanol. 128.8 g. (86.11%) of 9-anilino-6-methyl-4-oxo-6,7,8,9-tetrahydro-4H-pyrido[1,2-a]pyrimidine-3-carboxylic acid are obtained. Melting point: 198°-199° C.
Reaction SMILES: C[O:2][C:3]([C:5]1[C:13]2[N:12]=[C:11]([C:14]3[CH:19]=[CH:18][C:17]([F:20])=[C:16]([Cl:21])[CH:15]=3)[NH:10][C:9]=2[C:8]([OH:22])=[CH:7][CH:6]=1)=[O:4].O[Li].O>C1COCC1.CO.O>[Cl:21][C:16]1[CH:15]=[C:14]([C:11]2[NH:10][C:9]3[C:8]([OH:22])=[CH:7][CH:6]=[C:5]([C:3]([OH:4])=[O:2])[C:13]=3[N:12]=2)[CH:19]=[CH:18][C:17]=1[F:20]
Reactant: COC(=O)c1ccc(O)c2[nH]c(-c3ccc(F)c(Cl)c3)nc12
Agent: [Li]O
Solvent: C1CCOC1
Solvent: O
Solvent: CO
Product: O=C(O)c1ccc(O)c2[nH]c(-c3ccc(F)c(Cl)c3)nc12
Temperature: 25 °C
Yield: 89.4 %

Procedure:
Wang resin-supported 2-(3-chloro-4-fluoro-phenyl)-7-hydroxy-1H-benzoimidazole-4-carboxylic acid methyl ester (570 mg, 0.47 mmol) obtained in step 5 was dissolved in THF, LiOH.H2O (99 mg, 2.35 mmol) in MeOH—H2O was added thereto and the resulting mixture was refluxed for 5 hours. The resulting solution was cooled to room temperature and filtered. The filtrate was washed with MeOH and CH2Cl2, and dried to obtain the title compound (551 mg, 0.42 mmol) in a yield of 90%.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([O:8][CH3:9])=[CH:4][CH:3]=1.[S:10]([Cl:14])(=O)(=[O:12])[OH:11]>>[F:1][C:2]1[CH:7]=[CH:6][C:5]([O:8][CH3:9])=[C:4]([S:10]([Cl:14])(=[O:12])=[O:11])[CH:3]=1
Reactant: O=S(=O)(O)Cl
Reactant: COc1ccc(F)cc1
Product: COc1ccc(F)cc1S(=O)(=O)Cl
Temperature: 25 °C
Reaction time: 6 h
Yield: 84.5 %

Procedure:
1-fluoro-4-methoxybenzene (10.0 g, 0.079 mol) was added dropwise to sulfurochloridic acid (31.4 ml, 0.474 mol) at 0° C., The mixture was stirred at room temperature for about 6 h, after which it was added dropwise into ice water. The mixture was extracted with CH2Cl2 three times. The combined extracts were washed with brine, dried over sodium sulfate and concentrated in vacuo to give the title product (15.0 g, 84.6% yield).
Reaction SMILES: [N:1]1[N:2]=[C:3]([C:10]2[CH:19]=[CH:18][C:17]3[C:12](=[C:13]([O:21][C@H:22]4[C@H:28]([F:29])[CH2:27][CH2:26][N:25](C(OC(C)(C)C)=O)[CH2:24][CH2:23]4)[CH:14]=[C:15]([F:20])[CH:16]=3)[N:11]=2)[N:4]2[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=12.Cl>C(Cl)(Cl)Cl>[N:1]1[N:2]=[C:3]([C:10]2[CH:19]=[CH:18][C:17]3[C:12](=[C:13]([O:21][C@H:22]4[C@H:28]([F:29])[CH2:27][CH2:26][NH:25][CH2:24][CH2:23]4)[CH:14]=[C:15]([F:20])[CH:16]=3)[N:11]=2)[N:4]2[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=12
Reactant: CC(C)(C)OC(=O)N1CC[C@@H](F)[C@H](Oc2cc(F)cc3ccc(-c4nnc5ccccn45)nc23)CC1
Agent: Cl
Solvent: ClC(Cl)Cl
Product: Fc1cc(O[C@@H]2CCNCC[C@H]2F)c2nc(-c3nnc4ccccn34)ccc2c1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
Enantiomer 1 of trans-tert-butyl 4-(2-([1,2,4]triazolo[4,3-a]pyridin-3-yl)-6-fluoroquinolin-8-yloxy)-5-fluoroazepane-1-carboxylate (Peak 1 from Example 91, Step E; 0.210 g, 0.424 mmol) was dissolved in CHCl3 (4.3 mL). To this solution was added HCl (4.24 mL, 17.0 mmol, 4.0M Dioxane) and the mixture was stirred at ambient temperature for 3 hours. The mixture was filtered through a polypropylene filter and washed with CH2Cl2 and Et2O, slurried in hexanes and then dried carefully in vacuo to provide the desired product as white solid. MS ESI (+) m/z 396.1 (M+1) detected.