Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH:1]1([N:4]2[C:13]3[C:8](=[CH:9][C:10]([F:23])=[C:11]([N:16]4[CH2:21][CH2:20][NH:19][CH:18]([CH3:22])[CH2:17]4)[C:12]=3[O:14][CH3:15])[C:7](=[O:24])[C:6]([C:25]([OH:27])=[O:26])=[CH:5]2)[CH2:3][CH2:2]1.[S:28](=[O:32])(=[O:31])([OH:30])[OH:29]>>[S:28]([O-:32])([O-:31])(=[O:30])=[O:29].[CH3:22][CH:18]1[NH:19][CH2:20][CH2:21][N:16]([C:11]2[C:12]([O:14][CH3:15])=[C:13]3[N:4]([CH:1]4[CH2:3][CH2:2]4)[CH:5]=[C:6]([C:25]([OH:27])=[O:26])[C:7](=[O:24])[C:8]3=[CH:9][C:10]=2[F:23])[CH2:17]1
Reactant: O=S(=O)(O)O
Agent: COc1c(N2CCNC(C)C2)c(F)cc2c(=O)c(C(=O)O)cn(C3CC3)c12
Product: O=S(=O)([O-])[O-]

Procedure:
A method of treating an industrial waste liquor containing 1-cyclopropyl-7-(3-methyl-1-piperazinyl)-6-fluoro-8-methoxy-1,4-dihydro-4-oxo-3-quinolinecarboxylic acid (gatifloxacin), comprising adding aqueous sulfuric acid to said liquor to form a sulfate of said gatifloxacin, and/or a hydrate of said sulfate; and the sulfate, and/or hydrate of said sulfate, made by said method.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[CH:9]=[C:10]([NH:13][C:14]([NH2:16])=[S:15])[NH:11][N:12]=1.BrBr>CC(O)=O>[Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[C:9]2[S:15][C:14]([NH2:16])=[N:13][C:10]=2[NH:11][N:12]=1
Reactant: NC(=S)Nc1cc(-c2ccccc2Cl)n[nH]1
Agent: BrBr
Solvent: CC(=O)O
Product: Nc1nc2[nH]nc(-c3ccccc3Cl)c2s1
Temperature: 25 °C
Reaction time: 2 h
Yield: 66.3 %

Procedure:
To a solution of [5-(2-chloro-phenyl)-2H-pyrazol-3-yl]-thiourea (2.25 g, 8.9 mmol) in glacial AcOH (900 mL) was added a 1.5 M solution of bromine in AcOH (20 mL) dropwise under vigorous stirring. The resulting heterogeneous mixture was stirred at room temperature for 2 hours then it was concentrated to dryness. Water was added followed by a saturated solution of aqueous sodium bicarbonate to neutralize to pH 7. The resulting precipitate was filtered, washed with water and dried in vacuo. Recrystallization from isopropyl alcohol afforded 1.48 g (66% yield) of 3-(2-chloro-phenyl)-1H-pyrazolo[3,4-d]thiazol-5-ylamine as a tan solid. 1H-NMR (d4-MeOH) δ: 7.64 (broad s, 1H), 7.53 (d, 1H), 7.42 (m, 2H); HPLC/MS m/z: 251 [MH]+.
Reaction SMILES: [C:1]([C:4]1[CH:31]=[CH:30][C:7]([O:8][CH2:9][CH:10]([OH:29])[CH2:11][S:12][CH2:13][CH:14]2[S:18][C:17]3([CH2:22][CH2:21][CH:20]([CH2:23][C:24]([O:26]CC)=[O:25])[CH2:19]3)[O:16][CH2:15]2)=[C:6]([CH2:32][CH2:33][CH3:34])[C:5]=1[OH:35])(=[O:3])[CH3:2].[Li+].[OH-]>C(O)C>[C:1]([C:4]1[CH:31]=[CH:30][C:7]([O:8][CH2:9][CH:10]([OH:29])[CH2:11][S:12][CH2:13][CH:14]2[S:18][C:17]3([CH2:22][CH2:21][CH:20]([CH2:23][C:24]([OH:26])=[O:25])[CH2:19]3)[O:16][CH2:15]2)=[C:6]([CH2:32][CH2:33][CH3:34])[C:5]=1[OH:35])(=[O:3])[CH3:2]
Reactant: CCCc1c(OCC(O)CSCC2COC3(CCC(CC(=O)OCC)C3)S2)ccc(C(C)=O)c1O
Agent: [Li+]
Agent: [OH-]
Solvent: CCO
Product: CCCc1c(OCC(O)CSCC2COC3(CCC(CC(=O)O)C3)S2)ccc(C(C)=O)c1O
Temperature: 25 °C
Reaction time: 8 h

Procedure:
The product of Example 10 is saponified according to the procedure of Example 2 using 5.3 g (10 mmol) of the above ester and 2M LiOH solution (12.5 ml, 2.5 eq.) in ethanol (50 ml). After stirring overnight at room temperature, the solvent is removed in vacuo and the residue diluted with water. After acidification to pH 2.5 with 0.5N KHSO4, the mixture is extracted with ethyl acetate and dried over magnesium sulfate. The drying agent is filtered and the filtrate is concentrated in vacuo. Further drying of the resultant residue at 60° (0.5 torr) gives the titled compound.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:9](=[CH:10][C:11]=1[C:12]([F:15])([F:14])[F:13])[NH:8][CH:7]=[CH:6]2.C([BH3-])#N.[Na+]>C(O)(=O)C>[CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:9](=[CH:10][C:11]=1[C:12]([F:15])([F:13])[F:14])[NH:8][CH2:7][CH2:6]2
Reactant: COc1cc2cc[nH]c2cc1C(F)(F)F
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CC(=O)O
Product: COc1cc2c(cc1C(F)(F)F)NCC2
Yield: 99 %

Procedure:
The indole (D10) (67.63 g, 0.315 mol) was treated with sodium cyanoborohydride (40 g, 0.637 mol) in glacial acetic acid (500 ml) as in the method of Description 1 to afford the title indoline (67.73 g, 99%) as an off-white solid.
Reaction SMILES: [CH3:1][N:2]1[CH2:7][CH2:6][N:5]([C:8]2[N:13]=[CH:12][C:11]([C:14]3[S:15][C:16]4[CH:22]=[C:21]([C:23]([O:25]CC)=[O:24])[CH:20]=[CH:19][C:17]=4[N:18]=3)=[CH:10][CH:9]=2)[CH2:4][CH2:3]1.[ClH:28]>>[ClH:28].[CH3:1][N:2]1[CH2:3][CH2:4][N:5]([C:8]2[N:13]=[CH:12][C:11]([C:14]3[S:15][C:16]4[CH:22]=[C:21]([C:23]([OH:25])=[O:24])[CH:20]=[CH:19][C:17]=4[N:18]=3)=[CH:10][CH:9]=2)[CH2:6][CH2:7]1
Reactant: CCOC(=O)c1ccc2nc(-c3ccc(N4CCN(C)CC4)nc3)sc2c1
Agent: Cl
Product: CN1CCN(c2ccc(-c3nc4ccc(C(=O)O)cc4s3)cn2)CC1

Procedure:
Ethyl 2-[6-(4-methylpiperazin-1-yl)pyridin-3-yl]-1,3-benzothiazole-6-carboxylate (46 mg, 0.12 mmol) was heated at 110° C. in 6 M HCl (2 mL) for 3 h. The solvent was evaporated in vacuo, before co-evaporation with toluene three times, to give the title compound (46 mg) as a yellow solid. 1H NMR δ 10.90 (br. s., 1 H) 8.88 (d, 1 H) 8.73 (s, 1 H) 8.28 (dd, 1 H) 8.05 (s, 2 H) 6.97-7.40 (m, 2 H) 4.59 (d, 2 H) 3.51 (d, 2 H) 3.33-3.45 (m, 2 H) 3.02-3.16 (m, 2 H) 2.80 (d, 3 H); MS m/z (M+H) 355, (M−H) 353.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]([CH2:27][CH:28]([C:30]1[CH:35]=[CH:34][CH:33]=[C:32]([Cl:36])[CH:31]=1)[OH:29])[CH:9]([CH3:26])[CH2:10][C:11]1[CH:25]=[CH:24][C:14]2[O:15][C:16]([C:21]([OH:23])=[O:22])([C:18]([OH:20])=[O:19])[O:17][C:13]=2[CH:12]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2].Br[CH2:38][C:39]([O:41][CH:42]([CH3:44])[CH3:43])=[O:40]>>[CH:42]([O:41][C:39]([CH:38]([O:19][C:18]([C:16]1([C:21]([OH:23])=[O:22])[O:15][C:14]2[CH:24]=[CH:25][C:11]([CH2:10][CH:9]([N:8]([C:6]([O:5][C:1]([CH3:2])([CH3:3])[CH3:4])=[O:7])[CH2:27][CH:28]([C:30]3[CH:35]=[CH:34][CH:33]=[C:32]([Cl:36])[CH:31]=3)[OH:29])[CH3:26])=[CH:12][C:13]=2[O:17]1)=[O:20])[C:6]([O:5][CH:1]([CH3:3])[CH3:2])=[O:7])=[O:40])([CH3:44])[CH3:43]
Reactant: CC(C)OC(=O)CBr
Reactant: CC(Cc1ccc2c(c1)OC(C(=O)O)(C(=O)O)O2)N(CC(O)c1cccc(Cl)c1)C(=O)OC(C)(C)C
Product: CC(C)OC(=O)C(OC(=O)C1(C(=O)O)Oc2ccc(CC(C)N(CC(O)c3cccc(Cl)c3)C(=O)OC(C)(C)C)cc2O1)C(=O)OC(C)C

Procedure:
The title compound was prepared from 5-(2-{tert-butoxycarbonyl-[2-(3-chloro-phenyl)-2-hydroxy-ethyl]-amino}-propyl)-benzo[1,3]dioxole-2,2-dicarboxylic acid and isopropyl 2-bromoacetate according to the procedure of Example 24, step 3 as a colorless oil: 1H NMR (300 MHz, CDCl3): δ 1.15-1.30 (m, 15H), 1.40 (s, 9H), 2.45-2.70 (m, 2H), 3.06-3.15 (m, 1H), 3.45-3.60 (m, 1H), 4.05-4.18 (m, 2H), 4.70-4.80 (m, 4H), 5.06 (sept, J=6.3 Hz, 2H), 5.46 (brs, 1H), 6.60-6.90 (m, 3H), 7.20-7.35 (m, 3H), 7.41 (s, 1H).; MS (ES) m/z (relative intensity): 722 (M+, 100).
Reaction SMILES: [C:1]1([N:7]2[C:11]([C:12]3[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=3)=[C:10]([C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=3)[N:9]([CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][P:31]([O:36]CC)(=[O:35])[O:32]CC)[C:8]2=[O:39])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C[Si](I)(C)C>C(Cl)(Cl)Cl>[C:1]1([N:7]2[C:11]([C:12]3[CH:13]=[CH:14][CH:15]=[CH:16][CH:17]=3)=[C:10]([C:18]3[CH:19]=[CH:20][CH:21]=[CH:22][CH:23]=3)[N:9]([CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][P:31]([OH:36])(=[O:32])[OH:35])[C:8]2=[O:39])[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: CCOP(=O)(CCCCCCCn1c(-c2ccccc2)c(-c2ccccc2)n(-c2ccccc2)c1=O)OCC
Agent: C[Si](C)(C)I
Solvent: ClC(Cl)Cl
Product: O=c1n(CCCCCCCP(=O)(O)O)c(-c2ccccc2)c(-c2ccccc2)n1-c1ccccc1
Temperature: -40 °C
Reaction time: 2.5 h
Yield: 15 %

Procedure:
Diethyl 7-(3,4,5-triphenyl-2-oxo-2,3-dihydroimidazol-1-yl)heptanephosphonate (0.58 g) was dissolved in dry chloroform, cooled to -40° C. and to it was added trimethylsilyl iodide (1.05 g) over 2 mins under an atmosphere of nitrogen. The cooling bath was removed and the reaction mixture was stirred for 2.5 hours at room temperature then evaporated to an oil and re-evaporated from methanol, treated with excess aqueous sodium bicarbonate, evaporated to an oil and re-evaporated from methanol, water and ethanol respectively. The oil was taken up in ethanol, treated with excess aqueous sodium bicarbonate, evaporated to dryness then taken up in ethanol, filtered and the filtrate evaporated to an oil which solidified under ether. The solid was dissolved in water and passed down a Dowex 1×2-200 ion exchange resin in the formate form. Elution with aqueous formic acid gave on evaporation of the solvent 7-(3,4,5-triphenyl-2-oxo-2,3-dihydroimidazol-1-yl)heptanephosphonic acid (0.078 g, 15%) as a light brown foam.
Reaction SMILES: B.[Na].[C:3]([O:7][C:8]([NH:10][C@H:11]1[CH2:16][CH2:15][C@H:14]([C:17](O)=[O:18])[CH2:13][CH2:12]1)=[O:9])([CH3:6])([CH3:5])[CH3:4]>O1CCCC1>[C:3]([O:7][C:8]([NH:10][C@H:11]1[CH2:12][CH2:13][C@H:14]([CH2:17][OH:18])[CH2:15][CH2:16]1)=[O:9])([CH3:6])([CH3:5])[CH3:4]
Reactant: CC(C)(C)OC(=O)N[C@H]1CC[C@H](C(=O)O)CC1
Agent: B
Agent: [Na]
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)N[C@H]1CC[C@H](CO)CC1
Temperature: 0 °C

Procedure:
9.33 g of sodium boron hydride was suspended in 200 ml of tetrahydrofuran, and added thereto was boron trifluoride diethyl complex under ice-cooling. The mixture was stirred as such under ice-cooling for 30 minutes, and then, 150 ml of a tetrahydrofuran solution containing 40 g of trans-4-(tert-butoxycarbonylamino)cyclohexane carboxylic acid was added thereto under ice-cooling. The mixture was stirred at room temperature for 4 hours, and the reaction mixture was poured into ice water, and extracted with chloroform. The extract was washed with water and brine, dried over anhydrous sodium sulfate, and the solvent was removed under reduced pressure. The residue was recrystallized from ethyl acetate-hexane to obtain 20 g of N-tert-butoxycarbonyl-trans-4-(hydroxymethyl)cyclohexylamine.
Reaction SMILES: [N:1]([C:4]1[CH:5]=[CH:6][C:7]([CH3:30])=[C:8]([C:10]([C:12]2[CH:17]=[CH:16][C:15]([NH:18][C:19]3[CH:24]=[CH:23][C:22]([C:25]([F:28])(F)F)=C[CH:20]=3)=[CH:14][C:13]=2[Cl:29])=[O:11])[CH:9]=1)=[N+:2]=[N-:3].NC1C=CC(C)=C(C(C2C=CC(NC3C=CC=C(F)C=3)=CC=2Cl)=O)C=1>>[N:1]([C:4]1[CH:5]=[CH:6][C:7]([CH3:30])=[C:8]([C:10]([C:12]2[CH:17]=[CH:16][C:15]([NH:18][C:19]3[CH:24]=[CH:23][CH:22]=[C:25]([F:28])[CH:20]=3)=[CH:14][C:13]=2[Cl:29])=[O:11])[CH:9]=1)=[N+:2]=[N-:3]
Reactant: Cc1ccc(N=[N+]=[N-])cc1C(=O)c1ccc(Nc2ccc(C(F)(F)F)cc2)cc1Cl
Agent: Cc1ccc(N)cc1C(=O)c1ccc(Nc2cccc(F)c2)cc1Cl
Product: Cc1ccc(N=[N+]=[N-])cc1C(=O)c1ccc(Nc2cccc(F)c2)cc1Cl

Procedure:
The reaction was carried out similarly as described in the preparation of compound 416, using compound 458 (1.83 mmol). The crude product was purified by flash chromatography using EtOAc/petroleum ether (40-60) 1:9 and 1:6 as the eluent to afford the title compound as yellow foam.
Reaction SMILES: [CH3:1][N:2]([CH3:9])[CH:3]1[CH2:8][CH2:7][CH2:6][NH:5][CH2:4]1.[Br:10][C:11]1[C:12](F)=[C:13]2[C:19]([NH:20][C:21](=[O:28])[C:22]3[CH:27]=[CH:26][CH:25]=[N:24][CH:23]=3)=[CH:18][NH:17][C:14]2=[N:15][CH:16]=1>CCCCO>[Br:10][C:11]1[C:12]([N:5]2[CH2:6][CH2:7][CH2:8][CH:3]([N:2]([CH3:9])[CH3:1])[CH2:4]2)=[C:13]2[C:19]([NH:20][C:21](=[O:28])[C:22]3[CH:27]=[CH:26][CH:25]=[N:24][CH:23]=3)=[CH:18][NH:17][C:14]2=[N:15][CH:16]=1
Reactant: O=C(Nc1c[nH]c2ncc(Br)c(F)c12)c1cccnc1
Reactant: CN(C)C1CCCNC1
Solvent: CCCCO
Product: CN(C)C1CCCN(c2c(Br)cnc3[nH]cc(NC(=O)c4cccnc4)c23)C1
Temperature: 160 °C
Reaction time: 20 h
Yield: 45.4 %

Procedure:
N,N-Dimethylpiperidin-3-amine (115 mg, 0.895 mmol) was added to N-(5-bromo-4-fluoro-1H-pyrrolo[2,3-b]pyridin-3-yl)nicotinamide (100 mg, 0.298 mmol) in n-BuOH. The reaction was stirred at 160° C. for 20 hours in a sealed tube. After concentration, the residue was purified by C-18 reverse phase flash chromatography (Biotage SP4 unit, C-18 25M column, 0-60% CH3CN/water gradient; 20 CV) to yield N-(5-bromo-4-(3-(dimethylamino)piperidin-1-yl)-1H-pyrrolo[2,3-b]pyridin-3-yl)nicotinamide (60 mg, 45.4% yield) as a solid. The solid was dissolved in a minimal amount of methanol, and then the solution was added to 2N HCl in ether. The resulting precipitate was filtered and dried under high vacuum to yield N-(5-bromo-4-(3-(dimethylamino)piperidin-1-yl)-1H-pyrrolo[2,3-b]pyridin-3-yl)nicotinamide hydrochloride as a solid. 1H NMR (400 MHz, (CD3)2SO) δ 10.91 (d, 1H), 10.63 (br s, 1H), 9.47 (d, 1H), 8.99 (dd, 1H), 8.90 (d, 1H), 8.30 (s, 1H), 7.98 (dd, 1H), 7.59 (s, 1H), 3.67-3.59 (m, 1H), 3.27-3.06 (m, 3H), 2.76-2.67 (m, 1H), 2.68 (d, 3H), 2.65 (d, 3H), 2.14-2.04 (m, 1H), 1.74-1.66 (m, 1H), 1.59-1.32 (m, 2H); LCMS (APCI+) m/z 443, 445 (M+H)+, Retention time=1.90 minutes (Method 1).
Reaction SMILES: Cl.N1C=CC=CC=1.C[O:9][C:10]1[CH:19]=[CH:18][CH:17]=[C:16]2[C:11]=1[CH2:12][CH2:13][CH:14]=[C:15]2[CH2:20][CH2:21][C:22]([OH:24])=[O:23].Cl>O>[OH:9][C:10]1[CH:19]=[CH:18][CH:17]=[C:16]2[C:11]=1[CH2:12][CH2:13][CH:14]=[C:15]2[CH2:20][CH2:21][C:22]([OH:24])=[O:23]
Reactant: COc1cccc2c1CCC=C2CCC(=O)O
Agent: Cl
Solvent: c1ccncc1
Solvent: O
Product: O=C(O)CCC1=CCCc2c(O)cccc21
Temperature: 180 °C
Reaction time: 3 h

Procedure:
To pyridine hydrochloride (200 g), 3-(5-methoxy-3,4-dihydronaphthalen-1-yl)propanoic acid (25.1 g; known compound (see J. Chem. Soc. Perkin Trans. I., 1739–1742(1987)) was added, followed by stirring at 180° C. for 3 hours. The reaction mixture was cooled to room temperature, and diluted with water. The aqueous layer was acidified with a concentrated hydrochloric acid. The aqueous layer was extracted with an ethyl acetate. The extract was extracted with a saturated aqueous sodium hydrogen carbonate solution. The combined aqueous layer was acidified with a concentrated hydrochloric acid, followed by extracting with an ethyl acetate. The combined organic layer was washed with a saturated saline, dried with anhydrous sodium sulfate, and concentrated under reduced pressure to thereby obtain the title compound (11.8 g) having the following physical data.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5]([OH:12])=[C:6]([CH:11]=1)[C:7]([NH:9]O)=[O:8].C(N1C=CN=C1)(N1C=CN=C1)=O>C1COCC1>[Br:1][C:2]1[CH:3]=[CH:4][C:5]2[O:12][N:9]=[C:7]([OH:8])[C:6]=2[CH:11]=1
Reactant: O=C(NO)c1cc(Br)ccc1O
Agent: O=C(n1ccnc1)n1ccnc1
Solvent: C1CCOC1
Product: Oc1noc2ccc(Br)cc12
Yield: 97.4 %

Procedure:
5-bromo-N,2-dihydroxybenzamide (4.12 g, 17.76 mmol) was suspended in 100 mL THF. Carbonyldiimidazole (5.76 g, 35.5 mmol) was added and the mixture was heated under reflux for three hours. The solvent was evaporated under vacuum, 100 mL water was added and the solution was acidified to pH 1 with 1N HCl under rapid stirring. The formed precipitate was filtered, washed with water and dried, giving 5-bromobenzo[d]isoxazol-3-ol (3.71 g, 17.3 mmol) as off-white solid.
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:10]=[N:11][CH:12]=[C:13](Br)[CH:14]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH2:16]1[C@@H:20]2[CH2:21][NH:22][CH2:23][C@@H:19]2[CH2:18][N:17]1[C:24]([O:26][C:27]([CH3:30])([CH3:29])[CH3:28])=[O:25]>>[CH2:1]([O:8][C:9]1[CH:14]=[C:13]([N:22]2[CH2:21][C@@H:20]3[CH2:16][N:17]([C:24]([O:26][C:27]([CH3:30])([CH3:29])[CH3:28])=[O:25])[CH2:18][C@@H:19]3[CH2:23]2)[CH:12]=[N:11][CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: Brc1cncc(OCc2ccccc2)c1
Reactant: CC(C)(C)OC(=O)N1C[C@H]2CNC[C@H]2C1
Product: CC(C)(C)OC(=O)N1C[C@@H]2CN(c3cncc(OCc4ccccc4)c3)C[C@@H]2C1

Procedure:
3-(Benzyloxy)-5-bromopyridine and the product from Example 1C were processed as described in Example 53B to provide the title compound. MS (ESI) m/z 396 (M+H)+.
Reaction SMILES: [NH2:1][C:2]1[CH:9]=[CH:8][C:5]([CH2:6][NH2:7])=[CH:4][CH:3]=1.C([O-])(O)=O.[Na+].F[C:16]1[CH:21]=[CH:20][C:19]([N+:22]([O-:24])=[O:23])=[CH:18][C:17]=1[N+:25]([O-:27])=[O:26]>CN(C=O)C.O>[NH2:1][C:2]1[CH:9]=[CH:8][C:5]([CH2:6][NH:7][C:20]2[CH:21]=[CH:16][C:17]([N+:25]([O-:27])=[O:26])=[CH:18][C:19]=2[N+:22]([O-:24])=[O:23])=[CH:4][CH:3]=1
Reactant: O=[N+]([O-])c1ccc(F)c([N+](=O)[O-])c1
Reactant: NCc1ccc(N)cc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: Nc1ccc(CNc2ccc([N+](=O)[O-])cc2[N+](=O)[O-])cc1
Reaction time: 2 h
Yield: 99 %

Procedure:
To a solution of 4-aminobenzylamine (25.5 mL, 225 mmol) and powdered NaHCO3 (94.5 g, 1125 mmol) in anhydrous DMF (300 mL) was added 2,4-dinitrofluorbenzene (1) (18.8 mL, 150 mmol) dropwise at room temperature. After 2 hours, the solution was slowly diluted with water (1000 mL) to precipitate the product, which was collected on a fritted funnel while rinsing with water until the eluent was colorless. The solid was further dried under high vacuum to afford 43.0 g as a bright orange solid in 99% yield.
Reaction SMILES: Cl.Cl.[CH3:3][O:4][C:5]1[N:10]=[CH:9][C:8]([N:11]2[CH2:26][CH2:25][C:14]3[N:15]=[CH:16][N:17]=[C:18]([O:19][C@H:20]4[CH2:24][CH2:23][NH:22][CH2:21]4)[C:13]=3[CH2:12]2)=[CH:7][C:6]=1[C:27]([F:30])([F:29])[F:28].C(N(CC)CC)C.Cl.[CH3:39][N:40]1[CH2:45][CH2:44][N:43]([C:46](Cl)=[O:47])[CH2:42][CH2:41]1>C(Cl)Cl>[CH3:3][O:4][C:5]1[N:10]=[CH:9][C:8]([N:11]2[CH2:26][CH2:25][C:14]3[N:15]=[CH:16][N:17]=[C:18]([O:19][C@H:20]4[CH2:24][CH2:23][N:22]([C:46]([N:43]5[CH2:44][CH2:45][N:40]([CH3:39])[CH2:41][CH2:42]5)=[O:47])[CH2:21]4)[C:13]=3[CH2:12]2)=[CH:7][C:6]=1[C:27]([F:30])([F:28])[F:29]
Reactant: CN1CCN(C(=O)Cl)CC1
Reactant: COc1ncc(N2CCc3ncnc(O[C@H]4CCNC4)c3C2)cc1C(F)(F)F
Agent: Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: COc1ncc(N2CCc3ncnc(O[C@H]4CCN(C(=O)N5CCN(C)CC5)C4)c3C2)cc1C(F)(F)F
Temperature: 25 °C
Reaction time: 18 h
Yield: 82.6 %

Procedure:
To a solution of 6-(6-methoxy-5-trifluoromethyl-pyridin-3-yl)-4-((S)-pyrrolidin-3-yloxy)-5,6,7,8-tetrahydro-pyrido[4,3-d]pyrimidine (prepared using step 1, example 91 from intermediate 13) (23.0 mg, 0.058 mmol) and triethylamine (0.016 mL, 0.116 mmol) in CH2Cl2 (2 mL) was added 4-methylpiperazine-1-carbonyl chloride hydrochloride (11.6 mg, 0.058 mmol) and the mixture stirred at rt for 18 h. Diluted with CH2Cl2 (10 mL) and washed with sat. NaHCO3(aq) (2 mL). The organic layer was filtered through a phase separation tube and evaporated in vacuo. Purification was performed by reverse phase Gilson HPLC (Method A) and subsequent neutralization of the combined fractions by elution through an Isolute® SCX-2 cartridge, eluting with methanol, then with 2M ammonia in methanol. Basic fractions were concentrated in vacuo to give {(S)-3-[6-(6-methoxy-5-trifluoromethyl-pyridin-3-yl)-5,6,7,8-tetrahydro-pyrido[4,3-d]pyrimidin-4-yloxy]-pyrrolidin-1-yl}-(4-methyl-piperazin-1-yl)-methanone (25 mg, 58% yield) as a yellow powder. 1H NMR (400 MHz, CDCl3, 298K) δ ppm 2.17-2.27 (m, 2H) 2.55 (s, 3H) 2.65-2.78 (m, 4H) 3.07 (t, 2H) 3.45-3.73 (m, 9H) 3.86-3.95 (m, 1H) 4.02 (s, 3H) 4.13 (s, 2H) 5.66-5.73 (m, 1H) 7.62 (d, 1H) 8.06 (d, 1H) 8.64 (s, 1H) LCMS: [M+H]+=522.3, Rt(1)=1.21 min.
Reaction SMILES: [NH2:1][CH:2]1[CH2:6][N:5]([C:7]([O:9][C:10]([CH3:13])([CH3:12])[CH3:11])=[O:8])[CH2:4][C:3]1([F:15])[F:14].[CH3:16][S:17]([CH2:20][CH2:21][C:22](O)=[O:23])(=[O:19])=[O:18].CN1CCOCC1.C1C=CC2N(O)N=NC=2C=1.CCN=C=NCCCN(C)C.Cl>C(Cl)Cl>[F:14][C:3]1([F:15])[CH:2]([NH:1][C:22](=[O:23])[CH2:21][CH2:20][S:17]([CH3:16])(=[O:19])=[O:18])[CH2:6][N:5]([C:7]([O:9][C:10]([CH3:12])([CH3:11])[CH3:13])=[O:8])[CH2:4]1
Reactant: CC(C)(C)OC(=O)N1CC(N)C(F)(F)C1
Reactant: CS(=O)(=O)CCC(=O)O
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CN1CCOCC1
Solvent: ClCCl
Product: CC(C)(C)OC(=O)N1CC(NC(=O)CCS(C)(=O)=O)C(F)(F)C1
Temperature: 25 °C
Reaction time: 2 h
Yield: 75.7 %

Procedure:
To a reaction flask was added tert-butyl 4-amino-3,3-difluoropyrrolidine-1-carboxylate (1.36 g, 6.12 mmol), 3-(methylsulfonyl)propanoic acid (1.02 g, 6.73 mmol, 1.1 mol eq), DCM (31 mL, 0.4 M), NMM (1.35 mL, 12.2 mmol, 2 mol eq), HOBt (1.31 g, 9.2 mmol, 1.5 mol eq) and EDC-HCl (1.85 g, 9.2 mmol, 1.5 mol eq). The resulting suspension was stirred at ambient temperature under a nitrogen atmosphere for 2 hr. The reaction was diluted with DCM (80 mL), washed with aqueous NaHCO3 (2×30 mL) and the organic layer was dried over Na2SO4 and evaporated to give a residue that was purified via silica flash chromatography eluting with gradients from 100% heptane to 100% ethyl acetate to give the title product as a white foamy solid (1.65 g, 76% yield, >95% purity). 1H NMR (400 MHz, chloroform-d) δ ppm 6.45 (br. s., 1 H) 4.68-4.89 (m, 1 H) 3.94 (dd, J=10.70, 8.62 Hz, 1 H) 3.62-3.86 (m, 2 H) 3.43 (t, J=7.15 Hz, 2 H) 3.18 (br. s., 1 H) 2.97 (s, 3 H) 2.84 (td, J=7.15, 1.96 Hz, 2 H) 1.47 (s, 9 H). 19F NMR (376 MHz, chloroform-d) δ ppm −112.79-−110.52 (m, 1 F) −114.51-−113.30 (m, 1 F). m/z (APCI+) for C13H22F2N2O5S 257.1 (M+H)+.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]([C:17]2[CH:22]=[CH:21][C:20]([F:23])=[CH:19][CH:18]=2)=[CH:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][Br:16])=[CH:4][CH:3]=1.[H][H]>C(O)C.[Pd]>[F:1][C:2]1[CH:3]=[CH:4][C:5]([CH:8]([C:17]2[CH:18]=[CH:19][C:20]([F:23])=[CH:21][CH:22]=2)[CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][Br:16])=[CH:6][CH:7]=1
Reactant: [H][H]
Reactant: Fc1ccc(C(=CCCCCCCBr)c2ccc(F)cc2)cc1
Agent: [Pd]
Solvent: CCO
Product: Fc1ccc(C(CCCCCCCBr)c2ccc(F)cc2)cc1

Procedure:
9.7 g (25.5 mmol) 8,8-bis-(4-fluorophenyl)-oct-7-enyl bromide are dissolved in 350 ml ethanol and added to 0.5 g palladium (5%) on activated carbon. The mixture is stirred under hydrogen atmosphere (ca. one hour) until the theoretical amount of hydrogen to be taken up is consumed. Subsequently, the mixture is filtered off from a catalyst and the solvent is removed under vacuum. The residue is chromatographically purified over silica gel with petroleum ether/acetic acid ethyl ester (80/1 to 40/1)): Yield 8.6 g (89%).
Reaction SMILES: [CH3:1][C:2]1[CH:6]=[C:5]([C:7]2[CH:12]=[CH:11][C:10]([CH3:13])=[CH:9][CH:8]=2)[O:4][N:3]=1>[Pt](=O)=O.C(O)C>[NH2:3][C:2]([CH3:1])=[CH:6][C:5]([C:7]1[CH:8]=[CH:9][C:10]([CH3:13])=[CH:11][CH:12]=1)=[O:4]
Reactant: Cc1ccc(-c2cc(C)no2)cc1
Agent: O=[Pt]=O
Solvent: CCO
Product: CC(N)=CC(=O)c1ccc(C)cc1
Reaction time: 12 h

Procedure:
3-Methyl-5-(4-methylphenyl)isoxazole (1 g, 5.77 mmol) is introduced into 20 ml of ethanol, platinum(IV) oxide catalyst (100 mg) is added, and the mixture is then hydrogenated under atmospheric hydrogen for 12 h. The catalyst is filtered off and the filtrate is concentrated. 1.02 g (100% of theory) of the title compound are obtained as a white solid.
Reaction SMILES: C([SiH](C(C)C)C(C)C)(C)C.FC(F)(F)C(O)=O.[I:18][C:19]1[N:24]=[C:23]([O:25][CH3:26])[C:22]([O:27]CC2C=CC(OC)=CC=2)=[CH:21][CH:20]=1>C(Cl)(Cl)Cl>[I:18][C:19]1[N:24]=[C:23]([O:25][CH3:26])[C:22]([OH:27])=[CH:21][CH:20]=1
Reactant: COc1ccc(COc2ccc(I)nc2OC)cc1
Agent: CC(C)[SiH](C(C)C)C(C)C
Solvent: O=C(O)C(F)(F)F
Solvent: ClC(Cl)Cl
Product: COc1nc(I)ccc1O
Temperature: 0 °C
Reaction time: 1 h
Yield: 89.3 %

Procedure:
Triisopropylsilane (2.1 g) and trifluoroacetic acid (4.0 mL) were added to a solution of 6-iodo-2-methoxy-3-[(4-methoxybenzyl)oxy]pyridine (1 g) in chloroform (10 mL), and the mixture was stirred at 0° C. for one hour. The solvent was evaporated from the reaction solution under reduced pressure. The residue was purified by silica gel column chromatography (hexane:ethyl acetate=90:10→50:50) to give the title compound as a colorless powder (604 mg, 96%).
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([O:8][CH3:9])=[CH:4][C:3]=1[C:10]1([CH3:15])[O:14]CCO1.[NH2:16][C:17]1[CH:18]=[C:19]2[C:23]3=[C:24]([CH2:26][O:27][CH2:28][CH2:29][N:22]3[C@H:21]3[CH2:30][CH2:31][N:32](C(OC(C)(C)C)=O)[CH2:33][C@@H:20]23)[CH:25]=1>>[CH2:29]1[N:22]2[C:23]3[C:19]([C@@H:20]4[CH2:33][NH:32][CH2:31][CH2:30][C@@H:21]42)=[CH:18][C:17]([NH:16][C:2]2[CH:7]=[CH:6][C:5]([O:8][CH3:9])=[CH:4][C:3]=2[C:10](=[O:14])[CH3:15])=[CH:25][C:24]=3[CH2:26][O:27][CH2:28]1
Reactant: COc1ccc(Br)c(C2(C)OCCO2)c1
Reactant: CC(C)(C)OC(=O)N1CC[C@H]2[C@@H](C1)c1cc(N)cc3c1N2CCOC3
Product: COc1ccc(Nc2cc3c4c(c2)[C@@H]2CNCC[C@@H]2N4CCOC3)c(C(C)=O)c1

Procedure:
Using 2-(2-bromo-5-methoxyphenyl)-2-methyl-1,3-dioxolane and following the procedures described in EXAMPLE 116, tert-butyl (7bR,11aS)-6-amino-1,2,7b,10,11,11a-hexahydro-4H-[1,4]oxazepino[6,5,4-hi]pyrido[4,3-b]indole-9(8H)-carboxylate from EXAMPLE 56, Part B was converted into the title compound of EXAMPLE 118. 1H NMR (CDCl3) o: 9.95 (s, 1H), 7.22 (d, 1H, J=2.5 Hz), 6.99-6.92 (m, 2H), 6.86 (d, 1H, J=1.8 Hz), 6.75 (d, 1H, J=1.9 Hz), 4.58 (ABq, 2H, JAB=14.2 Hz), 4.20 (app d, 1H), 3.77 (s, 3H), 3.72 (app t, 1H), 3.42-3.37 (m, 1H), 3.35-3.20 (m, 2H), 3.10 (dd, 1H), 3.01-2.90 (m, 2H), 2.71 (app t, 1H), 2.59 (s, 3H), 2.50 (app t, 1H), 2.02-1.90 (m, 2H). LRMS (ES)+: 394.4 (M+H)+.