Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([C:4]1[C:5]([O:23][CH2:24][CH3:25])=[C:6]([CH:12]2[CH2:15][N:14]([C:16]([O:18][C:19]([CH3:22])([CH3:21])[CH3:20])=[O:17])[CH2:13]2)[C:7]([F:11])=[C:8]([Cl:10])[CH:9]=1)(=[O:3])[CH3:2].[BH4-].[Na+]>>[Cl:10][C:8]1[C:7]([F:11])=[C:6]([CH:12]2[CH2:13][N:14]([C:16]([O:18][C:19]([CH3:20])([CH3:22])[CH3:21])=[O:17])[CH2:15]2)[C:5]([O:23][CH2:24][CH3:25])=[C:4]([CH:1]([OH:3])[CH3:2])[CH:9]=1
Reactant: CCOc1c(C(C)=O)cc(Cl)c(F)c1C1CN(C(=O)OC(C)(C)C)C1
Agent: [BH4-]
Agent: [Na+]
Product: CCOc1c(C(C)O)cc(Cl)c(F)c1C1CN(C(=O)OC(C)(C)C)C1

Procedure:
This compound was prepared according to the procedure of Example 13 Step 5, using tert-butyl 3-(3-acetyl-5-chloro-2-ethoxy-6-fluorophenyl)azetidine-1-carboxylate and sodium tetrahydroborate as the starting materials. LCMS calculated for C18H25ClFNO4Na (M+Na)+: m/z=396.1; Found: 396.1.
Reaction SMILES: [N+:1]([C:4]1[N:8]=[CH:7][NH:6][N:5]=1)([O-:3])=[O:2].[C:9](Cl)([C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1)([C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1)[C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1.C(N(C(C)C)CC)(C)C>C1COCC1>[N+:1]([C:4]1[N:8]=[CH:7][N:6]([C:9]([C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)([C:22]2[CH:23]=[CH:24][CH:25]=[CH:26][CH:27]=2)[C:16]2[CH:17]=[CH:18][CH:19]=[CH:20][CH:21]=2)[N:5]=1)([O-:3])=[O:2]
Reactant: O=[N+]([O-])c1nc[nH]n1
Reactant: ClC(c1ccccc1)(c1ccccc1)c1ccccc1
Solvent: C1CCOC1
Solvent: CCN(C(C)C)C(C)C
Product: O=[N+]([O-])c1ncn(C(c2ccccc2)(c2ccccc2)c2ccccc2)n1
Yield: 92.8 %

Procedure:
A solution of 3-nitro-1H-1,2,4-triazole (1.00 g, 8.77 mmol), trityl chloride (4.89 g, 17.5 mmol) and diisopropylethylamine (3.05 mL, 17.5 mmol) in THF (50 mL) was stirred at room temperature for 15 hr. The mixture was concentrated under reduced pressure, and the residue was extracted with ethyl acetate and water. The organic layer was washed with saturated brine, dried over sodium sulfate, and concentrated. The residue was purified by silica gel column chromatography (15-30% ethyl acetate/hexane) to give the title compound as a white powder (2.90 g, 93%).
Reaction SMILES: [F:1][C:2]([F:36])([F:35])[C:3]1[CH:4]=[C:5]([C:13]([CH3:34])([CH3:33])[C:14]([N:16]([C:18]2[CH:19]=[N:20][C:21](Cl)=[CH:22][C:23]=2[C:24]2[CH:29]=[CH:28][C:27]([F:30])=[CH:26][C:25]=2[CH3:31])[CH3:17])=[O:15])[CH:6]=[C:7]([C:9]([F:12])([F:11])[F:10])[CH:8]=1.[CH3:37][C@@H:38]1[CH2:43][NH:42][CH2:41][CH2:40][NH:39]1.C(=O)([O-])[O-].[K+].[K+]>CS(C)=O.[OH-].[Na+]>[F:1][C:2]([F:36])([F:35])[C:3]1[CH:4]=[C:5]([C:13]([CH3:34])([CH3:33])[C:14]([N:16]([C:18]2[CH:19]=[N:20][C:21]([N:42]3[CH2:41][CH2:40][NH:39][C@H:38]([CH3:37])[CH2:43]3)=[CH:22][C:23]=2[C:24]2[CH:29]=[CH:28][C:27]([F:30])=[CH:26][C:25]=2[CH3:31])[CH3:17])=[O:15])[CH:6]=[C:7]([C:9]([F:12])([F:11])[F:10])[CH:8]=1
Reactant: Cc1cc(F)ccc1-c1cc(Cl)ncc1N(C)C(=O)C(C)(C)c1cc(C(F)(F)F)cc(C(F)(F)F)c1
Reactant: C[C@@H]1CNCCN1
Agent: O=C([O-])[O-]
Agent: [K+]
Agent: [Na+]
Solvent: CS(C)=O
Product: Cc1cc(F)ccc1-c1cc(N2CCN[C@H](C)C2)ncc1N(C)C(=O)C(C)(C)c1cc(C(F)(F)F)cc(C(F)(F)F)c1
Temperature: 180 °C
Yield: 52.9 %

Procedure:
A mixture of 0.20 g (0.38 mmol) 2-(3,5-bis-trifluoromethyl-phenyl)-N-[6-chloro-4-(4-fluoro-2-methyl-phenyl)-pyridin-3-yl]-N-methyl-isobutyramide, 0.11 g (1.1 mmol) (R)-2-methylpiperazine and 0.10 g (0.72 mmol) potassium carbonate in 0.3 ml dimethyl sulfoxide was heated at 180° C. under microwave irradiation in a sealed tube for 30 min. After cooling to room temperature the reaction mixture was diluted with a 0.3 M aqueous solution of sodium hydroxide and extracted with three portions of tert-butyl methyl ether. The combined organic extracts were dried over sodium sulfate and concentrated. Flash column chromatography gave 0.12 g (51%) of the title compound as an off-white solid.
Reaction SMILES: [O:1]1[CH2:24][CH:2]1[CH2:3][O:4][C:5]1[CH:10]=[CH:9][C:8]([O:11][CH3:12])=[CH:7][C:6]=1[CH:13]1[C:18](=[O:19])[NH:17][C:16]2[CH:20]=[CH:21][CH:22]=[CH:23][C:15]=2[S:14]1.[C:25]([NH2:29])([CH3:28])([CH3:27])[CH3:26]>C(O)C>[C:25]([NH:29][CH2:24][CH:2]([OH:1])[CH2:3][O:4][C:5]1[CH:10]=[CH:9][C:8]([O:11][CH3:12])=[CH:7][C:6]=1[CH:13]1[C:18](=[O:19])[NH:17][C:16]2[CH:20]=[CH:21][CH:22]=[CH:23][C:15]=2[S:14]1)([CH3:28])([CH3:27])[CH3:26]
Reactant: CC(C)(C)N
Reactant: COc1ccc(OCC2CO2)c(C2Sc3ccccc3NC2=O)c1
Solvent: CCO
Product: COc1ccc(OCC(O)CNC(C)(C)C)c(C2Sc3ccccc3NC2=O)c1
Yield: 93 %

Procedure:
3,4-Dihydro-2-[2-(2,3-epoxypropoxy)-5-methoxyphenyl]-3-oxo-2H-1,4-benzothiazine (compound No. 10, 0.8 g) and tert-butylamine (2.5 ml) are dissolved in ethanol (15 ml). The solution is refluxed for 1.5 hours, and after cooling, concentrated in vacuo. The residue is dissolved in chloroform, and the solution is washed with 2N HCl, water and N NaOH. The organic layer is dried over anhydrous sodium sulfate and concentrated in vacuo to give 0.9 g (93%) of the titled compound.
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][C:7]([CH2:10][NH:11][S:12]([CH3:15])(=[O:14])=[O:13])=[CH:6][CH:5]=1)([O-])=O.[H][H]>C(O)C.C(OCC)(=O)C.[Pd]=O>[NH2:1][C:4]1[CH:9]=[CH:8][C:7]([CH2:10][NH:11][S:12]([CH3:15])(=[O:14])=[O:13])=[CH:6][CH:5]=1
Reactant: CS(=O)(=O)NCc1ccc([N+](=O)[O-])cc1
Reactant: [H][H]
Agent: O=[Pd]
Solvent: CCOC(C)=O
Solvent: CCO
Product: CS(=O)(=O)NCc1ccc(N)cc1

Procedure:
A solution of N-[(4-nitrophenyl)methyl]methanesulphonamide (2.5 g) in a mixture of ethanol (90 ml) and ethyl acetate (90 ml) was hydrogenated at room temperature and pressure over palladium oxide on charcoal (10%; 50% paste with water, 1 g) until uptake of hydrogen ceased (15 min., 820 ml).
Reaction SMILES: C(OC(N1CCC2N(C)C3C(C(F)(F)F)=CC(NC4C=CC=CN=4)=CC=3C2C1)=O)(C)(C)C.C(OC([N:40]1[CH2:56][CH2:55][C@@H:43]2[N:44]([CH3:54])[C:45]3[C:46]([C:52]#[N:53])=[CH:47][C:48](Br)=[CH:49][C:50]=3[C@@H:42]2[CH2:41]1)=O)(C)(C)C.[Cl:57][C:58]1[C:63]([NH2:64])=[CH:62][C:61]([Cl:65])=[CH:60][N:59]=1.CC([O-])(C)C.[Na+]>>[Cl:57][C:58]1[C:63]([NH:64][C:48]2[CH:49]=[C:50]3[C:45](=[C:46]([C:52]#[N:53])[CH:47]=2)[N:44]([CH3:54])[C@H:43]2[CH2:55][CH2:56][NH:40][CH2:41][C@@H:42]32)=[CH:62][C:61]([Cl:65])=[CH:60][N:59]=1
Reactant: Nc1cc(Cl)cnc1Cl
Reactant: CN1c2c(C#N)cc(Br)cc2[C@@H]2CN(C(=O)OC(C)(C)C)CC[C@@H]21
Agent: CC(C)(C)[O-]
Agent: CN1c2c(cc(Nc3ccccn3)cc2C(F)(F)F)C2CN(C(=O)OC(C)(C)C)CCC21
Agent: [Na+]
Product: CN1c2c(C#N)cc(Nc3cc(Cl)cnc3Cl)cc2[C@@H]2CNCC[C@@H]21

Procedure:
The title compound was prepared by following the general method for (5-methyl-6-trifluoromethyl-2,3,4,4a,5,9b-hexahydro-1H-pyrido[4,3-b]indol-8-yl)-pyridin-3-yl-amine (Method A) as a yellow solid (60 mg, 32%) from (4aS,9bR)-8-bromo-6-cyano-5-methyl-1,3,4,4a,5,9b-hexahydro-pyrido[4,3-b]indole-2-carboxylic acid tert-butyl ester (Example 158, 196 mg, 0.5 mmol), 2,5-dichloro-pyridin-3-ylamine (186 mg, 1.5 mmol) and NaOt-Bu (144 mg, 1.5 mmol). MS (ESI): 375 (base, M+H).
Reaction SMILES: C([O:9][CH2:10][C@H:11]([C:35]1[CH:40]=[C:39]([C:41]([F:44])([F:43])[F:42])[CH:38]=[C:37]([C:45]([F:48])([F:47])[F:46])[CH:36]=1)[O:12][C@H:13]1[CH2:21][CH2:20][C@H:19]2[C@@H:15]([CH2:16][N:17]([C:22]3[O:23][CH2:24][C:25](=[O:27])[N:26]=3)[CH2:18]2)[C@@H:14]1[C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][C:29]=1[CH3:34])(=O)C1C=CC=CC=1.[OH-].[Na+]>CO.CCOCC>[F:47][C:45]([F:46])([F:48])[C:37]1[CH:36]=[C:35]([C@H:11]([O:12][C@H:13]2[CH2:21][CH2:20][C@H:19]3[C@@H:15]([CH2:16][N:17]([C:22]4[O:23][CH2:24][C:25](=[O:27])[N:26]=4)[CH2:18]3)[C@@H:14]2[C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][C:29]=2[CH3:34])[CH2:10][OH:9])[CH:40]=[C:39]([C:41]([F:42])([F:44])[F:43])[CH:38]=1
Reactant: Cc1ccccc1[C@H]1[C@@H]2CN(C3=NC(=O)CO3)C[C@H]2CC[C@@H]1O[C@H](COC(=O)c1ccccc1)c1cc(C(F)(F)F)cc(C(F)(F)F)c1
Agent: [Na+]
Agent: [OH-]
Solvent: CCOCC
Solvent: CO
Product: Cc1ccccc1[C@H]1[C@@H]2CN(C3=NC(=O)CO3)C[C@H]2CC[C@@H]1O[C@H](CO)c1cc(C(F)(F)F)cc(C(F)(F)F)c1
Temperature: 25 °C

Procedure:
To a solution of benzoate of Step D (4.0 g, 5.93 mmol) in 200 mL of methanol was added 6.0 mL of 2 M sodium hydroxide. The reaction mixture was maintained at ambient temperature for 1 hr, and diluted with 1200 mL ether. The organic layer was washed with 1 M sodium hydroxide (400 mL). The organic layer was then washed with water, dried over MgSO4, filtered, and concentrated to afford a white solid. The crude material was purified by flash chromatography (0-5% then 5-7% them 7% methanol in ethyl acetate. M++1: 571.2.
Reaction SMILES: [NH2:1]/[C:2](/OCC)=[CH:3]\[C:4](=O)[C:5]([F:8])([F:7])[F:6].Cl.[C:14]1([CH3:22])[CH:19]=[CH:18][C:17]([NH:20][NH2:21])=[CH:16][CH:15]=1.C(N(CC)CC)C>>[C:14]1([CH3:22])[CH:19]=[CH:18][C:17]([N:20]2[C:2]([NH2:1])=[CH:3][C:4]([C:5]([F:6])([F:7])[F:8])=[N:21]2)=[CH:16][CH:15]=1
Reactant: Cc1ccc(NN)cc1
Reactant: CCO/C(N)=C/C(=O)C(F)(F)F
Agent: Cl
Solvent: CCN(CC)CC
Product: Cc1ccc(-n2nc(C(F)(F)F)cc2N)cc1
Temperature: 95 °C
Yield: 61.8 %

Procedure:
According to the procedure described in Example 161A Step 3, (E)-4-amino-4-ethoxy-1,1,1-trifluorobut-3-en-2-one (2.747 g, 15 mmol), p-tolylhydrazine hydrochloride (2.379 g, 15 mmol) and triethylamine (2.03 g, 20 mmol) were heated at 95° C. for 8 hours. The crude product was purified by silica gel chromatography with 5-25% EtOAc/hexane as eluants to afford 1-p-tolyl-3-(trifluoromethyl)-1H-pyrazol-5-amine as solid (2.237 g, 62%). 1H NMR (300 MHz, CDCl3) δ 7.42 (d, 2H), 7.30 (d, 2H), 5.84 (s, 1H), 3.88 (br, 2H), 2.41 (s, 3H); LC-MS (ESI) m/z 242 (M+H)+.
Reaction SMILES: [N+:1]([CH2:4][C:5]12[CH2:12][CH2:11][CH2:10][N:9]1[CH2:8][CH2:7][CH2:6]2)([O-])=O.Cl>[Fe].C(O)C>[NH2:1][CH2:4][C:5]12[CH2:12][CH2:11][CH2:10][N:9]1[CH2:8][CH2:7][CH2:6]2
Reactant: O=[N+]([O-])CC12CCCN1CCC2
Agent: [Fe]
Agent: Cl
Solvent: CCO
Product: NCC12CCCN1CCC2
Temperature: 20 °C
Reaction time: 0.17 h
Yield: 90.8 %

Procedure:
To 5.0 ml of 80% ethanol, 7a-nitromethyl-2,3,5,6,7,7a-hexahydro-1H-pyrrolizine (300 mg, 1.76 mmol, obtained in Example 1) and concentrated hydrochloric acid (0.45 ml, 5.28 mmol) were added to stir for 10 minutes at 20° C. Then, iron powder (500 mg, 8.95 mmol) was added to the mixture to further stirr for 1 hour at 20° C. Insoluble matters were filtered off and the filtrate was concentrated, adding 0.5N NaOH (10 ml) to the residue, filtering the solution to further remove insoluble matters, extracting the filtrate with chloroform, drying the extract over anhydrous sodium sulfate, concentrating the extract, and distilling the resulting crude product to afford 224 mg of the desired compound (Yield: 91%).
Reaction SMILES: C([N:8]([CH2:30][CH2:31][O:32][C:33]1[CH:38]=[CH:37][C:36]([OH:39])=[C:35]([C:40](=[O:42])[NH2:41])[CH:34]=1)[CH2:9][CH:10]([OH:29])[CH2:11][O:12][C:13]1[CH:18]=[CH:17][C:16]([C:19]2[N:23]([CH3:24])[C:22]([C:25]([F:28])([F:27])[F:26])=[N:21][N:20]=2)=[CH:15][CH:14]=1)C1C=CC=CC=1>[Pd].CO>[C:40]([C:35]1[CH:34]=[C:33]([CH:38]=[CH:37][C:36]=1[OH:39])[O:32][CH2:31][CH2:30][NH:8][CH2:9][CH:10]([OH:29])[CH2:11][O:12][C:13]1[CH:14]=[CH:15][C:16]([C:19]2[N:23]([CH3:24])[C:22]([C:25]([F:28])([F:26])[F:27])=[N:21][N:20]=2)=[CH:17][CH:18]=1)(=[O:42])[NH2:41]
Reactant: Cn1c(-c2ccc(OCC(O)CN(CCOc3ccc(O)c(C(N)=O)c3)Cc3ccccc3)cc2)nnc1C(F)(F)F
Agent: [Pd]
Solvent: CO
Product: Cn1c(-c2ccc(OCC(O)CNCCOc3ccc(O)c(C(N)=O)c3)cc2)nnc1C(F)(F)F

Procedure:
With the addition of 3.0 g of palladium-on-carbon catalyst (10%), a solution of 16 g of crude 1-[N-benzyl-[2-(3-carbamoyl-4-hydroxyphenoxy)-ethylamino]]-3-[4-(4-methyl-5-trifluoromethyl-4H-1,2,4-triazol-3-yl)-phenoxy]-2-propanol in 160 ml of methanol is catalytically hydrogenated under normal conditions until, after 35 hours, the calculated quantity of hydrogen has been absorbed (an additional quantity of 2 g of catalyst is required for this purpose). Filtration and concentration by evaporation of the filtrate produce a semi-solid mass which, by recrystallisation from isopropanol using active carbon, yields 1-[2-(3-carbamoyl-4-hydroxyphenoxy)-ethylamino]-3-[4-(4-methyl-5-trifluoromethyl-4H-1,2,4-triazol-3-yl)-phenoxy]-2-propanol having a melting point of 151°-153°.
Reaction SMILES: [N:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][C:2]=1[CH2:11][O:12][C:13]1[CH:18]=[CH:17][C:16]([CH:19]([CH:23]2[CH2:29][CH2:28][CH2:27][CH2:26][CH2:25][CH2:24]2)[C:20](O)=[O:21])=[CH:15][CH:14]=1.C(N(CC)CC)C.S(Cl)(C)(=O)=O.[C:42]([NH2:45])(=[O:44])[CH3:43].CN(C1C=CC=CN=1)C>C1COCC1>[C:42]([NH:45][C:20](=[O:21])[CH:19]([C:16]1[CH:17]=[CH:18][C:13]([O:12][CH2:11][C:2]2[CH:3]=[CH:4][C:5]3[C:10](=[CH:9][CH:8]=[CH:7][CH:6]=3)[N:1]=2)=[CH:14][CH:15]=1)[CH:23]1[CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29]1)(=[O:44])[CH3:43]
Reactant: O=C(O)C(c1ccc(OCc2ccc3ccccc3n2)cc1)C1CCCCCC1
Reactant: CC(N)=O
Agent: CN(C)c1ccccn1
Agent: CS(=O)(=O)Cl
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: CC(=O)NC(=O)C(c1ccc(OCc2ccc3ccccc3n2)cc1)C1CCCCCC1
Temperature: 0 °C

Procedure:
8.0 g (0.02 mol) of 2-[4-(quinolin-2-yl-methoxy)phenyl]-2-cycloheptyl-acetic acid and 4.0 g (5.6 ml/0.04 mol) of triethylamine are dissolved in 80 ml of THF, the solution is cooled to 0° C., and 2.3 g (1.6 ml/0.02 mol) of mesyl chloride are added. 2.4 g (0.04 mol) of acetamide and 7.2 g (0.06 mol) of dimethylaminopyridine (DMAP), dissolved in 20 ml of THF, are added at 0° C. The mixture is allowed to react at room temperature for 48 hours (stirring) and is then concentrated to dryness in vacuo, and the residue is extracted by stirring with 50 ml of water and 50 ml of dichloromethane. The organic phase is separated off, dried and concentrated to a small volume, and the residue is separated by column chromatography (silica gel 60, mobile phase: toluene/ethyl acetate/ glacial acetic acid=8/1/1).
Reaction SMILES: [N:1]12[CH2:8][CH2:7][CH:4]([CH2:5][CH2:6]1)[C@@H:3]([O:9][C:10](N1C=CN=C1)=[O:11])[CH2:2]2.[Cl:17][C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=1[CH:24]([C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][C:27]=1[Cl:32])[OH:25]>>[Cl:17][C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=1[CH:24]([O:25][C:10](=[O:11])[O:9][C@@H:3]1[CH:4]2[CH2:5][CH2:6][N:1]([CH2:8][CH2:7]2)[CH2:2]1)[C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][C:27]=1[Cl:32]
Reactant: OC(c1ccccc1Cl)c1ccccc1Cl
Reactant: O=C(O[C@H]1CN2CCC1CC2)n1ccnc1
Product: O=C(OC(c1ccccc1Cl)c1ccccc1Cl)O[C@H]1CN2CCC1CC2

Procedure:
The desired product was prepared by reacting imidazole-1-carboxylic acid (R)-1-aza-bicyclo[2.2.2]oct-3-yl ester with bis(2-chlorophenyl)methanol.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([F:8])=[CH:4][C:3]=1[OH:9].Br[C:11]1([CH3:14])[CH2:13][CH2:12]1>>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([F:8])=[CH:4][C:3]=1[O:9][CH2:14][CH:11]1[CH2:13][CH2:12]1
Reactant: CC1(Br)CC1
Reactant: Oc1cc(F)ccc1Br
Product: Fc1ccc(Br)c(OCC2CC2)c1

Procedure:
Starting from commercially available 2-bromo-5-fluoro-phenol and commercially available bromo-methyl-cyclopropane the title compound is obtained as colorless oil after distillation at 5×103 mbar.
Reaction SMILES: [H-].[Na+].[CH2:3]=[C:4]([CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH3:26])[CH2:5][CH:6]([CH2:9][OH:10])[CH2:7][OH:8].[CH2:27](Br)[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]>CN(C)C=O>[CH2:42]([O:10][CH2:9][CH:6]([CH2:5][C:4](=[CH2:3])[CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH3:26])[CH2:7][OH:8])[CH2:41][CH2:40][CH2:39][CH2:38][CH2:37][CH2:36][CH2:35][CH2:34][CH2:33][CH2:32][CH2:31][CH2:30][CH2:29][CH2:28][CH3:27]
Reactant: CCCCCCCCCCCCCCCCBr
Reactant: C=C(CCCCCCCCCCCCCCCC)CC(CO)CO
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: C=C(CCCCCCCCCCCCCCCC)CC(CO)COCCCCCCCCCCCCCCCC

Procedure:
A solution of 80 mg of 60% sodium hydride in 20 ml of N,N-dimethylformamide is stirred at room temperature. A 680 mg portion of 2-(2-methyleneoctadecyl)-1,3-propanediol and 0.61 ml of hexadecylbromide are added and the mixture warmed very slowly to 60°-70° C. The mixture is evaporated, dissolved in ether, and is washed with water and brine then flash chromatographed (5% ethyl acetate:petroleum ether), to give 550 mg of the desired compound as colorless crystals, mp. 37°-38° C.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([O:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15]Br)=[CH:4][CH:3]=1.[CH3:17][C@H:18]1[O:23][C@@H:22]([CH3:24])[CH2:21][NH:20][CH2:19]1.C(=O)([O-])[O-].[K+].[K+].C(OCC)(=O)C>CN(C)C=O>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([O:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][N:20]2[CH2:19][C@H:18]([CH3:17])[O:23][C@H:22]([CH3:24])[CH2:21]2)=[CH:4][CH:3]=1
Reactant: BrCCCCCCCOc1ccc(Br)cc1
Reactant: C[C@@H]1CNC[C@H](C)O1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: C[C@@H]1CN(CCCCCCCOc2ccc(Br)cc2)C[C@H](C)O1
Temperature: 70 °C
Reaction time: 1 h

Procedure:
A mixture of 1-bromo-4-(7-bromoheptyloxy)benzene (4.405 g), cis-2,6-dimethylmorpholine (1.55 ml) and potassium carbonate (2.09 g) in N,N-dimethylformamide (22 ml) was stirred for 1 hour at 70° C. To the reaction mixture was added cis-2,6-dimethylmorpholine (7.75 ml) and stirred for 1 hour at 70° C. Ethyl acetate (100 ml) was added, and the mixture washed with water (50 ml×2) and brine. The separated organic layer was dried over magnesium sulfate and evaporated under reduced pressure to give a crude pale yellow oil (5.30 g). The crude oil was purified by silica gel chromatography (20:1-1:2 hexane-ethyl acetate) to give 4-[7-(4-bromophenoxy)heptyl]-cis-2,6-dimethylmorpholine (4.43 g) as a pale yellow oil.
Reaction SMILES: [NH2:1][C:2]1[C:3]2[C:8]([N:9]=[C:10]3[C:15]=1[C:14]1[NH:16][N:17]=[CH:18][C:13]=1[CH2:12][CH2:11]3)=[CH:7][CH:6]=[CH:5][CH:4]=2.[H-].[Na+].Br[CH2:22][C:23]([O:25][CH2:26][CH3:27])=[O:24]>CN(C=O)C>[CH2:26]([O:25][C:23](=[O:24])[CH2:22][N:17]1[CH:18]=[C:13]2[CH2:12][CH2:11][C:10]3[C:15]([C:14]2=[N:16]1)=[C:2]([NH2:1])[C:3]1[C:8](=[CH:7][CH:6]=[CH:5][CH:4]=1)[N:9]=3)[CH3:27]
Reactant: Nc1c2c(nc3ccccc13)CCc1cn[nH]c1-2
Reactant: CCOC(=O)CBr
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CCOC(=O)Cn1cc2c(n1)-c1c(nc3ccccc3c1N)CC2
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a solution of 11-amino-4,5-dihydro-1H-pyrazolo[3,4-a]acridine (10 g) in dry DMF (300 ml) was added NaH (60%)(2.12 g) slowly. The reaction was stirred at room temperature for two hours, ethyl bromoacetate (6.0 ml) was added and the reaction was stirred for one hour.
Reaction SMILES: [C:1]([NH:4][C:5]1[S:6][C:7]2[CH:13]=[CH:12][CH:11]=[C:10]([O:14][C:15]3[N:20]=[CH:19][N:18]=[C:17]([C:21]4[CH:26]=[CH:25][C:24]([C:27]([F:30])([F:29])[F:28])=[CH:23][C:22]=4[NH:31][C:32]([C@@H:34]4[CH2:38][CH2:37][C@H:36]([C:39]5[CH:44]=[CH:43][CH:42]=[CH:41][CH:40]=5)[NH:35]4)=[O:33])[CH:16]=3)[C:8]=2[N:9]=1)(=[O:3])[CH3:2].[CH3:45][C:46]([CH3:48])=O>>[C:1]([NH:4][C:5]1[S:6][C:7]2[CH:13]=[CH:12][CH:11]=[C:10]([O:14][C:15]3[N:20]=[CH:19][N:18]=[C:17]([C:21]4[CH:26]=[CH:25][C:24]([C:27]([F:28])([F:29])[F:30])=[CH:23][C:22]=4[NH:31][C:32]([C@@H:34]4[CH2:38][CH2:37][C@H:36]([C:39]5[CH:44]=[CH:43][CH:42]=[CH:41][CH:40]=5)[N:35]4[CH:46]([CH3:48])[CH3:45])=[O:33])[CH:16]=3)[C:8]=2[N:9]=1)(=[O:3])[CH3:2]
Reactant: CC(=O)Nc1nc2c(Oc3cc(-c4ccc(C(F)(F)F)cc4NC(=O)[C@@H]4CC[C@H](c5ccccc5)N4)ncn3)cccc2s1
Reactant: CC(C)=O
Product: CC(=O)Nc1nc2c(Oc3cc(-c4ccc(C(F)(F)F)cc4NC(=O)[C@@H]4CC[C@H](c5ccccc5)N4C(C)C)ncn3)cccc2s1
Yield: 78 %

Procedure:
(2S,5R)-N-(2-(6-(2-Acetamidobenzo[d]thiazol-4-yloxy)pyrimidin-4-yl)-5-(trifluoromethyl)phenyl)-5-phenylpyrrolidine-2-carboxamide, Example 60, (62 mg, 0.1 mmol) was reacted with acetone (0.009 mL, 0.12 mmol) under the conditions of Example 3(d) to give the title compound as a white solid (51 mg, 78%). MS (ESI, pos. ion.) m/z: 661 (M+1).
Reaction SMILES: [CH:1]([CH:3]1[CH2:11][C:10]2[C:5](=[CH:6][CH:7]=[C:8]([O:12][C:13]3[CH:21]=[CH:20][C:16]([C:17]([NH2:19])=[O:18])=[CH:15][N:14]=3)[CH:9]=2)[CH2:4]1)=O.COC(OC)OC.[CH2:29]([NH2:34])[CH2:30][CH:31]([CH3:33])[CH3:32]>CO>[CH3:32][CH:31]([CH3:33])[CH2:30][CH2:29][NH:34][CH2:1][CH:3]1[CH2:11][C:10]2[C:5](=[CH:6][CH:7]=[C:8]([O:12][C:13]3[CH:21]=[CH:20][C:16]([C:17]([NH2:19])=[O:18])=[CH:15][N:14]=3)[CH:9]=2)[CH2:4]1
Reactant: NC(=O)c1ccc(Oc2ccc3c(c2)CC(C=O)C3)nc1
Reactant: CC(C)CCN
Solvent: CO
Solvent: COC(OC)OC
Product: CC(C)CCNCC1Cc2ccc(Oc3ccc(C(N)=O)cn3)cc2C1
Temperature: 25 °C
Reaction time: 4.5 h
Yield: 25 %

Procedure:
Combine 6-(2-Formyl-indan-5-yloxy)-nicotinamide (Intermediate 32, 25.3 mg, 0.09 mmol), MeOH (2.4 mL), trimethylorthoformate (1.6 mL), and isopentyl amine (9 uL, 0.08 mmol). After the reaction stirs at room temperature under a nitrogen atmosphere for 4.5 hours, add NaBH (4.1 mg, 0.11 mmol), then stir at room temperature for another 12 hours. After that time, concentrate under reduced pressure then add ethyl acetate. Wash the organic phase with water, brine, and dry over Na2SO4. After concentration under reduced pressure the mixture, add to a 2 g SCX column, wash with MeOH and elute with 1N NH3-MeOH. After concentration, flash chromatograph using 2% 1N NH3-MeOH, 20% THF, 38% DCM to afford 7.0 mg, 0.02 mmol (25% yield) of the title compound: 1H NMR (500 MHz, d-Methanol); 0.9 (6H, d), 1.4-1.5 (2H, m), 1.6-1.7 (1H, m), 2.6-2.8 (6H, m), 3.1-3.2 (2H, m), 3.3-3.4 (1H, m), 6.8 (1H, d), 6.9 (1H, s), 7.1 (1H, d), 7.2 (1H, d), 8.1 (1H, d), 8.5 (1H, s); TLC 2% 1N NH3-MeOH:20% THF:78% CH2Cl2:Rf:=0.27.
Reaction SMILES: [CH3:1][C@@H:2]1[N:7]2[C:8]3[C:17]4[C:12](=[CH:13][C:14]([CH2:18][CH2:19][S:20]([CH3:23])(=[O:22])=[O:21])=[CH:15][CH:16]=4)[N:11]=[CH:10][C:9]=3[N:24]=[C:6]2[CH2:5][O:4][CH2:3]1.C1C=C(Cl)C=C(C(OO)=O)C=1.[NH4+:36].[OH-].C1(C)C=CC(S(Cl)(=O)=O)=CC=1>O.C(Cl)Cl>[CH3:1][C@@H:2]1[N:7]2[C:8]3[C:17]4[C:12](=[CH:13][C:14]([CH2:18][CH2:19][S:20]([CH3:23])(=[O:21])=[O:22])=[CH:15][CH:16]=4)[N:11]=[C:10]([NH2:36])[C:9]=3[N:24]=[C:6]2[CH2:5][O:4][CH2:3]1
Reactant: C[C@H]1COCc2nc3cnc4cc(CCS(C)(=O)=O)ccc4c3n21
Reactant: [NH4+]
Agent: Cc1ccc(S(=O)(=O)Cl)cc1
Agent: O=C(OO)c1cccc(Cl)c1
Agent: [OH-]
Solvent: O
Solvent: ClCCl
Product: C[C@H]1COCc2nc3c(N)nc4cc(CCS(C)(=O)=O)ccc4c3n21
Temperature: 25 °C

Procedure:
A 200-mL, round-bottomed flask was charged with (11S)-11-methyl-3-[2-(methylsulfonyl)ethyl]-10,11-dihydro-8H-[1,4]oxazino[4′,3′:1,2]imidazo[4,5-c]quinoline (0.45 g, 1.31 mmol) and CH2Cl2 (75 mL). The mixture was stirred at ambient temperature and MCPBA (0.45 g, 50% purity) was then added slowly in portions. The reaction was stirred at ambient temperature for 2 hours. Concentrated aqueous NH4OH solution (25 mL) was then slowly added to the reaction mixture followed by careful addition of p-toluenesulfonyl chloride (0.27 g, 1.44 mmol). The reaction was stirred rapidly at ambient temperature overnight. The reaction was then treated with H2O (100 mL) and vigorous stirring was maintained for 2 hours. The layers were then separated and the aqueous layer was extracted with CH2Cl2 (3×50 mL). The combined organic layers were concentrated under reduced pressure. Chromatography (SiO2, 0-15% CMA/CHCl3) gave a white solid that was crystallized from acetonitrile to give 0.12 g of (11S)-11-methyl-3-[2-(methylsulfonyl)ethyl]-10,11-dihydro-8H-[1,4]oxazino[4′,3′:1,2]imidazo[4,5-c]quinolin-6-amine as a white, crystalline solid, mp 205-206° C.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([N:10]2[CH:18]([CH:19]3[CH2:23][CH2:22][CH2:21][CH2:20]3)[CH:17]3[C:12]([C:13]4[CH:27]=[CH:26][C:25]([C:28]([OH:30])=[O:29])=[CH:24][C:14]=4[CH2:15][CH2:16]3)=[N:11]2)[CH:5]=[CH:6][C:7]=1[C:8]#[N:9].[CH:31]1([CH2:37]O)[CH2:36][CH2:35][CH2:34][CH2:33][CH2:32]1>>[Cl:1][C:2]1[CH:3]=[C:4]([N:10]2[CH:18]([CH:19]3[CH2:20][CH2:21][CH2:22][CH2:23]3)[CH:17]3[C:12]([C:13]4[CH:27]=[CH:26][C:25]([C:28]([O:30][CH2:37][CH:31]5[CH2:36][CH2:35][CH2:34][CH2:33][CH2:32]5)=[O:29])=[CH:24][C:14]=4[CH2:15][CH2:16]3)=[N:11]2)[CH:5]=[CH:6][C:7]=1[C:8]#[N:9]
Reactant: N#Cc1ccc(N2N=C3c4ccc(C(=O)O)cc4CCC3C2C2CCCC2)cc1Cl
Reactant: OCC1CCCCC1
Product: N#Cc1ccc(N2N=C3c4ccc(C(=O)OCC5CCCCC5)cc4CCC3C2C2CCCC2)cc1Cl
Yield: 67 %

Procedure:
The title compound was prepared from (±)-(3SR,3aRS)-2-(3-chloro-4-cyanophenyl)-3-cyclopentyl-3,3a,4,5-tetrahydro-2H-benzo[g]indazole-7-carboxylic acid, Example 15 and cyclohexylmethanol according to Method E (yellow solid, 165 mg, 0.320 mmol, 67% yield). ES-HRMS m/z calc. for C31H35ClN3O2 (M+H) 516.2412, found 516.2403.