Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH:1]1([CH:4]([C:17]2[CH:27]=[CH:26][C:20]3[O:21][C:22]([F:25])([F:24])[O:23][C:19]=3[CH:18]=2)[C:5]2[C:13]3[C:8](=[C:9]([CH2:14][S:15][CH3:16])[CH:10]=[CH:11][CH:12]=3)[NH:7][CH:6]=2)[CH2:3][CH2:2]1.ClC1C=CC(C(C2CC2)C2C3C(=C(CS(C)=[O:47])C=CC=3)NC=2)=CC=1>>[CH:1]1([CH:4]([C:17]2[CH:27]=[CH:26][C:20]3[O:21][C:22]([F:25])([F:24])[O:23][C:19]=3[CH:18]=2)[C:5]2[C:13]3[C:8](=[C:9]([CH2:14][S:15]([CH3:16])=[O:47])[CH:10]=[CH:11][CH:12]=3)[NH:7][CH:6]=2)[CH2:2][CH2:3]1
Reactant: CSCc1cccc2c(C(c3ccc4c(c3)OC(F)(F)O4)C3CC3)c[nH]c12
Reactant: CS(=O)Cc1cccc2c(C(c3ccc(Cl)cc3)C3CC3)c[nH]c12
Product: CS(=O)Cc1cccc2c(C(c3ccc4c(c3)OC(F)(F)O4)C3CC3)c[nH]c12

Procedure:
The title compound was prepared starting from 100 mg (0.26 mmol) of the compound from Example 231 in analogy to the synthesis of the compound from Example 235. 92 mg (88% of theory) of the target compound were obtained as mixture of diastereomers.
Reaction SMILES: [C@@H:1]1([C:10]([NH2:12])=O)[CH2:6][CH2:5][CH2:4][CH2:3][C@H:2]1[C:7](O)=[O:8].[BH4-].[Na+].B(F)(F)F.CCOCC>>[NH2:12][CH2:10][C@@H:1]1[CH2:6][CH2:5][CH2:4][CH2:3][C@H:2]1[CH2:7][OH:8]
Reactant: NC(=O)[C@@H]1CCCC[C@H]1C(=O)O
Agent: FB(F)F
Agent: [BH4-]
Agent: [Na+]
Solvent: CCOCC
Product: NC[C@@H]1CCCC[C@H]1CO

Procedure:
((1R,2R)-2-(aminomethyl)cyclohexyl)methanol was prepared by reduction of enantiomerically pure trans-1,2-cyclohexanedicarboxylic acid monoamide using sodium borohydride-boron trifluoride etherate.
Reaction SMILES: [Si]([O:8][CH:9]1[CH2:14][CH2:13][CH:12]([NH:15][C:16]2[C:28]3[C:27]4[CH:26]=[C:25]([F:29])[CH:24]=[CH:23][C:22]=4[NH:21][C:20]=3[C:19]([C:30]#[N:31])=[CH:18][N:17]=2)[CH2:11][CH:10]1[F:32])(C(C)(C)C)(C)C.CCCC[N+](CCCC)(CCCC)CCCC.[F-]>C1COCC1>[F:29][C:25]1[CH:24]=[CH:23][C:22]2[NH:21][C:20]3[C:19]([C:30]#[N:31])=[CH:18][N:17]=[C:16]([NH:15][CH:12]4[CH2:13][CH2:14][CH:9]([OH:8])[CH:10]([F:32])[CH2:11]4)[C:28]=3[C:27]=2[CH:26]=1
Reactant: CC(C)(C)[Si](C)(C)OC1CCC(Nc2ncc(C#N)c3[nH]c4ccc(F)cc4c23)CC1F
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: C1CCOC1
Product: N#Cc1cnc(NC2CCC(O)C(F)C2)c2c1[nH]c1ccc(F)cc12

Procedure:
To a stirred solution of 1-[(4-{[tert-butyl(dimethyl)silyl]oxy}-3-fluorocyclohexyl)amino]-8-fluoro-5H-pyrido[4,3-b]indole-4-carbonitrile (135 mg, 0.296 mmol) in THF (4 mL) was added TBAF (1.0 M, 0.89 mL, 0.89 mmol). After the reaction was complete, the reaction was quenched with sodium bicarbonate solution. The mixture was extracted with EtOAc, and the combined organics were dried, concentrated, and purified by prep-HPLC to afford the title compound. LRMS (APCI) calc'd for (C18H16F2N4O) [M+H]+, 343.1. found 343.0.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:9]([CH2:24][CH3:25])[C:10]3[C:15]([C:16]=2[C:17]#[N:18])=[CH:14][CH:13]=[C:12]([O:19][C:20]([F:23])([F:22])[F:21])[CH:11]=3)=[CH:4][CH:3]=1.[CH2:26]([S:28](Cl)(=[O:30])=[O:29])[CH3:27]>N1C=CC=CC=1.O>[C:17]([C:16]1[C:15]2[C:10](=[CH:11][C:12]([O:19][C:20]([F:23])([F:21])[F:22])=[CH:13][CH:14]=2)[N:9]([CH2:24][CH3:25])[C:8]=1[C:5]1[CH:4]=[CH:3][C:2]([NH:1][S:28]([CH2:26][CH3:27])(=[O:30])=[O:29])=[CH:7][CH:6]=1)#[N:18]
Reactant: CCn1c(-c2ccc(N)cc2)c(C#N)c2ccc(OC(F)(F)F)cc21
Reactant: CCS(=O)(=O)Cl
Solvent: O
Solvent: c1ccncc1
Product: CCn1c(-c2ccc(NS(=O)(=O)CC)cc2)c(C#N)c2ccc(OC(F)(F)F)cc21
Temperature: 25 °C
Reaction time: 8 h
Yield: 75.4 %

Procedure:
To a solution of the compound obtained in step C (31 mg, 0.1 mmol) in dry pyridine (1.0 mL) is added ethanesulfonyl chloride (14 μL, 0.15 mmol). The mixture is stirred at room temperature overnight and diluted with water (5 mL). The organic is extracted with DCM (5 mL) and washed with HCl (2N, 2×3 mL), water (2×4 mL) and brine (3 mL) and chromatographed (silica gel, EtOAc/DCM, 0.5/9.5) to provide the product, ethanesulfonic acid [4-(3-cyano-1-ethyl-6-trifluoromethoxyindol-2-yl)phenyl]amide (33 mg, 83%).
Reaction SMILES: [H][H].[C:3]([C:7]([C:10]([C:13]([C:16]([C:19]([F:22])([F:21])[F:20])([F:18])[F:17])(Cl)Cl)(Cl)Cl)([F:9])[F:8])([F:6])([F:5])[F:4]>[Pd]>[C:19]([C:16]([CH2:13][CH2:10][C:7]([C:3]([F:4])([F:5])[F:6])([F:8])[F:9])([F:18])[F:17])([F:22])([F:21])[F:20]
Reactant: FC(F)(F)C(F)(F)C(Cl)(Cl)C(Cl)(Cl)C(F)(F)C(F)(F)F
Reactant: [H][H]
Agent: [Pd]
Product: FC(F)(F)C(F)(F)CCC(F)(F)C(F)(F)F
Temperature: -78 °C
Yield: 80 %

Procedure:
The reactor in this Example consisted of a 1.25 inch diameter pyrex tube heated by means of electrical heating tape and an internal thermocouple to measure the temperature inside the tube. The reactor was packed with a mixture of 50 cm3 of 0.5% Pd/Al2O3 (1/8 inch pellets) and 100 cm3 of glass helices for a total bed volume of 150 cm3. The Pd/A12O3 pellets are available from Aldrich Chemical or Engelhard Industries. Effluent from the reactor was condensed into cold traps maintained at -30° C. and -78° C. Hydrogen was passed into the tube at 155 mL/min, while CF3CF2CC12CC12CF2CF3 was metered into the top of the vertically mounted reactor at a rate of about 10 g/h. The temperature inside the reactor during the reduction was 202°-206° C. After a total reaction time of 3.75 h (38.1 g total CF3CF2CC12CC12CF2CF3 added), 20.15 g of product was collected in the cold traps, which was 99% pure according to GC analysis. The product was identified as CF3CF2CH2CH2CF2CF3 (boiling point 66° C., 80% yield) based on nuclear magnetic resonance and mass spectroscopy analysis.
Reaction SMILES: [CH3:1][CH:2]1[C:11]2[C:6](=[CH:7][C:8]([OH:13])=[C:9]([OH:12])[CH:10]=2)[CH2:5][CH2:4][NH:3]1.C(N(CC)CC)C.[CH3:21][C:22]1[C:23](Cl)=[N:24][C:25]([Cl:29])=[N:26][C:27]=1[CH3:28]>CN(C)C=O>[CH3:21][C:22]1[C:23]([N:3]2[CH2:4][CH2:5][C:6]3[C:11](=[CH:10][C:9]([OH:12])=[C:8]([OH:13])[CH:7]=3)[CH:2]2[CH3:1])=[N:24][C:25]([Cl:29])=[N:26][C:27]=1[CH3:28]
Reactant: Cc1nc(Cl)nc(Cl)c1C
Reactant: CC1NCCc2cc(O)c(O)cc21
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: Cc1nc(Cl)nc(N2CCc3cc(O)c(O)cc3C2C)c1C
Yield: 75.9 %

Procedure:
After 1-methyl-6,7-dihydroxy-1,2,3,4-tetrahydroisoquinoline(1.6 g, 4.98 mmol) and triethylamine(0.7 ml, 4.98 mmol) were added to a suspension of 5,6-dimethyl-2,4-dichloropyrimidine(0.8 g, 4.53 mmol) in dimethylformamide, 1.1 g of the titled compound was obtained in accordance with the same procedure as in Step 1 of Example 35. (Yield: 76%)
Reaction SMILES: [C:1]([C:5]1[O:9][N:8]=[C:7]([NH:10][C:11]([NH:13][C:14]2[CH:19]=[CH:18][CH:17]=[C:16]([O:20][C:21]3[C:30]4[C:25](=[CH:26][C:27]([O:33][CH2:34][CH2:35][CH2:36]Cl)=[C:28]([O:31][CH3:32])[CH:29]=4)[N:24]=[CH:23][N:22]=3)[CH:15]=2)=[O:12])[CH:6]=1)([CH3:4])([CH3:3])[CH3:2].[NH:38]1[CH2:43][CH2:42][S:41](=[O:45])(=[O:44])[CH2:40][CH2:39]1.C(N(C(C)C)CC)(C)C>CN(C=O)C.[I-].C([N+](CCCC)(CCCC)CCCC)CCC>[C:1]([C:5]1[O:9][N:8]=[C:7]([NH:10][C:11]([NH:13][C:14]2[CH:19]=[CH:18][CH:17]=[C:16]([O:20][C:21]3[C:30]4[C:25](=[CH:26][C:27]([O:33][CH2:34][CH2:35][CH2:36][N:38]5[CH2:43][CH2:42][S:41](=[O:45])(=[O:44])[CH2:40][CH2:39]5)=[C:28]([O:31][CH3:32])[CH:29]=4)[N:24]=[CH:23][N:22]=3)[CH:15]=2)=[O:12])[CH:6]=1)([CH3:4])([CH3:3])[CH3:2]
Reactant: O=S1(=O)CCNCC1
Reactant: COc1cc2c(Oc3cccc(NC(=O)Nc4cc(C(C)(C)C)on4)c3)ncnc2cc1OCCCCl
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [I-]
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: COc1cc2c(Oc3cccc(NC(=O)Nc4cc(C(C)(C)C)on4)c3)ncnc2cc1OCCCN1CCS(=O)(=O)CC1
Temperature: 60 °C
Yield: 31.2 %

Procedure:
To a solution of 1-(5-tert-butyl-isoxazol-3-yl)-3-{3-[7-(3-chloro-propoxy)-6-methoxy-quinazolin-4-yloxy]-phenyl}-urea (described in Example 27B, 235 mg, 0.446 mmol) in DMF (3 mL) was added thiomorpholine 1,1-dioxide (181 mg, 1.338 mmol) followed by diisopropyl ethylamine (0.233 mL, 1.338 mmol) and tetrabutyl ammonium iodide (164 mg, 0.446 mmol). The reaction mixture was heated at 60° C. for 4 days. Formation of the product was determined by LCMS. The crude reaction mixture was purified by preparative HPLC (phenylhexyl reverse phase column eluted with gradient of solvent A=0.05% HOAc/H2O and solvent B=0.05% HOAc/CH3CN) to afford 1-(5-tert-butyl-isoxazol-3-yl)-3-(3-{7-[3-(1,1-dioxo-thiomorpholin-4-yl)-propoxy]-6-methoxy-quinazolin-4-yloxy}-phenyl)-urea as a white solid (87 mg, 31%). 1H NMR (300 MHz, DMSO-d6) δ 9.80-9.35 (brs, 2H), 8.52 (s, 1H), 7.55 (d, 2H), 7.35 (m, 3H), 7.25 (d, 1H), 6.92 (d, 1H), 6.45 (s, 1H), 4.25 (m, 2H), 3.95 (s, 3H), 3.10 (s, 4H), 2.80 (s, 4H), 2.60 (s, 2H), 1.95 (s, 1H), 1.20 (s, 9H); LC-MS (ESI) m/z 625 (M+H)+.
Reaction SMILES: [NH2:1][CH2:2][CH2:3][CH2:4][CH2:5][C@H:6]([NH:11][C:12]([O:14][C:15]([CH3:18])([CH3:17])[CH3:16])=[O:13])[C:7]([O:9][CH3:10])=[O:8].[O:19]=[C:20]1[CH2:23][CH:22]([C:24](O)=[O:25])[CH2:21]1.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C>CN(C=O)C.CCOC(C)=O>[NH2:1][CH2:2][CH2:3][CH2:4][CH2:5][C@H:6]([NH:11][C:12]([O:14][C:15]([CH3:18])([CH3:17])[CH3:16])=[O:13])[C:7]([O:9][CH3:10])=[O:8].[C:15]([O:14][C:12]([NH:11][C@@H:6]([CH2:5][CH2:4][CH2:3][CH2:2][NH:1][C:24]([CH:22]1[CH2:23][C:20](=[O:19])[CH2:21]1)=[O:25])[C:7]([O:9][CH3:10])=[O:8])=[O:13])([CH3:18])([CH3:17])[CH3:16]
Reactant: O=C1CC(C(=O)O)C1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: COC(=O)[C@H](CCCCN)NC(=O)OC(C)(C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Solvent: CCOC(C)=O
Product: COC(=O)[C@H](CCCCNC(=O)C1CC(=O)C1)NC(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A 1M stock solution of (S)-methyl 6-amino-2-(tert-butoxycarbonylamino)hexanoate in 20 mL DMF was prepared, and used. A 2 mL aliquot of the (S)-methyl 6-amino-2-(tert-butoxycarbonylamino)hexanoate stock solution, 3-oxocyclobutanecarboxylic acid (2) (Parkway *BX-102, 283 mg), HATU (800 mg), DIEA (1.0 mL) and 8 mL DMF were combined in a 40 mL glass vial, and stirred at ambient temperature overnight. The LC-MS analysis revealed a complete reaction. The reaction mixture was diluted with EtOAc, washed successively with water, sat aq. NaCl, dried over MgSO4, filtered and concentrated under reduced pressure. The crude material was purified by silica gel flash chromatography (hexanes/EtOAc), affording (S)-methyl 2-(tert-butoxycarbonylamino)-6-(3-oxocyclobutanecarboxamido)hexanoate (TU3000-140) as a clear viscous oil. MS (ESI+): calcd. 379.18. found 379.20 (MNa+), calcd. 257.15. found 257.20((M-Boc)H+). H-NMR (400 MHz, DMSO-d6):1.245 (4H, m), 1.371 (9H, s), 1.579 (2H, m), 3.065 (3H, m), 3.135 (4H, m), 3.608 (3H, s), 3.895 (1H, m), 7.209 (1 h, d, J=8.0 Hz), 8.123 (1H, t, J=5.4 Hz). C-NMR (100 MHz, DMSO-d6): 22.850, 27.185, 28.111, 28.551, 30.209, 38.276, 50.859, 51.639, 53.412, 53.529, 78.137, 155.507, 172.992, 173.167, 205.576.
Reaction SMILES: [CH2:1]([N:3]([C:15]1[CH:26]=[C:25]2[C:27]3[C:21]([CH3:28])([CH2:22][CH2:23][CH2:24]2)[CH2:20][CH2:19][CH2:18][C:17]=3[CH:16]=1)[C:4]1[CH:14]=[CH:13][C:7]([C:8]([O:10]CC)=[O:9])=[CH:6][CH:5]=1)[CH3:2].[OH-].[Na+].Cl>C(O)C>[CH2:1]([N:3]([C:15]1[CH:26]=[C:25]2[C:27]3[C:21]([CH3:28])([CH2:22][CH2:23][CH2:24]2)[CH2:20][CH2:19][CH2:18][C:17]=3[CH:16]=1)[C:4]1[CH:5]=[CH:6][C:7]([C:8]([OH:10])=[O:9])=[CH:13][CH:14]=1)[CH3:2]
Reactant: CCOC(=O)c1ccc(N(CC)c2cc3c4c(c2)CCCC4(C)CCC3)cc1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: CCN(c1ccc(C(=O)O)cc1)c1cc2c3c(c1)CCCC3(C)CCC2
Temperature: 50 °C
Reaction time: 8 h
Yield: 87.5 %

Procedure:
A suspension of ethyl 4-[N-ethyl-(6a-methyl-5,6,6a,7,8,9-hexahydro-4H-2-phenalenyl)amino]benzoate (0.058 g) in ethanol (5 ml) was added with 20% aqueous sodium hydroxide (1 ml), and the mixture was stirred overnight at 50° C. The reaction mixture was left to cool and then made acidic with 2 N aqueous hydrochloric acid, and the mixture was extracted with chloroform. The organic layer was washed with saturated brine, and dried over anhydrous sodium sulfate. The organic layer was concentrated under reduced pressure, and the resulting residue was recrystallized from ethanol to obtain the title compound (0.047 g, yield: 87%) as colorless needles (melting point: 279-280° C.).
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:16])[CH2:5][N:6]1[C:14]2[C:9](=[CH:10][CH:11]=[C:12]([OH:15])[CH:13]=2)[CH:8]=[CH:7]1)[CH3:2].[F:17][C:18]([F:32])([F:31])[C:19]1[CH:24]=[CH:23][C:22]([C:25]#[C:26][CH2:27][CH2:28][CH2:29]O)=[CH:21][CH:20]=1.CN(C)C(N=NC(N(C)C)=O)=O.C(P(CCCC)CCCC)CCC>>[CH2:1]([O:3][C:4](=[O:16])[CH2:5][N:6]1[C:14]2[C:9](=[CH:10][CH:11]=[C:12]([O:15][CH2:29][CH2:28][CH2:27][C:26]#[C:25][C:22]3[CH:21]=[CH:20][C:19]([C:18]([F:17])([F:31])[F:32])=[CH:24][CH:23]=3)[CH:13]=2)[CH:8]=[CH:7]1)[CH3:2]
Reactant: OCCCC#Cc1ccc(C(F)(F)F)cc1
Reactant: CCOC(=O)Cn1ccc2ccc(O)cc21
Agent: CCCCP(CCCC)CCCC
Agent: CN(C)C(=O)N=NC(=O)N(C)C
Product: CCOC(=O)Cn1ccc2ccc(OCCCC#Cc3ccc(C(F)(F)F)cc3)cc21

Procedure:
In analogy to the procedure described for example 1 d], (6-hydroxy-indol-1-yl)-acetic acid ethyl ester (example 1 c]) was reacted with 5-(4-trifluoromethyl-phenyl)-pent-4-yn-1-ol in the presence of N,N,N′,N′-tetramethyl azodicarboxamide and tributylphosphine to give the title compound as yellow oil.
Reaction SMILES: [ClH:1].[CH3:2][S:3]([NH:6][C:7]1[CH:8]=[CH:9][C:10]2[O:20][C:14]3([CH2:19][CH2:18][NH:17][CH2:16][CH2:15]3)[CH2:13][C:12](=[O:21])[C:11]=2[CH:22]=1)(=[O:5])=[O:4].C(=O)(O)[O-].[Na+].CS(O[CH2:33][CH2:34][C:35]1[CH:43]=[CH:42][C:38]2[N:39]=[CH:40][S:41][C:37]=2[CH:36]=1)(=O)=O.[I-].[K+]>C(#N)C>[ClH:1].[S:41]1[C:37]2[CH:36]=[C:35]([CH2:34][CH2:33][N:17]3[CH2:16][CH2:15][C:14]4([CH2:13][C:12](=[O:21])[C:11]5[CH:22]=[C:7]([NH:6][S:3]([CH3:2])(=[O:4])=[O:5])[CH:8]=[CH:9][C:10]=5[O:20]4)[CH2:19][CH2:18]3)[CH:43]=[CH:42][C:38]=2[N:39]=[CH:40]1
Reactant: CS(=O)(=O)Nc1ccc2c(c1)C(=O)CC1(CCNCC1)O2
Reactant: CS(=O)(=O)OCCc1ccc2ncsc2c1
Agent: Cl
Agent: O=C([O-])O
Agent: [I-]
Solvent: CC#N
Product: CS(=O)(=O)Nc1ccc2c(c1)C(=O)CC1(CCN(CCc3ccc4ncsc4c3)CC1)O2
Yield: 47.8 %

Procedure:
In a manner similar to that described in Example 92, Step B a mixture of 3,4-dihydro-6-methanesulfonamido-spiro[(2H)-1-benzopyran-2,4'-piperidine]-4-one hydrochloride (0.146 g, 0.42 mmol), sodium bicarbonate (0.143 g, 1.70 mmol), 6-benzothiazolylethyl methanesulfonate (0.108 g, 0.42 mmol), potassium iodide (0.070 g, 0.42 mmol) and acetonitrile (5 mL) was heated at reflux for 6.5 hours. Purification and crystallization as the hydrochloride salt from ethanol gave 0.102 g (48%) of the title compound as a white solid, mp 214°-215° C.
Reaction SMILES: [CH2:1]([C:3]1[N:4]([C@@H:16]([CH3:19])[CH2:17][OH:18])[C:5]2[C:14]3[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=3[N:8]=[CH:7][C:6]=2[N:15]=1)[CH3:2].BrN1C(=O)CCC1=O.C(Cl)(Cl)Cl>C(Cl)(Cl)(Cl)Cl>[CH3:2][CH:1]1[C:3]2=[N:15][C:6]3[CH:7]=[N:8][C:9]4[C:14]([C:5]=3[N:4]2[C@@H:16]([CH3:19])[CH2:17][O:18]1)=[CH:13][CH:12]=[CH:11][CH:10]=4
Reactant: CCc1nc2cnc3ccccc3c2n1[C@@H](C)CO
Agent: O=C1CCC(=O)N1Br
Solvent: ClC(Cl)(Cl)Cl
Solvent: ClC(Cl)Cl
Product: CC1OC[C@H](C)n2c1nc1cnc3ccccc3c12
Temperature: 25 °C
Reaction time: 20 h
Yield: 16.1 %

Procedure:
(2S)-2-(2-Ethyl-1H-imidazo[4,5-c]quinolin-1-yl)propan-1-ol (0.50 g, 1.96 mmol) was suspended in 20 mL of CCl4 under an atmosphere of N2. The mixture was treated with N-bromosuccinimide (0.35 g, 1.96 mmol), heated to reflux, and irradiated with a sunlamp. After ˜20 hours the reaction was allowed to cool to ambient temperature, then it was partitioned between CH2Cl2 and saturated NaHCO3 solution. The layers were separated; the organic layer was washed sequentially with saturated NaHCO3 solution and brine, dried over Na2SO4, filtered, and concentrated under reduced pressure to give a brown foam. Chromatography (AFC, SiO2, 0-15% CMA/CHCl3) gave (11S)-8,11-dimethyl-10,11-dihydro-8H-[1,4]oxazino[4′,3′:1,2]imidazo[4,5-c]quinoline (80 mg) as a light yellow solid.
Reaction SMILES: [CH:1]([C:4]1[N:8]([C:9]2[N:10]=[C:11]([N:31]3[CH2:36][CH2:35][O:34][CH2:33][CH2:32]3)[C:12]3[N:18]=[C:17]([CH2:19][CH:20]4[CH2:23][N:22](C(OC(C)(C)C)=O)[CH2:21]4)[CH:16]=[CH:15][C:13]=3[N:14]=2)[C:7]2[CH:37]=[CH:38][CH:39]=[CH:40][C:6]=2[N:5]=1)([CH3:3])[CH3:2].Cl>O1CCOCC1>[NH:22]1[CH2:23][CH:20]([CH2:19][C:17]2[CH:16]=[CH:15][C:13]3[N:14]=[C:9]([N:8]4[C:7]5[CH:37]=[CH:38][CH:39]=[CH:40][C:6]=5[N:5]=[C:4]4[CH:1]([CH3:3])[CH3:2])[N:10]=[C:11]([N:31]4[CH2:36][CH2:35][O:34][CH2:33][CH2:32]4)[C:12]=3[N:18]=2)[CH2:21]1
Reactant: CC(C)c1nc2ccccc2n1-c1nc(N2CCOCC2)c2nc(CC3CN(C(=O)OC(C)(C)C)C3)ccc2n1
Agent: Cl
Solvent: C1COCCO1
Product: CC(C)c1nc2ccccc2n1-c1nc(N2CCOCC2)c2nc(CC3CNC3)ccc2n1

Procedure:
tert-Butyl 3-((2-(2-isopropyl-1H-benzo[d]imidazol-1-yl)-4-morpholinopyrido[3,2-d]pyrimidin-6-yl)methyl)azetidine-1-carboxylate (0.2 g) was deprotected with 4N HCl in dioxane (0.9 mL) at room temperature over 1 hour. The reaction was concentrated to dryness to afford crude 4-(6-(azetidin-3-ylmethyl)-2-(2-isopropyl-1H-benzo[d]imidazol-1-yl)pyrido[3,2-d]pyrimidin-4-yl)morpholine which was reacted with methyl 2-bromo-2-methylpropanoate (3 eq) and potassium carbonate (6 eq) at 75° C. for 3 hours. The reaction mixture loaded onto a Biotage isolute cartridge, eluted with 2M NH3 in MeOH then purified by reverse phase HPLC to yield 17.9 mg of 117. MS (Q1) 544.3 (M)+
Reaction SMILES: [F:1][C:2]([F:18])([F:17])[C:3]1[CH:16]=[CH:15][C:6]([O:7][C:8]2[CH:13]=[CH:12][C:11]([OH:14])=[CH:10][CH:9]=2)=[CH:5][CH:4]=1.Br[CH:20]([CH:25](Br)[CH3:26])[CH2:21][C:22]([OH:24])=[O:23].C(=O)([O-])[O-].[K+].[K+]>O1CCCC1>[F:1][C:2]([F:17])([F:18])[C:3]1[CH:16]=[CH:15][C:6]([O:7][C:8]2[CH:9]=[CH:10][C:11]([O:14][CH:25]([CH3:26])[CH:20]=[CH:21][C:22]([OH:24])=[O:23])=[CH:12][CH:13]=2)=[CH:5][CH:4]=1
Reactant: Oc1ccc(Oc2ccc(C(F)(F)F)cc2)cc1
Reactant: CC(Br)C(Br)CC(=O)O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: C1CCOC1
Product: CC(C=CC(=O)O)Oc1ccc(Oc2ccc(C(F)(F)F)cc2)cc1
Yield: 74.9 %

Procedure:
In a reactor, 30 g of tetrahydrofuran was charged and 12.7 g (0.05 mole) of 4-(4-trifluoromethylphenoxy)phenol, 14.3 g (0.055 mole) of 3,4-dibromopentanoic acid and 16.6 g of potassium carbonate were charged. They were refluxed for 6 hours to react them. After the reaction, tetrahydrofurane was distilled off from the reaction mixture and then 50 ml of chlorobenzene was added to the resulting mixture and then conc. hydrochloric acid was added to the resulting mixture with stirring to be acidic and then, the water phase was separated and the organic phase washed with water and then, chlorobenzene and low boiling by-products were distilled off at 100° C. under a reduced pressure (0.02-0.05 mmHg) to obtain 13.2 g of 4-[4-(4-trifluoromethylphenoxy)phenoxy]-2-pentenoic acid. (nD20 1.5284). The yield was 75%.
Reaction SMILES: [C:1]([C:4]1[CH:5]=[C:6]([CH:12]=[CH:13][C:14]=1[F:15])[NH:7][S:8]([CH3:11])(=[O:10])=[O:9])(=[O:3])[CH3:2].[Br:16]Br>C(O)(=O)C>[Br:16][CH2:2][C:1]([C:4]1[CH:5]=[C:6]([CH:12]=[CH:13][C:14]=1[F:15])[NH:7][S:8]([CH3:11])(=[O:10])=[O:9])=[O:3]
Reactant: CC(=O)c1cc(NS(C)(=O)=O)ccc1F
Reactant: BrBr
Solvent: CC(=O)O
Product: CS(=O)(=O)Nc1ccc(F)c(C(=O)CBr)c1
Temperature: 0 °C
Yield: 88.6 %

Procedure:
3'-Acetyl-4'-fluoromethanesulfonanilide (32 g) was dissolved in 250 ml of acetic acid, then 22.1 g of bromine was dropped thereinto gradually at room temperature and the mixture was made to react at room temperature for 3 hours. The reaction mixture was added to ice water and the mixture-was extracted with ethyl acetate. The extract was washed with aqueous solution of sodium bicarbonate, then with water, dried and the solvent was evaporated therefrom followed by crystallizing from diisopropyl ether to give 38 g of 3'-(2-bromoacetyl)-4'-fluoromethanesulfonanilide, m.p. 110°-113° C.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:14])[CH:5]([CH3:13])[C:6]([C:8]1[O:9][CH:10]=[CH:11][CH:12]=1)=[O:7])[CH3:2].[O-][CH2:16]C.[Na+]>C(O)C>[CH2:1]([O:3][C:4](=[O:14])[C:5]([CH3:16])([CH3:13])[C:6]([C:8]1[O:9][CH:10]=[CH:11][CH:12]=1)=[O:7])[CH3:2]
Reactant: CCOC(=O)C(C)C(=O)c1ccco1
Reactant: CC[O-]
Agent: [Na+]
Solvent: CCO
Product: CCOC(=O)C(C)(C)C(=O)c1ccco1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
3-furan-2-yl-2-methyl-3-oxo-propionic acid ethyl ester (49 mg) was added sodium ethoxide (0.22 ml) and 0.5 ml ethanol. A solid precipitates. The solution was stirred at room temperature for 1 h, iodomethane was added and the suspension stirred at room temperature for 3 h. Concentration in vacuo and purification by HPLC gave the expected product.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:12][CH2:11][C@H:10]([CH2:13][OH:14])[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].C(Cl)Cl.CC1(C)N([O])C(C)(C)CCC1.[Br-].[K+].[O-]Cl.[Na+].O.C([O-])(O)=O.[Na+]>>[C:1]([O:5][C:6]([N:8]1[CH2:12][CH2:11][C@H:10]([CH:13]=[O:14])[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)OC(=O)N1CC[C@H](CO)C1
Agent: CC1(C)CCCC(C)(C)N1[O]
Agent: O=C([O-])O
Agent: [Br-]
Solvent: O
Solvent: ClCCl
Product: CC(C)(C)OC(=O)N1CC[C@H](C=O)C1
Temperature: 0 °C

Procedure:
To a solution of (S)-3-hydroxymethylpyrrolidine-1-carboxylic acid t-butyl ester (7.4 g, 37 mmol) in DCM (74 mL, 1.2 mol) was added TEMPO (100 mg, 0.7 mmol) and potassium bromide (200 mg, 2 mmol). This mixture was cooled to 0° C. and vigorously stirred as a pre-chilled (at 0° C.) 1:1 mixture of 0.7 M of NaOCl in water (78 mL, 55 mmol) and a saturated, aqueous NaHCO3 solution (75 mL) was added dropwise over a period of 10 minutes. The resultant mixture was extracted with DCM (3×100 mL). The combined organic layers were washed with water (2×100 mL), then saturated aqueous NaCl (1×100 mL). The organic layer was dried over anhydrous Na2SO4, filtered and concentrated in vacuo to yield the title compound, which was used without further purification (5.8 g).
Reaction SMILES: Cl[C:2]1[CH:11]=[C:10]2[C:5]([C:6](=[O:18])[C:7]([C:15]([OH:17])=[O:16])=[CH:8][N:9]2[CH:12]2[CH2:14][CH2:13]2)=[CH:4][C:3]=1[F:19].[C:20]1([S:26]([N:29]2[CH:33]=[CH:32][C:31]([CH:34]3[CH2:39][NH:38][CH2:37][CH2:36][NH:35]3)=[CH:30]2)(=[O:28])=[O:27])[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1>N1C=CC=CC=1>[CH:12]1([N:9]2[C:10]3[C:5](=[CH:4][C:3]([F:19])=[C:2]([N:38]4[CH2:37][CH2:36][NH:35][CH:34]([C:31]5[CH:32]=[CH:33][N:29]([S:26]([C:20]6[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=6)(=[O:28])=[O:27])[CH:30]=5)[CH2:39]4)[CH:11]=3)[C:6](=[O:18])[C:7]([C:15]([OH:17])=[O:16])=[CH:8]2)[CH2:14][CH2:13]1
Reactant: O=S(=O)(c1ccccc1)n1ccc(C2CNCCN2)c1
Reactant: O=C(O)c1cn(C2CC2)c2cc(Cl)c(F)cc2c1=O
Solvent: c1ccncc1
Product: O=C(O)c1cn(C2CC2)c2cc(N3CCNC(c4ccn(S(=O)(=O)c5ccccc5)c4)C3)c(F)cc2c1=O
Temperature: 135 °C
Yield: 42.1 %

Procedure:
A mixture of 337 mg of 7-chloro-1-cyclopropyl-6-fluoro-1,4-dihydro-4-oxo-3-quinolinecarboxylic acid, 1.2 g of 1-(phenylsulfonyl)-3-(2-piperazinyl)-1H-pyrrole and 5 ml of pyridine was heated in a pressure bottle at 135° C. for 16 hours, then allowed to cool and the pyridine removed under reduced pressure. The crude substance was purified by column chromatography using chloroform:methanol:water:triethylamine (9:0.5:0.01:0.01), giving 270 mg of 1-cyclopropyl-6-fluoro-1,4-dihydro-4-oxo-7-[3-[1-(phenylsulfonyl)-1H-pyrrol-3-yl]-1-piperazinyl]-3-quinolinecarboxylic acid.
Reaction SMILES: [CH3:1][N:2]([CH2:12][C:13]1[CH:18]=[CH:17][N:16]=[CH:15][CH:14]=1)[C:3]([NH:5][C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1)=[O:4].[H][H]>C(O)(=O)C.[Pt]=O>[CH3:1][N:2]([CH2:12][CH:13]1[CH2:14][CH2:15][NH:16][CH2:17][CH2:18]1)[C:3]([NH:5][CH:6]1[CH2:11][CH2:10][CH2:9][CH2:8][CH2:7]1)=[O:4]
Reactant: CN(Cc1ccncc1)C(=O)Nc1ccccc1
Reactant: [H][H]
Agent: O=[Pt]
Solvent: CC(=O)O
Product: CN(CC1CCNCC1)C(=O)NC1CCCCC1
Yield: 54.4 %

Procedure:
1-Methyl-1-(4-pyridylmethyl)-3-phenylurea (7.0 g) in glacial acetic acid (50 ml) was hydrogenated over platinum oxide at 60°/60 p.s.i. until uptake of hydrogen ceased. The catalyst was removed by filtration and the filtrate evaporated in vacuo. The resultant oil was basified with 5 N NaOH (to pH 12) and extracted with chloroform (2×50 ml). The combined extracts were dried (MgSO4) and evaporated with chloroform (2×50 ml). The combined extracts were dried (MgSO4) and evaporated to give 1-methyl-1-(4-piperidylmethyl)-3-cyclohexylurea as an oil (4.0 g). The n.m.r. and mass spectra were compatible with the required structure.