Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][N:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][C:10]=2[CH2:12]O)[CH2:5][CH2:4][CH2:3]1.S(Cl)([Cl:16])=O>ClCCl>[CH3:1][N:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][C:10]=2[CH2:12][Cl:16])[CH2:5][CH2:4][CH2:3]1
Reactant: O=S(Cl)Cl
Reactant: CN1CCCc2cccc(CO)c21
Solvent: ClCCl
Product: CN1CCCc2cccc(CCl)c21
Temperature: 45 °C
Reaction time: 2 h

Procedure:
1-Methyl-8-hydroxymethyl-1,2,3,4-tetrahydroquinoline (0.89 g) was dissolved in dichloromethane (30 ml), and thionyl chloride (1.09 ml) was added thereto, and the mixture was stirred for 2 hours at 45° C. After distilling off the solvent, n-hexane was added to the residue, and the solvent was distilled off under reduced pressure to give 1-methyl-8-chloromethyl-1,2,3,4-tetrahydroquinoline (1.1 g).
Reaction SMILES: [C:1]1([O:7][C:8](Cl)=[O:9])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH3:11][O:12][C:13](=[O:20])[C:14]1[CH:19]=[CH:18][CH:17]=[N:16][CH:15]=1.[CH2:21]([Mg]Br)[CH2:22][CH2:23][CH2:24][CH3:25]>O1CCCC1>[C:1]1([O:7][C:8]([N:16]2[CH:17]([CH2:21][CH2:22][CH2:23][CH2:24][CH3:25])[CH:18]=[CH:19][C:14]([C:13]([O:12][CH3:11])=[O:20])=[CH:15]2)=[O:9])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: COC(=O)c1cccnc1
Reactant: O=C(Cl)Oc1ccccc1
Reactant: CCCCC[Mg]Br
Solvent: C1CCOC1
Product: CCCCCC1C=CC(C(=O)OC)=CN1C(=O)Oc1ccccc1

Procedure:
Phenylchloroformate (1.83 mL, 14.6 mmol) was added dropwise to a solution of Nicotinic acid methyl ester (2.0 g, 14.6 mmol) in tetrahydrofuran (30 mL) at −20° C., and stirred for ten minutes. A solution of pentylmagnesium bromide (2 M in diethyl ether, 7.3 mL, 14.6 mmol) was added dropwise to the solution and stirred for 30 min at −20° C. The resulting solution was washed successively with saturated aqueous ammonium chloride and brine. The solution was dried over sodium sulfate, and the solvent was evaporated in vacuo to give the product mixed with another isomer. The crude mixture was used without purification in the subsequent step. MS: m/z 330 (MH+).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[C:7]([CH3:9])[C:6]([S:10]([N:13]([CH2:15][C:16]2[O:20][CH:19]=[C:18]([C:21]([OH:23])=O)[CH:17]=2)[CH3:14])(=[O:12])=[O:11])=[C:5]([CH3:24])[CH:4]=1.CCN=C=NCCCN(C)C.C1C=CC2N(O)N=NC=2C=1.CCN(C(C)C)C(C)C.Cl.Cl.[CH3:57][N:58]([CH3:76])[C:59]([CH:61]1[CH2:65][CH2:64][N:63]([CH2:66][C:67]2[CH:72]=[CH:71][C:70]([CH2:73][NH:74][CH3:75])=[CH:69][CH:68]=2)[CH2:62]1)=[O:60]>C(Cl)Cl>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH3:24])[C:6]([S:10]([N:13]([CH2:15][C:16]2[O:20][CH:19]=[C:18]([C:21]([N:74]([CH2:73][C:70]3[CH:69]=[CH:68][C:67]([CH2:66][N:63]4[CH2:64][CH2:65][CH:61]([C:59]([N:58]([CH3:57])[CH3:76])=[O:60])[CH2:62]4)=[CH:72][CH:71]=3)[CH3:75])=[O:23])[CH:17]=2)[CH3:14])(=[O:12])=[O:11])=[C:7]([CH3:9])[CH:8]=1
Reactant: CNCc1ccc(CN2CCC(C(=O)N(C)C)C2)cc1
Reactant: COc1cc(C)c(S(=O)(=O)N(C)Cc2cc(C(=O)O)co2)c(C)c1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: COc1cc(C)c(S(=O)(=O)N(C)Cc2cc(C(=O)N(C)Cc3ccc(CN4CCC(C(=O)N(C)C)C4)cc3)co2)c(C)c1

Procedure:
The title compound was prepared according to general procedure BH using 5-({[(4-methoxy-2,6-dimethylphenyl)sulfonyl](methyl)amino}methyl)furan-3-carboxylic acid (40 mg, 0.11 mmol), EDCI (29 mg, 0.15 mmol), HOBt (22 mg, 0.16 mmol), DIPEA (0.04 mL, 0.22 mmol), N,N-dimethyl-1-{4-[(methylamino)methyl]benzyl}pyrrolidine-3-carboxamide dihydrochloride (42 mg, 0.13 mmol) and DCM (5 mL).
Reaction SMILES: [CH3:1][C:2]1([CH3:22])[CH2:11][CH:10]([N:12]([CH2:18][CH2:19][CH3:20])[S:13]([CH2:16][CH3:17])(=[O:15])=[O:14])[C:9]2[C:4](=[CH:5][CH:6]=[C:7]([OH:21])[CH:8]=2)[O:3]1.[H-].[Na+].[CH3:25][O:26][CH2:27][CH2:28]Br>CC(N(C)C)=O>[CH3:25][O:26][CH2:27][CH2:28][O:21][C:7]1[CH:8]=[C:9]2[C:4](=[CH:5][CH:6]=1)[O:3][C:2]([CH3:1])([CH3:22])[CH2:11][CH:10]2[N:12]([CH2:18][CH2:19][CH3:20])[S:13]([CH2:16][CH3:17])(=[O:15])=[O:14]
Reactant: CCCN(C1CC(C)(C)Oc2ccc(O)cc21)S(=O)(=O)CC
Reactant: COCCBr
Agent: [H-]
Agent: [Na+]
Solvent: CC(=O)N(C)C
Product: CCCN(C1CC(C)(C)Oc2ccc(OCCOC)cc21)S(=O)(=O)CC

Procedure:
0.491 g (1.5 mmol) of N-[2,2-dimethyl-6-hydroxychroman-4-yl]-N-(1-propyl)ethanesulfonamide (Example 22b) was reacted with NaH and 2-methoxyethyl bromide in DMA. 0.27 g of the title compound was obtained from petroleum ether, m.p. 78-80° C.
Reaction SMILES: C([O:5][C:6](=[O:25])[CH2:7][O:8][C:9]1[CH:14]=[CH:13][C:12]([S:15][C:16]2[CH:21]=[CH:20][C:19]([OH:22])=[C:18]([CH3:23])[CH:17]=2)=[CH:11][C:10]=1[CH3:24])(C)(C)C.C([O-])([O-])=O.[Cs+].[Cs+].CN(C=O)C.[F:37][C:38]([F:48])([F:47])[C:39]1[CH:46]=[CH:45][C:42]([CH2:43]Br)=[CH:41][CH:40]=1>O>[CH3:24][C:10]1[CH:11]=[C:12]([S:15][C:16]2[CH:21]=[CH:20][C:19]([O:22][CH2:43][C:42]3[CH:41]=[CH:40][C:39]([C:38]([F:37])([F:47])[F:48])=[CH:46][CH:45]=3)=[C:18]([CH3:23])[CH:17]=2)[CH:13]=[CH:14][C:9]=1[O:8][CH2:7][C:6]([OH:5])=[O:25]
Reactant: Cc1cc(Sc2ccc(OCC(=O)OC(C)(C)C)c(C)c2)ccc1O
Reactant: FC(F)(F)c1ccc(CBr)cc1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: O
Solvent: CN(C)C=O
Product: Cc1cc(Sc2ccc(OCc3ccc(C(F)(F)F)cc3)c(C)c2)ccc1OCC(=O)O
Temperature: 25 °C
Reaction time: 8 h
Yield: 41.9 %

Procedure:
An oven-dried 100 mL round-bottomed flask was charged with compound 1.1 (400 mg, 1.1 mmol), finely powdered Cs2CO3 (405 mg, 1.2 mmol), and anhydrous DMF (2 mL). 4-(Trifluoromethyl)benzyl bromide (298 mg, 1.1 mmol, Aldrich) was added, and the reaction was stirred vigorously overnight at room temperature. The reaction mixture was poured into 60 mL of water and extracted with 3×20 mL of methylene chloride. The combined organics were washed with 2×50 mL of water, dried over Na2SO4, and concentrated to a slightly yellow oil (422 mg). This crude material was dissolved in methylene chloride (2.5 mL), and trifluoroacetic acid (1.2 mL) was slowly added. The reaction was stirred for 4 h, after which the volatile components were removed in vacuo to reveal a crude pink oil. The crude pink oil was purified using flash chromatography (SiO2 gel 60, eluted with 60% EtOAc/hexanes), and the resulting white solid was recrystallized from methylene chloride/hexanes to give fine white crystals (213 mg). MS ESI m/e: 461.1 (M−H). 1H NMR (400 MHz) (CDCl3) δ 7.65 (2H, d, J=8.4 Hz); 7.54 (2H, d, J=8.4 Hz); 7.20 (1H, s); 7.17-7.14 (2H, d, m); 7.10 (11H, dd, J=13.0, 2.4 Hz); 6.77 (1H, d, J=8.4 Hz); 6.65 (1H, d, J=8.4 Hz); 5.12 (2H, s); 4.66 (2H, s); 2.25 (3H, s); 2.24 (3H, s).
Reaction SMILES: [N+]([C:4]1[CH:11]=[CH:10][CH:9]=[C:8]([N+:12]([O-:14])=[O:13])[C:5]=1[C:6]#[N:7])([O-])=O.[CH:15]1([CH2:19][OH:20])[CH2:18][CH2:17][CH2:16]1>>[N+:12]([C:8]1[CH:9]=[CH:10][CH:11]=[C:4]([O:20][CH2:19][CH:15]2[CH2:18][CH2:17][CH2:16]2)[C:5]=1[C:6]#[N:7])([O-:14])=[O:13]
Reactant: N#Cc1c([N+](=O)[O-])cccc1[N+](=O)[O-]
Reactant: OCC1CCC1
Product: N#Cc1c(OCC2CCC2)cccc1[N+](=O)[O-]

Procedure:
Prepared as in Example 166d from 2,6-dinitrobenzonitrile and cyclobutylmethanol in 68% as a tan solid. 1H NMR (400 MHz, DMSO-d6) δ 1.93 (m, 4H), 2.10 (m, 2H), 2.79 (m, 1H), 4.25 (d, J=6.3 Hz, 2H), 7.74 (dd, J=8.5, 2.2 Hz, 1H), 7.91 (m, 2H).
Reaction SMILES: [F:1][CH:2]([F:25])[C:3]1[N:8]2[N:9]=[CH:10][C:11]([C:12](O)=[O:13])=[C:7]2[N:6]=[C:5]([C:15]2[CH:20]=[CH:19][C:18]([C:21]([F:24])([F:23])[F:22])=[CH:17][CH:16]=2)[CH:4]=1.[NH2:26][C:27]1[CH:28]=[C:29]([S:33]([NH:36][CH2:37][CH2:38][N:39]([CH3:41])[CH3:40])(=[O:35])=[O:34])[CH:30]=[CH:31][CH:32]=1>>[CH3:40][N:39]([CH3:41])[CH2:38][CH2:37][NH:36][S:33]([C:29]1[CH:28]=[C:27]([NH:26][C:12]([C:11]2[CH:10]=[N:9][N:8]3[C:3]([CH:2]([F:25])[F:1])=[CH:4][C:5]([C:15]4[CH:16]=[CH:17][C:18]([C:21]([F:24])([F:23])[F:22])=[CH:19][CH:20]=4)=[N:6][C:7]=23)=[O:13])[CH:32]=[CH:31][CH:30]=1)(=[O:35])=[O:34]
Reactant: CN(C)CCNS(=O)(=O)c1cccc(N)c1
Reactant: O=C(O)c1cnn2c(C(F)F)cc(-c3ccc(C(F)(F)F)cc3)nc12
Product: CN(C)CCNS(=O)(=O)c1cccc(NC(=O)c2cnn3c(C(F)F)cc(-c4ccc(C(F)(F)F)cc4)nc23)c1

Procedure:
The title compound was prepared from 7-difluoromethyl-5-(4-trifluoromethyl-phenyl)-pyrazolo[1,5-a]pyrimidine-3-carboxylic acid (example C.1) and 3-amino-N-(2-dimethylamino-ethyl)-benzenesulfonamide (example B.12) according to general procedure II. Yellow solid. MS (ISP) 583.4 [(M+H+]; mp 184° C.
Reaction SMILES: [CH2:1]([N:3]1[C:12]2[C:7](=[CH:8][C:9]([F:15])=[C:10](F)[C:11]=2[F:13])[C:6](=[O:16])[C:5]([C:17]([OH:19])=[O:18])=[CH:4]1)[CH3:2].[CH2:20]1[C:28]2[C:23](=[CH:24][CH:25]=[CH:26][CH:27]=2)[CH2:22][NH:21]1.C1CCN2C(=NCCC2)CC1>CN(C=O)C>[CH2:20]1[C:28]2[C:23](=[CH:24][CH:25]=[CH:26][CH:27]=2)[CH2:22][N:21]1[C:10]1[C:11]([F:13])=[C:12]2[C:7]([C:6](=[O:16])[C:5]([C:17]([OH:19])=[O:18])=[CH:4][N:3]2[CH2:1][CH3:2])=[CH:8][C:9]=1[F:15]
Reactant: c1ccc2c(c1)CNC2
Reactant: CCn1cc(C(=O)O)c(=O)c2cc(F)c(F)c(F)c21
Solvent: CN(C)C=O
Solvent: C1CCC2=NCCCN2CC1
Product: CCn1cc(C(=O)O)c(=O)c2cc(F)c(N3Cc4ccccc4C3)c(F)c21
Yield: 36.6 %

Procedure:
136 mg of 1-ethyl-6,7,8-trifluoro-1,4-dihydro-4- oxoquinoline-3-carboxylic acid, 179 mg of isoindoline, 152 mg of DBU, and 1.5 ml of anhydrous DMF were processed in the same manner as in Example 20 to produce 68 mg of the target compound.
Reaction SMILES: ClC(Cl)(O[C:5](=[O:11])OC(Cl)(Cl)Cl)Cl.[NH2:13][C:14]1[CH:23]=[CH:22][C:21]([C:24]([C:26]2[N:30]3[CH:31]=[CH:32][CH:33]=[CH:34][C:29]3=[C:28]([C:35]3[CH:40]=[CH:39][CH:38]=[C:37]([C:41]([O:43][CH3:44])=[O:42])[CH:36]=3)[N:27]=2)=[O:25])=[CH:20][C:15]=1[C:16]([O:18][CH3:19])=[O:17].[F:45][C:46]1[CH:53]=[CH:52][C:49]([CH2:50][NH2:51])=[CH:48][CH:47]=1.C(N(CC)CC)C>O1CCOCC1>[F:45][C:46]1[CH:53]=[CH:52][C:49]([CH2:50][NH:51][C:5]([NH:13][C:14]2[CH:23]=[CH:22][C:21]([C:24]([C:26]3[N:30]4[CH:31]=[CH:32][CH:33]=[CH:34][C:29]4=[C:28]([C:35]4[CH:40]=[CH:39][CH:38]=[C:37]([C:41]([O:43][CH3:44])=[O:42])[CH:36]=4)[N:27]=3)=[O:25])=[CH:20][C:15]=2[C:16]([O:18][CH3:19])=[O:17])=[O:11])=[CH:48][CH:47]=1
Reactant: O=C(OC(Cl)(Cl)Cl)OC(Cl)(Cl)Cl
Reactant: NCc1ccc(F)cc1
Reactant: COC(=O)c1cccc(-c2nc(C(=O)c3ccc(N)c(C(=O)OC)c3)n3ccccc23)c1
Solvent: C1COCCO1
Solvent: CCN(CC)CC
Product: COC(=O)c1cccc(-c2nc(C(=O)c3ccc(NC(=O)NCc4ccc(F)cc4)c(C(=O)OC)c3)n3ccccc23)c1
Yield: 94.7 %

Procedure:
2.14 g (7.2 mmol) of triphosgene are added, at ambient temperature under an inert atmosphere, to 2.58 g (6 mmol) of methyl 2-amino-5-({1-[3-(methoxycarbonyl)phenyl]imidazo[1,5-a]pyridin-3-yl}carbonyl)benzoate in 50 ml of dioxane. After refluxing for 7 hours, 2.25 g (18 mmol) of 4-fluorobenzylamine and 1.82 g (18 mmol) of triethylamine are added at ambient temperature. The reaction medium is refluxed for 3 hours and then concentrated under reduced pressure. The residue is triturated from water. After filtration, the solid is rinsed with methanol and then dried under reduced pressure at 40° C. overnight. 3.3 g of a yellow solid are obtained.
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][O:4][CH2:3][CH2:2]1.[F:7][C:8]1[CH:9]=[CH:10][C:11]([O:18][CH3:19])=[C:12]([S:14](Cl)(=[O:16])=[O:15])[CH:13]=1>C(Cl)Cl>[F:7][C:8]1[CH:9]=[CH:10][C:11]([O:18][CH3:19])=[C:12]([S:14]([N:1]2[CH2:6][CH2:5][O:4][CH2:3][CH2:2]2)(=[O:15])=[O:16])[CH:13]=1
Reactant: C1COCCN1
Reactant: COc1ccc(F)cc1S(=O)(=O)Cl
Solvent: ClCCl
Product: COc1ccc(F)cc1S(=O)(=O)N1CCOCC1
Temperature: 25 °C
Reaction time: 1 h
Yield: 91.3 %

Procedure:
To a mixture of morpholine (5.8 g, 66.9 mmol) and TEA (9.3 ml, 66.9 mol) in CH2Cl2 (20 ml) was added dropwise a solution of the product of example 82 (5.0 g, 22 mmol) in CH2Cl2 (10 ml) at 0° C. After stirring at room temperature for one hour, the mixture was diluted with CH2Cl2, washed with water, dried and concentrated under reduced pressure. The resulting residue was purified by column chromatography (PE/EA=10/1) to give the titled compound (5.53 g, yield 90.3%).
Reaction SMILES: [H-].[Na+].C(=N[OH:11])C1C=CC=CC=1.[H][H].[Cl:14][C:15]1[C:25]([Cl:26])=[C:24]([C:27](=[O:37])[C:28]2[CH:33]=[CH:32][C:31]([N+]([O-])=O)=[CH:30][CH:29]=2)[CH:23]=[CH:22][C:16]=1[O:17][CH2:18][C:19]([OH:21])=[O:20]>CN(C=O)C>[Cl:14][C:15]1[C:25]([Cl:26])=[C:24]([C:27](=[O:37])[C:28]2[CH:33]=[CH:32][C:31]([OH:11])=[CH:30][CH:29]=2)[CH:23]=[CH:22][C:16]=1[O:17][CH2:18][C:19]([OH:21])=[O:20]
Reactant: O=C(O)COc1ccc(C(=O)c2ccc([N+](=O)[O-])cc2)c(Cl)c1Cl
Reactant: ON=Cc1ccccc1
Reactant: [H][H]
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: O=C(O)COc1ccc(C(=O)c2ccc(O)cc2)c(Cl)c1Cl
Reaction time: 15 h
Yield: 88 %

Procedure:
In the above described equipment, 0.312 g. of sodium hydride in 17.5 ml. of DMF is stirred while dropwise adding 0.874 ml. of benzaldoxime. The exothermic reaction forms a heavy precipitate while generating hydrogen gas. When the H2 -evolution ceases, 1,4806 g. of 2,3-dichloro-4-(4-nitrobenzoyl)phenoxyacetic acid is added, which will start H2 -evolution again and produce a homogenous dark solution. Upon further stirring, a precipitate starts to form which after several hours may become heavy enough to interfere with the magnetic stirrer. After 15 hours, the mixture is diluted with 175 ml. of water and filtered. By acidifying the filtrate with concentrated HCl to a pH of 2, a milky oil separates which solidifies upon standing. After collecting the crystalline material by filtration, washing it with cold water and drying it at 60° C. under house vaccum, 1.1986 g. (88% of theory) of 2,3-dichloro-4-(4-hydroxybenzoyl)phenoxyacetic acid is obtained.
Reaction SMILES: C(Cl)(=O)C(Cl)=O.CS(C)=O.[OH:11][CH2:12][C@@H:13]1[C@@H:19]([C:20]2[CH:25]=[CH:24][C:23]([Cl:26])=[C:22]([Cl:27])[CH:21]=2)[CH2:18][C@H:17]2[N:28]([CH3:29])[C@@H:14]1[CH2:15][CH2:16]2.C(N(CC)CC)C>C(Cl)Cl>[CH:12]([C@@H:13]1[C@@H:19]([C:20]2[CH:25]=[CH:24][C:23]([Cl:26])=[C:22]([Cl:27])[CH:21]=2)[CH2:18][C@H:17]2[N:28]([CH3:29])[C@@H:14]1[CH2:15][CH2:16]2)=[O:11]
Reactant: CN1[C@H]2CC[C@@H]1[C@H](CO)[C@@H](c1ccc(Cl)c(Cl)c1)C2
Agent: O=C(Cl)C(=O)Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Solvent: CS(C)=O
Product: CN1[C@H]2CC[C@@H]1[C@H](C=O)[C@@H](c1ccc(Cl)c(Cl)c1)C2
Reaction time: 0.17 h

Procedure:
To a solution of oxalylchloride (2.3 ml) in absolute methylene chloride (60 ml) at -60° C., a solution of dimethylsulphoxide (4 ml) in absolute methylene chloride (10 ml) was added over 10 minutes. The mixture was stirred for 10 minutes and a suspension of (1R,2R,3S)-2-hydroxymethyl-3-(3,4-dichlorophenyl)tropane (7 g, 23.3 mmol) in absolute methylene chloride (400 ml) was added over 15 minutes. The resulting mixture was stirred for 10 minutes followed by addition of triethylamine (17 ml, 0.12 mmol) and stirring for another 10 minutes. The reaction mixture was allowed to reach ambient temperature and was quenched by addition of water (200 ml). The organic phase was washed twice with water, dried and concentrated in vacuo yielding the title compound as white crystals, m.p. 131°-135° C.
Reaction SMILES: OC[CH:3]1[CH2:8][CH:7]2[CH2:9][CH:4]1[CH:5]=[CH:6]2.[SH:10][CH2:11][CH2:12][OH:13].N(C(C)(C)C#N)=NC(C)(C)C#N>O1CCOCC1>[OH:13][CH2:12][CH2:11][S:10][CH:3]1[CH:4]2[CH2:9][CH:7]([CH2:6][CH2:5]2)[CH2:8]1
Reactant: OCCS
Reactant: OCC1CC2C=CC1C2
Agent: CC(C)(C#N)N=NC(C)(C)C#N
Solvent: C1COCCO1
Product: OCCSC1CC2CCC1C2
Reaction time: 8 h

Procedure:
In a nitrogen atmosphere, to a stirred solution of 12.4 grams (0.1 mole) of 2-hydroxymethyl-5-norbornene in 100 ml of dioxane was added in one portion 17.2 grams (0.22 mole) of 2-mercaptoethanol. The temperature rose from 25° to 50°. The mixture was then heated at 70° for 6.3 hours during which time a solution of 1.6 grams of α,α'-azobisisobutyronitrile in 20 ml of dioxane was added in portions. After standing overnight, the dioxane solvent and excess 2-mercaptoethanol were removed under reduced pressure. The residue was distilled to give the 2-methylol- 5 or 6-(2'-hydroxyethylthio)norbornane intermediate as a viscous oil with a boiling point of 140°-142°/0.05 mm in a yield of 15.0 grams (74%).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:16]=[CH:17][CH:18]=1)[CH2:5][C:6]1[CH:15]=[CH:14][C:9]([C:10]([O:12]C)=[O:11])=[CH:8][CH:7]=1.[OH-].[Li+]>O.C1COCC1>[F:1][C:2]1[CH:3]=[C:4]([CH:16]=[CH:17][CH:18]=1)[CH2:5][C:6]1[CH:15]=[CH:14][C:9]([C:10]([OH:12])=[O:11])=[CH:8][CH:7]=1
Reactant: COC(=O)c1ccc(Cc2cccc(F)c2)cc1
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Product: O=C(O)c1ccc(Cc2cccc(F)c2)cc1
Temperature: 60 °C
Yield: 100 %

Procedure:
A mixture of methyl 4-(3-fluorobenzyl)benzoate (0.574 g; 2.35 mmol) and lithium hydroxide (0.493 g; 11.75 mmol) in water (6 mL) and THF (6 mL) was heated at 60° C. for 3 hours and concentrated under reduced pressure. The resulting aqueous solution was acidified with a 6N solution of hydrochloric acid in water. The resulting precipitate was filtered off to give 0.541 g (quantitative) of 4-(3-fluorobenzyl)benzoic acid which was used without further purification.
Reaction SMILES: [ClH:1].[CH3:2][O:3][C:4]1[CH:5]=[C:6]2[C:11](=[CH:12][CH:13]=1)[O:10][C:9](=[O:14])[CH:8]=[C:7]2[NH:15][CH:16]1[CH2:21][CH2:20][NH:19][CH2:18][CH2:17]1.[F:22][C:23]1[CH:24]=[C:25]([CH:28]=[CH:29][C:30]=1[OH:31])[CH:26]=O>>[ClH:1].[F:22][C:23]1[CH:24]=[C:25]([CH:28]=[CH:29][C:30]=1[OH:31])[CH2:26][N:19]1[CH2:20][CH2:21][CH:16]([NH:15][C:7]2[C:6]3[C:11](=[CH:12][CH:13]=[C:4]([O:3][CH3:2])[CH:5]=3)[O:10][C:9](=[O:14])[CH:8]=2)[CH2:17][CH2:18]1
Reactant: O=Cc1ccc(O)c(F)c1
Reactant: COc1ccc2oc(=O)cc(NC3CCNCC3)c2c1
Agent: Cl
Product: COc1ccc2oc(=O)cc(NC3CCN(Cc4ccc(O)c(F)c4)CC3)c2c1
Yield: 95.4 %

Procedure:
According to Procedure C above, (I) (0.0223 g; 0.081 mmol) and 3-fluoro-4-hydroxy-benzaldehyde were allowed to react to give after the purification the corresponding mono-TFA salt. The product was then suspended in MeOH and hydrochloride salt was precipitated by addition of 4 N HCl solution in dioxane. The resulting white solid was triturated with Et2O/MeOH (2:1), washed with Et2O and dried under high vacuum to afford 33.6 mg (95.4%) of the title compound. MS (DCI/NH3)(+)Q1MS m/z 399 (M+H)+; 1H NMR (500 MHz, pyridine-d5) δ ppm 1.94 (m, 2H), 2.10 (m, 2H), 2.27 (m, 2H), 3.06 (m, 2H), 3.42 (s, 3H), 3.61 (m, 1H), 3.65 (s, 2H), 5.71 (s, 1H), 7.15 (m, 2H), 7.24 (m, 1H), 7.33 (d, J=9.05 Hz, 1H), 7.39 (m, 1H), 7.69 (m, 1H+1N H).
Reaction SMILES: [Br:1][CH2:2][C:3]1[CH:7]=[CH:6][S:5][C:4]=1[C:8]([O:10][CH3:11])=[O:9].[C:12]1([P:18]([C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=2)[C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1>C1(C)C=CC=CC=1>[Br-:1].[CH3:11][O:10][C:8]([C:4]1[S:5][CH:6]=[CH:7][C:3]=1[CH2:2][P+:18]([C:19]1[CH:20]=[CH:21][CH:22]=[CH:23][CH:24]=1)([C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1)[C:12]1[CH:13]=[CH:14][CH:15]=[CH:16][CH:17]=1)=[O:9]
Reactant: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Reactant: COC(=O)c1sccc1CBr
Solvent: Cc1ccccc1
Product: COC(=O)c1sccc1C[P+](c1ccccc1)(c1ccccc1)c1ccccc1
Product: [Br-]
Temperature: 25 °C
Reaction time: 48 h
Yield: 70.4 %

Procedure:
To a solution of methyl 3-bromomethyl-2-thiophenecarboxylate (7.31 g, 31.1 mmol) in toluene (90 ml) was added triphenylphosphine (7.92 g, 30.2 mmol) under ice cooling. The temperature of the mixture was raised to room temperature, followed by stirring for 2 days. The precipitated crystals were collected by filtration and dried to give 2-methoxycarbonylthiophen-3-ylmethyltriphenylphosphonium bromide (10.57 g, 70.4%). This product was subjected to the reaction of Reference Example 13 without purification.
Reaction SMILES: [CH3:1][N:2]1[C:6](=[O:7])[C:5]2([CH2:12][C:11]([CH3:14])([CH3:13])[NH:10][C:9]([CH3:16])([CH3:15])[CH2:8]2)[NH:4][C:3]1=[O:17].[O:18]1[CH2:29][CH:19]1[CH2:20][O:21][CH2:22][CH2:23][O:24][CH2:25][CH:26]1[O:28][CH2:27]1>C(O)CCCCCCC>[OH:18][CH:19]([CH2:29][N:10]1[C:11]([CH3:14])([CH3:13])[CH2:12][C:5]2([NH:4][C:3](=[O:17])[N:2]([CH3:1])[C:6]2=[O:7])[CH2:8][C:9]1([CH3:16])[CH3:15])[CH2:20][O:21][CH2:22][CH2:23][O:24][CH2:25][CH:26]([OH:28])[CH2:27][N:10]1[C:11]([CH3:13])([CH3:14])[CH2:12][C:5]2([NH:4][C:3](=[O:17])[N:2]([CH3:1])[C:6]2=[O:7])[CH2:8][C:9]1([CH3:16])[CH3:15]
Reactant: C(COCC1CO1)OCC1CO1
Reactant: CN1C(=O)NC2(CC(C)(C)NC(C)(C)C2)C1=O
Solvent: CCCCCCCCO
Product: CN1C(=O)NC2(CC(C)(C)N(CC(O)COCCOCC(O)CN3C(C)(C)CC4(CC3(C)C)NC(=O)N(C)C4=O)C(C)(C)C2)C1=O

Procedure:
To 50 ml of n-octanol were added 5.0 g of 3,7,7,9,9-pentamethyl-1,3,8-triazaspiro[4.5]decane-2,4-dione and 1.5 g of ethylene glycol bis(2,3-epoxypropyl) ether; the mixture was then reacted as described in Example 1 to give the desired Compound No. 340 in the form of a white powder. The compound had an Rf value of 0.54 on thin-layer chromatography on silica gel developed with a 20:1:1 by volume mixture of ethyl acetate, ethanol and triethylamine.
Reaction SMILES: [NH2:1][C:2]1[CH:31]=[CH:30][C:5]2[CH2:6][CH2:7][CH2:8][CH:9]([N:11]([CH2:19][C@H:20]([OH:29])[CH2:21][O:22][C:23]3[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=3)[CH2:12][C:13]3[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=3)[CH2:10][C:4]=2[CH:3]=1.Cl[C:33]([O:35][CH3:36])=[O:34].N1C=CC=CC=1.C(=O)([O-])O.[Na+]>CN(C)C1C=CN=CC=1.ClCCl>[CH3:36][O:35][C:33]([NH:1][C:2]1[CH:31]=[CH:30][C:5]2[CH2:6][CH2:7][CH2:8][CH:9]([N:11]([CH2:19][C@H:20]([OH:29])[CH2:21][O:22][C:23]3[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=3)[CH2:12][C:13]3[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=3)[CH2:10][C:4]=2[CH:3]=1)=[O:34]
Reactant: COC(=O)Cl
Reactant: Nc1ccc2c(c1)CC(N(Cc1ccccc1)C[C@H](O)COc1ccccc1)CCC2
Agent: CN(C)c1ccncc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: c1ccncc1
Solvent: ClCCl
Product: COC(=O)Nc1ccc2c(c1)CC(N(Cc1ccccc1)C[C@H](O)COc1ccccc1)CCC2

Procedure:
Under nitrogen, a solution of (2S)-1-(N-(3-amino-6,7,8,9-tetrahydro-5H-benzocyclohepten-6-yl)-N-benzylamino]-3-phenoxy-2-propanol (150 mg), methyl chloroformate (29 μl), pyridine (25 μl) and catalytic amounts of 4-dimethylaminopyridine in dichloromethane (3 ml) was stirred at room temperature for 1.5 hours. The resulting mixture was poured into saturated aqueous sodium hydrogencarbonate and extracted with ethyl acetate. The organic layer was washed with brine, dried over anhydrous magnesium sulfate and evaporated in vacuo. The residue was purified by column chromatography on silica gel (hexane:ethyl acetate=3:1) to give (2S)-1-[N-(3-methoxycarbonylamino-6,7,8,9-tetrahydro-5H-benzocyclohepten-6-yl)-N-benzylamino]-3-phenoxy-2-propanol (158 mg).
Reaction SMILES: C([Li:5])CCC.[CH2:6]([Si:8]([NH:11][Si:12]([CH3:16])([CH3:15])[CH2:13][CH3:14])([CH3:10])[CH3:9])[CH3:7]>CCCCCC>[CH2:13]([Si:12]([N-:11][Si:8]([CH3:9])([CH3:10])[CH2:6][CH3:7])([CH3:15])[CH3:16])[CH3:14].[Li+:5]
Reactant: CC[Si](C)(C)N[Si](C)(C)CC
Reactant: [Li]CCCC
Solvent: CCCCCC
Product: CC[Si](C)(C)[N-][Si](C)(C)CC
Product: [Li+]
Reaction time: 1 h

Procedure:
Lithium bis(ethyldimethylsilyl)amide was prepared by the slow addition via syringe of a hexane solution of butyl lithium (50.6 mL of 2.73 M solution, 138 mmol) to a stirred hexane solution (100 mL) of bis(ethyldimethylsilyl)amine (26.2 g, 138 mmol) at room temperature. Stirring was continued for one hour and the solution was then refluxed for one hour. The hexane was evaporated under vacuum, leaving a pale yellow liquid. It was distilled at a temperature of 123° C. and a pressure of 0.2 torr to yield 23.2 g (86%) of clear liquid lithium bis(ethyldimethylsilyl)amide. Its viscosity was measured to be 37.5 centipoise at 40° C. Its NMR parameters are as follows:
Reaction SMILES: OC(C(F)(F)F)=O.[C:8]([NH:12][C:13]([N:15]1[C:23]2[C:18](=[CH:19][C:20]([C:24]([F:27])([F:26])[F:25])=[CH:21][CH:22]=2)[C:17]([NH:28][CH2:29][C:30](=[O:36])[NH:31][CH:32]2[CH2:35][NH:34][CH2:33]2)=[N:16]1)=[O:14])([CH3:11])([CH3:10])[CH3:9].[CH2:37]([O:39][C:40]1[N:45]=[CH:44][C:43]([C:46]2([OH:53])[CH2:51][CH2:50][C:49](=O)[CH2:48][CH2:47]2)=[CH:42][CH:41]=1)[CH3:38]>>[C:8]([NH:12][C:13]([N:15]1[C:23]2[C:18](=[CH:19][C:20]([C:24]([F:26])([F:25])[F:27])=[CH:21][CH:22]=2)[C:17]([NH:28][CH2:29][C:30](=[O:36])[NH:31][CH:32]2[CH2:33][N:34]([CH:49]3[CH2:50][CH2:51][C:46]([C:43]4[CH:44]=[N:45][C:40]([O:39][CH2:37][CH3:38])=[CH:41][CH:42]=4)([OH:53])[CH2:47][CH2:48]3)[CH2:35]2)=[N:16]1)=[O:14])([CH3:11])([CH3:9])[CH3:10]
Reactant: CC(C)(C)NC(=O)n1nc(NCC(=O)NC2CNC2)c2cc(C(F)(F)F)ccc21
Reactant: CCOc1ccc(C2(O)CCC(=O)CC2)cn1
Solvent: O=C(O)C(F)(F)F
Product: CCOc1ccc(C2(O)CCC(N3CC(NC(=O)CNc4nn(C(=O)NC(C)(C)C)c5ccc(C(F)(F)F)cc45)C3)CC2)cn1

Procedure:
The title compound was prepared as a white solid from reaction of 3-[(azetidin-3-ylcarbamoylmethyl)-amino]-5-trifluoromethyl-indazole-1-carboxylic acid tert-butyl amide TFA salt (as prepared in Example 81, Step D) and 4-(6-ethoxy-pyridin-3-yl)-4-hydroxy-cyclohexanone using the procedure described in Step E of Example 1.