Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C(Cl)(=O)C(Cl)=O.CS(C)=O.[OH:11][C@H:12]1[CH2:33][CH2:32][C@@:31]2([CH3:34])[C@@H:14]([CH2:15][CH2:16][C@:17]3([CH3:48])[C@@H:30]2[CH2:29][CH:28]=[C:27]2[C@@:18]3([CH3:47])[CH2:19][CH2:20][C@:21]3([C:37]([O:39][CH2:40][C:41]4[CH:46]=[CH:45][CH:44]=[CH:43][CH:42]=4)=[O:38])[C@H:26]2[C@@H:25]([CH3:35])[C@H:24]([CH3:36])[CH2:23][CH2:22]3)[C:13]1([CH3:50])[CH3:49].C(N(CC)CC)C>C(Cl)Cl>[CH3:35][C@@H:25]1[C@@H:26]2[C@@:21]([C:37]([O:39][CH2:40][C:41]3[CH:42]=[CH:43][CH:44]=[CH:45][CH:46]=3)=[O:38])([CH2:20][CH2:19][C@:18]3([CH3:47])[C:27]2=[CH:28][CH2:29][C@H:30]2[C@@:17]3([CH3:48])[CH2:16][CH2:15][C@@H:14]3[C@:31]2([CH3:34])[CH2:32][CH2:33][C:12](=[O:11])[C:13]3([CH3:49])[CH3:50])[CH2:22][CH2:23][C@H:24]1[CH3:36]
Reactant: C[C@H]1[C@H](C)CC[C@]2(C(=O)OCc3ccccc3)CC[C@]3(C)C(=CC[C@@H]4[C@@]5(C)CC[C@H](O)C(C)(C)[C@@H]5CC[C@]43C)[C@H]12
Agent: O=C(Cl)C(=O)Cl
Solvent: ClCCl
Solvent: CS(C)=O
Solvent: CCN(CC)CC
Product: C[C@H]1[C@H](C)CC[C@]2(C(=O)OCc3ccccc3)CC[C@]3(C)C(=CC[C@@H]4[C@@]5(C)CCC(=O)C(C)(C)[C@@H]5CC[C@]43C)[C@H]12
Temperature: -50 °C
Reaction time: 0.25 h
Yield: 95.2 %

Procedure:
To a solution of oxalyl chloride (2.57 mL, 5.14 mmol) in methylene chloride (5 mL) at −78° C. under nitrogen was added dropwise a solution of DMSO (0.46 mL 6.4 mmol) in methylene chloride (5 mL). The mixture was allowed to warm to −50° C. To this was added a solution of the (1S,2R,4aS,6aS,6bR,8aR,10S,12aR,12bR,14bS)-benzyl 10-hydroxy-1,2,6a,6b,9,9,12a-heptamethyl-1,2,3,4,4a,5,6,6a,6b,7,8,8a,9,10,11,12,12a,12b,13,14b-icosahydropicene-4-a-carboxylate (intermediate A1) (2.34 gm, 4.28 mmol) in methylene chloride (15 mL) forming a white milky suspension. The mixture was stirred for an additional 15 minutes at −50° C. after the addition, it was then treated with triethylamine (1.79 mL, 12.84 mmol) and the reaction mixture was slowly warmed to RT. It was diluted with methylene chloride (100 mL), washed with water (2×100 mL), followed by brine (50 mL). The organic phase was separated out, dried over anhydrous sodium sulfate, and concentrated in vacuo to a syrup. This crude material was partitioned over a silica gel column, eluted with 9:1, hexanes:ethyl acetate solvent to give the title compound as a pale solid (2.22 g, 95%). 1H NMR (400 MHz, CHLOROFORM-d) δ ppm 0.69 (s, 3H), 0.87 (d, J=6.53 Hz, 3H), 0.93-0.97 (m, 3H), 1.03 (s, 3H), 1.05 (s, 3H), 1.09 (s, 6H), 1.26-1.40 (m, 4H), 1.40-1.54 (m, 5H), 1.59 (d, J=9.03 Hz, 2H), 1.70 (br. s., 2H), 1.93 (dd, J=9.54, 3.26 Hz, 4H), 1.97-2.08 (m, 2H), 2.29 (d, J=11.04 Hz, 1H), 2.38 (ddd, J=15.94, 6.90, 3.76 Hz, 1H), 2.49-2.61 (m, 1H), 4.97-5.03 (m, 1H), 5.10-5.15 (m, 1H), 5.27 (t, J=3.51 Hz, 1H), 7.31-7.39 (m, 5H).
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([S:16]([NH2:19])(=[O:18])=[O:17])[CH:5]=[N:6][C:7]=1[O:8][CH2:9][CH:10]1[CH2:15][CH2:14][O:13][CH2:12][CH2:11]1.C([Sn](CCCC)(CCCC)[C:25]1[S:26][CH:27]=[CH:28][N:29]=1)CCC>O1CCOCC1.C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.[Pd]>[O:13]1[CH2:14][CH2:15][CH:10]([CH2:9][O:8][C:7]2[N:6]=[CH:5][C:4]([S:16]([NH2:19])(=[O:18])=[O:17])=[CH:3][C:2]=2[C:25]2[S:26][CH:27]=[CH:28][N:29]=2)[CH2:11][CH2:12]1
Reactant: NS(=O)(=O)c1cnc(OCC2CCOCC2)c(Br)c1
Reactant: CCCC[Sn](CCCC)(CCCC)c1nccs1
Agent: [Pd]
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1COCCO1
Product: NS(=O)(=O)c1cnc(OCC2CCOCC2)c(-c2nccs2)c1

Procedure:
A mixture of EXAMPLE 329B (0.070 g), 2-(tributylstannyl)thiazole (0.090 g), and tetrakis(triphenylphosphine)palladium(O) (0.069 g) in dioxane (2 mL) was heated at 90° C. for 4 hours. After cooling, the mixture was loaded onto a silica gel column and eluting with 1:3 ethyl acetate:hexanes to give the title compound.
Reaction SMILES: O[C:2]1([C:15]2[CH:20]=[CH:19][CH:18]=[C:17]([O:21][CH3:22])[CH:16]=2)[CH2:7][CH2:6][N:5](C(OC(C)(C)C)=O)[CH2:4][CH2:3]1.C(N(S(F)(F)[F:29])CC)C.[ClH:32]>>[ClH:32].[CH3:22][O:21][C:17]1[CH:16]=[C:15]([C:2]2([F:29])[CH2:7][CH2:6][NH:5][CH2:4][CH2:3]2)[CH:20]=[CH:19][CH:18]=1
Reactant: COc1cccc(C2(O)CCN(C(=O)OC(C)(C)C)CC2)c1
Reactant: CCN(CC)S(F)(F)F
Agent: Cl
Product: COc1cccc(C2(F)CCNCC2)c1
Yield: 76 %

Procedure:
This material was prepared from the reaction of tert-Butyl 4-hydroxy-4-(3-methoxyphenyl)piperidine-1-carboxylate with diethylaminosulfur trifluoride and deprotection of the crude product using methanolic hydrogen chloride as described in Step 2 of Example 1 to afford 4-(3-methoxyphenyl)-4-fluoropiperidine hydrochloride in 76% yield.
Reaction SMILES: [CH3:1][C:2]1([CH3:29])[CH2:15][CH2:14][C:13]([CH3:17])([CH3:16])[C:12]2[CH:11]=[C:10]3[C:5]([CH:6]=[CH:7][CH:8]=[C:9]3[CH:18](O)[C:19]3[CH:27]=[CH:26][C:22]([C:23]([OH:25])=[O:24])=[CH:21][CH:20]=3)=[CH:4][C:3]1=2.C([SiH](CC)CC)C.B(F)(F)F.CCOCC.CCO>ClCCl.O.CCOC(C)=O>[CH3:1][C:2]1([CH3:29])[CH2:15][CH2:14][C:13]([CH3:16])([CH3:17])[C:12]2[CH:11]=[C:10]3[C:5]([CH:6]=[CH:7][CH:8]=[C:9]3[CH2:18][C:19]3[CH:27]=[CH:26][C:22]([C:23]([OH:25])=[O:24])=[CH:21][CH:20]=3)=[CH:4][C:3]1=2
Reactant: CC1(C)CCC(C)(C)c2cc3c(C(O)c4ccc(C(=O)O)cc4)cccc3cc21
Agent: CC[SiH](CC)CC
Agent: FB(F)F
Solvent: CCOCC
Solvent: O
Solvent: CCOC(C)=O
Product: CC1(C)CCC(C)(C)c2cc3c(Cc4ccc(C(=O)O)cc4)cccc3cc21
Reaction time: 0.17 h
Yield: 57.5 %

Procedure:
A solution of 4-[(5,6,7,8-tetrahydro-5,5,8,8-tetramethyl-anthracen-1-yl)-hydroxymethyl]-benzoic acid (from Example 37, 30 mg, 0.07 mmol) in dichloromethane (5 mL) was treated with excess triethylsilane (0.2 mL) and BF3-Et2O (0.16 mL) at 0° C. The solution was allowed to stir for 10 min and then EtOH was added. The mixture was diluted with water and EtOAc. The organic solution was washed with water and brine, dried (Na2SO4), filtered, and concentrated to yield 4-(5,6,7,8-tetrahydro-5,5,8,8-tetramethyl-anthracen-1-ylmethyl)-benzoic acid (139) 15 mg (55%) as a colorless oil: 1H NMR (400 MHz, CDCl3) δ 8.01(½ABq, J=8.2 Hz, 2H, ArH), 7.81(s, 1H, ArH), 7,77(s, 1H, ArH), 7.66(d, J=8.2 Hz, 1H, ArH), 7.32(m, 3H, ArH), 7.24(s, 1H, ArH), 7.19(d, J=6.7 Hz, 1H, ArH), 4.45(s, 2H, CH2), 1.72(m, 4H, 2CH2), 1.35(s, 6H, 2CH3), 1.24(s, 6H, 2CH3).
Reaction SMILES: C[C:2]1[CH:6]=C(C)[N:4]([C:8](=[NH:19])[NH:9][S:10]([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)(=[O:12])=[O:11])[N:3]=1.CS(O)(=O)=O.NN1CC[O:29][CH2:28][CH2:27]1>>[NH2:19][C:8]([NH:4][N:3]1[CH2:2][CH2:6][O:29][CH2:28][CH2:27]1)=[N:9][S:10]([C:13]1[CH:14]=[CH:15][CH:16]=[CH:17][CH:18]=1)(=[O:11])=[O:12]
Reactant: Cc1cc(C)n(C(=N)NS(=O)(=O)c2ccccc2)n1
Reactant: NN1CCOCC1
Agent: CS(=O)(=O)O
Product: NC(=NS(=O)(=O)c1ccccc1)NN1CCOCC1

Procedure:
The compound of Example 29 was prepared according to the accompanying synthesis procedure from 0.5 ml of N-[(3,5-dimethylpyrazol-1-yl)-iminomethyl]-benzenesulfonamide solution (0.2 M, acetonitrile) with 19 mg of methanesulfonic acid and 0.5 ml of N-aminomorpholine solution (1.0 M, acetonitrile) and filed in a substance databank. Calculated mol. wt. 284.34; found mol. wt. (M+H) 285.3; 569.1 (Dimer)
Reaction SMILES: [Cl:1][C:2]1[CH:11]=[C:10]2[C:5]([C:6](=[O:20])[NH:7][C:8]([N:12]3[CH:16]=[C:15]([C:17]([OH:19])=[O:18])[CH:14]=[N:13]3)=[N:9]2)=[CH:4][C:3]=1[S:21][C:22]([F:25])([F:24])[F:23].C([O:28]C(C1C=NN(C2NC(=O)C3C(=CC=C(SC)C=3)N=2)C=1)=O)C>>[Cl:1][C:2]1[CH:11]=[C:10]2[C:5]([C:6](=[O:20])[NH:7][C:8]([N:12]3[CH:16]=[C:15]([C:17]([OH:19])=[O:18])[CH:14]=[N:13]3)=[N:9]2)=[CH:4][C:3]=1[S:21]([C:22]([F:24])([F:23])[F:25])=[O:28]
Reactant: O=C(O)c1cnn(-c2nc3cc(Cl)c(SC(F)(F)F)cc3c(=O)[nH]2)c1
Reactant: CCOC(=O)c1cnn(-c2nc3ccc(SC)cc3c(=O)[nH]2)c1
Product: O=C(O)c1cnn(-c2nc3cc(Cl)c(S(=O)C(F)(F)F)cc3c(=O)[nH]2)c1

Procedure:
The titled compound was prepared in a manner analogous to Example 157 using 1-(7-chloro-4-oxo-6-trifluoromethanesulfanyl-3,4-dihydro-quinazolin-2-yl)-1H-pyrazole-4-carboxylic acid (Intermediate from Example 159, product from Step A) for 1-(6-methylsulfanyl-4-oxo-3,4-dihydro-quinazolin-2-yl)-1H-pyrazole-4-carboxylic acid ethyl ester in step A. MS (ESI/Cl): mass calcd. for C13H6ClF3N4O4S, 406.0; m/z found, 407.0 [M+H]+; 405.0 [M−H]−. 1H NMR (400 MHz, DMSO-d6): 13.46 (br s, 1H), 13.12 (s, 1H), 8.97 (d, J=0.6 Hz, 1H), 8.54 (s, 1H), 8.33 (s, 1H), 8.03 (s, 1H).
Reaction SMILES: C(Cl)(=O)C(Cl)=O.CS(C)=O.[CH2:11]([O:18][C@H:19]1[C@H:24]([O:25][CH2:26][C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=2)[C@@H:23]([O:33][CH2:34][C:35]2[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=2)[C@@:22]([C:43]2[CH:48]=[CH:47][C:46]([Cl:49])=[C:45]([CH2:50][C:51]3[CH:56]=[CH:55][C:54]([O:57][CH3:58])=[C:53]([F:59])[C:52]=3[F:60])[CH:44]=2)([O:41][CH3:42])[O:21][C@@H:20]1[CH2:61][OH:62])[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1.C(N(CC)CC)C>C(Cl)Cl>[CH2:11]([O:18][C@H:19]1[C@H:24]([O:25][CH2:26][C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=2)[C@@H:23]([O:33][CH2:34][C:35]2[CH:36]=[CH:37][CH:38]=[CH:39][CH:40]=2)[C@@:22]([C:43]2[CH:48]=[CH:47][C:46]([Cl:49])=[C:45]([CH2:50][C:51]3[CH:56]=[CH:55][C:54]([O:57][CH3:58])=[C:53]([F:59])[C:52]=3[F:60])[CH:44]=2)([O:41][CH3:42])[O:21][C@@H:20]1[CH:61]=[O:62])[C:12]1[CH:13]=[CH:14][CH:15]=[CH:16][CH:17]=1
Reactant: COc1ccc(Cc2cc([C@]3(OC)O[C@H](CO)[C@@H](OCc4ccccc4)[C@H](OCc4ccccc4)[C@H]3OCc3ccccc3)ccc2Cl)c(F)c1F
Agent: O=C(Cl)C(=O)Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Solvent: CS(C)=O
Product: COc1ccc(Cc2cc([C@]3(OC)O[C@H](C=O)[C@@H](OCc4ccccc4)[C@H](OCc4ccccc4)[C@H]3OCc3ccccc3)ccc2Cl)c(F)c1F
Temperature: -78 °C
Reaction time: 0.67 h
Yield: 99.4 %

Procedure:
Oxalyl chloride was dissolved in 5 mL methylene chloride and cooled to −78° C., followed by dropwise addition of 3 ml solution of dimethyl sulfoxide ((0.26 mL, 3.59 mmol) in methylene chloride. The reaction mixture was stirred for 15 minutes, before 5 mL solution of [(2R,3R,4S,5R,6S)-3,4,5-tribenzyloxy-6-[4-chloro-3-[(2,3-difluoro-4-methoxy-phenyl)methyl]phenyl]-6-methoxy-tetrahydropyran-2-yl]methanol 2j (1.25 g, 1.71 mmol) in methylene chloride was dropwise added. The mixture was stirred for 40 minutes. The triethylamine (1.19 mL, 8.55 mmol) was dropwise added, before the reaction mixture was warmed to room temperature and stirred for 1.5 hours. Thereafter, the reaction mixture was washed with 5 mL 1 M hydrochloric acid and the organic extract was collected, dried over anhydrous magnesium sulfate, and filtered. The filtrate was concentrated under reduced pressure to obtain the title compound (2S,3S,4S,5R,6S)-3,4,5-tribenzyloxy-6-[4-chloro-3-[(2,3-difluoro-4-methoxy-phenyl)methyl]phenyl]-6-methoxy-tetrahydropyran-2-carbaldehyde 2k (1.24 g, yellow solid), which was used in the next step without purification.
Reaction SMILES: FC(F)(F)C(O)=O.[Cl:8][C:9]1[CH:10]=[C:11]([CH:15]2[C:19]([C:22]3[CH:27]=[CH:26][C:25]([Cl:28])=[CH:24][CH:23]=3)([C:20]#[N:21])[CH:18]([CH2:29][C:30]([CH3:33])([CH3:32])[CH3:31])[NH:17][CH:16]2[C:34](O)=[O:35])[CH:12]=[CH:13][CH:14]=1.[CH:37]1([CH2:40][CH2:41][NH2:42])[CH2:39][CH2:38]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>C(Cl)Cl>[CH:37]1([CH2:40][CH2:41][NH:42][C:34]([CH:16]2[CH:15]([C:11]3[CH:12]=[CH:13][CH:14]=[C:9]([Cl:8])[CH:10]=3)[C:19]([C:22]3[CH:23]=[CH:24][C:25]([Cl:28])=[CH:26][CH:27]=3)([C:20]#[N:21])[CH:18]([CH2:29][C:30]([CH3:31])([CH3:32])[CH3:33])[NH:17]2)=[O:35])[CH2:39][CH2:38]1
Reactant: NCCC1CC1
Reactant: CC(C)(C)CC1NC(C(=O)O)C(c2cccc(Cl)c2)C1(C#N)c1ccc(Cl)cc1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: CC(C)(C)CC1NC(C(=O)NCCC2CC2)C(c2cccc(Cl)c2)C1(C#N)c1ccc(Cl)cc1
Yield: 59.6 %

Procedure:
In a manner similar to the method described in Example 1e, rac-(2R,3R,4R,5S)-3-(3-chloro-phenyl)-4-(4-chloro-phenyl)-4-cyano-5-(2,2-dimethyl-propyl)-pyrrolidine-2-carboxylic acid trifluoroacetic acid prepared in Example 25a (0.16 g, 0.37 mmol) was reacted with 2-cyclopropylethylamine (Bridge Organics) (0.1 g, 1.1 mmol), HATU (0.2 g, 0.5 mmol) and iPr2NEt (0.3 g, 2 mmol) in CH2Cl2 (20 mL) at room temperature for 20 h to give rac-(2R,3R,4R,5S)-3-(3-chloro-phenyl)-4-(4-chloro-phenyl)-4-cyano-5-(2,2-dimethyl-propyl)-pyrrolidine-2-carboxylic acid (2-cyclopropyl-ethyl)-amide as a white solid (0.11 g, 37%).
Reaction SMILES: C[C@@H](N)C1C=CC=CC=1.[CH3:10][O:11][C:12]1[CH:21]=[C:20]2[C:15]([CH2:16][CH2:17][CH:18]([C:22]([OH:24])=[O:23])[CH2:19]2)=[CH:14][CH:13]=1.Cl>CC(C)=O.O>[CH3:10][O:11][C:12]1[CH:21]=[C:20]2[C:15]([CH2:16][CH2:17][C@H:18]([C:22]([OH:24])=[O:23])[CH2:19]2)=[CH:14][CH:13]=1
Reactant: COc1ccc2c(c1)CC(C(=O)O)CC2
Agent: C[C@@H](N)c1ccccc1
Agent: Cl
Solvent: O
Solvent: CC(C)=O
Product: COc1ccc2c(c1)C[C@@H](C(=O)O)CC2

Procedure:
(R)-(+)-α-methylbenzylamine (25.8 ml, 0.2 mol) is added to a solution of 7-methoxy-1,2,3,4-tetrahydronaphthalen-2-carboxylic acid racemate (41 g, 0.2 mol) in acetone (800 ml) and after 2 hours at room temperature the obtained salt is recovered by filtration (45.2 g) and crystallized twelve times from acetone until a product with constant [α] of -20.5° (c=1.4%, CHCl3) is obtained. This product is then taken up in water (30 ml) and the obtained solution is made acidic by the addition of concentrated HCl and extracted with ethyl ether. The organic phase is dried and evaporated to dryness and the obtained residue is crystallised from benzene (20 ml) affording 0.9 g of 7-methoxy-1,2,3,4-tetrahydronaphthalen-2(S)-carboxylic acid; m.p. 133°-135° C.; [α]=-45.1° (c=1.4%, CHCl3). To determine its absolute configuration, the thus obtained product is converted into the corresponding 2-amino-7-methoxy-1,2,3,4 -tetrahydronaphthalene by the Curtius reaction.
Reaction SMILES: C(OC(=O)[NH:7][C:8]1[CH:13]=[CH:12][C:11]([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=2[F:20])=[CH:10][C:9]=1[NH:21][C:22](=[O:40])[CH2:23][C:24]([C:26]1[CH:31]=[CH:30][CH:29]=[C:28]([C:32]2[N:33]=[N:34][C:35]([O:38][CH3:39])=[CH:36][CH:37]=2)[CH:27]=1)=O)(C)(C)C.C(O)(C(F)(F)F)=O>C(Cl)Cl>[F:20][C:15]1[CH:16]=[CH:17][CH:18]=[CH:19][C:14]=1[C:11]1[CH:12]=[CH:13][C:8]2[N:7]=[C:24]([C:26]3[CH:31]=[CH:30][CH:29]=[C:28]([C:32]4[N:33]=[N:34][C:35]([O:38][CH3:39])=[CH:36][CH:37]=4)[CH:27]=3)[CH2:23][C:22](=[O:40])[NH:21][C:9]=2[CH:10]=1
Reactant: COc1ccc(-c2cccc(C(=O)CC(=O)Nc3cc(-c4ccccc4F)ccc3NC(=O)OC(C)(C)C)c2)nn1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: COc1ccc(-c2cccc(C3=Nc4ccc(-c5ccccc5F)cc4NC(=O)C3)c2)nn1

Procedure:
The title compound was prepared from (2′-fluoro-3-{3-[3-(6-methoxy-pyridazin-3-yl)-phenyl]-3-oxo-propionylamino}-biphenyl-4-yl)-carbamic acid tert-butyl ester (Example M37) (308 mg, 0.55 mmol) by treatment with TFA in CH2Cl2 according to the general procedure N. Obtained as a light yellow solid (178 mg).
Reaction SMILES: [C:1]([C:5]1[CH:10]=[CH:9][C:8]([CH2:11][OH:12])=[CH:7][C:6]=1[O:13][CH3:14])([CH3:4])([CH3:3])[CH3:2].C1C(=O)N([Br:22])C(=O)C1>C(Cl)(Cl)(Cl)Cl.OS([O-])=O.[Na+]>[Br:22][C:9]1[CH:10]=[C:5]([C:1]([CH3:4])([CH3:2])[CH3:3])[C:6]([O:13][CH3:14])=[CH:7][C:8]=1[CH2:11][OH:12]
Reactant: O=C1CCC(=O)N1Br
Reactant: COc1cc(CO)ccc1C(C)(C)C
Agent: O=S([O-])O
Agent: [Na+]
Solvent: ClC(Cl)(Cl)Cl
Product: COc1cc(CO)c(Br)cc1C(C)(C)C
Reaction time: 0.25 h
Yield: 99.2 %

Procedure:
step b—To a solution of 345 (2.08 g, 10.70 mmol) in CCl4 (75 mL) was added NBS (2.10 g, 11.80 mmol). The reaction was stirred for 15 min then diluted with a cold 10% aqueous NaHSO3. The reaction mixture was extracted with DCM. The organic extract was washed with brine, dried (MgSO4), filtered and concentrated. The residue was taken up in hexanes (80 mL) and then concentrated to afford 2.9 g (100%) of 344a as a white solid.
Reaction SMILES: C[O:2][C:3](=[O:20])/[CH:4]=[CH:5]/[CH:6]=[C:7](/[C:13]1[CH:18]=[CH:17][C:16]([F:19])=[CH:15][CH:14]=1)\[CH2:8][CH2:9][CH2:10][CH2:11][CH3:12].[OH-].[Na+]>CO>[F:19][C:16]1[CH:15]=[CH:14][C:13](/[C:7](/[CH2:8][CH2:9][CH2:10][CH2:11][CH3:12])=[CH:6]/[CH:5]=[CH:4]/[C:3]([OH:20])=[O:2])=[CH:18][CH:17]=1
Reactant: CCCCC/C(=C\C=C\C(=O)OC)c1ccc(F)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: CCCCC/C(=C\C=C\C(=O)O)c1ccc(F)cc1
Yield: 80.9 %

Procedure:
As described in Example 99, (E,E)-5-(4-fluorophenyl)-2,4-decadienoic acid methyl ester (6.5 g) was saponified in a refluxing mixture of methanol (30 mL) and 2N NaOH (30 mL). After 2 hours the crude acid was isolated in the usual way and crystallized from hexane to yield 4.99 g of (E,E)-5-(4-fluorophenyl)-2,4-decadienoic acid, mp 116.5°-117.5° C.
Reaction SMILES: [CH:1]1([C:7](Cl)=[O:8])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[CH3:10][O:11][C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=1[N:18]1[CH2:23][CH2:22][N:21]([CH2:24][CH:25]2[CH2:30][CH2:29][CH2:28][NH:27][CH2:26]2)[CH2:20][CH2:19]1.C(N(CC)CC)C>C(Cl)Cl>[CH:1]1([C:7]([N:27]2[CH2:28][CH2:29][CH2:30][CH:25]([CH2:24][N:21]3[CH2:22][CH2:23][N:18]([C:13]4[CH:14]=[CH:15][CH:16]=[CH:17][C:12]=4[O:11][CH3:10])[CH2:19][CH2:20]3)[CH2:26]2)=[O:8])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: O=C(Cl)C1CCCCC1
Reactant: COc1ccccc1N1CCN(CC2CCCNC2)CC1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: COc1ccccc1N1CCN(CC2CCCN(C(=O)C3CCCCC3)C2)CC1
Temperature: 0 °C
Reaction time: 16 h
Yield: 80.8 %

Procedure:
Cyclohexanecarbonyl chloride (0.506 g, 3.5 mmol) was added to a solution of 1-(2-methoxyphenyl)-4-piperidin-3-ylmethyl-piperazine (1.0 g, 3.5 mmol) from example 6 and triethylamine (2 equivalents, 1 mL) in CH2Cl2 (30 mL) and the solution stirred under N2 at 0° C. for 16 hours. The mixture was concentrated under vacuum, water (50 mL) added and the product extracted into ethyl acetate (3×25 mL). The combined organics were washed with water (25 mL), saturated sodium bicarbonate (20 mL) and brine (25 mL). After drying over sodium sulfate, filtration and concentration under vacuum afforded the titled product (1.13 g, 81% yield). An ethanolic solution of the product was treated with a hot ethanolic solution of fumaric acid (1.0 equivalents) and afforded the fumarate salt of the titled compound as a light yellow colored solid.
Reaction SMILES: Cl[C:2]1[N:7]=[N:6][C:5]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)=[N:4][C:3]=1[CH2:14][C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1.[Cl:21][C:22]1[CH:23]=[C:24]([N:28]2[CH2:33][CH2:32][NH:31][CH2:30][CH2:29]2)[CH:25]=[CH:26][CH:27]=1>C(O)CCC>[C:8]1([C:5]2[N:6]=[N:7][C:2]([N:31]3[CH2:30][CH2:29][N:28]([C:24]4[CH:25]=[CH:26][CH:27]=[C:22]([Cl:21])[CH:23]=4)[CH2:33][CH2:32]3)=[C:3]([CH2:14][C:15]3[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=3)[N:4]=2)[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1
Reactant: Clc1cccc(N2CCNCC2)c1
Reactant: Clc1nnc(-c2ccccc2)nc1Cc1ccccc1
Solvent: CCCCO
Product: Clc1cccc(N2CCN(c3nnc(-c4ccccc4)nc3Cc3ccccc3)CC2)c1
Temperature: 120 °C

Procedure:
Suspend 2 mmol (570 mg) of 6-chloro-5-benzyl-3-phenyl-1,2,4-triazine obtained in Step A of Example 57 in 40 ml of butanol, and add 4 equivalents of 1-(3-chlorophenyl)piperazine. Heat for 12 hours at 120° C., concentrate the solution, take up in ether, filter the resulting precipitate and recrystallise it from ethanol.
Reaction SMILES: [CH2:1]([N:4]1[C:8]2[CH:9]=[C:10]([N+:14]([O-])=O)[C:11]([F:13])=[CH:12][C:7]=2[N:6]=[C:5]1[C:17]([F:20])([F:19])[F:18])[C:2]#[CH:3].C(OCC)(=O)C.O>C(O)(=O)C.[Fe]>[CH2:1]([N:4]1[C:8]2[CH:9]=[C:10]([NH2:14])[C:11]([F:13])=[CH:12][C:7]=2[N:6]=[C:5]1[C:17]([F:19])([F:20])[F:18])[C:2]#[CH:3]
Reactant: C#CCn1c(C(F)(F)F)nc2cc(F)c([N+](=O)[O-])cc21
Agent: [Fe]
Solvent: CC(=O)O
Solvent: O
Solvent: CCOC(C)=O
Product: C#CCn1c(C(F)(F)F)nc2cc(F)c(N)cc21
Temperature: 60 °C
Yield: 101.1 %

Procedure:
A stirred mixture of 1.5 grams (0.005 mole) of 1-(2-propyn-1-yl)-2-trifluoromethyl-5-fluoro-6-nitrobenzimidazole, 1.0 gram (0.018 mole) of iron powder, and 10 mL of ethyl acetate in 35 mL of acetic acid was heated at 60° C. for two hours. The reaction mixture was then poured into water, and the mixture was extracted thoroughly with portions of ethyl acetate. The combined extracts were washed with aqueous solutions saturated with sodium bicarbonate and sodium chloride. The organic layer was dried with sodium sulfate and filtered. The filtrate was concentrated under reduced pressure to a residual oil, which was triturated with water, and the resultant solid collected by filtration. The solid was dried, yielding 1.3 grams of 1-(2-propyn-1-yl)-2-trifluoromethyl-5-fluoro-6-aminobenzimidazole. The NMR spectrum was consistent with the proposed structure.
Reaction SMILES: [CH2:1]([O:8][C:9]1[C:14]([CH2:15][CH3:16])=[CH:13][C:12](B(O)O)=[C:11]([O:20][CH3:21])[CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Br[C:23]1[CH:28]=[CH:27][CH:26]=[C:25]([N:29]2[C:33]([CH3:34])=[CH:32][CH:31]=[C:30]2[CH3:35])[N:24]=1.C(=O)([O-])[O-].[Na+].[Na+].CO.O>C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.C(O)C.O.O1CCCC1>[CH2:1]([O:8][C:9]1[C:14]([CH2:15][CH3:16])=[CH:13][C:12]([C:23]2[CH:28]=[CH:27][CH:26]=[C:25]([N:29]3[C:33]([CH3:34])=[CH:32][CH:31]=[C:30]3[CH3:35])[N:24]=2)=[C:11]([O:20][CH3:21])[CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CCc1cc(B(O)O)c(OC)cc1OCc1ccccc1
Reactant: Cc1ccc(C)n1-c1cccc(Br)n1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CCO
Solvent: O
Solvent: C1CCOC1
Product: CCc1cc(-c2cccc(-n3c(C)ccc3C)n2)c(OC)cc1OCc1ccccc1

Procedure:
Reacting the 4-benzyloxy-5-ethyl-2-methoxy-phenylboronic acid (5) with 2-bromo-6-(2,5-dimethylpyrrol-1-yl)pyridine, sodium carbonate and tetrakis(triphenylphosphine)palladium(0) in a polar solvent such as methanol/water, ethanol/water, or tetrahydrofuran (THF)/water, preferably ethanol/water, at a temperature from about room temperature to about the reflux temperature of the reaction mixture, preferably at about the reflux temperature, yields 2-(4-benzyloxy-5-ethyl-2-methoxy-phenyl)-6-(2,5-dimethyl-pyrrol-1-yl)-pyridine (6).
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:20])[CH2:5][CH:6]([N:10]1[C:14]2[CH:15]=[CH:16][CH:17]=[CH:18][C:13]=2[NH:12][C:11]1=[O:19])[CH2:7][CH2:8][CH3:9])[CH3:2].[I-].[Cl:22][C:23]1[CH:31]=[C:30]([Cl:32])[C:29]2[N:25]([C:26]([CH3:37])=[CH:27][C:28]=2[CH2:33]N(C)C)[CH:24]=1.C([O-])([O-])=O.[K+].[K+].O>CN(C=O)C>[CH2:1]([O:3][C:4](=[O:20])[CH2:5][CH:6]([N:10]1[C:14]2[CH:15]=[CH:16][CH:17]=[CH:18][C:13]=2[N:12]([CH2:33][C:28]2[CH:27]=[C:26]([CH3:37])[N:25]3[C:29]=2[C:30]([Cl:32])=[CH:31][C:23]([Cl:22])=[CH:24]3)[C:11]1=[O:19])[CH2:7][CH2:8][CH3:9])[CH3:2]
Reactant: CCCC(CC(=O)OCC)n1c(=O)[nH]c2ccccc21
Reactant: Cc1cc(CN(C)C)c2c(Cl)cc(Cl)cn12
Agent: O=C([O-])[O-]
Agent: [I-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: CCCC(CC(=O)OCC)n1c(=O)n(Cc2cc(C)n3cc(Cl)cc(Cl)c23)c2ccccc21
Yield: 38 %

Procedure:
To a solution of 3-(2-Oxo-2,3-dihydro-benzimidazol-1-yl)-hexanoic acid ethyl ester (30 mg, 0.11 mmol) in DMF (10 mL) were added (6,8-Dichloro-3-methyl-indolizin-1-ylmethyl)-dimethyl-amine iodide, CAS: (6,8-Dichloro-3-methyl-indolizin-1-ylmethyl)-dimethyl-amine iodide (65 mg, 0.16 mmol). and K2CO3 (45 mg, 0.33 mmol) at room temperature under nitrogen atmosphere. The solution was heated to 100 C for 2 hours. The solution was cooled down and water was added. The solution was extracted with EtOAc and the combined organic layer was dried with MgSO4. The solution was filtered and the filtrate was concentrated. The residue was purified by CombiFlash with 20% EtOAc in Hexane as the eluent to afford the desirable product 3-[3-(6,8-Dichloro-3-methyl-indolizin-1-ylmethyl)-2-oxo-2,3-dihydro-benzimidazol-1-yl]-hexanoic acid ethyl ester (20 mg, 38%) as a yellow foam.
Reaction SMILES: Br[C:2]1[N:3]=[C:4]([O:10][CH3:11])[C:5]([NH2:9])=[N:6][C:7]=1[CH3:8].C([O-])=O.[NH4+]>CO.[Pd]>[CH3:11][O:10][C:4]1[C:5]([NH2:9])=[N:6][C:7]([CH3:8])=[CH:2][N:3]=1
Reactant: COc1nc(Br)c(C)nc1N
Agent: [Pd]
Agent: O=C[O-]
Agent: [NH4+]
Solvent: CO
Product: COc1ncc(C)nc1N
Temperature: 25 °C
Yield: 86.2 %

Procedure:
To a solution of 5-bromo-3-methoxy-6-methyl-2-pyrazinamine (Example 118c) (0.8 g) and ammonium formate (0.4 g) in methanol (20 mL) was added palladium on carbon (0.2 g) and the reaction mixture heated at reflux for 5h. After cooling to room temperature, the reaction mixture was filtered through a plug of celite, and the filtrate evaporated. The residue was partitioned between dichloromethane and water, and the organic phase dried (MgSO4), filtered and evaporated to give the title compound as a white solid (0.44 g).