Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([O:5][C:6](=[O:25])[NH:7][C:8]1[CH:13]=[C:12]([N:14]([CH2:16][CH:17]([CH3:19])[CH3:18])[CH3:15])[C:11]([C:20]([F:23])([F:22])[F:21])=[CH:10][C:9]=1[NH2:24])([CH3:4])([CH3:3])[CH3:2].C([O:30][C:31](=O)[CH2:32][C:33](=[O:45])[C:34]1[CH:39]=[CH:38][CH:37]=[C:36]([N:40]2[CH:44]=[CH:43][N:42]=[N:41]2)[CH:35]=1)(C)(C)C>>[C:1]([O:5][C:6](=[O:25])[NH:7][C:8]1[CH:13]=[C:12]([N:14]([CH2:16][CH:17]([CH3:19])[CH3:18])[CH3:15])[C:11]([C:20]([F:23])([F:22])[F:21])=[CH:10][C:9]=1[NH:24][C:31](=[O:30])[CH2:32][C:33](=[O:45])[C:34]1[CH:39]=[CH:38][CH:37]=[C:36]([N:40]2[CH:44]=[CH:43][N:42]=[N:41]2)[CH:35]=1)([CH3:3])([CH3:4])[CH3:2]
Reactant: CC(C)(C)OC(=O)CC(=O)c1cccc(-n2ccnn2)c1
Reactant: CC(C)CN(C)c1cc(NC(=O)OC(C)(C)C)c(N)cc1C(F)(F)F
Product: CC(C)CN(C)c1cc(NC(=O)OC(C)(C)C)c(NC(=O)CC(=O)c2cccc(-n3ccnn3)c2)cc1C(F)(F)F

Procedure:
The title compound was prepared from [2-amino-5-(isobutyl-methyl-amino)-4-trifluoromethyl-phenyl]-carbamic acid tert-butyl ester (Example J41) (460 mg, 1.27 mmol) and 3-oxo-3-(3-[1,2,3]triazol-1-yl-phenyl)-propionic acid tert-butyl ester (Example K23) (364 mg, 1.27 mmol) according to the general procedure M. Obtained as a light brown oil (480 mg, 69%).
Reaction SMILES: [C:1]([C@H:5]1[CH2:10][CH2:9][C@H:8]([O:11][C:12]2[C:13]([C:38]([F:41])([F:40])[F:39])=[C:14]3[C:19](=[CH:20][CH:21]=2)[CH2:18][C@@H:17]([C@:22]([NH:30]C(=O)OC(C)(C)C)([CH3:29])[CH2:23][O:24][P:25]([OH:28])([OH:27])=[O:26])[CH2:16][CH2:15]3)[CH2:7][CH2:6]1)([CH3:4])([CH3:3])[CH3:2].FC(F)(F)C(O)=O.C(Cl)Cl>>[P:25]([OH:27])([OH:28])([O:24][CH2:23][C@:22]([NH2:30])([C@H:17]1[CH2:16][CH2:15][C:14]2[C:19](=[CH:20][CH:21]=[C:12]([O:11][C@H:8]3[CH2:9][CH2:10][C@H:5]([C:1]([CH3:2])([CH3:3])[CH3:4])[CH2:6][CH2:7]3)[C:13]=2[C:38]([F:39])([F:41])[F:40])[CH2:18]1)[CH3:29])=[O:26]
Reactant: CC(C)(C)OC(=O)N[C@@](C)(COP(=O)(O)O)[C@H]1CCc2c(ccc(O[C@H]3CC[C@H](C(C)(C)C)CC3)c2C(F)(F)F)C1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CC(C)(C)[C@H]1CC[C@H](Oc2ccc3c(c2C(F)(F)F)CC[C@H]([C@@](C)(N)COP(=O)(O)O)C3)CC1
Reaction time: 1 h

Procedure:
tert-Butyl (R)-2-((S)-6-(trans-4-tert-butylcyclohexyloxy)-5-(trifluoromethyl)-1,2,3,4-tetrahydronaphthalen-2-yl)-1-(phosphonooxy)propan-2-ylcarbamate (22.0 mg, 0.0000362 mol) was dissolved in trifluoroacetic Acid (1.0 mL, 0.013 mol) and methylene chloride (1.0 mL, 0.016 mol) was added and the mixture was stirred for 1 h. Concentration and lypholyzing gave pure (R)-2-amino-2-((S)-6-(trans-4-tert-butylcyclohexyloxy)-5-(trifluoromethyl)-1,2,3,4-tetrahydronaphthalen-2-yl)propyl dihydrogen phosphate as a white solid (18.0 mg, 98%). LCMS: Rf=1.74 min 508.41 [M+1]. 1H NMR (400 MHz, MeOD) δ=7.25 (d, J=9.0 Hz, 1H), 7.00 (d, J=8.6 Hz, 1H), 4.23 (dd, J=4.9, 11.2 Hz, 1H), 4.18 (m, 1H), 4.03 (dd, J=4.1, 11.3 Hz, 1H), 3.22-2.82 (m, 3H), 2.77-2.64 (m, 1H), 2.15 (d, J=12.6 Hz, 2H), 2.02 (d, J=10.6 Hz, 1H), 1.87 (d, J=13.2 Hz, 2H), 1.56-1.35 (m, 2H), 1.33 (s, 3H), 1.24-1.01 (m, 2H), is 0.89 (s, 9H).
Reaction SMILES: [OH:1][CH2:2][C:3]([C:6]1[S:10][C:9]([NH:11][C:12](=[O:29])[CH:13]([NH:17][C:18](=[O:28])[CH2:19][C:20]2[CH:25]=[C:24]([F:26])[CH:23]=[C:22]([F:27])[CH:21]=2)[CH2:14][CH2:15][CH3:16])=[N:8][N:7]=1)([CH3:5])[CH3:4].CC(OI1(OC(C)=O)(OC(C)=O)OC(=O)C2C=CC=CC1=2)=O>C(Cl)Cl>[CH3:4][C:3]([C:6]1[S:10][C:9]([NH:11][C:12](=[O:29])[CH:13]([NH:17][C:18](=[O:28])[CH2:19][C:20]2[CH:25]=[C:24]([F:26])[CH:23]=[C:22]([F:27])[CH:21]=2)[CH2:14][CH2:15][CH3:16])=[N:8][N:7]=1)([CH3:5])[CH:2]=[O:1]
Reactant: CCCC(NC(=O)Cc1cc(F)cc(F)c1)C(=O)Nc1nnc(C(C)(C)CO)s1
Agent: CC(=O)OI1(OC(C)=O)(OC(C)=O)OC(=O)c2ccccc21
Solvent: ClCCl
Product: CCCC(NC(=O)Cc1cc(F)cc(F)c1)C(=O)Nc1nnc(C(C)(C)C=O)s1
Temperature: 25 °C
Reaction time: 3 h
Yield: 5.1 %

Procedure:
A mixture of 2-[2-(3,5-difluoro-phenyl)-acetylamino]-pentanoic acid [5-(2-hydroxy-1,1-dimethyl-ethyl)-[1,3,4]thiadiazol-2-yl]-amide (40 mg, 0.93 mmol) and Dess-Martin periodinane (1,1,1-tris(acetyloxy)-1,1-dihydro-1,2-benziodoxol-3-(1H)-one) (90 mg) in methylene chloride (3 ml) was stirred at rt for 3 hr. The mixture was quenched with water, methylene chloride and filtered through celite. The filtrate was transferred to separatory funnel and the organic layer was separated, dried and concentrated to give 42 mg of crude material. The crude material was purified by silica gel column chromatography using methylene chloride to 1% methanol in methylene chloride as eluent to give 20 mg of the title compound as a tan glass solid. APCI M+1=425.2.
Reaction SMILES: C(OC([NH:8][C@@H:9]([C:16](=[O:18])[NH2:17])[CH2:10][CH2:11][C:12]([O:14][CH3:15])=[O:13])=O)(C)(C)C.[F:19][C:20]([F:25])([F:24])[C:21]([OH:23])=[O:22]>>[F:19][C:20]([F:25])([F:24])[C:21]([OH:23])=[O:22].[NH2:8][C@@H:9]([C:16](=[O:18])[NH2:17])[CH2:10][CH2:11][C:12]([O:14][CH3:15])=[O:13]
Reactant: COC(=O)CC[C@@H](NC(=O)OC(C)(C)C)C(N)=O
Solvent: O=C(O)C(F)(F)F
Product: COC(=O)CC[C@@H](N)C(N)=O

Procedure:
Methyl t-butyloxycarbonyl-D-isoglutaminate (651 mg, 2.5 mmol) was treated with cold trifluoroacetic acid (5 ml) in a similar manner to that described in Example 33 (IV) to obtain methyl D-isoglutaminate trifluoroacetic acid salt. This salt was then dissolved in ethyl acetate (5 ml), and neutralized by adding TEA (0.35 ml) with cooling. To the resulting solution was added a solution of t-butyloxycarbonyl-O-benzyl-L-serine HONB active ester in ethyl acetate (5 ml), and the reaction was carried out at room temperature for 16 hours. The work-up similar to that described in Example 33 (I) and recrystallization from ethyl acetate/ether gave methyl t-butyloxycarbonyl-O-benzyl-L-seryl-D-isoglutaminate (0.78 g). m.p. 103°-104° C. [α]D22 +7.0 (C 0.5, ethanol). Rf5 =0.40.
Reaction SMILES: [N:1]1[N:2]=[CH:3][N:4]([CH2:6][CH2:7][O:8][C:9]2[CH:14]=[CH:13][C:12]([NH2:15])=[CH:11][CH:10]=2)[CH:5]=1.[Cl:16][C:17]1[CH:22]=[C:21]([C:23]([F:26])([F:25])[F:24])[CH:20]=[CH:19][C:18]=1[C:27]#[C:28][C:29](O)=[O:30]>ClCCl.CO>[N:1]1[N:2]=[CH:3][N:4]([CH2:6][CH2:7][O:8][C:9]2[CH:14]=[CH:13][C:12]([NH:15][C:29](=[O:30])[C:28]#[C:27][C:18]3[CH:19]=[CH:20][C:21]([C:23]([F:25])([F:24])[F:26])=[CH:22][C:17]=3[Cl:16])=[CH:11][CH:10]=2)[CH:5]=1
Reactant: O=C(O)C#Cc1ccc(C(F)(F)F)cc1Cl
Reactant: Nc1ccc(OCCn2cnnc2)cc1
Solvent: CO
Solvent: ClCCl
Product: O=C(C#Cc1ccc(C(F)(F)F)cc1Cl)Nc1ccc(OCCn2cnnc2)cc1

Procedure:
Prepared analogously to Example 2.3.f. from 4-(2-[1.2.4]triazol-4-ylethoxy)phenylamine and (2-chloro-4-trifluoromethylphenyl)propynoic acid. Yield: 51 mg (39.4% of theory); melting point: 223° C.-227° C.; C20H14ClF3N4O2 (M=434.80); calc.: molecular ion peak (M+H)+: 435/437; found: molecular ion peak (M+H)+: 435/437; Rf value: 0.31 (silica gel, dichloromethane/methanol (9:1)).
Reaction SMILES: [CH2:1]([C@@H:7]1[CH2:11][O:10]C(C)(C)[O:8]1)[CH2:2]/[CH:3]=[CH:4]\[CH2:5][CH3:6]>CC(O)=O>[CH2:11]([OH:10])[C@H:7]([OH:8])[CH2:1][CH2:2]/[CH:3]=[CH:4]\[CH2:5][CH3:6]
Reactant: CC/C=C\CC[C@@H]1COC(C)(C)O1
Solvent: CC(=O)O
Product: CC/C=C\CC[C@@H](O)CO

Procedure:
(R,Z)-4-(hex-3-enyl)-2,2-dimethyl-1,3-dioxolane (5.95 g, 32.3 mmol) was stirred in 80% aq. AcOH (50 mL) for 20 h. The mixture was concentrated in vacuo and purified by silica gel chromatography (40% EtOAc in hexanes gradient to 70% EtOAc in hexanes) to give (R,Z)-oct-5-ene-1,2-diol as a clear oil. 1H NMR (400 MHz, CDCl3): δ 5.45 (1H, m), 5.36 (1H, m), 3.75 (1H, m), 3.67 (1H, dd, J=10.8, 2.8 Hz), 3.45 (1H, dd, J=11.2, 7.6 Hz), 2.16 (2H, m), 2.04 (2H, m), 1.50 (2H, m), 0.96 (3H, t, J=7.6 Hz).
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:13]=[CH:12][C:11]([CH2:14][CH2:15][CH3:16])=[CH:10][C:9]=2[F:17])=[C:4]([F:18])[CH:3]=1.[Mg].[CH2:20]([CH:25]1[CH2:30][CH2:29][SiH:28](OC)[CH2:27][CH2:26]1)[CH2:21][CH2:22][CH2:23][CH3:24]>C1COCC1>[CH2:20]([C@H:25]1[CH2:26][CH2:27][Si@H:28]([C:2]2[CH:7]=[CH:6][C:5]([C:8]3[CH:13]=[CH:12][C:11]([CH2:14][CH2:15][CH3:16])=[CH:10][C:9]=3[F:17])=[C:4]([F:18])[CH:3]=2)[CH2:29][CH2:30]1)[CH2:21][CH2:22][CH2:23][CH3:24]
Reactant: CCCCCC1CC[SiH](OC)CC1
Reactant: CCCc1ccc(-c2ccc(Br)cc2F)c(F)c1
Agent: [Mg]
Solvent: C1CCOC1
Product: CCCCC[C@H]1CC[Si@H](c2ccc(-c3ccc(CCC)cc3F)c(F)c2)CC1

Procedure:
6.2 g (20 mmol) of 4-bromo-2,2'-difluoro-4'-propylbiphenyl was dripped into a mixture of 0.5 g of magnesium (21 mmol) and 50 ml of THF to obtain a Grignard's reagent. This solution was then dripped into a 50 ml THF solution of 4.0 g (20 mmol) of 4-n-pentyl-1-methoxy-1-silacyclohexane to obtain 4'-(trans-4-n-pentyl-1-silacyclohexyl)-2,2'-difluoro-4-propylbiphenyl. The silacyclohexane rings of this product were a mixture of trans isomers and cis isomers. They were separated by means of chromatography to obtain 6.4 g of the trans isomers (yield 80%).
Reaction SMILES: [CH3:1][C:2]1S[C:5]([C:7]2[C:20]3[C:11](=[CH:12][C:13]4[C:18]([CH:19]=3)=[C:17]([C:21]3[CH:31]=[CH:30][C:24]([C:25]([O:27][CH2:28][CH3:29])=[O:26])=[CH:23][CH:22]=3)[CH:16]=[CH:15][CH:14]=4)[C:10]([CH3:33])([CH3:32])[CH2:9][CH:8]=2)=[CH:4][CH:3]=1.C[C:35]1C=CC(C2(C=O)C3C(=CC=CC=3)C(C)(C)CC2)=C[N:36]=1.C(OP(C(OC)(OC)CCC1C=CC(C(OCC)=O)=CC=1)(OCC)=O)C.COC(OC)C/C(/C1C=CC(C(OCC)=O)=CC=1)=C\C1C=C2C(C(C)(C)CC=C2C2C=CC(C)=CC=2)=CC=1.Cl[Sn](Cl)(Cl)Cl>ClCCl>[CH3:1][C:2]1[N:36]=[CH:35][C:5]([C:7]2[C:20]3[C:11](=[CH:12][C:13]4[C:18]([CH:19]=3)=[C:17]([C:21]3[CH:31]=[CH:30][C:24]([C:25]([O:27][CH2:28][CH3:29])=[O:26])=[CH:23][CH:22]=3)[CH:16]=[CH:15][CH:14]=4)[C:10]([CH3:33])([CH3:32])[CH2:9][CH:8]=2)=[CH:4][CH:3]=1
Reactant: CCOC(=O)c1ccc(-c2cccc3cc4c(cc23)C(c2ccc(C)s2)=CCC4(C)C)cc1
Reactant: Cc1ccc(C2(C=O)CCC(C)(C)c3ccccc32)cn1
Agent: CCOC(=O)c1ccc(/C(=C/c2ccc3c(c2)C(c2ccc(C)cc2)=CCC3(C)C)CC(OC)OC)cc1
Agent: CCOC(=O)c1ccc(CCC(OC)(OC)P(=O)(OCC)OCC)cc1
Agent: Cl[Sn](Cl)(Cl)Cl
Solvent: ClCCl
Product: CCOC(=O)c1ccc(-c2cccc3cc4c(cc23)C(c2ccc(C)nc2)=CCC4(C)C)cc1

Procedure:
This compound is prepared in accordance with the procedure described for the preparation of ethyl 4-[1(5-methyl-thien-2-yl)3,4-dihydro-4,4-dimethyl-anthracen-8-yl]-benzoate (Compound 3), from 1(2-methyl-pyrid-5-yl)3,4-dihydro-4,4-dimethyl-naphthaldehyde (Compound K) by reaction with ethyl 4-(diethoxyphosphoryl-3,3-dimethoxypropyl)benzoate (Compound D) and proceeding through the intermediate ethyl 4-[1-(2,2-dimethoxyethyl)-2-{1-(tol-4-yl)3,4-dihydro-4,4-dimethyl-naphthalen-7-yl}-(E)-ethen-1-yl]-benzoate which is cyclized by treatment with SnCl4 in dichloromethane to give the title compoud.
Reaction SMILES: [CH2:1]([N:3]([CH2:19][CH3:20])[C:4]([C:6]1[CH:14]=[C:13]2[C:9]([C:10]([CH2:15][C@H:16]([NH2:18])[CH3:17])=[CH:11][NH:12]2)=[CH:8][CH:7]=1)=[O:5])[CH3:2].[CH2:21]([O:28][C:29]1[CH:34]=[CH:33][C:32]([C@@H:35]([O:38][Si:39]([CH2:44][CH3:45])([CH2:42][CH3:43])[CH2:40][CH3:41])[CH2:36]I)=[CH:31][C:30]=1[NH:46][S:47]([CH3:50])(=[O:49])=[O:48])[C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1>C(#N)C>[CH2:19]([N:3]([CH2:1][CH3:2])[C:4]([C:6]1[CH:14]=[C:13]2[C:9]([C:10]([CH2:15][C@H:16]([NH:18][CH2:36][C@@H:35]([C:32]3[CH:33]=[CH:34][C:29]([O:28][CH2:21][C:22]4[CH:23]=[CH:24][CH:25]=[CH:26][CH:27]=4)=[C:30]([NH:46][S:47]([CH3:50])(=[O:49])=[O:48])[CH:31]=3)[O:38][Si:39]([CH2:40][CH3:41])([CH2:42][CH3:43])[CH2:44][CH3:45])[CH3:17])=[CH:11][NH:12]2)=[CH:8][CH:7]=1)=[O:5])[CH3:20]
Reactant: CC[Si](CC)(CC)O[C@@H](CI)c1ccc(OCc2ccccc2)c(NS(C)(=O)=O)c1
Reactant: CCN(CC)C(=O)c1ccc2c(C[C@@H](C)N)c[nH]c2c1
Solvent: CC#N
Product: CCN(CC)C(=O)c1ccc2c(C[C@@H](C)NC[C@H](O[Si](CC)(CC)CC)c3ccc(OCc4ccccc4)c(NS(C)(=O)=O)c3)c[nH]c2c1
Temperature: 110 °C
Reaction time: 21 h
Yield: 36.7 %

Procedure:
To a solution of (R)-3-(2-aminopropyl)-1H-indole-6-carboxylic acid diethylamide (20.0 mg, 0.0742 mmol) in acetonitrile (1.0 ml) is added (R)—N-[2-benzyloxy-5-(2-iodo-1-triethylsilyloxyethyl)phenyl]-methanesulfonamide (41.1 mg, 0.0742 mmol), and the mixture is stirred at 110° C. for 21 hours in a sealed vessel. The reaction solution is concentrated under reduced pressure, and the residue is purified by preparative TLC (a saturated ammonia solution in chloroform/methanol=50/1) to give 3-{(2R)-2-[2-(4-benzyloxy-3-methanesulfonylamino-phenyl)-(2R)-2-(triethylsilyloxy) ethylamino]propyl}-1H-indole-6-carboxylic acid diethylamide (19.2 mg, 0.0272 mmol, 37%).
Reaction SMILES: ClC1C=C(N[C@H](C2CC2)C(N[C@@H]2CCCN(C(OC(C)(C)C)=O)C2)=O)C=C(F)C=1.[Cl:30][C:31]1[CH:32]=[C:33]([NH:38][CH2:39][C:40]([NH:42][C@@H:43]2[CH2:48][CH2:47][CH2:46][N:45]([C:49](OC(C)(C)C)=O)[CH2:44]2)=[O:41])[CH:34]=[C:35]([Cl:37])[CH:36]=1.NC1C(C#N)=C(Cl)N=CN=1.ClC1[C:68]2[CH2:75][C:74](=[O:76])[NH:73][C:69]=2[N:70]=[CH:71][N:72]=1>>[Cl:37][C:35]1[CH:34]=[C:33]([NH:38][CH2:39][C:40]([NH:42][C@@H:43]2[CH2:48][CH2:47][CH2:46][N:45]([C:49]3[C:68]4[CH2:75][C:74](=[O:76])[NH:73][C:69]=4[N:70]=[CH:71][N:72]=3)[CH2:44]2)=[O:41])[CH:32]=[C:31]([Cl:30])[CH:36]=1
Reactant: CC(C)(C)OC(=O)N1CCC[C@@H](NC(=O)CNc2cc(Cl)cc(Cl)c2)C1
Reactant: O=C1Cc2c(Cl)ncnc2N1
Agent: CC(C)(C)OC(=O)N1CCC[C@@H](NC(=O)[C@H](Nc2cc(F)cc(Cl)c2)C2CC2)C1
Agent: N#Cc1c(N)ncnc1Cl
Product: O=C1Cc2c(ncnc2N2CCC[C@@H](NC(=O)CNc3cc(Cl)cc(Cl)c3)C2)N1

Procedure:
The title compound of Example 146 was prepared in similar manner as described in Example 134 except the key intermediate (R)-tert-butyl 3-((R)-2-(3-chloro-5-fluorophenylamino)-2-cyclopropylacetamido)piperidine-1-carboxylate was replaced with (R)-tert-butyl 3-(2-(3,5-dichlorophenylamino)acetamido)piperidine-1-carboxylate and the 4-amino-6-chloropyrimidine-5-carbonitrile was substituted for 4-chloro-5H-pyrrolo[2,3-d]pyrimidin-6(7H)-one. 1H NMR (300 MHz, DMSO-d6) δ 10.99 (s, 1H), 8.17 (s, 1H), 8.03 (d, J=7.18 Hz, 1H), 6.62 (t, J=1.70 Hz, 1H), 6.54 (d, J=1.89 Hz, 2H), 4.13 (d, J=12.46 Hz, 3H), 3.69 (dd, J=11.33, 15.86 Hz, 10H), 2.84-3.22 (m, 2H), 1.82 (d, J=3.40 Hz, 1H), 1.66-1.76 (m, 1H), 1.43-1.63 (m, 2H). EIMS (m/z): calcd. for C19H20Cl2N6O (M+1H) 435. found 435.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:26])[CH2:4][C:5]1[C:14]([CH3:15])=[C:13](B2OC(C)(C)C(C)(C)O2)[C:12]2[C:7](=[CH:8][CH:9]=[C:10]([Cl:25])[CH:11]=2)[CH:6]=1.Br[C:28]1[CH:33]=[CH:32][C:31]([S:34][C:35]2[CH:40]=[CH:39][C:38]([O:41][C:42]([F:45])([F:44])[F:43])=[CH:37][CH:36]=2)=[CH:30][CH:29]=1.C(=O)(O)[O-].[Na+].O>C(COC)OC.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>[CH3:1][O:2][C:3](=[O:26])[CH2:4][C:5]1[C:14]([CH3:15])=[C:13]([C:28]2[CH:29]=[CH:30][C:31]([S:34][C:35]3[CH:40]=[CH:39][C:38]([O:41][C:42]([F:44])([F:43])[F:45])=[CH:37][CH:36]=3)=[CH:32][CH:33]=2)[C:12]2[C:7](=[CH:8][CH:9]=[C:10]([Cl:25])[CH:11]=2)[CH:6]=1
Reactant: FC(F)(F)Oc1ccc(Sc2ccc(Br)cc2)cc1
Reactant: COC(=O)Cc1cc2ccc(Cl)cc2c(B2OC(C)(C)C(C)(C)O2)c1C
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: O
Solvent: COCCOC
Product: COC(=O)Cc1cc2ccc(Cl)cc2c(-c2ccc(Sc3ccc(OC(F)(F)F)cc3)cc2)c1C
Yield: 46.4 %

Procedure:
A stirred solution of [6-chloro-3-methyl-4-(4,4,5,5-tetra methyl-[1,3,2]-dioxaborolan-2-yl)-naphthalen-2-yl]-acetic acid methyl ester (0.2 g, 0.53 mmol) in dimethoxyethane (5 mL) was purged with argon for 5 minutes at room temperature. Tetrakis(triphenylphosphine)palladium(0) (0.031 g, 0.027 mmol), crude 1-bromo-4-(4-(trifluoro-methoxy)phenylsulfanyl)benzene (0.334 g) and 1.0 M aqueous sodium bicarbonate (5 mL, 5 mmol) were added simultaneously to the reaction mixture under argon. The reaction mixture was refluxed for 2 hours and then brought to room temperature. Water was added and the resulting mixture was extracted twice with ethyl acetate. The combined organic extracts were washed with water and brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure to give the crude product, which was finally purified using flash chromatography (0-3% ethyl acetate in hexanes) to obtain {6-chloro-3-methyl-4-[4-(4-trifluoromethoxyphenylsulfanyl)-phenyl]-naphthalen-2-yl}-acetic acid methyl ester (0.127 g, 44%) as a solid.
Reaction SMILES: Cl.[CH:2]1([C:8]2[C:16]3[C:11](=[CH:12][C:13]([C:17]([O:19][CH3:20])=[O:18])=[CH:14][CH:15]=3)[NH:10][C:9]=2[C:21]2[CH:26]=[CH:25][C:24]([O:27][CH3:28])=[CH:23][C:22]=2[O:29]COC)[CH2:7][CH2:6][CH2:5][CH2:4][CH2:3]1>CO>[CH:2]1([C:8]2[C:16]3[C:11](=[CH:12][C:13]([C:17]([O:19][CH3:20])=[O:18])=[CH:14][CH:15]=3)[NH:10][C:9]=2[C:21]2[CH:26]=[CH:25][C:24]([O:27][CH3:28])=[CH:23][C:22]=2[OH:29])[CH2:7][CH2:6][CH2:5][CH2:4][CH2:3]1
Reactant: COCOc1cc(OC)ccc1-c1[nH]c2cc(C(=O)OC)ccc2c1C1CCCCC1
Agent: Cl
Solvent: CO
Product: COC(=O)c1ccc2c(C3CCCCC3)c(-c3ccc(OC)cc3O)[nH]c2c1
Temperature: 80 °C
Reaction time: 2 h
Yield: 95 %

Procedure:
3 M HCl (aq) (4 eq) was added to a stirred mixture of methyl 3-cyclohexyl-2-[4-methoxy-2-(methoxymethoxy)phenyl]-1H-indole-6-carboxylate in MeOH (0.05 M) and the mixture was stirred at 80° C. for 2 h. The mixture was cooled, solvents were concentrated in vacuo and the residue diluted with EtOAc, washed with sat. aq. NaHCO3, brine, dried (Na2SO4), filtered and the solvent was removed in vacuo to afford the title compound (95%). (ES+) m/z 380 (M+H)+.
Reaction SMILES: Br[C:2]1[S:6][CH:5]=[N:4][CH:3]=1.[CH3:7][NH:8][CH2:9][CH2:10][NH2:11]>C(O)(C)C.[Cu].[Cu]Cl>[CH3:7][N:8]([C:2]1[S:6][CH:5]=[N:4][CH:3]=1)[CH2:9][CH2:10][NH2:11]
Reactant: CNCCN
Reactant: Brc1cncs1
Agent: Cl[Cu]
Agent: [Cu]
Solvent: CC(C)O
Product: CN(CCN)c1cncs1
Yield: 6.7 %

Procedure:
37 mg (0.6 mmol) copper and 172 mg (1.7 mmol) copper(I) chloride were added to a solution of 1.15 ml (10.5 mmol) 5-bromothiazol and 5.6 ml (63.0 mmol) N-methyl-ethylene-diamine in isopropanol (6 ml). Heating was subsequently performed for 1 h to 70° C. Concentration was subsequently performed in a vacuum. The residue was received with brine (40 ml) and DCM (20 ml) and the phases were separated. The organic phase was dried over MgSO4, filtered and concentrated in a vacuum. CC (DCE/EtOH/conc. NH4OH 5:1:0.06) was performed with the residue, whereby 104 mg (0.7 mmol, 6%) N1-methyl-N1-(thiazol-5-yl)ethane-1,2-diamine was obtained.
Reaction SMILES: [CH3:1][CH:2]1[C:15]2[C:14]3[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=3[NH:8][C:7]=2[C:6]([C:16]([O:18][CH2:19][CH3:20])=[O:17])=[CH:5][NH:4][CH2:3]1.[F:21][C:22]1[CH:30]=[CH:29][C:25]([C:26](Cl)=[O:27])=[CH:24][CH:23]=1>>[F:21][C:22]1[CH:30]=[CH:29][C:25]([C:26]([N:4]2[CH2:3][CH:2]([CH3:1])[C:15]3[C:14]4[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=4[NH:8][C:7]=3[C:6]([C:16]([O:18][CH2:19][CH3:20])=[O:17])=[CH:5]2)=[O:27])=[CH:24][CH:23]=1
Reactant: CCOC(=O)C1=CNCC(C)c2c1[nH]c1ccccc21
Reactant: O=C(Cl)c1ccc(F)cc1
Product: CCOC(=O)C1=CN(C(=O)c2ccc(F)cc2)CC(C)c2c1[nH]c1ccccc21

Procedure:
In a manner similar to Example 2, the title compound was prepared from ethyl 1-methyl-1,2,3,6-tetrahydroazepino[4,5-b]indole-5-carboxylate and 4-fluorobenzoyl chloride. 1H-NMR (CDCl3): δ 10.54 (1H, br s), 7.97 (1H, s), 7.63-7.68 (2H, m), 7.58 (1H, d), 7.39 (1H, d), 7.09-7.23 (4H, m), 5.28 (1H, dd), 4.25 (2H, m), 3.85 (1H, m), 3.18 (1H, d), 1.34 (3H, d), 1.22 (3H, t); MS(ESI): 393 (MH+).
Reaction SMILES: [Cl:1][C:2]1[N:3]=[C:4](Cl)[C:5]2[CH:10]=[CH:9][N:8]([CH:11]([CH3:13])[CH3:12])[C:6]=2[N:7]=1.[NH2:15][CH2:16][CH2:17][C:18]1[CH:23]=[CH:22][C:21]([OH:24])=[CH:20][CH:19]=1>>[Cl:1][C:2]1[N:3]=[C:4]([NH:15][CH2:16][CH2:17][C:18]2[CH:23]=[CH:22][C:21]([OH:24])=[CH:20][CH:19]=2)[C:5]2[CH:10]=[CH:9][N:8]([CH:11]([CH3:13])[CH3:12])[C:6]=2[N:7]=1
Reactant: CC(C)n1ccc2c(Cl)nc(Cl)nc21
Reactant: NCCc1ccc(O)cc1
Product: CC(C)n1ccc2c(NCCc3ccc(O)cc3)nc(Cl)nc21

Procedure:
Following the procedure of Example 128b, 2,4-dichloro-7-isopropyl-7H-pyrrolo[2,3-d]pyrimidine (b) (0.278 g, 1.21 mmol) was reacted with tyramine. The crude residue was purified by silica gel chromatography (25 to 75% ethyl acetate in hexane eluant) to afford the title compound as a solid. MS m/z 331.1 (M+1).
Reaction SMILES: [CH:1]1[C:10]2[C:11]3[CH2:16][N:15]=[CH:14][CH2:13][C:12]=3[N:8]3[C:9]=2[C:4]([CH2:5][CH2:6][CH2:7]3)=[CH:3][CH:2]=1.Cl[CH2:18][CH2:19][CH2:20][C:21]([C:23]1[CH:28]=[CH:27][C:26]([F:29])=[CH:25][CH:24]=1)=[O:22].C([O-])([O-])=O.[K+].[K+]>>[F:29][C:26]1[CH:25]=[CH:24][C:23]([C:21](=[O:22])[CH2:20][CH2:19][CH2:18][N:15]2[CH2:14][CH2:13][C:12]3[N:8]4[C:9]5[C:4](=[CH:3][CH:2]=[CH:1][C:10]=5[C:11]=3[CH2:16]2)[CH2:5][CH2:6][CH2:7]4)=[CH:28][CH:27]=1
Reactant: O=C(CCCCl)c1ccc(F)cc1
Reactant: C1=NCc2c(n3c4c(cccc24)CCC3)C1
Agent: O=C([O-])[O-]
Agent: [K+]
Product: O=C(CCCN1CCc2c(c3cccc4c3n2CCC4)C1)c1ccc(F)cc1
Yield: 28 %

Procedure:
The title compound (0.060 g, 28%) was prepared by the general method of Example 402 from 5,6,8,11-tetrahydro-4H-pyrido[3′,4′:4,5]pyrrolo[3,2,1-ij]quinoline (0.12 g, 0.57 mmol), 4-chloro-4′-fluorobutyrophenone (0.40 g, 2.0 mmol), KI (catalytic) and K2CO3(0.28 g, 2.0 mmol) after chromatographic purification as a white amorphous solid. 1H NMR (CDCl3, 300 MHz) δ 1.80–2.15 (m, 2H), 2.15–2.30 (m, 2H), 2.71 (t, J=7.0 Hz, 2H), 2.82 (d, J=5.1 Hz, 2H), 2.90 (t, J=5.8 Hz, 2H), 2.97 (t, J=6.1 Hz, 2H), 3.02–3.20 (m, 2H), 3.73 (s, 2H), 3.98 (t, J=5.7 Hz, 2H), 6.84 (d, J=6.9 Hz, 1H), 6.97 (t, J=7.5 Hz, 1H), 7.02–7.20 (m, 2H), 7.25 (d, J=7.7 Hz, 1H), 7.20–7.25 (m, 1H), 7.95–8.20 (m, 2H) ppm.
Reaction SMILES: [F:1][C:2]([F:19])([F:18])[C:3](=[O:17])[CH2:4][C:5]([C:8]1[CH:13]=[CH:12][C:11]([F:14])=[CH:10][C:9]=1[O:15][CH3:16])([CH3:7])[CH3:6].[Br:20]Br>C(O)(=O)C>[Br:20][C:12]1[C:11]([F:14])=[CH:10][C:9]([O:15][CH3:16])=[C:8]([C:5]([CH3:7])([CH3:6])[CH2:4][C:3](=[O:17])[C:2]([F:1])([F:18])[F:19])[CH:13]=1
Reactant: BrBr
Reactant: COc1cc(F)ccc1C(C)(C)CC(=O)C(F)(F)F
Solvent: CC(=O)O
Product: COc1cc(F)c(Br)cc1C(C)(C)CC(=O)C(F)(F)F
Yield: 97.4 %

Procedure:
To a solution of 300 mg (1.078 mmol) of 1,1,1-trifluoro-4-(4-fluoro-2-methoxyphenyl)-4-methylpentan-2-one (Example 26) in 0.5 mL of acetic acid was added 70 μL (1.35 mmol) of bromine. The reaction was monitored by TLC (EtOAc-hexanes (1:9)) by partitioning an aliquot between saturated aqueous sodium bicarbonate and EtOAc. A new slightly more polar product was observed. The reaction was made basic with saturated aqueous sodium bicarbonate and extracted with three 15 mL portion of EtOAc. The combined organic layers were washed with two 10 mL portions of saturated aqueous sodium bicarbonate and 10 mL of brine, dried over magnesium sulfate, filtered, and concentrated. The residue was dissolved in hexanes and passed through a pad of silica gel, eluting with EtOAc-hexanes (0.5:99.5) to afford 375 mg (97%) of the title compound.
Reaction SMILES: [C:1]1([CH:7]2[CH2:11][CH2:10][NH:9][CH2:8]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[C:12](Cl)(=[O:18])[CH2:13][CH2:14][CH2:15][CH2:16][CH3:17].C(N(CC)CC)C>ClCCl>[C:1]1([CH:7]2[CH2:11][CH2:10][N:9]([C:12](=[O:18])[CH2:13][CH2:14][CH2:15][CH2:16][CH3:17])[CH2:8]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: CCCCCC(=O)Cl
Reactant: c1ccc(C2CCNC2)cc1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CCCCCC(=O)N1CCC(c2ccccc2)C1
Temperature: 25 °C
Reaction time: 6 h
Yield: 82.5 %

Procedure:
A solution of 3-phenylpyrrolidine (294 mg, 2 mmol) in dry dichloromethane (6 mL) is cooled in an ice bath, and hexanoyl chloride (336.5 mg, 2.5 mmol, 1.25 eq) and triethylamine (417 μL, 3 mmol, 1.5 eq) are added. After stirring for 6 hours at room temperature the reaction mixture is diluted with dichloromethane (10 mL). The organic solution is subsequently washed with 1 M KHSO4, 5% NaHCO3 and brine. After drying over Na2SO4, dichloromethane is removed in vacuo and the crude material is purified by flash chromatography (silicagel, ethyl acetate/toluene 1:4). The fractions containing 1-(3-phenylpyrrolidin-1-yl)hexan-1-one are collected and the solvent is removed in vacuo to give 405 mg of colorless oil.