Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([C@H:8]1[CH2:13][N:12]([C:14]2[CH:19]=[CH:18][C:17]([O:20][CH3:21])=[C:16]([O:22][CH:23]3[CH2:27][CH2:26][CH2:25][CH2:24]3)[CH:15]=2)[CH2:11][CH2:10][N:9]1[C:28](=[O:35])[CH2:29][C:30](OCC)=[O:31])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[BH4-].[Na+].CO>C1COCC1>[CH2:1]([C@H:8]1[CH2:13][N:12]([C:14]2[CH:19]=[CH:18][C:17]([O:20][CH3:21])=[C:16]([O:22][CH:23]3[CH2:27][CH2:26][CH2:25][CH2:24]3)[CH:15]=2)[CH2:11][CH2:10][N:9]1[C:28](=[O:35])[CH2:29][CH2:30][OH:31])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CCOC(=O)CC(=O)N1CCN(c2ccc(OC)c(OC3CCCC3)c2)C[C@@H]1Cc1ccccc1
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Solvent: C1CCOC1
Product: COc1ccc(N2CCN(C(=O)CCO)[C@@H](Cc3ccccc3)C2)cc1OC1CCCC1
Yield: 58.1 %

Procedure:
A solution of ((S)-ethyl 3-(2-benzyl-4-(3-(cyclopentyloxy)-4-methoxyphenyl)piperazin-1-yl)-3-oxopropanoate (96 mg, 0.20 mmol) and sodium borohydride (30 mg, 0.80 mmol) in THF (4 mL) was brought to reflux and MeOH (242 μL, 6.0 mmol) added drop-wise over a 1 h period. The reaction mixture was allowed to heat at reflux for an additional 16 h and then quenched with a few drops of a 1 N HCl solution. The reaction was partitioned between EtOAc (10 mL) and a saturated aqueous solution of NaHCO3 (10 mL). The organic extract was further washed with brine then dried over MgSO4, filtered, and evaporated to an oil that was purified by silica gel flash chromatography with EtOAc as eluant to afford the title compound as an oil (51 mg, 58%). LC/MS (Method A) 4.34 min, [M+1]+ 439.
Reaction SMILES: [Br:1]Br.[CH2:3]([N:10]1[C:14]2=[C:15]([O:19][CH2:20][C:21]3[CH:26]=[CH:25][C:24]([F:27])=[CH:23][CH:22]=3)[N:16]=[N:17][CH:18]=[C:13]2[CH:12]=[C:11]1[CH3:28])[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1>ClCCl>[CH2:3]([N:10]1[C:14]2=[C:15]([O:19][CH2:20][C:21]3[CH:22]=[CH:23][C:24]([F:27])=[CH:25][CH:26]=3)[N:16]=[N:17][CH:18]=[C:13]2[C:12]([Br:1])=[C:11]1[CH3:28])[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1
Reactant: BrBr
Reactant: Cc1cc2cnnc(OCc3ccc(F)cc3)c2n1Cc1ccccc1
Solvent: ClCCl
Product: Cc1c(Br)c2cnnc(OCc3ccc(F)cc3)c2n1Cc1ccccc1
Temperature: 0 °C
Reaction time: 1 h
Yield: 79.4 %

Procedure:
A solution of 180 μl (3.5 mmol) of bromine in 7 ml of anhydrous dichloromethane is added dropwise at 0° C. to a solution of 910 mg (2.6 mmol) of 1-benzyl-7-(4-fluorobenzyloxy)-2-methylpyrrolo[2,3-d]pyridazine in 15 ml of anhydrous dichloromethane in the course of 30 min. The solution is kept at 0° C. for a further 1 h, then treated with 50 ml of ice-water and extracted. The organic phase is separated off, washed with 3×25 ml of water, dried over magnesium sulfate and concentrated. The residue is chromatographed on silica gel (eluent: ethyl acetate). The fractions of Rf=0.6 are concentrated and crystallized from diisopropyl ether/cyclohexane. 880 mg (79%) of the title compound are isolated. M.p.: 128°-130° C.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:27])[C:4]1[CH:9]=[CH:8][C:7]([NH:10][C:11](=[O:26])[CH:12]([C:19]2[CH:24]=[CH:23][C:22]([NH2:25])=[CH:21][CH:20]=2)[CH2:13][CH:14]2[CH2:18][CH2:17][CH2:16][CH2:15]2)=[N:6][CH:5]=1.C(N(CC)C(C)C)(C)C.Cl.[C:38](Cl)(=[O:45])[C:39]1[CH:44]=[CH:43][CH:42]=[N:41][CH:40]=1>O1CCCC1>[CH3:1][O:2][C:3](=[O:27])[C:4]1[CH:9]=[CH:8][C:7]([NH:10][C:11](=[O:26])[CH:12]([C:19]2[CH:20]=[CH:21][C:22]([NH:25][C:38]([C:39]3[CH:40]=[N:41][CH:42]=[CH:43][CH:44]=3)=[O:45])=[CH:23][CH:24]=2)[CH2:13][CH:14]2[CH2:15][CH2:16][CH2:17][CH2:18]2)=[N:6][CH:5]=1
Reactant: O=C(Cl)c1cccnc1
Reactant: COC(=O)c1ccc(NC(=O)C(CC2CCCC2)c2ccc(N)cc2)nc1
Agent: Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: C1CCOC1
Product: COC(=O)c1ccc(NC(=O)C(CC2CCCC2)c2ccc(NC(=O)c3cccnc3)cc2)nc1
Temperature: 25 °C
Reaction time: 48 h
Yield: 72.6 %

Procedure:
A solution of 6-[2-(4-amino-phenyl)-3-cyclopentyl-propionylamino]-nicotinic acid methyl ester (236.1 mg, 0.65 mmol) in tetrahydrofuran (15 mL) at 25° C. was treated with N,N-diisopropylethylamine (0.27 mL, 1.54 mmol) and nicotinoyl chloride hydrochloride (115 mg, 0.64 mmol). The reaction mixture was stirred at 25° C. for 48 h. At this time, the reaction was concentrated in vacuo. Flash chromatography (Merck Silica gel 60, 230-400 mesh, 90/10 ethyl acetate/hexanes) afforded 6-(3-cyclopentyl-2-{4-[(pyridine-3-carbonyl)-amino]phenyl}-propionylamino)-nicotinic acid methyl ester (219.6 mg, 72.3%) as a white solid: mp 110-1 15° C.; EI-HRMS m/e calcd for C27H28N4O4 (M+) 472.2110, found 472.2109.
Reaction SMILES: [NH:1]1[CH:5]=[CH:4][CH:3]=[N:2]1.Br[C:7]1[CH:12]=[CH:11][C:10]([CH3:13])=[CH:9][CH:8]=1>>[C:10]1([CH3:13])[CH:11]=[CH:12][C:7]([N:1]2[CH:5]=[CH:4][CH:3]=[N:2]2)=[CH:8][CH:9]=1
Reactant: c1cn[nH]c1
Reactant: Cc1ccc(Br)cc1
Product: Cc1ccc(-n2cccn2)cc1

Procedure:
Following General Procedure A (125° C., 24 hours), 1H-pyrazole (102 mg, 1.5 mmol) is coupled with 1-bromo-4-methylbenzene (122 μL, 1.0 mmol). The crude brown oil is purified by flash chromatography on silica gel (eluent: dichloromethane/hexanes=70/30) to provide 90 mg (57% isolated yield) of the desired product as an uncolored oil.
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1([CH3:19])[CH2:10][CH2:9][C:8]2[C:11]([CH3:18])=[C:12]([OH:17])[C:13]([CH3:16])=[C:14]([CH3:15])[C:7]=2[O:6]1)=[O:4].[Br:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25]Br>>[CH3:1][O:2][C:3]([C:5]1([CH3:19])[CH2:10][CH2:9][C:8]2[C:11]([CH3:18])=[C:12]([O:17][CH2:25][CH2:24][CH2:23][CH2:22][CH2:21][Br:20])[C:13]([CH3:16])=[C:14]([CH3:15])[C:7]=2[O:6]1)=[O:4]
Reactant: BrCCCCCBr
Reactant: COC(=O)C1(C)CCc2c(C)c(O)c(C)c(C)c2O1
Product: COC(=O)C1(C)CCc2c(C)c(OCCCCCBr)c(C)c(C)c2O1
Yield: 90 %

Procedure:
Using the procedure and molar proportions of example 71, 1 g of racemic-6-hydroxy-3,4-dihydro-2,5,7,8-tetramethyl-2H-1-benzopyran-2-carboxylic acid methyl ester was alkylated with 1,5-dibromopentane giving racemic-6-[(5-bromopentyl)oxy]-3,4-dihydro-2,5,7,8-tetramethyl-2H-1-benzopyran-2-carboxylic acid methyl ester as a colorless solid, mp 72.5°-74.5° C. in 90% yield after purification by chromatography on silica gel.
Reaction SMILES: [CH3:1][O:2][C@H:3]([C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1)[C:4]([OH:6])=O.[NH2:13][CH2:14][C:15]1[CH:22]=[CH:21][C:18]([C:19]#[N:20])=[CH:17][CH:16]=1>>[C:14]([C:15]1[CH:22]=[CH:21][C:18]([CH2:19][NH:20][C:4](=[O:6])[C@H:3]([O:2][CH3:1])[C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=2)=[CH:17][CH:16]=1)#[N:13]
Reactant: N#Cc1ccc(CN)cc1
Reactant: CO[C@@H](C(=O)O)c1ccccc1
Product: CO[C@@H](C(=O)NCc1ccc(C#N)cc1)c1ccccc1

Procedure:
(R)-(+)-Methoxyphenylacetic acid was coupled with 4-aminomethyl benzonitrile (CAS No: 10406-25-4) according to general procedure C to give (R)-N-(4-cyano-benzyl)-2-methoxy-2-phenyl-acetamide as an off-white solid. MS 281.1 ([M+H]+)
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]23[CH2:17][CH:12]4[CH2:13][CH:14]([CH2:16][CH:10]([CH2:11]4)[CH2:9]2)[CH2:15]3)=[CH:4][C:3]=1[C:18]1[CH:23]=[C:22]([C:24]23[CH2:33][CH:28]4[CH2:29][CH:30]([CH2:32][CH:26]([CH2:27]4)[CH2:25]2)[CH2:31]3)[CH:21]=[CH:20][C:19]=1[CH3:34].C[C:36]1[CH:41]=[CH:40][C:39]([C:42]23CC4CC(CC(Br)(C4)[CH2:43]2)C3)=[CH:38][C:37]=1[C:53]1C=C(C23CC4CC(CC(Br)(C4)C2)C3)C=C[C:54]=1C>>[CH3:34][C:19]1[CH:20]=[CH:21][C:22]([C:24]23[CH2:25][CH:26]4[CH2:27][CH:28]([CH2:29][C:30]([C:7]5[CH:6]=[C:5]([C:8]#[CH:9])[CH:4]=[C:3]([C:18]#[CH:19])[CH:2]=5)([CH2:32]4)[CH2:31]2)[CH2:33]3)=[CH:23][C:18]=1[C:3]1[CH:4]=[C:5]([C:8]23[CH2:9][CH:10]4[CH2:16][CH:14]([CH2:13][C:12]([C:41]5[CH:40]=[C:39]([C:42]#[CH:43])[CH:38]=[C:37]([C:53]#[CH:54])[CH:36]=5)([CH2:11]4)[CH2:17]2)[CH2:15]3)[CH:6]=[CH:7][C:2]=1[CH3:1]
Reactant: Cc1ccc(C23CC4CC(CC(C4)C2)C3)cc1-c1cc(C23CC4CC(CC(C4)C2)C3)ccc1C
Reactant: Cc1ccc(C23CC4CC(CC(Br)(C4)C2)C3)cc1-c1cc(C23CC4CC(CC(Br)(C4)C2)C3)ccc1C
Product: C#Cc1cc(C#C)cc(C23CC4CC(C2)CC(c2ccc(C)c(-c5cc(C67CC8CC(CC(c9cc(C#C)cc(C#C)c9)(C8)C6)C7)ccc5C)c2)(C4)C3)c1
Yield: 73.5 %

Procedure:
From the obtained 2,2′-dimethyl-5,5′-bis(1-adamantyl)-biphenyl 10 g, the same method as in Synthesis Example 7 was used to synthesize 2,2′-dimethyl-5,5′-bis(3-bromo-1-adamantyl)biphenyl 4.5 g, then the same method as in Synthesis Example 3 was used to obtain 2,2′-dimethyl-5,5′-bis(3-(3,5-diethynylphenyl)-1-adamantyl)biphenyl 3.8 g.
Reaction SMILES: ClN1C(=O)CCC1=O.[CH:9](=[N:11][OH:12])[CH3:10].[C:13]([C:15]1[CH:20]=[C:19]([O:21][C:22]2[CH:23]=[CH:24][C:25]([NH:29][C:30](=[O:32])[CH3:31])=[N:26][C:27]=2[CH3:28])[CH:18]=[CH:17][N:16]=1)#[CH:14].O>CN(C=O)C>[CH3:28][C:27]1[N:26]=[C:25]([NH:29][C:30](=[O:32])[CH3:31])[CH:24]=[CH:23][C:22]=1[O:21][C:19]1[CH:18]=[CH:17][N:16]=[C:15]([C:13]2[O:12][N:11]=[C:9]([CH3:10])[CH:14]=2)[CH:20]=1
Reactant: CC=NO
Reactant: C#Cc1cc(Oc2ccc(NC(C)=O)nc2C)ccn1
Agent: O=C1CCC(=O)N1Cl
Solvent: O
Solvent: CN(C)C=O
Product: CC(=O)Nc1ccc(Oc2ccnc(-c3cc(C)no3)c2)c(C)n1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 88.8 %

Procedure:
A solution of N-chlorosuccinimide (0.153 g, 1.145 mmol) in DMF (1 mL) was treated with acetaldoxime (0.068 g, 1.145 mmol), stirred at RT for 30 min, then added to a solution of N-(5-((2-ethynylpyridin-4-yl)oxy)-6-methylpyridin-2-yl)acetamide (0.102 g, 0.382 mmol) and TEA (0.5 mL) in DMF (1 mL) and heated at 60° C. for 1 h. The mixture was cooled to RT, treated with H2O, extracted with EtOAc (2×) and the combined organics were washed with H2O, then brine, dried over Na2SO4, concentrated to dryness and purified via silica gel chromatography (MeOH/DCM) to afford N-(6-methyl-5-((2-(3-methylisoxazol-5-yl)pyridin-4-yl)oxy)pyridin-2-yl)acetamide (110 mg, 89%) as a white solid. 1H NMR (400 MHz, DMSO-d6): δ 10.64 (s, 1H), 8.55 (d, J=5.7 Hz, 1H), 8.03 (d, J=8.8 Hz, 1H), 7.64 (d, J=8.8 Hz, 1H), 7.35 (d, J=2.5 Hz, 1H), 6.96 (m, 2H), 2.28 (s, 3H), 2.25 (s, 3H), 2.08 (s, 3H); MS (ESI) m/z: 325.1 (M+H+).
Reaction SMILES: CO[CH:3]([O:13]C)[C:4]1[CH:12]=[CH:11][C:7]([C:8]([OH:10])=O)=[CH:6][CH:5]=1.CCN=C=NCCCN(C)C.[CH2:26]([NH2:32])[C:27]1[O:31][CH:30]=[CH:29][CH:28]=1>CN(C1C=CN=CC=1)C.C1COCC1.C(Cl)Cl>[CH:8]([C:7]1[CH:6]=[CH:5][C:4]([C:3]([NH:32][CH2:26][C:27]2[O:31][CH:30]=[CH:29][CH:28]=2)=[O:13])=[CH:12][CH:11]=1)=[O:10]
Reactant: COC(OC)c1ccc(C(=O)O)cc1
Reactant: NCc1ccco1
Agent: CCN=C=NCCCN(C)C
Agent: CN(C)c1ccncc1
Solvent: C1CCOC1
Solvent: ClCCl
Product: O=Cc1ccc(C(=O)NCc2ccco2)cc1
Reaction time: 2 h
Yield: 58 %

Procedure:
A solution of 4-(dimethoxymethyl)benzoic acid 5 (2.94 g, 15 mmol), EDCI (5.75 g, 30 mmol), furfurylamine (3.5 mL, 37.5 mmol), and DMAP (122 mg, 1 mmol) in THF (200 mL) and CH2Cl2 (50 mL) was stirred at r.t. for 16 h. The solvent was removed by rotary evaporation and the resulting yellow oil was dissolved in CHCl3 and was washed twice with 0.5 M HCl. The organic solution was then vigorously stirred with 1.0 M HCl for 2 h. The layers were separated and the organic phase was washed twice more with 1.0 M HCl and once with brine. The organic phase was dried over Na2SO4 and the solvent was removed by rotary evaporation. The crude product was crystallized from hot EtOAc, yielding the title compound as a pale yellow solid in 2 crops (2.09 g, 58% yield). 1H NMR (400 MHz, CDCl3): δ 10.09 (s, 1H), 7.97 (s, 4H), 7.42 (m, 1H), 6.54 (br s, 1H), 6.39 (dd, J=2.0, 3.3 Hz, 1H), 6.35 (d, J=3.3 Hz, 1H), 4.69 (d, J=5.3 Hz, 2H).
Reaction SMILES: [Li]CCCC.[NH:6]1[CH:10]=[CH:9][CH:8]=[CH:7]1.[F:11][C:12]([F:24])([F:23])[C:13]1[CH:18]=[CH:17][C:16]([S:19](Cl)(=[O:21])=[O:20])=[CH:15][CH:14]=1>C1COCC1.CCOC(C)=O>[F:24][C:12]([F:11])([F:23])[C:13]1[CH:14]=[CH:15][C:16]([S:19]([N:6]2[CH:10]=[CH:9][CH:8]=[CH:7]2)(=[O:21])=[O:20])=[CH:17][CH:18]=1
Reactant: O=S(=O)(Cl)c1ccc(C(F)(F)F)cc1
Reactant: c1cc[nH]c1
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: O=S(=O)(c1ccc(C(F)(F)F)cc1)n1cccc1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 86.6 %

Procedure:
n-BuLi (56 mL, 89.7 mmol) was added to a solution of 1H-pyrrole (6.02 g, 89.7 mmol) in THF (179 mL) at −78° C. over 10 minutes. 4-(trifluoromethyl)benzene-1-sulfonyl chloride (26.3 g, 107.6 mmol) was dissolved in THF (20 mL) and added to the reaction mixture over 30 minutes. The reaction was stirred for 30 minutes then allowed to warm to room temperature and stirred for a further 18 h. The solution was diluted with EtOAc washed with brine and the organic phase was separated, dried (Na2SO4), filtered and concentrated under vacuum and purified on a silica gel column (eluant hexane/EtOAc 99/1 to 4/1, v/v) to give compound 111 (21.4 g, 77.7 mmol, 87%). MS (ESI) 276.1 (M+H).
Reaction SMILES: Br[CH2:2][C:3]1[S:11][C:10]2[C:9]([N:12]3[CH2:17][CH2:16][O:15][CH2:14][CH2:13]3)=[N:8][C:7]([Cl:18])=[N:6][C:5]=2[CH:4]=1.[CH3:19][S:20]([CH2:23][CH2:24][CH2:25][NH2:26])(=[O:22])=[O:21].C(=O)([O-])[O-].[K+].[K+]>C(#N)C>[Cl:18][C:7]1[N:8]=[C:9]([N:12]2[CH2:17][CH2:16][O:15][CH2:14][CH2:13]2)[C:10]2[S:11][C:3]([CH2:2][NH:26][CH2:25][CH2:24][CH2:23][S:20]([CH3:19])(=[O:22])=[O:21])=[CH:4][C:5]=2[N:6]=1
Reactant: CS(=O)(=O)CCCN
Reactant: Clc1nc(N2CCOCC2)c2sc(CBr)cc2n1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: CS(=O)(=O)CCCNCc1cc2nc(Cl)nc(N3CCOCC3)c2s1
Temperature: 80 °C

Procedure:
To a solution of 6-bromomethyl-2-chloro-4-morpholin-4-yl-thieno[3,2-d]pyrimidine (200 mg) in acetonitrile (10 mL) was added 3-methanesulfonyl-propylamine (86 mg) and potassium carbonate (317 mg) and the reaction heated at 80° C. for 16 h. After cooling to room temperature, the solvent was reduced in vacuo and the residue redissolved in dicholoromethane (20 mL). The solution was washed with saturated aqueous sodium hydrogen carbonate solution (20 mL), aqueous brine solution (2×20 mL), dried (MgSO4), reduced in vacuo and purified by column chromatography to give (2-chloro-4-morpholin-4-yl-thieno[3,2-d]pyrimidin-6-ylmethyl)-(3-methanesulfonyl-propyl)-amine as a yellow solid.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:39]=[CH:40][C:41]=1[Cl:42])[CH2:5][O:6][C:7]1[CH:12]=[CH:11][C:10]([C@H:13]2[CH2:38][O:37][C:16]3=[CH:17][C:18]4[CH2:19][C@@H:20]([C:34](O)=[O:35])[N:21]([C@H:25]([C:28]5[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=5)[CH2:26][CH3:27])[CH2:22][C:23]=4[CH:24]=[C:15]3[O:14]2)=[CH:9][CH:8]=1.Cl.Cl.C[O:46][C:47](=[O:65])[C@@H:48]([NH2:64])[CH2:49][C:50]1[CH:55]=[CH:54][C:53]([C:56]2[CH:61]=[CH:60][N:59]=[C:58]([CH3:62])[C:57]=2[CH3:63])=[CH:52][CH:51]=1>>[Cl:1][C:2]1[CH:3]=[C:4]([CH:39]=[CH:40][C:41]=1[Cl:42])[CH2:5][O:6][C:7]1[CH:8]=[CH:9][C:10]([C@H:13]2[CH2:38][O:37][C:16]3=[CH:17][C:18]4[CH2:19][C@@H:20]([C:34]([NH:64][C@@H:48]([CH2:49][C:50]5[CH:55]=[CH:54][C:53]([C:56]6[CH:61]=[CH:60][N:59]=[C:58]([CH3:62])[C:57]=6[CH3:63])=[CH:52][CH:51]=5)[C:47]([OH:46])=[O:65])=[O:35])[N:21]([C@H:25]([C:28]5[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=5)[CH2:26][CH3:27])[CH2:22][C:23]=4[CH:24]=[C:15]3[O:14]2)=[CH:11][CH:12]=1
Reactant: CC[C@@H](c1ccccc1)N1Cc2cc3c(cc2C[C@H]1C(=O)O)OC[C@H](c1ccc(OCc2ccc(Cl)c(Cl)c2)cc1)O3
Reactant: COC(=O)[C@@H](N)Cc1ccc(-c2ccnc(C)c2C)cc1
Agent: Cl
Product: CC[C@@H](c1ccccc1)N1Cc2cc3c(cc2C[C@H]1C(=O)N[C@@H](Cc1ccc(-c2ccnc(C)c2C)cc1)C(=O)O)OC[C@H](c1ccc(OCc2ccc(Cl)c(Cl)c2)cc1)O3

Procedure:
The title compound (110 mg) was prepared from (3S,8S)-3-[4-(3,4-dichloro-benzyloxy)-phenyl]-7-((S)-1-phenyl-propyl)-2,3,6,7,8,9-hexahydro-[1,4]dioxino[2,3-g]isoquinoline-8-carboxylic acid and (S)-2-amino-3-[4-(2,3-dimethyl-pyridin-4-yl)-phenyl]-propionic acid methyl ester dihydrochloride according to General Procedures L and B. LCMS (m/z): 857. 1H NMR (400 MHz, acetone-d6): 8.18 (d, 1H), 7.86 (d, 1H), 7.59 (d, 1H), 7.49 (d, 1H), 7.36 (dd, 1H), 7.23-7.18 (m, 4H), 7.15 (m, 1H), 7.11-7.07 (m, 4H), 6.86 (d, 1H), 6.78-6.72 (m, 4H), 6.61 (s, 1H), 6.52 (s, 1H), 5.03 (s, 2H), 4.93 (dd, 1H), 4.72 (m, 1H), 4.14 (dd, 1H), 3.67 (dd, 1H), 3.54 (dd, 1H), 3.45 (d, 1H), 3.39 (dd, 1H), 3.23 (d, 1H), 3.03 (dd, 1H), 2.89-2.79 (m, 2H), 2.66 (dd, 1H), 2.38 (s, 3H), 2.02 (s, 3H), 1.87-1.75 (m, 1H), 1.72-1.61 (m, 1H), 0.48 (t, 3H).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2([OH:21])[CH2:13][CH2:12][N:11]([C:14]([O:16][C:17]([CH3:20])([CH3:19])[CH3:18])=[O:15])[CH2:10][CH2:9]2)=[CH:4][CH:3]=1.[H-].[Na+].[CH3:24]I>CN(C)C=O>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2([O:21][CH3:24])[CH2:9][CH2:10][N:11]([C:14]([O:16][C:17]([CH3:18])([CH3:20])[CH3:19])=[O:15])[CH2:12][CH2:13]2)=[CH:6][CH:7]=1
Reactant: CC(C)(C)OC(=O)N1CCC(O)(c2ccc(Cl)cc2)CC1
Reactant: CI
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: COC1(c2ccc(Cl)cc2)CCN(C(=O)OC(C)(C)C)CC1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
790 mg tert-butyl 4-(4-chlorophenyl)-4-hydroxypiperidine-1-carboxylate are placed in 5 ml dimethylformamide and 193 mg sodium hydride (60% in mineral oil) are added. The reaction mixture is stirred for 30 min at ambient temperature, then 267 μl methyl iodide are added. After 1 h the reaction mixture is poured onto ice and the product is extracted with diethyl ether. 650 mg product are obtained in the form of an oil. Analytical HPLC-MS (method B): RT==1.88 min.
Reaction SMILES: [CH3:1][C:2]1([CH2:7][CH2:8][CH2:9][CH2:10][N:11]2[CH:15]=[C:14]([NH2:16])[CH:13]=[N:12]2)[O:6]CCO1.[F:17][C:18]([F:32])([F:31])[O:19][C:20]1[CH:21]=[C:22](/[CH:26]=[CH:27]/[C:28](O)=[O:29])[CH:23]=[CH:24][CH:25]=1>>[O:6]=[C:2]([CH3:1])[CH2:7][CH2:8][CH2:9][CH2:10][N:11]1[CH:15]=[C:14]([NH:16][C:28](=[O:29])/[CH:27]=[CH:26]/[C:22]2[CH:23]=[CH:24][CH:25]=[C:20]([O:19][C:18]([F:31])([F:32])[F:17])[CH:21]=2)[CH:13]=[N:12]1
Reactant: O=C(O)/C=C/c1cccc(OC(F)(F)F)c1
Reactant: CC1(CCCCn2cc(N)cn2)OCCO1
Product: CC(=O)CCCCn1cc(NC(=O)/C=C/c2cccc(OC(F)(F)F)c2)cn1

Procedure:
Following general procedure B followed by either C or D, starting from 1-[4-(2-methyl-[1,3]dioxolan-2-yl)-butyl]-1H-pyrazol-4-ylamine and (E)-3-(3-trifluoromethoxy-phenyl)-acrylic acid.
Reaction SMILES: C(OC([N:8]1[CH2:13][CH2:12][CH2:11][CH2:10][CH:9]1/[CH:14]=[CH:15]/[C:16]1[CH:21]=[CH:20][C:19]([N:22]2[CH2:26][C:25](=[O:27])[N:24]([CH2:28][CH2:29][Si:30]([CH3:33])([CH3:32])[CH3:31])[S:23]2(=[O:35])=[O:34])=[C:18]([O:36][CH2:37][C:38]2[CH:43]=[CH:42][CH:41]=[CH:40][CH:39]=2)[CH:17]=1)=O)(C)(C)C>C(O)(C(F)(F)F)=O.C(Cl)Cl>[CH2:37]([O:36][C:18]1[CH:17]=[C:16](/[CH:15]=[CH:14]/[CH:9]2[CH2:10][CH2:11][CH2:12][CH2:13][NH:8]2)[CH:21]=[CH:20][C:19]=1[N:22]1[S:23](=[O:34])(=[O:35])[N:24]([CH2:28][CH2:29][Si:30]([CH3:31])([CH3:33])[CH3:32])[C:25](=[O:27])[CH2:26]1)[C:38]1[CH:39]=[CH:40][CH:41]=[CH:42][CH:43]=1
Reactant: CC(C)(C)OC(=O)N1CCCCC1/C=C/c1ccc(N2CC(=O)N(CC[Si](C)(C)C)S2(=O)=O)c(OCc2ccccc2)c1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: C[Si](C)(C)CCN1C(=O)CN(c2ccc(/C=C/C3CCCCN3)cc2OCc2ccccc2)S1(=O)=O

Procedure:
A solution of 2-((E)-2-{3-benzyloxy-4-[1,1,4-trioxo-5-(2-trimethylsilanylethyl)-1,2,5-thiadiazolidin-2-yl]-phenyl}-vinyl)-piperidine-1-carboxylic acid tert-butyl ester (Example 62, step B) (240 mg, 0.353 mmol) in TFA/methylene chloride (3:8) is stirred at RT for 75 min. The solvent is removed under reduced pressure and the residue purified by preparative HPLC to give the title compound.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([CH:8]2[CH2:17][C:16]([CH3:19])([CH3:18])[C:15]3[C:10](=[C:11]([Cl:22])[CH:12]=[C:13]([C:20]#[N:21])[CH:14]=3)[NH:9]2)[CH:5]=[CH:6][CH:7]=1.[NH2:23][C:24]([CH3:29])([CH3:28])[C:25]([OH:27])=[O:26].C(=O)([O-])[O-].[K+].[K+]>CS(C)=O.[Cu]I>[Cl:22][C:11]1[CH:12]=[C:13]([C:20]#[N:21])[CH:14]=[C:15]2[C:10]=1[NH:9][CH:8]([C:4]1[CH:3]=[C:2]([NH:23][C:24]([CH3:29])([CH3:28])[C:25]([OH:27])=[O:26])[CH:7]=[CH:6][CH:5]=1)[CH2:17][C:16]2([CH3:19])[CH3:18]
Reactant: CC1(C)CC(c2cccc(Br)c2)Nc2c(Cl)cc(C#N)cc21
Reactant: CC(C)(N)C(=O)O
Agent: [Cu]I
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CS(C)=O
Product: CC(C)(Nc1cccc(C2CC(C)(C)c3cc(C#N)cc(Cl)c3N2)c1)C(=O)O
Temperature: 25 °C
Yield: 29.9 %

Procedure:
A solution of 2-(3-bromo-phenyl)-8-chloro-4,4-dimethyl-1,2,3,4-tetrahydro-quinoline-6-carbonitrile (374.0 mg, 1.0 mmol), copper(I) iodide (57.0 mg, 0.3 mmol), 2-amino-2-methyl-propionic acid (309.0 mg, 3.0 mmol) and potassium carbonate (415.0 mg, 3.0 mmol) in dimethyl sulfoxide (2.0 mL) was stirred at 120° C. for 16 h. Then the reaction mixture was cooled to room temperature and extracted with ethyl acetate (150 mL×2), washed with water (50 mL×2) and saturated aqueous ammonium chloride solution (50 mL×2), dried over anhydrous sodium sulfate and then concentrated in vacuo. Purification by Waters automated flash system (column: Xterra 30 mm×100 mm, sample manager 2767, pump 2525, detector: ZQ mass and UV 2487, solvent system: acetonitrile and 0.1% ammonium hydroxide in water) afforded 2-[3-(8-chloro-6-cyano-4,4-dimethyl-1,2,3,4-tetrahydro-quinolin-2-yl)-phenylamino]-2-methylpropionic acid (118.8 mg, 30%) as a white solid: LC/MS m/e obsd. (ESI+) [(M+H)+] 398.2.
Reaction SMILES: C(O[C:6]([NH:8][CH2:9][CH2:10][O:11][C:12]1[CH:17]=[CH:16][C:15]([CH2:18][C@H:19]([O:29][C:30]2[CH:35]=[CH:34][C:33]([CH:36]([CH3:38])[CH3:37])=[CH:32][CH:31]=2)[C:20]([O:22][CH2:23][CH2:24][Si:25]([CH3:28])([CH3:27])[CH3:26])=[O:21])=[CH:14][CH:13]=1)=[O:7])(C)(C)C.[N:39]1[CH:44]=[CH:43][CH:42]=[CH:41][C:40]=1[C:45]1[CH:53]=[CH:52][C:48](C(O)=O)=[CH:47][CH:46]=1.C(P(=O)(OCC)OCC)#N>C(N(CC)CC)C>[CH:36]([C:33]1[CH:32]=[CH:31][C:30]([O:29][C@@H:19]([CH2:18][C:15]2[CH:16]=[CH:17][C:12]([O:11][CH2:10][CH2:9][NH:8][C:6](=[O:7])[C:48]3[CH:47]=[CH:46][C:45]([C:40]4[CH:41]=[CH:42][CH:43]=[CH:44][N:39]=4)=[CH:53][CH:52]=3)=[CH:13][CH:14]=2)[C:20]([O:22][CH2:23][CH2:24][Si:25]([CH3:28])([CH3:27])[CH3:26])=[O:21])=[CH:35][CH:34]=1)([CH3:37])[CH3:38]
Reactant: CC(C)c1ccc(O[C@@H](Cc2ccc(OCCNC(=O)OC(C)(C)C)cc2)C(=O)OCC[Si](C)(C)C)cc1
Reactant: O=C(O)c1ccc(-c2ccccn2)cc1
Agent: CCOP(=O)(C#N)OCC
Solvent: CCN(CC)CC
Product: CC(C)c1ccc(O[C@@H](Cc2ccc(OCCNC(=O)c3ccc(-c4ccccn4)cc3)cc2)C(=O)OCC[Si](C)(C)C)cc1
Yield: 56.8 %

Procedure:
In a similar manner to that described in Example 73, a reaction was carried out using 2-trimethylsilylethyl (S)-3-[4-(2-t-butoxycarbonylaminoethoxy)phenyl]-2-(4-isopropylphenoxy)propionate (0.95 g), 4-pyridine-2-ylbenzoic acid (382 mg), diethyl cyanophosphonate (0.29 ml) and triethylamine (0.53 ml) and the reaction mixture was treated to afford the title compound (0.62 g) as a colorless oil.
Reaction SMILES: [CH3:1][C:2]1([C:8]2[CH:13]=[CH:12][C:11]([S:14](Cl)(=[O:16])=[O:15])=[CH:10][CH:9]=2)[CH2:7][CH2:6][O:5][CH2:4][CH2:3]1.[NH2:18][C:19]1[CH:24]=[CH:23][C:22]([Cl:25])=[CH:21][C:20]=1[C:26]([C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][N:29]=1)=[O:27]>>[Cl:25][C:22]1[CH:23]=[CH:24][C:19]([NH:18][S:14]([C:11]2[CH:12]=[CH:13][C:8]([C:2]3([CH3:1])[CH2:7][CH2:6][O:5][CH2:4][CH2:3]3)=[CH:9][CH:10]=2)(=[O:16])=[O:15])=[C:20]([C:26]([C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][N:29]=2)=[O:27])[CH:21]=1
Reactant: CC1(c2ccc(S(=O)(=O)Cl)cc2)CCOCC1
Reactant: Nc1ccc(Cl)cc1C(=O)c1ccccn1
Product: CC1(c2ccc(S(=O)(=O)Nc3ccc(Cl)cc3C(=O)c3ccccn3)cc2)CCOCC1

Procedure:
The title compound was prepared by the reacting 4-(4-methyl-tetrahydro-pyran-4-yl)-benzenesulfonyl chloride with (2-amino-5-chloro-phenyl)-pyridin-2-yl-methanone according to the general procedure described for the preparation of (N-aryl-benzenesulfonamides. MS: m/z 471 (M++1).
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[N:7]([CH3:16])[C:8]2[C:13]([C:14]=1[OH:15])=[CH:12][CH:11]=[CH:10][CH:9]=2)=[O:5])[CH3:2].Br[CH2:18][C:19]([O:21][CH2:22][CH3:23])=[O:20]>>[CH2:1]([O:3][C:4]([C:6]1[N:7]([CH3:16])[C:8]2[C:13]([C:14]=1[O:15][CH2:18][C:19]([O:21][CH2:22][CH3:23])=[O:20])=[CH:12][CH:11]=[CH:10][CH:9]=2)=[O:5])[CH3:2]
Reactant: CCOC(=O)CBr
Reactant: CCOC(=O)c1c(O)c2ccccc2n1C
Product: CCOC(=O)COc1c(C(=O)OCC)n(C)c2ccccc12

Procedure:
Prepared by the procedure described in Example 1 from 3-hydroxy-1-methyl-1H-indole-2-carboxylic acid ethyl ester and ethyl bromoacetate. The crude oil product obtained after evaporation was used for further synthesis without additional purification.