Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br[C:2]1[CH:11]=[CH:10][CH:9]=[C:8]2[C:3]=1[CH:4]=[CH:5][C:6]([S:12]([O:15][CH2:16][C:17]([F:20])([F:19])[F:18])(=[O:14])=[O:13])=[CH:7]2.C[N:22]1[C:26]([C:27]2[CH:32]=[C:31]([C:33]([F:36])([F:35])[F:34])[CH:30]=[CH:29][C:28]=2B(O)O)=[CH:25][CH:24]=[N:23]1.[O-]P([O-])([O-])=O.[K+].[K+].[K+].O1CCOC[CH2:49]1>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.O>[CH3:49][N:23]1[CH:24]=[CH:25][C:26]([C:27]2[CH:32]=[C:31]([C:33]([F:36])([F:35])[F:34])[CH:30]=[CH:29][C:28]=2[C:2]2[CH:11]=[CH:10][CH:9]=[C:8]3[C:3]=2[CH:4]=[CH:5][C:6]([S:12]([O:15][CH2:16][C:17]([F:20])([F:19])[F:18])(=[O:14])=[O:13])=[CH:7]3)=[N:22]1
Reactant: O=S(=O)(OCC(F)(F)F)c1ccc2c(Br)cccc2c1
Reactant: C1COCCO1
Reactant: Cn1nccc1-c1cc(C(F)(F)F)ccc1B(O)O
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=P([O-])([O-])[O-]
Agent: [K+]
Solvent: O
Product: Cn1ccc(-c2cc(C(F)(F)F)ccc2-c2cccc3cc(S(=O)(=O)OCC(F)(F)F)ccc23)n1
Temperature: 80 °C
Reaction time: 2 h

Procedure:
A reaction vial was charged with 2,2,2-trifluoroethyl 5-bromonaphthalene-2-sulfonate (0.082 g, 0.222 mmol), (2-(1-methyl-1H-pyrazol-5-yl)-4-(trifluoromethyl)phenyl)boronic acid (0.072 g, 0.267 mmol), potassium phosphate tribasic (0.074 mL, 0.889 mmol) and Pd(PPh3)4 (0.026 g, 0.022 mmol). To this solid mixture was added dioxane (1.010 mL) followed by water (0.101 mL). The head space of the vial was swept with nitrogen and the vial was heated in an oil bath to 80° C. After stirring for 2 hours, LC/MS indicated that the reaction was complete. This reaction mixture was transferred to a separatory funnel containing water and the aqueous layer was washed three times with EtOAc. The organic layers were combined, dried with MgSO4, filtered and concentrated to an oil. The mixture was concentrated and purified by MPLC using 80 g of silica gel eluting with 0 to 40% EtOAc in hexanes to afford 0.11 g of 2,2,2-trifluoroethyl 5-(2-(1-methyl-1H-pyrazol-3-yl)-4-(trifluoromethyl)phenyl)naphthalene-2-sulfonate.
Reaction SMILES: [C:1]([C:3]1[CH:8]=[CH:7][C:6]([OH:9])=[CH:5][CH:4]=1)#[N:2].[Br:10]N1C(=O)CCC1=O>C(O)(=O)C>[Br:10][C:5]1[CH:4]=[C:3]([CH:8]=[CH:7][C:6]=1[OH:9])[C:1]#[N:2]
Reactant: O=C1CCC(=O)N1Br
Reactant: N#Cc1ccc(O)cc1
Solvent: CC(=O)O
Product: N#Cc1ccc(O)c(Br)c1
Temperature: 25 °C
Reaction time: 18 h

Procedure:
A solution of 4-cyanophenol (30.0 g, 252 mmol) in acetic acid (450 ml) was treated with N-bromosuccinimide (44.8 g, 252 mmol). The reaction mixture was stirred at RT for 18 h, filtered and the filtrate was concentrated under reduced pressure. The crude material was purified by column chromatography (silica) eluting with chloroform and methanol (99:1) to afford the title compound as a brown solid.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([N:14]2[CH:18]=[C:17]([C:19]3[CH:20]=[N:21][C:22]([NH2:34])=[C:23](B4OC(C)(C)C(C)(C)O4)[CH:24]=3)[CH:16]=[N:15]2)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[Cl:35][C:36]1[CH:45]=[CH:44][C:43]([F:46])=[C:42]2[C:37]=1[CH:38]=[C:39](OS(C(F)(F)F)(=O)=O)[N:40]=[CH:41]2.C([O-])([O-])=O.[Cs+].[Cs+].O1CCOCC1.O>CCOC(C)=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:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([N:14]2[CH:18]=[C:17]([C:19]3[CH:20]=[N:21][C:22]([NH2:34])=[C:23]([C:39]4[N:40]=[CH:41][C:42]5[C:37]([CH:38]=4)=[C:36]([Cl:35])[CH:45]=[CH:44][C:43]=5[F:46])[CH:24]=3)[CH:16]=[N:15]2)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)N1CCC(n2cc(-c3cnc(N)c(B4OC(C)(C)C(C)(C)O4)c3)cn2)CC1
Reactant: O=S(=O)(Oc1cc2c(Cl)ccc(F)c2cn1)C(F)(F)F
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: [Cs+]
Solvent: C1COCCO1
Solvent: CCOC(C)=O
Solvent: O
Product: CC(C)(C)OC(=O)N1CCC(n2cc(-c3cnc(N)c(-c4cc5c(Cl)ccc(F)c5cn4)c3)cn2)CC1
Temperature: 100 °C

Procedure:
4-{4-[6-Amino-5-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-pyridin-3-yl]-pyrazol-1-yl}-piperidine-1-carboxylic acid tert-butyl ester (0.065 g, 0.14 mmol) (BB3), trifluoromethanesulfonic acid 5-chloro-8-fluoroisoquinolin-3-yl ester (0.040 g, 0.12 mmol), Cs2CO3 (75 mg, 0.23 mmol), and Pd(PPh3)4 (7 mg, 0.006 mmol) were placed in a sealable microwave tube, taken up in 1,4-dioxane (2 mL, 30 mmol) and H2O (0.54 mL, 30 mmol), flushed with nitrogen, sealed and heated in the microwave reactor at 100° C. for 30 minutes. The reaction mixture was diluted with EtOAc washed with water, brine, dried over Na2SO4, filtered and concentrated. The compound was purified by prep-TLC with 5% 7M NH3 in MeOH and DCM mixture yielding the title compound as pale yellow solid. MS (ES+): m/z=523.15/525.12 (100/40) [MH+]. HPLC: tR=3.03 min (ZQ2, polar—5 min).
Reaction SMILES: [Cl:1][C:2]1[C:7]([N+:8]([O-:10])=[O:9])=[CH:6][CH:5]=[C:4]([Cl:11])[C:3]=1[S:12](Cl)(=[O:14])=[O:13].Cl.[O:17]1[CH2:21][CH2:20][CH2:19][NH:18]1.C([N:24](CC)CC)C>>[O:17]1[CH2:21][CH2:20][CH2:19][N:18]1[C:6]1[CH:5]=[C:4]([Cl:11])[C:3]([S:12]([NH2:24])(=[O:14])=[O:13])=[C:2]([Cl:1])[C:7]=1[N+:8]([O-:10])=[O:9]
Reactant: O=[N+]([O-])c1ccc(Cl)c(S(=O)(=O)Cl)c1Cl
Reactant: C1CNOC1
Reactant: CCN(CC)CC
Agent: Cl
Product: NS(=O)(=O)c1c(Cl)cc(N2CCCO2)c([N+](=O)[O-])c1Cl
Yield: 67.4 %

Procedure:
Following the general procedure for sulfonamide formation outlined in example 1, 2,6-dichloro-3-nitrobenzenesulfonyl chloride (1.5 g, 5.2 mmol), isoxazolidine hydrochloride (0.56 g, 5.2 mmol) and triethylamine (2.2 mL, 15.5 mmol) were reacted to form the desired product (1.2 g, 71%). EI-MS m/z 327 (M+).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([Cl:8])[C:3]=1[C:9]1[C:34](=[O:35])[N:33]([CH3:36])[C:12]2[N:13]=[C:14]([NH:17][C:18]3[CH:23]=[CH:22][C:21]([O:24][CH2:25][CH2:26][N:27]4[CH2:32][CH2:31][CH2:30][CH2:29][CH2:28]4)=[CH:20][CH:19]=3)[N:15]=[CH:16][C:11]=2[CH:10]=1.[Br:37][CH2:38][C:39]1[N:43]([CH3:44])[CH:42]=[N:41][C:40]=1[N+:45]([O-:47])=[O:46].CCOCC>CN1C(=O)CCC1>[Br-:37].[Cl:8][C:4]1[CH:5]=[CH:6][CH:7]=[C:2]([Cl:1])[C:3]=1[C:9]1[C:34](=[O:35])[N:33]([CH3:36])[C:12]2[N:13]=[C:14]([NH:17][C:18]3[CH:19]=[CH:20][C:21]([O:24][CH2:25][CH2:26][N+:27]4([CH2:38][C:39]5[N:43]([CH3:44])[CH:42]=[N:41][C:40]=5[N+:45]([O-:47])=[O:46])[CH2:28][CH2:29][CH2:30][CH2:31][CH2:32]4)=[CH:22][CH:23]=3)[N:15]=[CH:16][C:11]=2[CH:10]=1
Reactant: Cn1c(=O)c(-c2c(Cl)cccc2Cl)cc2cnc(Nc3ccc(OCCN4CCCCC4)cc3)nc21
Reactant: Cn1cnc([N+](=O)[O-])c1CBr
Solvent: CN1CCCC1=O
Solvent: CCOCC
Product: Cn1cnc([N+](=O)[O-])c1C[N+]1(CCOc2ccc(Nc3ncc4cc(-c5c(Cl)cccc5Cl)c(=O)n(C)c4n3)cc2)CCCCC1
Product: [Br-]
Yield: 30.5 %

Procedure:
To a stirred solution of 6-(2,6-dichlorophenyl)-8-methyl-2-{4-[2-(1-piperidinyl)ethoxy]anilino}pyrido[2,3-d]pyrimidin-7(8H)-one (PD 166285 analogue B; Klutchko et al, J Med Chem, 1998, 41(17), 3276-3292) (230 mg, 0.44 mmol) in dry NMP (5 mL) was added 5-(bromomethyl)-1-methyl-4-nitro-1H-imidazole (122) (116 mg, 0.53 mmol). The resulting solution was then stirred at room temperature for 12 days before Et2O was added. The resulting precipitate was filtered and washed with EtOAc and CH2Cl2. The crude product was purified by precipitation from NMP/EtOAc (×2). The precipitate was filtered and dried under vacuum to give 1-[2-(4-{[6-(2,6-dichlorophenyl)-8-methyl-7-oxo-7,8-dihydropyrido[2,3-d]pyrimidin-2-yl]amino}phenoxy)ethyl]-1-[(1-methyl-4-nitro-1H-imidazol-5-yl)methyl]piperidinium bromide (143) (100 mg, 31%) as a pale yellow powder, m.p. 176-178° C. 1H NMR [(CD3)2SO] δ 10.14 (s, 1H), 8.82 (s, 1H), 8.14 (s, 1H), 7.89 (s, 1H), 7.80 (d, J=8.9 Hz, 2H), 7.59 (dd, J=8.1, 0.7 Hz, 2H), 7.46 (dd, J=8.8, 7.4 Hz, 1H), 7.10 (d, J=9.1 Hz, 2H), 5.22 (bs, 2H), 4.61 (t, J=4.4 Hz, 2H), 4.17 (bs, 2H), 3.86 (s, 3H), 3.72-3.64 (m, 2H), 3.65 (s, 3H), 2.10-1.95 (m, 4H), 1.74 (bd, J=14.3 Hz, 2H), 1.60 (bd, J=14.3 Hz, 1H), 1.46-1.31 (m, 1H), 2 protons not observed. Analysis found: C, 48.33; H, 4.64; N, 13.32. C32H33BrCl2N8O4.3H2O.¼EtOAc requires: C, 48.31; H, 5.04; N, 13.66.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][CH:6]=[C:5]2[CH2:11][CH2:12][NH:13][C:14](=[O:22])[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=1I.B(O)(O)[C:24]1[CH:25]=[CH:26][C:27]([CH3:30])=[CH:28][CH:29]=1.C(=O)([O-])[O-].[Na+].[Na+]>C(COC)OC.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>[Cl:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][CH:6]=[C:5]2[CH2:11][CH2:12][NH:13][C:14]([C:15]1[C:16]([C:24]2[CH:29]=[CH:28][C:27]([CH3:30])=[CH:26][CH:25]=2)=[CH:17][CH:18]=[CH:19][CH:20]=1)=[O:22]
Reactant: Cc1ccc(B(O)O)cc1
Reactant: O=C(NCCc1c[nH]c2ccc(Cl)cc12)c1ccccc1I
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: COCCOC
Solvent: O
Product: Cc1ccc(-c2ccccc2C(=O)NCCc2c[nH]c3ccc(Cl)cc23)cc1
Yield: 70.1 %

Procedure:
N-(2-(5-chloro-1H-indol-3-yl)ethyl)-4′-methylbiphenyl-2-carboxamide was prepared according to method B with N-(2-(5-chloro-1H-indol-3-yl)ethyl)-2-iodobenzamide (0.075 g; 0.176 mmol), p-tolylboronic acid (0.025 g; 0.176 mmol), tetrakis(triphenylphosphine)palladium (0.010 g; 0.009 mmol), sodium carbonate (0.037 g; 0.353 mmol), in dimethoxyethane (3 mL) and water (1 mL), irradiated in a microwave oven at 130° C. for 15 minutes. Flash chromatography on silica gel (eluent 2 to 10% ethyl acetate in dichloromethane) furnished 0.048 g (70%) of N-(2-(5-chloro-1H-indol-3-yl)ethyl)-4′-methylbiphenyl-2-carboxamide as a white solid.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:34])[C:4]1[C:9]([CH3:10])=[C:8]([O:11][CH3:12])[CH:7]=[C:6]([O:13][Si:14]([CH3:22])([CH3:21])[C:15]([CH3:20])([CH3:19])[CH:16]([CH3:18])[CH3:17])[C:5]=1[CH2:23][S:24][CH2:25][C@H:26]([NH2:33])[C:27]1[O:31][N:30]=[C:29]([CH3:32])[N:28]=1.[C:35](N1C=CC=CC1=O)(N1C=CC=CC1=O)=[S:36].[C:51]([NH2:59])(=[NH:58])[C:52]1[CH:57]=[CH:56][CH:55]=[CH:54][CH:53]=1>ClCCl>[CH3:1][O:2][C:3](=[O:34])[C:4]1[C:9]([CH3:10])=[C:8]([O:11][CH3:12])[CH:7]=[C:6]([O:13][Si:14]([CH3:21])([CH3:22])[C:15]([CH3:19])([CH3:20])[CH:16]([CH3:17])[CH3:18])[C:5]=1[CH2:23][S:24][CH2:25][C@H:26]([NH:33][C:35]([NH:58][C:51](=[NH:59])[C:52]1[CH:57]=[CH:56][CH:55]=[CH:54][CH:53]=1)=[S:36])[C:27]1[O:31][N:30]=[C:29]([CH3:32])[N:28]=1
Reactant: COC(=O)c1c(C)c(OC)cc(O[Si](C)(C)C(C)(C)C(C)C)c1CSC[C@H](N)c1nc(C)no1
Reactant: O=c1ccccn1C(=S)n1ccccc1=O
Reactant: N=C(N)c1ccccc1
Solvent: ClCCl
Product: COC(=O)c1c(C)c(OC)cc(O[Si](C)(C)C(C)(C)C(C)C)c1CSC[C@H](NC(=S)NC(=N)c1ccccc1)c1nc(C)no1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 91.3 %

Procedure:
To a stirred solution of 400 mg of (R)-2-[2-amino-2-(3-methyl-1,2,4-oxadiazol-5-yl)-ethylsulfanyl-methyl]-3-[dimethyl-(1,1,2-trimethyl-propyl)-silanyloxy]-5-methoxy-6-methyl-benzoic acid methyl ester in 20 ml of dry dichloromethane were added slowly 186 mg of 1,1'-thiocarbonyldi-2(1H)-pyridone. The red solution was stirred for 30 min at room temperature and then cooled in an ice bath. Upon the addition of 94 mg of benzamidine (~85%), stirring was continued for 1 h at 0° C. and for 10 h at 20° C. . The solution was evaporated in vacuo and the residue was chromatographed on silica gel using ethyl acetate/hexane (2:1, v/v) as eluent to afford 480 mg of (R)-3-[dimethyl-(1,1,2-trimethyl-propyl)-silanyloxy]-2-[2-[3-(iminophenyl-methyl)-thioureido]-2-(3-methyl-1,2,4-oxadiazol-5-yl)ethylsulfanylmethyl]-5-methoxy-6-methyl-benzoic acid methyl ester as a colorless oil.
Reaction SMILES: [C:1]([O:5][C:6]([C:8]1[CH:19]=[C:18]([O:20][C:21]2[CH:26]=[CH:25][C:24]([S:27]([CH3:30])(=[O:29])=[O:28])=[CH:23][CH:22]=2)[C:11]2[CH2:12][CH:13]([CH2:15][O:16][CH3:17])[O:14][C:10]=2[CH:9]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[C:31](OC(C1C=C(OC2C=CC(S(C)(=O)=O)=CC=2)C2CC(CO)(C)OC=2C=1)=O)(C)(C)C.CI>>[C:1]([O:5][C:6]([C:8]1[CH:19]=[C:18]([O:20][C:21]2[CH:26]=[CH:25][C:24]([S:27]([CH3:30])(=[O:29])=[O:28])=[CH:23][CH:22]=2)[C:11]2[CH2:12][C:13]([CH2:15][O:16][CH3:17])([CH3:31])[O:14][C:10]=2[CH:9]=1)=[O:7])([CH3:3])([CH3:4])[CH3:2]
Reactant: CC(C)(C)OC(=O)c1cc(Oc2ccc(S(C)(=O)=O)cc2)c2c(c1)OC(C)(CO)C2
Reactant: COCC1Cc2c(Oc3ccc(S(C)(=O)=O)cc3)cc(C(=O)OC(C)(C)C)cc2O1
Solvent: CI
Product: COCC1(C)Cc2c(Oc3ccc(S(C)(=O)=O)cc3)cc(C(=O)OC(C)(C)C)cc2O1

Procedure:
The title compound was prepared in a similar manner as described for Intermediate 201a, from 2-hydroxymethyl-4-(4-methanesulfonyl-phenoxy)-2-methyl-2,3-dihydro-benzofu ran-6-carboxylic acid tert-butyl ester (227d) and methyl iodide. 1H NMR (400 MHz, CDCl3) δ 7.88-7.93 (m, J=9.47, 2.78, 2.40 Hz, 2 H) 7.28 (s, 1 H) 7.21 (d, J=1.26 Hz, 1 H) 7.04-7.10 (m, 2 H) 3.41-3.50 (m, 2 H) 3.40 (s, 3 H) 3.10 (d, J=16.67 Hz, 1 H) 3.07 (s, 3 H) 2.75 (d, J=16.67 Hz, 1 H) 1.56 (s, 9 H) 1.46 (s, 3 H); LCMS for C23H28O7S m/z 449.00 (M+H)+.
Reaction SMILES: [H-].[Na+].C1COCC1.C(O[C:11](=[O:19])[C:12]1[CH:17]=[CH:16][C:15]([Cl:18])=[CH:14][CH:13]=1)C.[C:20](#[N:22])[CH3:21]>CCOCC>[Cl:18][C:15]1[CH:14]=[CH:13][C:12]([C:11]([CH2:21][C:20]#[N:22])=[O:19])=[CH:17][CH:16]=1
Reactant: CCOC(=O)c1ccc(Cl)cc1
Reactant: CC#N
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CCOCC
Product: N#CCC(=O)c1ccc(Cl)cc1
Temperature: 25 °C
Reaction time: 72 h

Procedure:
A 50% oil dispersion of NaH (24 grams) was placed in a 2 l. 3-necked flask and covered with 250 ml. THF. After heating to reflux, a solution composed of 55 ml. THF, ethyl-4-chlorobenzoate (57 grams), and acetonitrile (20.5 grams) was added in dropwise fashion. The reaction mixture started to solidify after the reactants were added so an additional 200 ml. of THF was added. The mixture was then heated to reflux for 21/2 hours, cooled to room temperature, treated with 1 l. ether, and allowed to stand for 72 hours.
Reaction SMILES: [CH3:1][O:2][C:3]1[C:8]([N+:9]([O-])=O)=[CH:7][CH:6]=[C:5]([O:12][CH3:13])[C:4]=1[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=1[CH3:20]>CO.[Pd]>[CH3:1][O:2][C:3]1[C:8]([NH2:9])=[CH:7][CH:6]=[C:5]([O:12][CH3:13])[C:4]=1[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=1[CH3:20]
Reactant: COc1ccc([N+](=O)[O-])c(OC)c1-c1ccccc1C
Agent: [Pd]
Solvent: CO
Product: COc1ccc(N)c(OC)c1-c1ccccc1C
Temperature: 50 °C
Yield: 78.8 %

Procedure:
Pd/C (0.1 g) was added to 2,6-dimethoxy-2′-methyl-3-nitrobiphenyl (0.2 g, 0.73 mmol) in methanol (20 ml), and under 1 atm of Hz, the mixture was heated at 50° C. for 2 h. Filtration and concentration gave 2,6-dimethoxy-2′-methylbiphenyl-3-ylamine (0.14 g) as a colorless oil, which was directly reacted further.
Reaction SMILES: [C:1]([CH2:4][CH2:5][NH:6][C:7]([C@:9]12[CH2:43][CH2:42][C@@H:41]([C:44]([CH3:46])=[CH2:45])[C@@H:10]1[C@@H:11]1[C@@:24]([CH3:27])([CH2:25][CH2:26]2)[C@@:23]2([CH3:28])[C@@H:14]([C@:15]3([CH3:40])[C@@H:20]([CH2:21][CH2:22]2)[C:19]([CH3:30])([CH3:29])[C:18]([C:31]2[CH:39]=[CH:38][C:34]([C:35]([OH:37])=[O:36])=[CH:33][CH:32]=2)=[CH:17][CH2:16]3)[CH2:13][CH2:12]1)=[O:8])([OH:3])=[O:2].C(N/C(=N/C(C)C)/O[CH2:53][CH2:54][Si:55]([CH3:58])([CH3:57])[CH3:56])(C)C>C1COCC1.CCOC(C)=O>[CH3:27][C@:24]12[C@@:23]3([CH3:28])[C@@H:14]([C@:15]4([CH3:40])[C@@H:20]([CH2:21][CH2:22]3)[C:19]([CH3:30])([CH3:29])[C:18]([C:31]3[CH:32]=[CH:33][C:34]([C:35]([O:37][CH2:53][CH2:54][Si:55]([CH3:58])([CH3:57])[CH3:56])=[O:36])=[CH:38][CH:39]=3)=[CH:17][CH2:16]4)[CH2:13][CH2:12][C@@H:11]1[C@H:10]1[C@H:41]([C:44]([CH3:46])=[CH2:45])[CH2:42][CH2:43][C@:9]1([C:7](=[O:8])[NH:6][CH2:5][CH2:4][C:1](=[O:3])[O:2][CH2:53][CH2:54][Si:55]([CH3:56])([CH3:57])[CH3:58])[CH2:26][CH2:25]2
Reactant: C=C(C)[C@@H]1CC[C@]2(C(=O)NCCC(=O)O)CC[C@]3(C)[C@H](CC[C@@H]4[C@@]5(C)CC=C(c6ccc(C(=O)O)cc6)C(C)(C)[C@@H]5CC[C@]43C)[C@@H]12
Reactant: CC(C)/N=C(/NC(C)C)OCC[Si](C)(C)C
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: C=C(C)[C@@H]1CC[C@]2(C(=O)NCCC(=O)OCC[Si](C)(C)C)CC[C@]3(C)[C@H](CC[C@@H]4[C@@]5(C)CC=C(c6ccc(C(=O)OCC[Si](C)(C)C)cc6)C(C)(C)[C@@H]5CC[C@]43C)[C@@H]12
Reaction time: 16 h
Yield: 88.3 %

Procedure:
A mixture of 4-((1R,3aS,5aR,5bR,7aR,11aS,11bR,13aR,13bR)-3a-(2-carboxyethylcarbamoyl)-5a,5b,8,8,11a-pentamethyl-1-(prop-1-en-2-yl)-2,3,3a,4,5,5a,5b,6,7,7a,8,11,11a,11b,12,13,13a,13b-octadecahydro-1H-cyclopenta[a]chrysen-9-yl)benzoic acid (35 mg, 0.056 mmol) and (Z)-2-(trimethylsilyl)ethyl N,N′-diisopropylcarbamimidate (27.2 mg, 0.111 mmol) was refluxed in THF (1 mL) for 4 h. Then the mixture was placed at room temperature for 16 h. TLC showed no starting material and a new less polar product Rf=0.4 in 10% AcOEt/Hex. The solvent was removed in vacuo. The residue was dissolved in methylene chloride and purified in silica gel (0-10% AcOEt/Hex) to afford 2-(trimethylsilyl)ethyl 4-((1R,3aS,5aR,5bR,7aR,11aS,11bR,13aR,13bR)-5a,5b,8,8,11a-pentamethyl-3a-(3-oxo-3-(2-(trimethylsilyl)ethoxy)propylcarbamoyl)-1-(prop-1-en-2-yl)-2,3,3a,4,5,5a,5b,6,7,7a,8,11,11a,11b,12,13,13a,13b-octadecahydro-1H-cyclopenta[a]chrysen-9-yl)benzoate (43 mg, 0.049 mmol, 89% yield) as a white solid. 1H NMR (400 MHz, CHLOROFORM-d) δ ppm 7.93 (d, J=8.28 Hz, 2H), 7.20 (d, J=8.03 Hz, 2H), 6.24 (t, J=6.02 Hz, 1H), 5.30 (d, J=4.77 Hz, 1H), 4.76 (d, J=1.51 Hz, 1H), 4.61 (s, 1H), 4.49-4.37 (m, 2H), 4.28-4.17 (m, 2H), 3.65-3.52 (m, 1H), 3.52-3.39 (m, 1H), 3.15 (td, J=10.85, 3.64 Hz, 1H), 2.63-2.43 (m, 3H), 2.11 (dd, J=17.19, 6.40 Hz, 1H), 2.02-1.90 (m, 2H), 1.80-1.04 (m, 22H), 1.70 (s, 3H), 1.01 (s, 3H), 1.00 (s, 3H), 0.98 (s, 3H), 0.93 (s, 6H), 0.10 (s, 9H), 0.06 (s, 9H).
Reaction SMILES: [NH2:1][C:2]1[C:7]([NH2:8])=[CH:6][CH:5]=[CH:4][C:3]=1[OH:9].[OH-:10].[Na+].[CH3:12][O:13][C:14]1[CH:22]=[CH:21][C:17]([C:18](Cl)=[O:19])=[CH:16][CH:15]=1>C(Cl)Cl>[CH3:12][O:13][C:14]1[CH:22]=[CH:21][C:17]([C:18]([O:10][O:9][C:3]2[CH:4]=[CH:5][CH:6]=[C:7]([NH:8][C:18](=[O:19])[C:17]3[CH:21]=[CH:22][C:14]([O:13][CH3:12])=[CH:15][CH:16]=3)[C:2]=2[NH:1][C:18](=[O:19])[C:17]2[CH:21]=[CH:22][C:14]([O:13][CH3:12])=[CH:15][CH:16]=2)=[O:19])=[CH:16][CH:15]=1
Reactant: Nc1cccc(O)c1N
Reactant: COc1ccc(C(=O)Cl)cc1
Reactant: [OH-]
Agent: [Na+]
Solvent: ClCCl
Product: COc1ccc(C(=O)Nc2cccc(OOC(=O)c3ccc(OC)cc3)c2NC(=O)c2ccc(OC)cc2)cc1
Temperature: 25 °C
Reaction time: 18 h
Yield: 74 %

Procedure:
2,3-Diaminophenol (2.48 g, 20 mmol) was dissolved in methylene chloride (200 mL) and the solution was cooled to ice-water bath temperature. Aqueous 5 N sodium hydroxide solution (126 mL) was added followed by 4-methoxybenzoyl chloride (8.6 mL, 63 mmol). The mixture was allowed to warm to room temperature and stirred for 18 h. The organic layer was separated and washed with dilute aqueous sodium hydroxide solution, dilute aqueous hydrochloric acid, and saturated aqueous sodium chloride solution. The organic layer was dried (sodium sulfate), filtered, and concentrated in vacuo to give 7.75 g (74%) of the title compound as a brown foam. This material was used without further purification.
Reaction SMILES: [OH:1][C:2]1[C:11]2[C:10]([CH3:13])([CH3:12])[CH2:9][CH2:8][C:7]([CH3:15])([CH3:14])[C:6]=2[C:5]([CH3:16])=[CH:4][CH:3]=1.[C:17](O)(=[O:19])C.C1N2CN3CN(C2)CN1C3.O>C1(C)C=CC=CC=1>[CH:17]([C:3]1[CH:4]=[C:5]([CH3:16])[C:6]2[C:7]([CH3:15])([CH3:14])[CH2:8][CH2:9][C:10]([CH3:12])([CH3:13])[C:11]=2[C:2]=1[OH:1])=[O:19]
Reactant: Cc1ccc(O)c2c1C(C)(C)CCC2(C)C
Reactant: CC(=O)O
Agent: C1N2CN3CN1CN(C2)C3
Solvent: Cc1ccccc1
Solvent: O
Product: Cc1cc(C=O)c(O)c2c1C(C)(C)CCC2(C)C
Temperature: 20 °C
Reaction time: 2.5 h

Procedure:
Formylation. 1-Hydroxy-4,5,5,8,8-pentamethyl-5,6,7,8-tetrahydronaphthalene (78 g, 0.358 mol) was stirred with glacial acetic acid (632 mL) and hexamethylenetetramine (93.6 g, 0.669 mol). The mixture was heated at 105°-110° C. for 10 h. Hot water (632 mL) was added and the heating was continued for an additional 2.5 h at 100° C. The mixture was cooled to 20° C., toluene (250 mL) was added, and the mixture was stirred vigorously. The organic layer was separated, washed with water (2×50 mL), then neutralized with 5% NaHCO3 solution, and finally washed with brine (50 mL). The solvent was removed by distillation and the residue distilled to yield 2-formyl-1-hydroxy-4,5,5,8,8-pentamethyl-5,6,7,8-tetrahydronaphthalene (45 g), bp 138°-146° C./1 mm, GLC purity 95%. 1H-NMR (CDCl3) δ11.63 (1H, s), 9.73 (1H, s), 7.09 (1H, s), 2.52 (3H, s), 1.66 (3H, s), 1.47 (6H, s), 1.42 (6H, s). 13C-NMR (CDCl3) δ196 (1C, d), 159 (1C, s), 155 (1C, s), 134.7 (1C, d), 134.1 (1C, s), 128 (1C, s), 118.1 (1C, s), 39.3 (1C, t), 37.8 (1C, t), 36.5 (1C, s), 35.2 (1C, s), 28.7 (2C, q), 27.9 (2C, q), 23.5 (1C, q). IR (KBr) 1637 cm- 1, MS (m/e) 246.2 (M+, 36.1), 231.2 (100.0), 161.2 (41.6), 189.1 (27.9).
Reaction SMILES: [N:1]1([CH2:6][C:7]2[CH:12]=[CH:11][C:10]([NH2:13])=[CH:9][C:8]=2[C:14]([F:17])([F:16])[F:15])[CH2:5][CH2:4][CH2:3][CH2:2]1.N1C=[CH:22][CH:21]=[CH:20][CH:19]=1.C([O-])([O-])=O.[Na+].[Na+].O.[CH3:31][CH2:32][O:33][C:34](C)=[O:35]>C1COCC1>[C:32]1([O:33][C:34](=[O:35])[NH:13][C:10]2[CH:11]=[CH:12][C:7]([CH2:6][N:1]3[CH2:5][CH2:4][CH2:3][CH2:2]3)=[C:8]([C:14]([F:15])([F:16])[F:17])[CH:9]=2)[CH:22]=[CH:21][CH:20]=[CH:19][CH:31]=1
Reactant: c1ccncc1
Reactant: Nc1ccc(CN2CCCC2)c(C(F)(F)F)c1
Reactant: CCOC(C)=O
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: O
Product: O=C(Nc1ccc(CN2CCCC2)c(C(F)(F)F)c1)Oc1ccccc1
Temperature: 0 °C
Reaction time: 1 h

Procedure:
A solution of 49 μl (0.39 mMol) phenyl chloroformiate in 1.5 ml THF is cooled to −70° C. Then a solution of 81 mg (0.33 mMol) 4-pyrrolidin-1-ylmethyl-3-trifluoromethyl-phenylamine and 0.3 ml pyridine in 1.5 ml THF is added dropwise. After 1 h, it is poured into a mixture of 20 g ice, 40 ml sat. Na2CO3/water 1:3 and 40 ml EtOAc. The aqueous layer is separated off and extracted 2× with EtOAc. The organic phases are washed with water and brine, dried (Na2SO4) and concentrated to the title compound: MS: [M+1]+=365; HPLC: AtRet=11.1.
Reaction SMILES: [NH2:1][CH2:2][CH2:3][CH2:4][N:5]1[C:13]([O:14][CH3:15])=[N:12][C:11]2[C:6]1=[N:7][C:8]([O:17][CH2:18][CH2:19][CH2:20][CH3:21])=[N:9][C:10]=2[NH2:16].[CH:22]([C:24]1[CH:29]=[CH:28][C:27]([CH2:30][C:31]([OH:33])=[O:32])=[CH:26][CH:25]=1)=O.[BH4-].[Na+]>C1COCC1.CO>[NH2:16][C:10]1[N:9]=[C:8]([O:17][CH2:18][CH2:19][CH2:20][CH3:21])[N:7]=[C:6]2[C:11]=1[N:12]=[C:13]([O:14][CH3:15])[N:5]2[CH2:4][CH2:3][CH2:2][NH:1][CH2:22][C:24]1[CH:25]=[CH:26][C:27]([CH2:30][C:31]([OH:33])=[O:32])=[CH:28][CH:29]=1
Reactant: CCCCOc1nc(N)c2nc(OC)n(CCCN)c2n1
Reactant: O=Cc1ccc(CC(=O)O)cc1
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Solvent: C1CCOC1
Product: CCCCOc1nc(N)c2nc(OC)n(CCCNCc3ccc(CC(=O)O)cc3)c2n1
Temperature: 25 °C
Reaction time: 4 h

Procedure:
The product from step (vii) (9.7 g) and (4-formylphenyl)acetic acid (5.4 g) were dissolved in THF (100 ml) and stirred at rt for 4 h. Sodium borohydride (1.9 g) and 5 drops of methanol was added and stirred at a rt overnight. The mixture was quenched with water and concentrated under reduced pressure. Water was added and washed with diethyl ether. 0.1N—HCl was added to acidify the solution to pH 6. The suspension was filtered and the solid collected and dried under reduced pressure to give the subtitle compound. Yield 13 g.
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[C:9]([Cl:12])[CH:10]=2)[CH:5]=[C:4]([N:13]([C:15]2[CH:28]=[CH:27][C:18]([O:19][CH:20]([CH3:26])[C:21]([O:23]CC)=[O:22])=[CH:17][CH:16]=2)[CH3:14])[N:3]=1.[CH3:29][O-:30].[Na+].C1(C)C=CC=CC=1>O>[Cl:12][C:9]1[CH:10]=[C:11]2[C:6]([CH:5]=[C:4]([N:13]([C:15]3[CH:28]=[CH:27][C:18]([O:19][CH:20]([CH3:26])[C:21]([OH:23])=[O:22])=[CH:17][CH:16]=3)[CH3:14])[N:3]=[C:2]2[O:30][CH3:29])=[CH:7][CH:8]=1
Reactant: CCOC(=O)C(C)Oc1ccc(N(C)c2cc3ccc(Cl)cc3c(Cl)n2)cc1
Reactant: C[O-]
Agent: [Na+]
Solvent: O
Solvent: Cc1ccccc1
Product: COc1nc(N(C)c2ccc(OC(C)C(=O)O)cc2)cc2ccc(Cl)cc12

Procedure:
A mixture of ethyl 2-{4-[N-(1,7-dichloroisoquinolin-3-yl)-N-methylamino]phenoxy}propionate (1.25 g), sodium methoxide (0.63 g) and toluene was heated under reflux for 4 hrs. The mixture was cooled, poured into water and extracted with ethyl acetate. The organic fraction was dried (MgSO4) and evaporated to give 2-{4-[N-(7-chloro-1-methoxyisoquinolin-3-yl)-N-methylamino]phenoxy}propionic acid.