Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl[C:2]1[C:7]([C:8]#[N:9])=[CH:6][C:5]([C:10]2[C:19]3[C:14](=[CH:15][C:16]([S:20]([NH:23][C:24]4[S:25][CH:26]=[N:27][N:28]=4)(=[O:22])=[O:21])=[CH:17][CH:18]=3)[CH:13]=[CH:12][N:11]=2)=[C:4]([O:29][CH3:30])[CH:3]=1.[F:31][C:32]1[CH:33]=[C:34](B(O)O)[CH:35]=[CH:36][CH:37]=1.C1(P(C2CCCCC2)C2C=CC=CC=2C2C(OC)=CC=CC=2OC)CCCCC1.P([O-])([O-])([O-])=O.[K+].[K+].[K+]>>[C:8]([C:7]1[CH:6]=[C:5]([C:10]2[C:19]3[C:14](=[CH:15][C:16]([S:20]([NH:23][C:24]4[S:25][CH:26]=[N:27][N:28]=4)(=[O:21])=[O:22])=[CH:17][CH:18]=3)[CH:13]=[CH:12][N:11]=2)[C:4]([O:29][CH3:30])=[CH:3][C:2]=1[C:36]1[CH:35]=[CH:34][CH:33]=[C:32]([F:31])[CH:37]=1)#[N:9]
Reactant: COc1cc(Cl)c(C#N)cc1-c1nccc2cc(S(=O)(=O)Nc3nncs3)ccc12
Reactant: OB(O)c1cccc(F)c1
Agent: COc1cccc(OC)c1-c1ccccc1P(C1CCCCC1)C1CCCCC1
Agent: O=P([O-])([O-])[O-]
Agent: [K+]
Product: COc1cc(-c2cccc(F)c2)c(C#N)cc1-c1nccc2cc(S(=O)(=O)Nc3nncs3)ccc12
Temperature: 120 °C
Yield: 48.8 %

Procedure:
A vial was charged with 1-(4-chloro-5-cyano-2-methoxyphenyl)-N-(1,3,4-thiadiazol-2-yl)isoquinoline-6-sulfonamide (Example 337, 55.6 mg, 0.121 mmol) (3-fluorophenyl)boronic acid (34.0 mg, 0.243 mmol), dicyclohexyl(2′,6′-dimethoxy-[1,1′-biphenyl]-2-yl)phosphine (2.492 mg, 6.07 μmol), chloro(2-dicyclohexylphosphino-2′,6′-dimethoxy-1,1′-biphenyl)[2-(2-aminoethylphenyl)]palladium(ii) dichloromethane (9.20 mg, 0.012 mmol), and potassium phosphate (129 mg, 0.607 mmol). The vial was flushed with Ar (g), then 1,4-dioxane (552 μl) and water (55.2 μl) were added. The vial was sealed and heated in a Biotage Initiator microwave reactor for 1 h at 120° C. The mixture was extracted with EtOAc (2×) and 10% MeOH/EtOAc (2×) and the combined organic extracts were dried over sodium sulfate, filtered, and concentrated. The residue was purified by chromatography on silica gel (12-g Redi-Sep Gold column, 0-7.5% MeOH/DCM, a few colored fractions were discarded). The resulting tan solid was taken up in DCM and filtered. The collected solid was washed with DCM (2×), dried under a stream of N2 (g), then dried under vacuum to give 1-(2-cyano-3′-fluoro-5-methoxy-[1,1′-biphenyl]-4-yl)-N-(1,3,4-thiadiazol-2-yl)isoquinoline-6-sulfonamide (30.69 mg, 0.059 mmol, 48.8% yield) as a white solid. 1H NMR (400 MHz, DMSO-d6) δ=14.49 (br. s., 1H), 8.79 (s, 1H), 8.73 (d, J=5.7 Hz, 1H), 8.59 (d, J=1.7 Hz, 1H), 8.17 (d, J=5.8 Hz, 1H), 7.96 (s, 1H), 7.90 (dd, J=1.9, 8.9 Hz, 1H), 7.80 (d, J=8.8 Hz, 1H), 7.68-7.57 (m, 3H), 7.45 (s, 1H), 7.41 (dt, J=1.7, 8.5 Hz, 1H), 3.82 (s, 3H). m/z (ESI) 518.2 (M+H)+.
Reaction SMILES: F[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[S:8]([NH:11][C:12]1[C:21]([C:22]([OH:24])=[O:23])=[C:20]2[C:15]([CH:16]3[CH2:25][CH:17]3[CH2:18][O:19]2)=[CH:14][CH:13]=1)(=[O:10])=[O:9].[CH2:26]([N:28]1[CH2:31][CH:30]([CH2:32][NH2:33])[CH2:29]1)[CH3:27]>CS(C)=O>[CH2:26]([N:28]1[CH2:31][CH:30]([CH2:32][NH:33][C:2]2[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=2[S:8]([NH:11][C:12]2[C:21]([C:22]([OH:24])=[O:23])=[C:20]3[C:15]([CH:16]4[CH2:25][CH:17]4[CH2:18][O:19]3)=[CH:14][CH:13]=2)(=[O:10])=[O:9])[CH2:29]1)[CH3:27]
Reactant: CCN1CC(CN)C1
Reactant: O=C(O)c1c(NS(=O)(=O)c2ccccc2F)ccc2c1OCC1CC21
Solvent: CS(C)=O
Product: CCN1CC(CNc2ccccc2S(=O)(=O)Nc2ccc3c(c2C(=O)O)OCC2CC32)C1

Procedure:
A mixture of (1aRS,7bSR)-5-(2-fluorobenzenesulfonylamino)-1,1a,2,7b-tetrahydrocyclopropa-[c]chromene-4-carboxylic (Intermediate 67, 0.07 g) and (1-ethylazetidin-3-yl)methylamine (Intermediate 149, 0.7 g) in DMSO (1.4 mL) was divided evenly between 7 microwave vials and each was irradiated in the microwave at 130° C. for 4 hours. After cooling, the combined mixture was concentrated under vacuum and the residue was purified by chromatography on silica, eluting with a mixture of methanol and DCM (10%). The product was repurified by HPLC (C18) to give (1aRS,7bSR)-5-{2-[(1-ethylazetidin-3-ylmethyl)amino]benzenesulfonylamino}-1,1a,2,7b-tetrahydrocyclopropa[c]chromene-4-carboxylic acid (0.012 g) as an off-white solid.
Reaction SMILES: Cl[CH2:2][CH2:3][CH2:4][C:5]#[C:6][CH2:7][CH2:8][CH2:9][CH2:10][CH3:11].[Br-:12].[Li+].CCOCC>C1COCC1>[Br:12][CH2:2][CH2:3][CH2:4][C:5]#[C:6][CH2:7][CH2:8][CH2:9][CH2:10][CH3:11]
Reactant: CCCCCC#CCCCCl
Reactant: [Br-]
Agent: [Li+]
Solvent: C1CCOC1
Solvent: CCOCC
Product: CCCCCC#CCCCBr

Procedure:
1-Bromodec-4-yne was prepared from 1-chlorodec-4-yne. The 1-chlorodec-4-yne (10.6 g, 61 mmol) and 25 g of lithium bromide were refluxed in 80 ml of THF for 21 hours. The conversion was 74%. Ether was added, the reaction mixture was washed with water (2×) and brine, dried over magnesium sulfate and stripped. The product was dissolved in 70 ml of THF and refluxed for 8 hours with an additional 25 g of lithium bromide. This gave 95% conversion of the chloride to the bromide. The same workup provided 11.36 g of 1-bromodec-4-yne.
Reaction SMILES: [CH3:1][N:2]1[CH2:7][CH2:6][C:5]2([C:18]3[C:10](=[CH:11][C:12]4[CH2:13][CH2:14][NH:15][C:16]=4[CH:17]=3)[O:9][CH2:8]2)[CH2:4][CH2:3]1.[CH3:19][C:20]1[O:24][N:23]=[C:22]([C:25]2[CH:30]=[CH:29][C:28]([C:31]3[CH:36]=[CH:35][C:34]([C:37](O)=[O:38])=[CH:33][CH:32]=3)=[CH:27][CH:26]=2)[N:21]=1>>[CH3:1][N:2]1[CH2:3][CH2:4][C:5]2([C:18]3[C:10](=[CH:11][C:12]4[CH2:13][CH2:14][N:15]([C:37]([C:34]5[CH:33]=[CH:32][C:31]([C:28]6[CH:29]=[CH:30][C:25]([C:22]7[N:21]=[C:20]([CH3:19])[O:24][N:23]=7)=[CH:26][CH:27]=6)=[CH:36][CH:35]=5)=[O:38])[C:16]=4[CH:17]=3)[O:9][CH2:8]2)[CH2:6][CH2:7]1
Reactant: Cc1nc(-c2ccc(-c3ccc(C(=O)O)cc3)cc2)no1
Reactant: CN1CCC2(CC1)COc1cc3c(cc12)NCC3
Product: Cc1nc(-c2ccc(-c3ccc(C(=O)N4CCc5cc6c(cc54)C4(CCN(C)CC4)CO6)cc3)cc2)no1

Procedure:
The title compound was prepared from 1'-methyl-2,3,6,7-tetrahydrospiro [furo[2,3-f]indole-3,4'-piperidine] (D8) and 4'-(5-methyl-1,2,4-oxadiazol-3-yl)biphenyl-4-carboxylic acid (D15), using a procedure similar to that of Example 1 (57%).
Reaction SMILES: Cl[CH2:2][CH2:3][CH2:4][S:5]([O:8][CH2:9][C:10]([CH3:36])([CH3:35])[C@@H:11]([O:27][CH2:28][C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1)[C:12]([O:14][CH2:15][CH2:16][O:17][C:18]([O:20][CH:21]1[CH2:26][CH2:25][CH2:24][CH2:23][CH2:22]1)=[O:19])=[O:13])(=[O:7])=[O:6].[N-:37]=[N+:38]=[N-:39].[Na+]>CS(C)=O>[N:37]([CH2:2][CH2:3][CH2:4][S:5]([O:8][CH2:9][C:10]([CH3:36])([CH3:35])[C@@H:11]([O:27][CH2:28][C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1)[C:12]([O:14][CH2:15][CH2:16][O:17][C:18]([O:20][CH:21]1[CH2:26][CH2:25][CH2:24][CH2:23][CH2:22]1)=[O:19])=[O:13])(=[O:7])=[O:6])=[N+:38]=[N-:39]
Reactant: CC(C)(COS(=O)(=O)CCCCl)[C@@H](OCc1ccccc1)C(=O)OCCOC(=O)OC1CCCCC1
Reactant: [N-]=[N+]=[N-]
Agent: [Na+]
Solvent: CS(C)=O
Product: CC(C)(COS(=O)(=O)CCCN=[N+]=[N-])[C@@H](OCc1ccccc1)C(=O)OCCOC(=O)OC1CCCCC1
Yield: 86.3 %

Procedure:
Following the general procedure for the preparation of azides of Description 16, 0.4 g (0.73 mmol) of (cyclohexyloxycarbonyloxy)ethyl (2R)-4-[(3-chloropropyl)sulfonyloxy]-3,3-dimethyl-2-(phenylmethoxy)butanoate (43a) dissolved in 4 mL of anhydrous dimethyl sulfoxide (DMSO) was reacted with 0.16 g (2.5 mmol) of sodium azide (NaN3). After work-up, 0.35 g (85% yield) of the title compound (43b) was obtained as a colorless oil. Rf=0.35 (EtOAc/Hxn=1:4). 1H NMR (400 MHz, CDCl3, both diastereomers): δ=1.06-1.08 (m, 6H), 1.25-1.58 (br. m, 9H), 1.72-1.78 (br. m, 2H), 1.88-1.96 (br. m, 2H), 2.03-2.10 (m, 2H), 3.10-3.16 (m, 2H), 3.44-3.48 (m, 2H), 3.84-3.85 (2s, 1H), 3.94-3.96 (2d, J=9.2, 8.8 Hz, 1H), 4.18-4.23 (2d, J=9.2, 9.2 Hz, 1H), 4.33-4.38 (2d, J=11.2 Hz, 11.6 Hz, 1H), 4.54-4.72 (m, 2H), 6.81-6.87 (m, 1H), 7.30-7.38 (m, 5H) ppm. MS (ESI) m/z 577.89 (M+Na)+. The analytical data was consistent with the proposed structure.
Reaction SMILES: CS(C)=O.C(Cl)(=O)C(Cl)=O.[Cl:11][C:12]1[C:17]2[O:18][C:19]3[C:28]([CH3:29])=[CH:27][C:26]([CH2:30][OH:31])=[CH:25][C:20]=3[S:21](=[O:24])(=[O:23])[CH2:22][C:16]=2[CH:15]=[C:14]([N:32]2[CH2:37][CH2:36][NH:35][CH2:34][CH2:33]2)[CH:13]=1.C(N(CC)CC)C>ClCCl>[Cl:11][C:12]1[C:17]2[O:18][C:19]3[C:28]([CH3:29])=[CH:27][C:26]([CH:30]=[O:31])=[CH:25][C:20]=3[S:21](=[O:23])(=[O:24])[CH2:22][C:16]=2[CH:15]=[C:14]([N:32]2[CH2:33][CH2:34][NH:35][CH2:36][CH2:37]2)[CH:13]=1
Reactant: Cc1cc(CO)cc2c1Oc1c(Cl)cc(N3CCNCC3)cc1CS2(=O)=O
Agent: O=C(Cl)C(=O)Cl
Solvent: ClCCl
Solvent: CS(C)=O
Solvent: CCN(CC)CC
Product: Cc1cc(C=O)cc2c1Oc1c(Cl)cc(N3CCNCC3)cc1CS2(=O)=O
Temperature: 22 °C
Reaction time: 0.5 h

Procedure:
DMSO (2.6 mL, 37.5 mmol) was added at −70° C. to a solution of oxalyl chloride (0.46 mL, 37.5 mmol) in dichloromethane (10 mL). Reaction mixture was stirred for 5 minutes and to this (4-chloro-6-methyl-10,10-dioxo-2-piperazin-1-yl-10,11-dihydro-5-oxa-10lambda*6*-thia-dibenzo[a,d]-cyclohepten-8-yl)-methanol (0.489 g, 1.19 mmol) [obtained by following the procedure described in Example 34] in dichloromethane (5 mL) was added. Reaction mixture was stirred for 5 minutes and to this triethylamine (8.4 mL, 62.5 mmol) was added. Reaction mixture was warmed to room temperature (22° C.) and stirred for 0.5 h. the reaction mixture was diluted with dichloromethane (200 mL), washed with water (100 mL), brine (50 mL) and dried over sodium sulphate. The crude product obtained was purified by column chromatography (silica gel, ethylacetate-pet ether) to obtain the title compound. Yield: 0.2 g (42%); 1H NMR (DMSO-d6, 300 MHz): δ 2.64 (s, 3H, CH3), 3.20 (s, 4H, 2CH2), 3.20 (s, 4H, 2CH2), 5.15 (s, 2H, CH2), 7.14 (d, 2H, Ar), 8.03 (s, 1H, Ar), 8.24 (s, 1H, Ar), 9.97 (s, 1H, CHO); MS: m/e (EI) 406 (M+).
Reaction SMILES: [CH3:1][C:2]1[C:3]([CH2:20][CH2:21][C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][C:23]=2[C:28]2([C:31]([NH2:33])=[O:32])[CH2:30][CH2:29]2)=[N:4][C:5]([NH:8][C:9]2[CH:10]=[N:11][N:12]([CH:14]3[CH2:19][CH2:18][NH:17][CH2:16][CH2:15]3)[CH:13]=2)=[N:6][CH:7]=1.C=O.[C:36](O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>CO>[CH3:1][C:2]1[C:3]([CH2:20][CH2:21][C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][C:23]=2[C:28]2([C:31]([NH2:33])=[O:32])[CH2:29][CH2:30]2)=[N:4][C:5]([NH:8][C:9]2[CH:10]=[N:11][N:12]([CH:14]3[CH2:19][CH2:18][N:17]([CH3:36])[CH2:16][CH2:15]3)[CH:13]=2)=[N:6][CH:7]=1
Reactant: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Reactant: Cc1cnc(Nc2cnn(C3CCNCC3)c2)nc1CCc1ccccc1C1(C(N)=O)CC1
Agent: C=O
Agent: [Na+]
Solvent: CO
Product: Cc1cnc(Nc2cnn(C3CCN(C)CC3)c2)nc1CCc1ccccc1C1(C(N)=O)CC1
Temperature: 25 °C
Reaction time: 4 h
Yield: 53 %

Procedure:
To a solution of 1-(2-(2-(5-methyl-2-((1-(piperidin-4-yl)-1H-pyrazol-4-yl)amino)pyrimidin-4-yl)ethyl)phenyl)cyclopropanecarboxamide A44 (0.064 g, 0.14 mmol) in MeOH (12 mL) was added formaldehyde solution (37% in water, 32 μL, 0.43 mmol) and sodium triacetoxyborohydride (0.122 g, 0.575 mmol) under a nitrogen atmosphere. The mixture was stirred at room temperature for 4 hours before concentrating under reduced pressure. The mixture was diluted with sat. aq. NaHCO3 (20 mL) and the aqueous phase was extracted with EtOAc (3×25 mL). The combined organics were washed with brine, and dried (MgSO4) before the solvent was removed in vacuo to give the title compound 48 as a white solid (0.035 g, 53%). LCMS-D: rt 2.89 min; m/z 460 [M+H]+.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[N:4][C:5](I)=[N:6][CH:7]=1.[CH2:9]([Sn](CCCC)(CCCC)C=C)[CH2:10]CC>C1COCC1.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>[Br:1][C:2]1[CH:3]=[N:4][C:5]([CH:9]=[CH2:10])=[N:6][CH:7]=1
Reactant: Brc1cnc(I)nc1
Reactant: C=C[Sn](CCCC)(CCCC)CCCC
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: C=Cc1ncc(Br)cn1
Temperature: 140 °C
Yield: 68.2 %

Procedure:
5-Bromo-2-iodo-pyrimidine (9.15 g, 32.11 mmol) was dissolved in THF (150 ml) and Pd(PPh3)4 (18.85 g, 1.60 mmol) was added, followed by tributyl-vinyl-stannane (9.38 ml, 32.11 mmol). The resulting mixture was heated at 140° C. for 20 min under microwave irradiations, next filtered through a pad of celite and concentrated. The crude material was diluted with CH2Cl2 and washed with water. Separation of the layers, drying (Na2SO4) of the organic phase, filtration and evaporation in vacuo provided the crude material, which was purified by flash column chromatography (CH2Cl2) to give the title compound (4.05 g, 68%) as a volatile yellow oil crystallizing at 4° C.
Reaction SMILES: [Cl:1][C:2]1[CH:27]=[CH:26][C:5]2[N:6]3[C:10]([CH2:11][NH:12][CH2:13][C:4]=2[CH:3]=1)=[N:9][N:8]=[C:7]3[CH:14]1[CH2:19][CH2:18][N:17]([C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][N:21]=2)[CH2:16][CH2:15]1.Br[CH2:29][C:30]([O:32][CH3:33])=[O:31].C(=O)([O-])[O-].[K+].[K+]>CN(C)C=O>[CH3:33][O:32][C:30](=[O:31])[CH2:29][N:12]1[CH2:11][C:10]2[N:6]([C:7]([CH:14]3[CH2:15][CH2:16][N:17]([C:20]4[CH:25]=[CH:24][CH:23]=[CH:22][N:21]=4)[CH2:18][CH2:19]3)=[N:8][N:9]=2)[C:5]2[CH:26]=[CH:27][C:2]([Cl:1])=[CH:3][C:4]=2[CH2:13]1
Reactant: COC(=O)CBr
Reactant: Clc1ccc2c(c1)CNCc1nnc(C3CCN(c4ccccn4)CC3)n1-2
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: COC(=O)CN1Cc2cc(Cl)ccc2-n2c(nnc2C2CCN(c3ccccn3)CC2)C1
Temperature: 25 °C
Reaction time: 72 h

Procedure:
A mixture of the amine from example 4 (500 mg, 1.31 mmol), methyl bromoacetate (260 mg, 1.70 mmol) and potassium carbonate (220 mg, 1.59 mmol) in N,N-dimethylformamide (15 ml) was stirred at room temperature for 72 hours. The mixture was evaporated under reduced pressure and the residue purified directly by column chromatography on silica gel using dichloromethane:methanol (93:7) as eluant to afford the title compound.
Reaction SMILES: Cl[C:2]1[C:9]([Cl:10])=[CH:8][CH:7]=[CH:6][C:3]=1[C:4]#[N:5].[C:11]([O:15][CH3:16])(=[O:14])[CH2:12][SH:13].C(=O)([O-])[O-].[Na+].[Na+].CCCCCC.CCOC(C)=O>CO>[NH2:5][C:4]1[C:3]2[CH:6]=[CH:7][CH:8]=[C:9]([Cl:10])[C:2]=2[S:13][C:12]=1[C:11]([O:15][CH3:16])=[O:14]
Reactant: COC(=O)CS
Reactant: N#Cc1cccc(Cl)c1Cl
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CCCCCC
Solvent: CO
Solvent: CCOC(C)=O
Product: COC(=O)c1sc2c(Cl)cccc2c1N
Yield: 12 %

Procedure:
The product from Example 56B (1.7 g, 10 mmol) was treated with 1 eq of methyl thioglycolate and 1 eq sodium carbonate in methanol as described in Example 41A to give after chromatography (4:1 hexane/EtOAc) the title compound in 12% yield. 1H NMR (300 MHz, CDCl3) d 3.81 (s, 3H), 5.90 (bs, 2H), 7.34 (t, J=8 Hz, 1H), 7.48 (dd, J=8.1 Hz, 1H), 7.56 (dd, J=8,1 Hz, 1H). MS (DCI/NH3) m/e 259 (M+NH4)+.
Reaction SMILES: [NH2:1][C@H:2]1[C@H:8]([C:9]2[CH:14]=[CH:13][C:12]([Cl:15])=[C:11]([Cl:16])[CH:10]=2)[O:7][CH2:6][CH2:5][N:4]([C:17]([O:19][C:20]([CH3:23])([CH3:22])[CH3:21])=[O:18])[CH2:3]1.[CH3:24][NH:25][S:26](=O)(=[O:35])[O:27]C1C=CC=CC=1O.C(N(CC)CC)C>C(#N)C.CN(C1C=CN=CC=1)C.C(OCC)(=O)C>[Cl:16][C:11]1[CH:10]=[C:9]([C@@H:8]2[O:7][CH2:6][CH2:5][N:4]([C:17]([O:19][C:20]([CH3:23])([CH3:22])[CH3:21])=[O:18])[CH2:3][C@H:2]2[NH:1][S:26](=[O:35])(=[O:27])[NH:25][CH3:24])[CH:14]=[CH:13][C:12]=1[Cl:15]
Reactant: CC(C)(C)OC(=O)N1CCO[C@@H](c2ccc(Cl)c(Cl)c2)[C@H](N)C1
Reactant: CNS(=O)(=O)Oc1ccccc1O
Agent: CN(C)c1ccncc1
Solvent: CC#N
Solvent: CCOC(C)=O
Solvent: CCN(CC)CC
Product: CNS(=O)(=O)N[C@@H]1CN(C(=O)OC(C)(C)C)CCO[C@H]1c1ccc(Cl)c(Cl)c1
Temperature: 80 °C
Reaction time: 8 h
Yield: 64.4 %

Procedure:
To a solution of tert-butyl (6R,7S)-6-amino-7-(3,4-dichlorophenyl)-1,4-oxazepane-4-carboxylate (100 mg) in acetonitrile (3 mL) were added 2-hydroxyphenyl methylsulfamate (86 mg), triethylamine (56 mg) and N,N-dimethyl-4-aminopyridine (3.3 mg) at room temperature, and the mixture was stirred at 80° C. overnight. The reaction mixture was diluted with ethyl acetate. The diluted solution was washed with distilled water and brine, and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure, and the residue was purified by silica gel chromatography (hexane/ethyl acetate) to give the title compound (81 mg).
Reaction SMILES: [CH3:1][O:2][C:3]([C@H:5]1[C@H:10](OS(C)(=O)=O)[CH2:9][CH2:8][C:7]2([CH2:20][CH2:19][CH2:18][CH2:17][CH2:16]2)[CH2:6]1)=[O:4].N12CCCN=C1CCCCC2.Cl>O1CCCC1>[CH3:1][O:2][C:3]([C:5]1[CH2:6][C:7]2([CH2:20][CH2:19][CH2:18][CH2:17][CH2:16]2)[CH2:8][CH2:9][CH:10]=1)=[O:4]
Reactant: COC(=O)[C@@H]1CC2(CCCCC2)CC[C@H]1OS(C)(=O)=O
Agent: Cl
Solvent: C1CCOC1
Solvent: C1CCC2=NCCCN2CC1
Product: COC(=O)C1=CCCC2(CCCCC2)C1
Temperature: 70 °C
Reaction time: 6 h
Yield: 92.6 %

Procedure:
To a solution of trans-3-methanesulfonyloxy-spiro[5.5]undecane-2-carboxylic acid methyl ester (3.0 g) obtained in Step 5 in tetrahydrofuran (20 mL) was added 1,8-diazabicyclo[5.4.0]undec-7-ene (2.65 mL), followed by stirring the reaction mixture at 70° C. for 6 hours. After cooling down to room temperature and adding 2N aqueous hydrochloric acid solution, the reaction mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine, dried and concentrated to give spiro[5.5]undec-2-ene-2-carboxylic acid methyl ester (1.9 g).
Reaction SMILES: O[C:2]1([CH3:28])[CH:7]([C:8]([O:10][CH3:11])=[O:9])[CH:6]([C:12]2[CH:17]=[CH:16][C:15]([C:18]([F:21])([F:20])[F:19])=[CH:14][CH:13]=2)[C:5]([C:22]([O:24][CH3:25])=[O:23])=[C:4]([NH:26][CH3:27])[CH2:3]1.S(Cl)(Cl)=O>N1C=CC=CC=1>[CH3:28][C:2]1[CH2:3][C:4]([NH:26][CH3:27])=[C:5]([C:22]([O:24][CH3:25])=[O:23])[CH:6]([C:12]2[CH:13]=[CH:14][C:15]([C:18]([F:19])([F:20])[F:21])=[CH:16][CH:17]=2)[C:7]=1[C:8]([O:10][CH3:11])=[O:9]
Reactant: CNC1=C(C(=O)OC)C(c2ccc(C(F)(F)F)cc2)C(C(=O)OC)C(C)(O)C1
Solvent: O=S(Cl)Cl
Solvent: c1ccncc1
Product: CNC1=C(C(=O)OC)C(c2ccc(C(F)(F)F)cc2)C(C(=O)OC)=C(C)C1
Temperature: 60 °C
Reaction time: 0.17 h

Procedure:
Dimethyl 6-methyl-4-methylamino-2-(4-trifluommethyl-phenyl)cyclohexa-3,5-diene-1,3-dicarboxylate (3) ##STR8## 10.0 g (25 mmol) of dimethyl 6-hydroxy-6-methyl-4-methylamino-2-(4-trifluoromethylphenyl)-cyclohex-3-ene-1,3-dicarboxylate (preparation analogous to Example II) are heated to 60° C. in 100 ml of pyridine and treated with 2.5 ml of thionyl chloride. The mixture is stirred at 60° C. for 10 minutes and concentrated, and the residue is taken up in methylene chloride, washed three times with water, dried and concentrated. The residue is grossly purified on 200 g of silica gel (petroleum ether/AcOEt=3:1) and then separated by MPLC (methylene chloride/AcOEt=30:1). Two fractions are obtained. 224 mg (2.3%) of dimethyl 4-methyl-6-methylamino-2-(4-trifluoromethylphenyl)-cyclohexa-3,6-diene-1,3-dicarboxylate (non-polar isomer (2)) crystallize from ether/petroleum ether. From the 2nd fraction, 2.29 g (22%) of the polar isomer, dimethyl 6-methyl-4-methylamino-2-(4-trifluoromethylphenyl)-cyclohexa-3,5-diene-1,3-dicarboxylate (3) are precipitated from AcOEt as the hydrochloride (Rf =0.47 (c)).
Reaction SMILES: [Br:1][C:2]1[S:6][C:5]([C:7](N(OC)C)=[O:8])=[C:4]([Cl:13])[CH:3]=1.[CH3:14][Mg+].[Br-]>C1COCC1>[Br:1][C:2]1[S:6][C:5]([C:7](=[O:8])[CH3:14])=[C:4]([Cl:13])[CH:3]=1
Reactant: CON(C)C(=O)c1sc(Br)cc1Cl
Reactant: C[Mg+]
Agent: [Br-]
Solvent: C1CCOC1
Product: CC(=O)c1sc(Br)cc1Cl
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 71.6 %

Procedure:
To a stirred solution of 5-bromo-3-chloro-N-methoxy-N-methylthiophene-2-carboxamide (1 g, 3.5 mmol) in THF (10 mL) was added MeMgBr (1.1 mL, 3.5 mmol) under N2 at RT. The mixture was stirred at RT for 0.5 h and quenched by aqueous NH4Cl. The resulting solution was extracted with EtOAc. The organic layers were dried over Na2SO4, concentrated and purified by column to give 0.6 g of 1-(5-bromo-3-chlorothiophen-2-yl)ethanone. MS (M+H): 239, 241. 1H NMR (400 MHz, CDCl3): δ 6.95 (s, 1H), 2.57 (s, 3H).
Reaction SMILES: [NH2:1][C:2]1[N:3]([CH2:14][C:15]2[CH:20]=[CH:19][C:18]([Cl:21])=[CH:17][CH:16]=2)[C:4]2[N:5]([CH2:11][CH2:12][N:13]=2)[C:6](=[O:10])[C:7]=1[N:8]=[O:9].[C:22](=S)=[S:23]>[Pd].CO>[OH2:9].[Cl:21][C:18]1[CH:19]=[CH:20][C:15]([CH2:14][N:3]2[C:2]3[NH:1][C:22](=[S:23])[NH:8][C:7]=3[C:6](=[O:10])[N:5]3[CH2:11][CH2:12][N:13]=[C:4]23)=[CH:16][CH:17]=1
Reactant: S=C=S
Reactant: NC1=C(N=O)C(=O)N2CCN=C2N1Cc1ccc(Cl)cc1
Agent: [Pd]
Solvent: CO
Product: O
Product: O=C1c2[nH]c(=S)[nH]c2N(Cc2ccc(Cl)cc2)C2=NCCN12
Temperature: 25 °C
Reaction time: 16 h

Procedure:
A mixture of 5% palladium on carbon (1 g.) and 2.0 g. (0.0066 mole) of the product of Procedure 1 in MeOH (50 ml.) was hydrogenated until H2 uptake ceased. The catalyst was removed and carbon disulfide (0.5 g. 0.0066 mole) was added. The solution was refluxed for 4 hrs. and stirred at room temperature for 16 hrs. The mixture was concentrated in vacuo and the residue suspended in H2O (50 ml.), and refluxed for 6 hrs., cooled, and 1.55 g. of solid collected by filtration. The solid was dissolved in dil. NaOH, treated with activated carbon, and reprecipitated with HOAc to give 1.18 g. of product, m.p. 232°-235°.
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[N:5]=[C:4]([N:12]2[CH2:18][CH2:17][CH2:16][C:15]3[CH:19]=[CH:20][CH:21]=[CH:22][C:14]=3[CH2:13]2)[CH:3]=1.[C:23]([O:27][C:28]([N:30]1[C@@H:34]([CH:35]=[CH2:36])[CH2:33][O:32][C:31]1([CH3:38])[CH3:37])=[O:29])([CH3:26])([CH3:25])[CH3:24].CN(C1CCCCC1)C1CCCCC1.CN(C)C=O>C(OCC)(=O)C.CC(C)([P](C(C)(C)C)([Pd][P](C(C)(C)C)(C(C)(C)C)C(C)(C)C)C(C)(C)C)C>[CH3:37][C:31]1([CH3:38])[N:30]([C:28]([O:27][C:23]([CH3:26])([CH3:25])[CH3:24])=[O:29])[C@@H:34](/[CH:35]=[CH:36]/[C:2]2[C:11]3[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=3)[N:5]=[C:4]([N:12]3[CH2:18][CH2:17][CH2:16][C:15]4[CH:19]=[CH:20][CH:21]=[CH:22][C:14]=4[CH2:13]3)[CH:3]=2)[CH2:33][O:32]1
Reactant: C=C[C@H]1COC(C)(C)N1C(=O)OC(C)(C)C
Reactant: Clc1cc(N2CCCc3ccccc3C2)nc2ccccc12
Agent: CC(C)(C)[P]([Pd][P](C(C)(C)C)(C(C)(C)C)C(C)(C)C)(C(C)(C)C)C(C)(C)C
Agent: CN(C1CCCCC1)C1CCCCC1
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: CC(C)(C)OC(=O)N1[C@@H](/C=C/c2cc(N3CCCc4ccccc4C3)nc3ccccc23)COC1(C)C
Temperature: 120 °C
Reaction time: 2.5 h
Yield: 76.1 %

Procedure:
The mixture of 2-(4-chloroquinolin-2-yl)-2,3,4,5-tetrahydro-1H-2-benzazepine (310 mg, 1.0 mmol), (S)-2,2-dimethyl-4-vinyl-oxazolidine-3-carboxylic acid tert-butyl ester (273 mg, 1.2 mmol), bis(tri-tert-butylphosphine)palladium(0) (51 mg, 0.1 mmol), methyl dicyclohexylamine (293 mg, 1.5 mmol) and N,N-dimethylformamide (6 mL) was heated with stirring in a 20 mL microwave process vial for 2.5 hours at 120° C. under microwave irradiation. The reaction mixture was diluted with ethyl acetate and washed with brine. The organic layer was dried over sodium sulfate, and then concentrated under reduced pressure to give a residue which was purified by flash column to give 380 mg of product as a white solid (yield was 76%). MS obsd. (ESI+) [(M+H)+] 500.
Reaction SMILES: [OH:1][CH2:2][C@@H:3]1[CH2:7][C:6](=[CH2:8])[CH2:5][C@H:4]1[C:9]1[CH:14]=[CH:13][CH:12]=[C:11]([F:15])[CH:10]=1.[CH2:16](Br)[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1.[H-].[Na+]>CN(C=O)C.CCOCC>[CH2:16]([O:1][CH2:2][C@H:3]1[CH2:7][C:6](=[CH2:8])[CH2:5][C@@H:4]1[C:9]1[CH:14]=[CH:13][CH:12]=[C:11]([F:15])[CH:10]=1)[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1
Reactant: BrCc1ccccc1
Reactant: C=C1C[C@@H](CO)[C@H](c2cccc(F)c2)C1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CCOCC
Product: C=C1C[C@H](COCc2ccccc2)[C@@H](c2cccc(F)c2)C1
Temperature: 25 °C
Reaction time: 24 h
Yield: 90.4 %

Procedure:
To a solution of (+)-trans-1-hydroxymethyl-4-methylene-2-(3-fluorophenyl)cyclopentane (5.0 g, 26.5 mmol) from Example 1, Step C and benzyl bromide (4.7 mL, 40 mmol) in DMF (130 mL) was added 60% sodium hydride in mineral oil (0.77 g, 32 mmol). The reaction was stirred at room temperature for 24 h was then diluted with ether and slowly quenched into aq. sodium bicarbonate. After three ether extractions, the organic layers were combined, washed with brine, dried over sodium sulfate, filtered and concentrated in vacuo. The residue was purified by FC (2–5% ethyl acetate in hexanes) to afford the title compound (7.1 g).