Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]([F:30])([F:29])[C:3]1[CH:4]=[C:5]([C@H:13]2[O:17][C:16](=[O:18])[N:15]([CH2:19][C:20]3[C:25](Br)=[CH:24][CH:23]=[C:22]([Cl:27])[N:21]=3)[C@H:14]2[CH3:28])[CH:6]=[C:7]([C:9]([F:12])([F:11])[F:10])[CH:8]=1.C(=O)([O-])[O-].[K+].[K+].[F:37][C:38]1[C:43]([CH:44]([CH3:46])[CH3:45])=[CH:42][C:41](B(O)O)=[C:40]([O:50][CH3:51])[CH:39]=1>C1COCC1>[F:1][C:2]([F:30])([F:29])[C:3]1[CH:4]=[C:5]([C@H:13]2[O:17][C:16](=[O:18])[N:15]([CH2:19][C:20]3[C:25]([C:41]4[CH:42]=[C:43]([CH:44]([CH3:46])[CH3:45])[C:38]([F:37])=[CH:39][C:40]=4[O:50][CH3:51])=[CH:24][CH:23]=[C:22]([Cl:27])[N:21]=3)[C@H:14]2[CH3:28])[CH:6]=[C:7]([C:9]([F:12])([F:11])[F:10])[CH:8]=1
Reactant: C[C@H]1[C@@H](c2cc(C(F)(F)F)cc(C(F)(F)F)c2)OC(=O)N1Cc1nc(Cl)ccc1Br
Reactant: COc1cc(F)c(C(C)C)cc1B(O)O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: C1CCOC1
Product: COc1cc(F)c(C(C)C)cc1-c1ccc(Cl)nc1CN1C(=O)O[C@H](c2cc(C(F)(F)F)cc(C(F)(F)F)c2)[C@@H]1C
Temperature: 32 °C
Yield: 78 %

Procedure:
To (4S,5R)-5-[3,5-bis(trifluoromethyl)phenyl]-3-[(3-bromo-6-chloropyridin-2-yl)methyl]-4-methyl-1,3-oxazolidin-2-one (INTERMEDIATE 32) (460 mg, 0.889 mmol) in THF (10 mL) was added potassium carbonate (2 M in water, 1.3 mL, 2.67 mmol), 1,1′-bis(diphenylphosphino)ferrocene-palladium(II)dichloride dichloromethane complex (57.9 mg, 0.089 mmol) and (4-fluoro-5-isopropyl-2-methoxyphenyl)boronic acid (INTERMEDIATE 59) (283 mg, 1.33 mmol). The reaction was degassed with nitrogen and heated at 32° C. for 16 hr. The reaction was then poured into brine and extracted with ethyl acetate (2×10 mL). The combined extracts were dried over sodium sulfate, filtered, and concentrated. The residue was purified via flash chromatography on silica gel to afford (4S,5R)-5-[3,5-bis(trifluoromethyl)phenyl]-3-({6-chloro-3-[4-fluoro-2-methoxy-5-(propan-2-yl)phenyl]pyridin-2-yl}methyl)-4-methyl-1,3-oxazolidin-2-one (419.4 mg, 0.693 mmol) LCMS calc.=605.1. found=605.1.
Reaction SMILES: C[O:2][C:3](=[O:31])[C:4]1[CH:9]=[CH:8][C:7]([NH:10][C:11]([NH:13][C:14]2[CH:23]=[CH:22][C:21]3[CH:20]([N:24]([CH:26]4[CH2:28][CH2:27]4)[CH3:25])[CH2:19][CH2:18][C:17]([CH3:30])([CH3:29])[C:16]=3[CH:15]=2)=[O:12])=[CH:6][CH:5]=1.[OH-].[Na+].Cl>CO.O1CCCC1>[CH:26]1([N:24]([CH3:25])[CH:20]2[CH2:19][CH2:18][C:17]([CH3:29])([CH3:30])[C:16]3[CH:15]=[C:14]([NH:13][C:11](=[O:12])[NH:10][C:7]4[CH:6]=[CH:5][C:4]([C:3]([OH:31])=[O:2])=[CH:9][CH:8]=4)[CH:23]=[CH:22][C:21]2=3)[CH2:28][CH2:27]1
Reactant: COC(=O)c1ccc(NC(=O)Nc2ccc3c(c2)C(C)(C)CCC3N(C)C2CC2)cc1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CO
Product: CN(C1CC1)C1CCC(C)(C)c2cc(NC(=O)Nc3ccc(C(=O)O)cc3)ccc21
Temperature: 25 °C
Reaction time: 8 h
Yield: 27.8 %

Procedure:
A solution of 4-{3-[5-(cyclopropyl-methyl-amino)-8,8-dimethyl-5,6,7,8-tetrahydro-naphthalen-2-yl]-ureido}-benzoic acid methyl ester (Intermediate 59, 0.045 g, 0.106 mmol) in methanol (2 mL) and tetrahydrofuran (3 mL) was treated with a 2M solution of sodium hydroxide (1 mL, 2 mmol) and the resulting reaction mixture was stirred at ambient temperature overnight. The reaction mixture was neutralized with 5% aqueous hydrochloric acid and extracted with ethyl acetate. The organic phase was washed with water and brine, and dried over anhydrous magnesium sulfate, filtered and evaporated in vacuo to afford a solid that was recrystallized from hot acetonitrile to afford the title product as a white solid (0.012 g, 28%).
Reaction SMILES: [CH:1](Br)=[CH2:2].[Mg].[Cl:5][C:6]1[CH:19]=[CH:18][C:9]([C:10]([C:12]2[CH:13]=[N:14][CH:15]=[CH:16][CH:17]=2)=[O:11])=[CH:8][CH:7]=1.[Cl-].[NH4+]>O1CCCC1.O>[Cl:5][C:6]1[CH:19]=[CH:18][C:9]([C:10]([C:12]2[CH:13]=[N:14][CH:15]=[CH:16][CH:17]=2)([OH:11])[CH:1]=[CH2:2])=[CH:8][CH:7]=1
Reactant: C=CBr
Reactant: O=C(c1ccc(Cl)cc1)c1cccnc1
Agent: [Cl-]
Agent: [Mg]
Agent: [NH4+]
Solvent: C1CCOC1
Solvent: O
Product: C=CC(O)(c1ccc(Cl)cc1)c1cccnc1
Yield: 88.8 %

Procedure:
A solution of vinylbromide (38.4 g, 359 mmol) in 100 ml tetrahydrofuran was added to a mixture of magnesium (9.15 g, 377 mmol) in 40 ml tetrahydrofuran under a nitrogen atmosphere at 50° to 60° C. After reflux for 1 h 3-(4-chlorobenzoyl)pyridine (62.4 g, 287 mmol) in 250 ml tetrahydrofuran was added at 10° C. After stirring for 1 h a solution of 20 g ammonium chloride in 100 ml water was added and the mixture filtered. The organic phase was evaporated and the residue taken up in ether and treated with charcoal. After filtration the solvent was evaporated to give 62.6 g (89%) of a brownish oil which solidified. Recrystallisation from toluene gave a product having m.p. 82.5°-84° C.
Reaction SMILES: [CH3:1][NH:2][CH2:3][CH2:4][C:5]1[CH:10]=[CH:9][C:8]([C:11]2[N:15]=[CH:14][N:13]([C:16]3[CH:21]=[CH:20][C:19]([O:22][C:23]([F:26])([F:25])[F:24])=[CH:18][CH:17]=3)[N:12]=2)=[CH:7][CH:6]=1.[CH:27]([C:30]1[CH:35]=[CH:34][C:33]([CH3:36])=[CH:32][C:31]=1[N:37]1[C:41](=[O:42])[CH2:40][S:39]/[C:38]/1=[N:43]\[C:44](=[O:55])OC1C=CC([N+]([O-])=O)=CC=1)([CH3:29])[CH3:28]>>[CH:27]([C:30]1[CH:35]=[CH:34][C:33]([CH3:36])=[CH:32][C:31]=1[N:37]1[C:41](=[O:42])[CH2:40][S:39]/[C:38]/1=[N:43]\[C:44](=[O:55])[N:2]([CH3:1])[CH2:3][CH2:4][C:5]1[CH:10]=[CH:9][C:8]([C:11]2[N:15]=[CH:14][N:13]([C:16]3[CH:21]=[CH:20][C:19]([O:22][C:23]([F:24])([F:26])[F:25])=[CH:18][CH:17]=3)[N:12]=2)=[CH:7][CH:6]=1)([CH3:28])[CH3:29]
Reactant: CNCCc1ccc(-c2ncn(-c3ccc(OC(F)(F)F)cc3)n2)cc1
Reactant: Cc1ccc(C(C)C)c(N2C(=O)CS/C2=N\C(=O)Oc2ccc([N+](=O)[O-])cc2)c1
Product: Cc1ccc(C(C)C)c(N2C(=O)CS/C2=N\C(=O)N(C)CCc2ccc(-c3ncn(-c4ccc(OC(F)(F)F)cc4)n3)cc2)c1

Procedure:
The title compound was prepared as described in Example 95 using N-methyl-2-(4-(1-(4-(trifluoromethoxy)phenyl)-1H-1,2,4-triazol-3-yl)phenyl)ethanamine (CB24) and (Z)-4-nitrophenyl (3-(2-isopropyl-5-methylphenyl)-4-oxothiazolidin-2-ylidene)carbamate (CA50), purified by flash column chromatography using 0-100% ethyl acetate/B, where B=1:1 dichloromethane/hexanes, as eluent and isolated as a pale orange foam (0.160 g, 63%).
Reaction SMILES: [CH:1]1([O:7][CH2:8][C:9]2[N:13]3[CH:14]=[CH:15][C:16]([SH:18])=[CH:17][C:12]3=[N:11][C:10]=2[CH:19]([CH3:21])[CH3:20])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.C(N(CC)CC)C.[CH3:29][N:30]([CH3:34])[C:31](Cl)=[O:32].C(=O)([O-])O.[Na+]>ClCCCl>[CH3:29][N:30]([CH3:34])[C:31](=[O:32])[S:18][C:16]1[CH:15]=[CH:14][N:13]2[C:9]([CH2:8][O:7][CH:1]3[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6]3)=[C:10]([CH:19]([CH3:21])[CH3:20])[N:11]=[C:12]2[CH:17]=1
Reactant: CC(C)c1nc2cc(S)ccn2c1COC1CCCCC1
Reactant: CN(C)C(=O)Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCCl
Solvent: CCN(CC)CC
Product: CC(C)c1nc2cc(SC(=O)N(C)C)ccn2c1COC1CCCCC1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 46.6 %

Procedure:
3-Cyclohexyloxymethyl-2-isopropylimidazo[1,2-a]pyridine-7-thiol (210 mg, 0.691 mmol) obtained in step 1 was dissolved in 1,2-dichloroethane (2.0 mL). Under ice-cooled condition, triethylamine (0.140 mL, 1.00 mmol) and dimethylcarbamoyl chloride (0.0770 mL, 0.834 mmol) were added, and the mixture was stirred at room temperature for 30 minutes. After adding a saturated sodium hydrogen carbonate aqueous solution to the reaction mixture, the reaction mixture was filtered through a Presep (registered trademark; diatomaceous earth, granular type M, 4.5 g/25 mL). The solvent was then evaporated under reduced pressure. The residue was purified by silica gel column chromatography (hexane/ethyl acetate=70/30) to give S-3-(cyclohexyloxymethyl)-2-isopropylimidazo[1,2-a]pyridin-7-yl dimethylthiocarbamate (121 mg, yield 47%).
Reaction SMILES: C([O:8][C:9]1[CH:10]=[CH:11][CH:12]=[C:13]2[C:17]=1[NH:16][CH:15]=[C:14]2[CH2:18][CH2:19][OH:20])C1C=CC=CC=1.C([O-])=O.[NH4+]>C(O)C.[Pd]>[OH:20][CH2:19][CH2:18][C:14]1[C:13]2[C:17](=[C:9]([OH:8])[CH:10]=[CH:11][CH:12]=2)[NH:16][CH:15]=1
Reactant: OCCc1c[nH]c2c(OCc3ccccc3)cccc12
Agent: [Pd]
Agent: O=C[O-]
Agent: [NH4+]
Solvent: CCO
Product: OCCc1c[nH]c2c(O)cccc12
Temperature: 25 °C
Yield: 76.3 %

Procedure:
To a solution of 2-(7-(benzyloxy)-1H-indol-3-yl)ethanol (6.31 g, 23.6 mmol) in ethanol (130 mL) are added ammonium formate (6.3 g, 99.9 mmol) and 10% palladium on carbon (50% wet, 555 mg), and the mixture is refluxed for one hour. The reaction solution is cooled to room temperature, and filtered through celite. The solvent is evaporated, and the obtained crude product is purified by silica gel column chromatography (n-hexane:ethyl acetate=1:1) to give 3-(2-hydroxyethyl)-1H-indol-7-ol (3.19 g, 18.0 mmol, yield: 76%).
Reaction SMILES: [SH:1][CH2:2][CH2:3][NH:4][C:5](=[O:11])[O:6][C:7]([CH3:10])([CH3:9])[CH3:8].[CH2:12]([O:19][C:20]([NH:22]/[C:23](=[CH:28]\[C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1)/[C:24]([O:26][CH3:27])=[O:25])=[O:21])[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1.C(N(CC)CC)C>CO>[CH2:12]([O:19][C:20]([NH:22][CH:23]([CH:28]([S:1][CH2:2][CH2:3][NH:4][C:5]([O:6][C:7]([CH3:8])([CH3:10])[CH3:9])=[O:11])[C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1)[C:24]([O:26][CH3:27])=[O:25])=[O:21])[C:13]1[CH:14]=[CH:15][CH:16]=[CH:17][CH:18]=1
Reactant: CC(C)(C)OC(=O)NCCS
Reactant: COC(=O)/C(=C/c1ccccc1)NC(=O)OCc1ccccc1
Solvent: CO
Solvent: CCN(CC)CC
Product: COC(=O)C(NC(=O)OCc1ccccc1)C(SCCNC(=O)OC(C)(C)C)c1ccccc1
Temperature: 25 °C
Reaction time: 72 h

Procedure:
Using a method similar to that described in Example 1, part b (Method B) a solution of tert-butyl N-(2-mercaptoethyl)carbamate (2.4 mL), methyl (2Z)-2-{[(benzyloxy)carbonyl]amino}-3-phenylprop-2-enoate (0.87 g), triethylamine (0.39 mL) and methanol (15 mL) was stirred at RT for 3 days. Removal of the solvent and chromatograpy of the resultant crude oil on silica gel (10% to 25% ethyl acetate/hexanes) returned the title compound as a viscous oil (1.22 g, 90%). The proton NMR displayed a mixture of diastereomers of approximate ratio 7:3; the major diastereomer is reported. 1HNMR (300 MHz, CDCl3) δ 1.41 (s, 9H), 2.48 (t, 2H), 3.19 (br, 2H), 3.65 (s, 3H), 4.12 (q, 1H), 4.35 (t, 1H), 4.73 (t, 2H), 5.09 (d, 2H), 7.27-7.34 (m, 10H). MS APCI, m/z=389(M−t-BuOCO)+. HPLC Method A: 3.47 min.
Reaction SMILES: [Br-:1].[Br-].[Br-].C1([N+](C)(C)C)C=CC=CC=1.C1([N+](C)(C)C)C=CC=CC=1.C1([N+](C)(C)C)C=CC=CC=1.[F:34][C:35]1[CH:40]=[CH:39][C:38]([C:41]2([CH3:46])[O:45][CH2:44][CH2:43][O:42]2)=[CH:37][C:36]=1[S:47]([NH2:50])(=[O:49])=[O:48]>CC#N>[Br:1][CH2:46][C:41]1([C:38]2[CH:39]=[CH:40][C:35]([F:34])=[C:36]([S:47]([NH2:50])(=[O:49])=[O:48])[CH:37]=2)[O:45][CH2:44][CH2:43][O:42]1
Reactant: [Br-]
Reactant: CC1(c2ccc(F)c(S(N)(=O)=O)c2)OCCO1
Agent: C[N+](C)(C)c1ccccc1
Solvent: CC#N
Product: NS(=O)(=O)c1cc(C2(CBr)OCCO2)ccc1F
Temperature: 25 °C
Reaction time: 1 h
Yield: 61.5 %

Procedure:
A solution of 8.4 g (0.0225 mole) of phenyltrimethylammonium tribromide in 20 mL of CH3CN was added dropwise to a solution of 5.2 g (0.022 mole) 2-fluoro-5(2-methyl-[1,3]dioxolan-2-yl)-benzenesulfonamide III in 100 mL of CH3CN. The reaction was stirred at room temperature for 1 hr. The solvent was evaporated in vacuo. The residue was dissolved in EtOAc, washed with water, dried over Na2SO4 and evaporated. The residue was purified by column chromatography on silica gel eluting with CH2Cl2/Et2O::9/1 to give 4.6 g of IV (62%) as an oil. CH2Cl2/Et2O::9/1 single-spot material Rƒ 0.30.1H NMR (300 MHz CDCl3) δ: (3.68, s, 2H), (3.80,m , 2H), (4.21, m, 2H), 5.15, broad s, 2H), (7.26, t, 1H), (7.75, m, 1H), 8.15, dd, 1H).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[N:9]([S:10]([C:13]3[CH:18]=[CH:17][C:16]([O:19][CH3:20])=[CH:15][CH:14]=3)(=[O:12])=[O:11])[C:8](=[O:21])[N:7]([CH:22]([C:44]3[CH:49]=[CH:48][CH:47]=[CH:46][CH:45]=3)[C:23]([N:25]3[CH2:30][CH2:29][N:28]([CH:31]4[CH2:36][CH2:35][N:34](C(OC(C)(C)C)=O)[CH2:33][CH2:32]4)[CH2:27][CH2:26]3)=[O:24])[C:6]=2[CH:50]=1.FC(F)(F)C(O)=O>ClCCl>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[N:9]([S:10]([C:13]3[CH:14]=[CH:15][C:16]([O:19][CH3:20])=[CH:17][CH:18]=3)(=[O:12])=[O:11])[C:8](=[O:21])[N:7]([CH:22]([C:44]3[CH:45]=[CH:46][CH:47]=[CH:48][CH:49]=3)[C:23](=[O:24])[N:25]3[CH2:26][CH2:27][N:28]([CH:31]4[CH2:32][CH2:33][NH:34][CH2:35][CH2:36]4)[CH2:29][CH2:30]3)[C:6]=2[CH:50]=1
Reactant: COc1ccc(S(=O)(=O)n2c(=O)n(C(C(=O)N3CCN(C4CCN(C(=O)OC(C)(C)C)CC4)CC3)c3ccccc3)c3cc(Cl)ccc32)cc1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: COc1ccc(S(=O)(=O)n2c(=O)n(C(C(=O)N3CCN(C4CCNCC4)CC3)c3ccccc3)c3cc(Cl)ccc32)cc1
Temperature: 25 °C

Procedure:
122 mg (0.17 mmol) of tert-butyl 4-(4-{2-[6-chloro-3-(4-methoxybenzenesulfonyl)-2-oxo-2,3-dihydrobenzimidazol-1-yl]-2-phenylacetyl}piperazin-1-yl)piperidine-1-carboxylate (Example 127) were dissolved in dichloromethane (3 ml) and while stirring at room temperature, trifluoroacetic acid (3 ml) was added. The reaction solution was stirred for 2 h and then the solvent and excess trifluoroacetic acid were removed in vacuo. The residue was taken up again in toluene, concentrated in vacuo and then dried in vacuo. The residue was dissolved in 15 ml of dichloromethane/methanol (9:1), mixed with 4 eq. of Si-carbonate (Silicycle, 0.69 mmol/g) and stirred at room temperature for 2 h. The solid phase reagent was filtered off and washed with dichloromethane. The filtrate was concentrated under reduced pressure and dried in vacuo. Yield: 105 mg (100%) of colorless oil.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:9]2([CH:13]([NH2:17])[CH2:14][CH2:15][CH3:16])[CH2:12][CH2:11][CH2:10]2)[CH:5]=[CH:6][C:7]=1[Cl:8].[C:18]([O:22][CH3:23])(=[O:21])[CH:19]=[CH2:20]>C1(C)C=CC=CC=1>[Cl:1][C:2]1[CH:3]=[C:4]([C:9]2([CH:13]([NH:17][CH2:20][CH2:19][C:18]([O:22][CH3:23])=[O:21])[CH2:14][CH2:15][CH3:16])[CH2:12][CH2:11][CH2:10]2)[CH:5]=[CH:6][C:7]=1[Cl:8]
Reactant: C=CC(=O)OC
Reactant: CCCC(N)C1(c2ccc(Cl)c(Cl)c2)CCC1
Solvent: Cc1ccccc1
Product: CCCC(NCCC(=O)OC)C1(c2ccc(Cl)c(Cl)c2)CCC1
Reaction time: 20 h

Procedure:
A mixture of 1-[1-(3,4-dichlorophenyl)cyclobutyl]butylamine (2 g), methyl acrylate (2 g) and toluene (10 ml) was heated under reflux with stirring for a total of 20 hours. Methyl acrylate (0.5 ml) was added, and heating under reflux and stirring were continued for 3 days. The solvent was removed in vacuo, and the oily residue as purified by chromatography on a silica column using a mixture of 9 parts petroleum ether (b.p. 40°-60°) and 1 part acetone as eluant. From the eluate methyl 3-{1-[1-(3,4-dichlorophenyl)cyclobutyl]butylamino}propanoate was obtained as a pale yellow oil, the physical properties of which were not determined.
Reaction SMILES: [OH:1][CH2:2]/[CH:3]=[CH:4]/[C:5]1[CH:14]=[CH:13][C:8]2[C:9](=[O:12])[O:10][CH2:11][C:7]=2[CH:6]=1.ClC1C=C(C=CC=1)C(O)=[O:20]>C(Cl)Cl>[OH:1][CH2:2][CH:3]1[O:20][CH:4]1[C:5]1[CH:14]=[CH:13][C:8]2[C:9](=[O:12])[O:10][CH2:11][C:7]=2[CH:6]=1
Reactant: O=C1OCc2cc(/C=C/CO)ccc21
Reactant: O=C(O)c1cccc(Cl)c1
Solvent: ClCCl
Product: O=C1OCc2cc(C3OC3CO)ccc21
Reaction time: 2 h

Procedure:
A solution of 5-[(1E)-3-hydroxyprop-1-en-1-yl]-2-benzofuran-1(3H)-one (2.0 g, 10.5 mmol) in 50 mL of DCM was cooled to 0° C. and meta-chlorobenzoic acid (2.14 g, 10.53 mmol) in DCM (100 mL) was added dropwise. The temperature of the reaction mixture was then allowed to rise to RT. After 2 hours, the mixture was filtered and the filtrate was partitioned between DCM and water. The organic layer was washed with water (20 mL) and brine (20 mL), dried over Na2SO4, and concentrated in vacuo. The residue was purified with silica gel chromatography (petrol ether/EtOAc=2:1) to give the title product.
Reaction SMILES: [NH2:1][C@@H:2]([CH:5]([CH2:8][CH3:9])[CH2:6][CH3:7])[CH2:3][OH:4].[Cl:10][C:11]1[S:15][C:14]([S:16](Cl)(=[O:18])=[O:17])=[CH:13][CH:12]=1>CCN(CC)CC>[Cl:10][C:11]1[S:15][C:14]([S:16]([NH:1][C@H:2]([CH2:3][OH:4])[CH:5]([CH2:8][CH3:9])[CH2:6][CH3:7])(=[O:18])=[O:17])=[CH:13][CH:12]=1
Reactant: CCC(CC)[C@H](N)CO
Reactant: O=S(=O)(Cl)c1ccc(Cl)s1
Solvent: CCN(CC)CC
Product: CCC(CC)[C@@H](CO)NS(=O)(=O)c1ccc(Cl)s1
Yield: 91 %

Procedure:
Accordingly, the intermediate (S)-2-amino-3-ethyl pentan-1-ol (9) is condensed with 5-chlorothiophene-2-sulfonyl chloride in the presence of Et3N to obtain (S)—N-(5-chlorothiophene-2-sulfonyl)-β,β-diethylalaninol, in 91% yield and 98% ee (determined by chiral HPLC).
Reaction SMILES: [CH:1]1[C:10]2CCCC[C:5]=2C=C[C:2]=1[OH:11].O.Cl[C:14]1[C:15](=O)[C:16](C#N)=[C:17]([C:22]#[N:23])[C:18](=[O:21])[C:19]=1Cl>O1CCOCC1>[OH:21][C:18]1[C:17]([C:22]#[N:23])=[CH:16][C:15]2[C:2](=[O:11])[CH2:1][CH2:10][CH2:5][C:14]=2[CH:19]=1
Reactant: N#CC1=C(C#N)C(=O)C(Cl)=C(Cl)C1=O
Reactant: Oc1ccc2c(c1)CCCC2
Solvent: C1COCCO1
Solvent: O
Product: N#Cc1cc2c(cc1O)CCCC2=O
Temperature: 25 °C
Reaction time: 3 h
Yield: 40 %

Procedure:
5,6,7,8-tetrahydro-2-naphthalenol prepared in method II-2 (1.5 g, 8.7 mmol) was dissolved in 1,4-dioxane (8 mL) in a 100 mL round bottom flask. To this was added water (2 mL), and 2,3-dichloro-5,6-dicyano-1,4-benzoquinone (DDQ) (4.1 g, 18.2 mmol, 2.1 eq) in anhydrous 1,4-dioxane (16 mL) dropwise. The reaction mixture turned to black immediately after addition and resulting mixture was stirred at room temperature for 3 h. The mixture was filtered and the filtrate was evaporated in vacuo. The residue was participated between EtOAc and saturated aqueous sodium bicarbonate. The aqueous layer was acidified to about pH 3 and was extracted with EtOAc three times. The organic layers were combined and evaporated in vacuo. Purification using MPLC chromatography (Biotage) gave 0.64 g (40%) of 3-hydroxy-8-oxo-5,6,7,8-tetrahydronaphthalene-2-carbonitrile as a light brown solid.
Reaction SMILES: [S:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[C:6]1[CH:11]=[CH:10][C:9]([CH2:12]O)=[CH:8][N:7]=1.C(N(C(C)C)CC)(C)C.FC(F)(F)S(OS(C(F)(F)F)(=O)=O)(=O)=O.C([N:57]1[CH:61]=[C:60]([CH2:62][C:63]2[CH:68]=[CH:67][C:66]([C:69]#[N:70])=[CH:65][CH:64]=2)[N:59]=[CH:58]1)(C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>ClCCl>[S:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[C:6]1[CH:11]=[CH:10][C:9]([CH2:12][N:59]2[C:60]([CH2:62][C:63]3[CH:68]=[CH:67][C:66]([C:69]#[N:70])=[CH:65][CH:64]=3)=[CH:61][N:57]=[CH:58]2)=[CH:8][N:7]=1
Reactant: N#Cc1ccc(Cc2cn(C(c3ccccc3)(c3ccccc3)c3ccccc3)cn2)cc1
Reactant: OCc1ccc(-c2cccs2)nc1
Agent: O=S(=O)(OS(=O)(=O)C(F)(F)F)C(F)(F)F
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: N#Cc1ccc(Cc2cncn2Cc2ccc(-c3cccs3)nc2)cc1
Temperature: -78 °C
Reaction time: 1 h

Procedure:
To a solution of 2-(thien-2-yl)-5-hydroxymethylpyridine (255 mg, 1.33 mmol) and diisopropylethylamine (0.464 mL, 2.66 mmol) in dichloromethane (7 mL) at -78° C. is added trifluoromethanesulfonic anhydride (0.224 mL, 1.33 mmol) and the mixture stirred at -78° C. for 1 hour. To this mixture is added a solution of 1-trityl-4-(4-cyanobenzyl)-imidazole (566 mg, 1.33 mmol) in dichloromethane (5 mL). The mixture is allowed to warm to ambient temperature and stirred for 2 hours. The solvent is evaporated in vacuo. The residue is dissolved in methanol (50 mL), heated at reflux for 1 hour, and the solvent is evaporated in vacuo. The residue is partitioned between dichloromethane and sat. aq. NaHCO3 solution. The organic layer is dried, (Na2SO4) and the solvent evaporated in vacuo. The residue is chromatographed to afford the title compound.
Reaction SMILES: [Br:1][C:2]1[S:6][C:5]([C:7]([O:9][CH3:10])=[O:8])=[C:4]([NH:11]C(=O)C(F)(F)F)[CH:3]=1.C(=O)([O-])[O-].[K+].[K+].CO>O>[NH2:11][C:4]1[CH:3]=[C:2]([Br:1])[S:6][C:5]=1[C:7]([O:9][CH3:10])=[O:8]
Reactant: COC(=O)c1sc(Br)cc1NC(=O)C(F)(F)F
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CO
Product: COC(=O)c1sc(Br)cc1N
Temperature: 25 °C
Reaction time: 2 h
Yield: 87.6 %

Procedure:
A mixture of methyl 5-bromo-3-[(trifluoroacetyl)amino]thiophene-2-carboxylate (5.3 g), potassium carbonate (10 g), methanol (100 mL) and water (25 mL) was stirred at room temperature for 2 hr. The reaction system was concentrated under reduced pressure, and ethyl acetate and water were poured thereinto. The mixture was extracted with ethyl acetate, washed with brine, and dried over anhydrous sodium sulfate. Insoluble material was removed by filtration, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate/hexane) to give the title compound (3.3 g) as a yellow solid.
Reaction SMILES: C([O:5][C:6]([C:8]1[CH:21]=[CH:20][C:11]2[CH2:12][CH2:13][O:14][C:15](=[O:19])[N:16]([CH2:17][CH3:18])[C:10]=2[CH:9]=1)=[O:7])(C)(C)C>C(O)(C(F)(F)F)=O.C(Cl)Cl>[CH2:17]([N:16]1[C:10]2[CH:9]=[C:8]([C:6]([OH:7])=[O:5])[CH:21]=[CH:20][C:11]=2[CH2:12][CH2:13][O:14][C:15]1=[O:19])[CH3:18]
Reactant: CCN1C(=O)OCCc2ccc(C(=O)OC(C)(C)C)cc21
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CCN1C(=O)OCCc2ccc(C(=O)O)cc21
Yield: 99.5 %

Procedure:
A solution of 5-ethyl-6-oxo-5,6,8,9-tetrahydro-7-oxa-5-aza-benzocycloheptene-3-carboxylic acid tert-butyl ester (0.91 g, 3.12 mmol) was stirred in TFA/DCM (1:1, 3 mL) for 16 hours. The reaction was concentrated to provide 5-ethyl-6-oxo-5,6,8,9-tetrahydro-7-oxa-5-aza-benzocycloheptene-3-carboxylic acid (0.73 g).
Reaction SMILES: [Cl:1][C:2]1[C:3]([C:22]2[S:26][C:25]([C:27]3([F:31])[CH2:30][CH2:29][CH2:28]3)=[N:24][CH:23]=2)=[C:4]2[CH:10]=[C:9](I)[N:8]([S:12]([C:15]3[CH:21]=[CH:20][C:18]([CH3:19])=[CH:17][CH:16]=3)(=[O:14])=[O:13])[C:5]2=[N:6][CH:7]=1.CC1(C)C(C)(C)OB([C:40]2[CH:41]=[N:42][N:43]([CH2:45][CH2:46][N:47]3[CH2:52][CH2:51][O:50][CH2:49][CH2:48]3)[CH:44]=2)O1.C(=O)(O)[O-]>CN(C)C=O.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>[Cl:1][C:2]1[C:3]([C:22]2[S:26][C:25]([C:27]3([F:31])[CH2:30][CH2:29][CH2:28]3)=[N:24][CH:23]=2)=[C:4]2[CH:10]=[C:9]([C:40]3[CH:41]=[N:42][N:43]([CH2:45][CH2:46][N:47]4[CH2:52][CH2:51][O:50][CH2:49][CH2:48]4)[CH:44]=3)[N:8]([S:12]([C:15]3[CH:21]=[CH:20][C:18]([CH3:19])=[CH:17][CH:16]=3)(=[O:14])=[O:13])[C:5]2=[N:6][CH:7]=1
Reactant: Cc1ccc(S(=O)(=O)n2c(I)cc3c(-c4cnc(C5(F)CCC5)s4)c(Cl)cnc32)cc1
Reactant: CC1(C)OB(c2cnn(CCN3CCOCC3)c2)OC1(C)C
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: O=C([O-])O
Solvent: CN(C)C=O
Product: Cc1ccc(S(=O)(=O)n2c(-c3cnn(CCN4CCOCC4)c3)cc3c(-c4cnc(C5(F)CCC5)s4)c(Cl)cnc32)cc1
Temperature: 70 °C

Procedure:
To a stirred ambient solution of 5-(5-chloro-2-iodo-1-tosyl-1H-pyrrolo[2,3-b]pyridin-4-yl)-2-(1-fluorocyclobutyl)thiazole (Example 114A) (60 mg, 0.102 mmol) and 4-(2-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazol-1-yl)ethyl)morpholine (37.6 mg, 0.122 mmol) in N,N-dimethylformamide (0.765 mL) was added saturated aqueous bicarbonate solution (0.765 mL) followed by bis(triphenylphosphine)palladium dichloride (5.01 mg, 7.14 μmol). The mixture was heated to 70° C. for 4 hours and was then quenched by the addition of water and ethyl acetate. The layers were separated, and the aqueous layer was extracted with additional ethyl acetate. The combined organics were dried with anhydrous sodium sulfate, filtered and concentrated under reduced pressure. MS ESI(+) m/z 641.2 [M+H]+.
Reaction SMILES: [CH3:1][N:2]([CH3:20])[CH2:3][CH2:4][CH2:5][O:6][C:7]1[CH:12]=[CH:11][C:10]([NH2:13])=[CH:9][C:8]=1[C:14]1[N:15]([CH3:19])[N:16]=[CH:17][CH:18]=1.[CH3:21][O:22][C:23]1[CH:28]=[CH:27][C:26]([N:29]=[C:30]=[O:31])=[CH:25][CH:24]=1>>[CH3:20][N:2]([CH3:1])[CH2:3][CH2:4][CH2:5][O:6][C:7]1[CH:12]=[CH:11][C:10]([NH:13][C:30]([NH:29][C:26]2[CH:27]=[CH:28][C:23]([O:22][CH3:21])=[CH:24][CH:25]=2)=[O:31])=[CH:9][C:8]=1[C:14]1[N:15]([CH3:19])[N:16]=[CH:17][CH:18]=1
Reactant: CN(C)CCCOc1ccc(N)cc1-c1ccnn1C
Reactant: COc1ccc(N=C=O)cc1
Product: COc1ccc(NC(=O)Nc2ccc(OCCCN(C)C)c(-c3ccnn3C)c2)cc1
Reaction time: 2 h
Yield: 89.6 %

Procedure:
To a solution of 4-(3-dimethylamino-propoxy)-3-(2-methyl-2H-pyrazol-3-yl)-phenylamine (38.3 mg, 0.140 mmol) in CH3Cl2 (2 mL) was added 4-methoxyphenyl isocyanate (0.21 μL, 0.162 mmol) and stirred for two hours. The resulting material was purified by solid phase extraction (SCX, 1 gram cartridge), eluting with methanol (30 mL) followed by 2M NH3 in methanol (30 mL). The NH3 containing fractions were dried in vacuo to afford Compound 131 as a colorless solid (53.1 mg, 90%). LCMS m/z (%)=424 (MH+) (100), 1H NMR (400 MHz, DMSO-d6) δ: 8.49 (bs, 1H), 8.43 (bs, 1H), 7.44 (d, J=1.86 Hz, 1H), 7.42 (dd, J=8.92, 2.73 Hz, 1H), 7.36 (d, J=2.71 Hz, 1H), 7.33 (d, J=9.09 Hz, 2H), 7.07 (d, J=8.96 Hz, 1H), 6.85 (d, J=9.09 Hz, 2H), 6.23 (d, J=1.82 Hz, 1H), 3.96 (t, J=6.35 Hz, 2H), 3.71 (s, 3H), 3.65 (s, 3H), 2.18 (t, J=7.05 Hz, 2H), 2.07 (s, 6H), 1.77-1.69 (m, 2H).