Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: F[B-](F)(F)F.[F:6][S:7]([F:19])([F:18])([F:17])([F:16])[C:8]1[CH:13]=[CH:12][C:11]([N+]#N)=[CH:10][CH:9]=1.[CH3:20][C:21]1[CH:28]=[CH:27][C:24]([CH:25]=[CH2:26])=[CH:23][CH:22]=1>C(O)C.C([O-])(=O)C.[Pd+2].C([O-])(=O)C>[CH3:20][C:21]1[CH:28]=[CH:27][C:24](/[CH:25]=[CH:26]/[C:11]2[CH:12]=[CH:13][C:8]([S:7]([F:19])([F:18])([F:17])([F:16])[F:6])=[CH:9][CH:10]=2)=[CH:23][CH:22]=1
Reactant: C=Cc1ccc(C)cc1
Reactant: N#[N+]c1ccc(S(F)(F)(F)(F)F)cc1
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: F[B-](F)(F)F
Solvent: CCO
Product: Cc1ccc(/C=C/c2ccc(S(F)(F)(F)(F)F)cc2)cc1
Temperature: 70 °C
Yield: 82.3 %

Procedure:
A solution of 1 (10.0 mg, 0.0315 mmol) in 0.4 mL of 95% aqueous ethanol was added dropwise to a solution of 4-methylstyrene (9.0 mg, 0.076 mmol) and palladium(II) acetate (0.2 mg, 0.0009 mmol) in 0.12 g of 95% aqueous ethanol. The reaction mixture was heated on an oil bath at 70° C. for 5 h. After cooling, the mixture was filtered through a pad of Celite 545 and purified by SiO2 column chromatography (9:1 hexane/CH2Cl2) to give 2c (8.3 mg, 82% yield) as colorless crystals; m.p. 165.2-166.5° C. IR (ATR): {tilde over (v)}=1593, 1514, 1450, 1416, 1329, 1265, 1098, 972, 962, 841 cm−1. MS (GC, EI): m/z=320 [M+], 193 [M+-F5S], 178 [M+-CH3F5S]. 1H NMR (500 MHz, CDCl3): δ=7.72 (d, J=8.8 Hz, 2H), 7.54 (d, J=8.5 Hz, 2H), 7.43 (d, J=8.1 Hz, 2H), 7.19 (d, J=8.0 Hz, 2H), 7.16 (d, J=16.4 Hz, 1H), 7.04 (d, J=16.4 Hz, 1H), 2.38 (s, 3H) ppm. 13C NMR (125 MHz, CDCl3): δ=152.3 (C), 140.8 (C), 138.6 (C), 133.6 (C), 131.9 (CH), 129.5 (2CH), 126.7 (2CH), 126.3 (2CH), 126.2 (2CH), 125.3 (CH), 21.3 (CH3) ppm. 19F NMR (470 MHz, CDCl3): δ=85.1 (quint, J=150 Hz, 1 F), 63.1 (d, J=150 Hz, 4 F) ppm.
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>C(Cl)(Cl)Cl>[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: COC(=O)[C@]1(C)CCc2c(C)c(O)c(C)c(C)c2O1
Reactant: BrCCCCCBr
Solvent: ClC(Cl)Cl
Product: COC(=O)[C@]1(C)CCc2c(C)c(OCCCCCBr)c(C)c(C)c2O1
Yield: 88.5 %

Procedure:
Using the procedure and molar proportions of example 71, (S)-(-)-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 (S)-(-)-6-[(5-bromopentyl)oxy]-3,4-dihydro-2,5,7,8-tetramethyl-2H-1-benzopyran-2-carboxylic acid methyl ester, [α]D25 -35.60° (c2, CHCl3), in 88.5% yield.
Reaction SMILES: [CH2:1]1[O:13][C:12]2[CH:11]=[C:10]3[C:5]([C:6](=O)[CH2:7][CH:8]=[N:9]3)=[CH:4][C:3]=2[O:2]1.O=P(Cl)(Cl)[Cl:17]>>[Cl:17][C:6]1[C:5]2[C:10](=[CH:11][C:12]3[O:13][CH2:1][O:2][C:3]=3[CH:4]=2)[N:9]=[CH:8][CH:7]=1
Reactant: O=C1CC=Nc2cc3c(cc21)OCO3
Reactant: O=P(Cl)(Cl)Cl
Product: Clc1ccnc2cc3c(cc12)OCO3

Procedure:
6,7-Methylenedioxy-4-quinolone (5.0 g, 26.5 mmol) was boiled in POCl3 (75 mL) for 45 min and then cooled. Excess phosphohoryl chloride was removed under reduced pressure and ice water (100 mL) was added to hydrolyze any residual phosphoryl chloride. The mixture was basified (pH 9) with ammonium hydroxide, and the solid precipitate was filtered. This material was extracted into ethyl ether (8×100 mL), and the ether solution was dried (MgSO4) and evaporated to provide 4.55 g as a white solid, in 83%; mp 127.5-128° C. (lit. mp 129° C.); 1H NMR (CDCl3) δ 6.15 (s, 2H), 7.35 (d, 1H, J=4.7), 7.39 (s, 1H), 7.49 (s, 1H), 8.56 (d, 1H, J=4.7); 13C NMR (CDCl3) δ 99.8, 102.2, 106.1, 119.9, 123.7, 129.8, 141.2, 147.7, 149.1, 151.4.
Reaction SMILES: Cl[C:2]([O:4][C:5]1[CH:10]=[CH:9][C:8]([N+:11]([O-:13])=[O:12])=[CH:7][CH:6]=1)=[O:3].N1C=CC=CC=1.[CH:20]1([CH2:26][C@H:27]([OH:36])[C:28]([N:30]2[CH2:35][CH2:34][O:33][CH2:32][CH2:31]2)=[O:29])[CH2:25][CH2:24][CH2:23][CH2:22][CH2:21]1>O1CCOCC1>[C:2](=[O:3])([O:4][C:5]1[CH:6]=[CH:7][C:8]([N+:11]([O-:13])=[O:12])=[CH:9][CH:10]=1)[O:36][C@H:27]([C:28]([N:30]1[CH2:31][CH2:32][O:33][CH2:34][CH2:35]1)=[O:29])[CH2:26][CH:20]1[CH2:25][CH2:24][CH2:23][CH2:22][CH2:21]1
Reactant: O=C([C@@H](O)CC1CCCCC1)N1CCOCC1
Reactant: O=C(Cl)Oc1ccc([N+](=O)[O-])cc1
Solvent: c1ccncc1
Solvent: C1COCCO1
Product: O=C(Oc1ccc([N+](=O)[O-])cc1)O[C@@H](CC1CCCCC1)C(=O)N1CCOCC1
Temperature: 70 °C
Reaction time: 0.08 h
Yield: 73.3 %

Procedure:
A solution of 4-nitrophenyl chloroformate (20.55 g, 102 mmol) in dioxane (150 mL) is treated with pyridine (50 mL) resulting in a suspension. This material is heated to 70° C. and a solution of 3 (12.30 g, 51.0 mmol) in dioxane (50 mL) is added via pressure equalizing dropping funnel over ˜5 minutes. After stirring for an additional 5 minutes, the reaction is allowed to cool to room temperature and the solvent is removed by rotary evaporation. The resulting mass is partitioned between ethyl acetate and water. The organic layer is collected and the aqueous phase is extracted once more with ethyl acetate and discarded. The combined organics are dried over MgSO4 and the solvent is removed. The resulting solid is dissolved in a minimal amount of hot dichloroethane and treated with dichloromethane. The mixture is then kept in a −4° C. refrigerator overnight and filtered. The mother liquor is concentrated and purified over 330 g of silica gel using a gradient of 0-100% ethyl acetate in hexane to afford 15.2 g (73% yield) of (S)-2-cyclohexyl-1-(morpholine-4-carbonyl)ethyl 4-nitro-phenyl carbonate (4) as a slightly yellow oil; 1H NMR (CDCl3, 400 MHz) δ 0.97-1.08 (m, 2H), 1.09-1.36 (m, 3H), 1.48-4.62 (m, 2H), 1.65-1.68 (m, 4H), 1.82-1.97 (m, 2H), 3.41-3.60 (m, 3H), 3.64-3.80 (m, 5H), 5.29-5.36 (m, 1H), 7.38-7.44 (m, 2H), 8.24-8.30 (m, 2H); HPLC-MS calculated for C20H26N2O7 (M+H+) 407.2, found 407.4.
Reaction SMILES: [CH2:1]([N:4]([C:21]1[S:22][CH:23]=[CH:24][N:25]=1)[S:5]([C:8]1[CH:9]=[N:10][C:11]([N:14]2[CH2:18][CH2:17][C@@H:16](O)[C:15]2=[O:20])=[CH:12][CH:13]=1)(=[O:7])=[O:6])[CH:2]=[CH2:3].C(N(C(C)C)CC)(C)C.S(OS(C(F)(F)F)(=O)=O)(C(F)(F)F)(=O)=O.[Cl:50][C:51]1[CH:52]=[C:53]2[C:58](=[CH:59][CH:60]=1)[NH:57][CH2:56][CH2:55][CH2:54]2>C(Cl)Cl>[CH2:1]([N:4]([C:21]1[S:22][CH:23]=[CH:24][N:25]=1)[S:5]([C:8]1[CH:9]=[N:10][C:11]([N:14]2[CH2:18][CH2:17][C@H:16]([N:57]3[C:58]4[C:53](=[CH:52][C:51]([Cl:50])=[CH:60][CH:59]=4)[CH2:54][CH2:55][CH2:56]3)[C:15]2=[O:20])=[CH:12][CH:13]=1)(=[O:7])=[O:6])[CH:2]=[CH2:3]
Reactant: Clc1ccc2c(c1)CCCN2
Reactant: C=CCN(c1nccs1)S(=O)(=O)c1ccc(N2CC[C@@H](O)C2=O)nc1
Agent: O=S(=O)(OS(=O)(=O)C(F)(F)F)C(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: C=CCN(c1nccs1)S(=O)(=O)c1ccc(N2CC[C@H](N3CCCc4cc(Cl)ccc43)C2=O)nc1
Temperature: -40 °C
Reaction time: 0.5 h
Yield: 88.7 %

Procedure:
Prepared using General Procedure 4, Method A. To a stirring solution of (R)-N-allyl-6-(3-hydroxyl-2-oxopyrrolidin-1-yl)-N-(thiazol-2-yl)pyridine-3-sulfonamide (75 mg, 0.20 mmol) in DCM (0.6 mL), under N2, was added diisopropylethylamine (70 μL, 0.40 mmol). The solution was then cooled to −40° C. in a dry ice/acetone bath and triflic anhydride was added (37 μL, 0.22 mmol). The reaction was stirred at −40° C. for 30 minutes then a solution of 6-chloro-1,2,3,4-tetrahydroquinoline (50 mg, 0.30 mmol) dissolved in DCM (0.3 mL) was added. The solution was allowed to warm to −20° C. and was placed in the −20° C. freezer overnight. The solution was then allowed to warm to room temperature and was washed with saturated aqueous NaHCO3 (5 mL), and the aqueous layer extracted once with DCM (5 mL). The organic layers were combined and concentrated. The residue was purified by silica gel chromatography with 5%-70% EtOAc in hexanes to give (S)-N-allyl-6-(3-(6-chloro-3,4-dihydroquinolin-1(2H)-yl)-2-oxopyrrolidin-1-yl)-N-(thiazol-2-yl)pyridine-3-sulfonamide (94 mg) in 89% yield. LC/MS (10%-99% CH3CN/H2O (0.05% TFA)), m/z: M+1 obs=530.1, tR=2.05 min.
Reaction SMILES: [CH:1]1([C:5](Cl)=[O:6])[CH2:4][CH2:3][CH2:2]1.Cl.[CH3:9][N:10]1[CH2:15][CH2:14][N:13]([C:16]2[CH:21]=[C:20]([C:22]3[CH:31]=[C:30]4[C:25]([CH2:26][CH2:27][NH:28][CH2:29]4)=[CH:24][CH:23]=3)[N:19]=[C:18]([NH2:32])[N:17]=2)[CH2:12][CH2:11]1>>[CH:1]1([C:5]([N:28]2[CH2:27][CH2:26][C:25]3[C:30](=[CH:31][C:22]([C:20]4[CH:21]=[C:16]([N:13]5[CH2:12][CH2:11][N:10]([CH3:9])[CH2:15][CH2:14]5)[N:17]=[C:18]([NH2:32])[N:19]=4)=[CH:23][CH:24]=3)[CH2:29]2)=[O:6])[CH2:4][CH2:3][CH2:2]1
Reactant: O=C(Cl)C1CCC1
Reactant: CN1CCN(c2cc(-c3ccc4c(c3)CNCC4)nc(N)n2)CC1
Agent: Cl
Product: CN1CCN(c2cc(-c3ccc4c(c3)CN(C(=O)C3CCC3)CC4)nc(N)n2)CC1

Procedure:
This compound was prepared from cyclobutanecarboxylic acid chloride and 4-(4-methylpiperazin-1-yl)-6-(1,2,3,4-tetrahydroisoquinolin-7-yl)pyrimidin-2-amine HCl salt using procedures analogous to those for Example 2. Analytic LCMS (M+H)+: m/z=407.4.
Reaction SMILES: C1C=CN=CC=1.[FH:7].S(F)(=O)(=O)O.O[C:14]([CH3:21])([CH3:20])[C:15]([O:17][CH2:18][CH3:19])=[O:16]>>[F:7][C:14]([CH3:21])([CH3:20])[C:15]([O:17][CH2:18][CH3:19])=[O:16]
Reactant: F
Reactant: CCOC(=O)C(C)(C)O
Agent: O=S(=O)(O)F
Solvent: c1ccncc1
Product: CCOC(=O)C(C)(C)F
Temperature: 0 °C
Yield: 52 %

Procedure:
Into a 50-ml autoclave having a teflon-made internal cylinder were placed 9 ml of a hydrogen fluoride/pyridine mixture [hydrogen fluoride/pyridne =70/30 (wt/wt), containing about 300 mM of hydrogen fluoride] and 9.15 g (91.5 mM) of fluorosulfuric acid. The autoclave contents were cooled to 0° C. Thereto was added 4.0 g (30.5 mM) of ethyl 2-hydroxyisobutyrate. The resulting mixture was subjected to a reaction at 40° C. for 4 hours. After the completion of the reaction, the reaction mixture was poured into ice water. The resulting mixture was extracted with methylene chloride. The extract was dried over anhydrous sodium sulfate and subjected to vacuum distillation to remove methylene chloride. The resulting residue was subjected to distillation to obtain 2.1 g (yield: 52%) of ethyl 2-fluoroisobutyrate having a boiling point of 124°-126° C.
Reaction SMILES: [F:1][C:2]([F:22])([F:21])[O:3][C:4]1[CH:9]=[CH:8][C:7]([N:10]2[CH2:14][CH2:13][C:12]3([CH2:19][CH2:18][NH:17][CH2:16][CH2:15]3)[C:11]2=[O:20])=[CH:6][CH:5]=1.[Cl:23][C:24]1[CH:29]=[CH:28][CH:27]=[C:26]([CH3:30])[C:25]=1[S:31](Cl)(=[O:33])=[O:32].CCN(CC)CC>C(Cl)Cl>[Cl:23][C:24]1[CH:29]=[CH:28][CH:27]=[C:26]([CH3:30])[C:25]=1[S:31]([N:17]1[CH2:16][CH2:15][C:12]2([C:11](=[O:20])[N:10]([C:7]3[CH:8]=[CH:9][C:4]([O:3][C:2]([F:1])([F:21])[F:22])=[CH:5][CH:6]=3)[CH2:14][CH2:13]2)[CH2:19][CH2:18]1)(=[O:32])=[O:33]
Reactant: O=C1N(c2ccc(OC(F)(F)F)cc2)CCC12CCNCC2
Reactant: Cc1cccc(Cl)c1S(=O)(=O)Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: Cc1cccc(Cl)c1S(=O)(=O)N1CCC2(CCN(c3ccc(OC(F)(F)F)cc3)C2=O)CC1
Temperature: 25 °C
Reaction time: 16 h
Yield: 24 %

Procedure:
A mixture of 37.7 mg (0.12 mmol) 2-(4-Trifluoromethoxy-phenyl)-2,8-diaza-spiro[4.5]decan-1-one, 29.7 mg (example 251, step A), 0.132 mmol), 2-chloro-6-methylbenzene-1-sulfonyl chloride and 36.4 mg (0.36 mmol) NEt3 in 2 mL DCM was stirred for 16 h at room temperature. The mixture was evaporated to dryness and the residue was subjected to purification by preparative HPLC on reversed phase eluting with a gradient formed from acetonitrile, water and formic acid. The product containing fractions were evaporated to yield 14.7 mg (24%) of the title compound. MS (ESI): 503.4 (MH+).
Reaction SMILES: [CH3:1][C:2]1[CH:11]=[CH:10][CH:9]=[C:8]2[C:3]=1[CH:4]=[CH:5][NH:6][C:7]2=[O:12].[Br:13]Br.CCOCC>C(Cl)Cl>[Br:13][C:4]1[C:3]2[C:8](=[CH:9][CH:10]=[CH:11][C:2]=2[CH3:1])[C:7](=[O:12])[NH:6][CH:5]=1
Reactant: Cc1cccc2c(=O)[nH]ccc12
Reactant: BrBr
Solvent: CCOCC
Solvent: ClCCl
Product: Cc1cccc2c(=O)[nH]cc(Br)c12
Yield: 66.7 %

Procedure:
To a stirred solution of 5-methylisoquinolin-1(2H)-one (Intermediate-3) (10 g, 63 mmol) in CH2Cl2 (100 mL) was added, Br2 (11.1 g, 69.3 mmol) drop wise and the mixture was stirred at RT (room temperature) overnight. Et2O (200 mL) was added to it, stirred for few min after which, a yellow solid precipitated out. It was filtered, washed with MeOH (10 mL), and dried to give desired intermediate (10 g, 67%) as white solid.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:32]=[CH:33][C:34]=1[O:35][CH3:36])[CH2:6][CH:7]1[C:13]2[CH:14]=[C:15]([O:20][CH3:21])[C:16]([O:18][CH3:19])=[CH:17][C:12]=2[CH2:11][CH2:10][CH2:9][N:8]1[CH:22]([C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1)[C:23](O)=[O:24].[F:37][C:38]([F:42])([F:41])[CH2:39][NH2:40]>>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:32]=[CH:33][C:34]=1[O:35][CH3:36])[CH2:6][CH:7]1[C:13]2[CH:14]=[C:15]([O:20][CH3:21])[C:16]([O:18][CH3:19])=[CH:17][C:12]=2[CH2:11][CH2:10][CH2:9][N:8]1[CH:22]([C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1)[C:23]([NH:40][CH2:39][C:38]([F:42])([F:41])[F:37])=[O:24]
Reactant: COc1ccc(CC2c3cc(OC)c(OC)cc3CCCN2C(C(=O)O)c2ccccc2)cc1OC
Reactant: NCC(F)(F)F
Product: COc1ccc(CC2c3cc(OC)c(OC)cc3CCCN2C(C(=O)NCC(F)(F)F)c2ccccc2)cc1OC

Procedure:
prepared by reaction of [1-(3,4-dimethoxy-benzyl)-7,8-dimethoxy-1,3,4,5-tetrahydro-benzo[c]azepin-2-yl]-phenyl-acetic acid with 2,2,2-trifluoroethylamine.
Reaction SMILES: [OH:1][CH2:2][C:3]1[C:8]([O:9][CH3:10])=[C:7]([O:11][CH3:12])[C:6]([O:13][CH3:14])=[CH:5][C:4]=1[N+:15]([O-:17])=[O:16].C(N(CC)C1C=CC=CC=1)C.Cl[CH2:30][O:31][CH3:32]>C(Cl)(Cl)Cl>[CH3:30][O:31][CH2:32][O:1][CH2:2][C:3]1[C:8]([O:9][CH3:10])=[C:7]([O:11][CH3:12])[C:6]([O:13][CH3:14])=[CH:5][C:4]=1[N+:15]([O-:17])=[O:16]
Reactant: COCCl
Reactant: COc1cc([N+](=O)[O-])c(CO)c(OC)c1OC
Solvent: CCN(CC)c1ccccc1
Solvent: ClC(Cl)Cl
Product: COCOCc1c([N+](=O)[O-])cc(OC)c(OC)c1OC
Temperature: 25 °C
Reaction time: 8 h
Yield: 99.3 %

Procedure:
To a mixture of 2-hydroxymethyl-1-nitro-3,4,5-trimethoxybenzene (6.5 g, 26.7 mmol) and N,N-diethylaniline (9.96 g, 66.8 mmol) in dry chloroform (150 ml) was added dropwise chloromethylmethyl ether (4.28 g, 53.5 mmol) in an ice-bath. After stirring at room temperature overnight, the reaction mixture was washed successively with 1% hydrochloric acid, water, 10% sodium bicarbonate solution and water, and dried over sodium sulfate. The solvent was removed by evaporation in vacuo and the residue was crystallized from hexane to give 7.62 g (99%) of 2-methoxymethoxymethyl-1-nitro-3,4,5-trimethoxybenzene, mp. 39-40 ° C. 1H-NMR (CDCl3): δ3.40 (3H, s, CH2OMe), 3.93 (6H, s, 2×OMe), 3.94 (3H, s, 1×OMe), 4.73 and 4.82 (each 2H, s, 2 ×CH2), 7.29 (1H, s, H-6). Analyses: Calculated for C12H17NO7 : C, 50.17; H, 5.59; N, 4.88. Found: C, 50.18; H, 5.92; N, 4.80.
Reaction SMILES: Cl.[CH2:2]([N:4]([CH2:8][CH3:9])[CH2:5][CH2:6][SH:7])[CH3:3].CO.[OH-].[Na+].Br[CH2:15][CH2:16][OH:17]>O>[CH2:2]([N:4]([CH2:8][CH3:9])[CH2:5][CH2:6][S:7][CH2:15][CH2:16][OH:17])[CH3:3]
Reactant: CCN(CC)CCS
Reactant: OCCBr
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CO
Product: CCN(CC)CCSCCO
Temperature: 25 °C
Yield: 87.5 %

Procedure:
2-(Diethylamino)ethanethiol hydrochloride (5.0 g, 29 mmol) was added to a 250 mL round-bottom flask, 20 mL methanol was added, and the solution cooled in an ice bath with stirring. Sodium hydroxide (2.34 g, 58 mmol), dissolved in water (15 mL), was added, followed by slow addition of 2-bromoethanol (5.9 g, 47 mmol). Stirring was continued while the reaction mixture was allowed to warm to room temperature overnight. The methanol and water were removed under reduced pressure, and the residue dissolved in ethyl acetate (100 mL), washed with water (3×20 mL), dried over magnesium sulfate, and concentrated under reduced pressure to give 2-[2-(diethylamino)-ethylthio]ethanol as a yellow oil (4.5 g, 87% yield). LC-MS (ES+): m/z=178 [C8H19NOS+H+] for product peak. A 1.0 g aliquot of the crude 2-[2-(diethylamino)ethylthio]ethanol was purified by flash chromatography on silica cartridges, eluting with a gradient of 100% hexane to 100% ethyl acetate over 5 minutes, to give 0.78 g pure 2-[2-(diethylamino)ethylthio]ethanol as a colorless oil after evaporation of the solvents, and the remaining 3.5 g similarly purified, eluting with a gradient of 100% hexane to 100% ethyl acetate over 20 minutes, to give an additional 3.11 g pure 2-[2-(diethylamino)ethylthio]ethanol.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH2:10][NH:11][C:12]2[C:21]3[C:16](=[CH:17][CH:18]=[C:19]([C:22]#[N:23])[CH:20]=3)[N:15]=[CH:14][C:13]=2C(O)=O)[CH:5]=[CH:6][C:7]=1[O:8][CH3:9].C1(OC2C=CC=CC=2)C=CC=CC=1>CCCCCC>[Cl:1][C:2]1[CH:3]=[C:4]([CH2:10][NH:11][C:12]2[C:21]3[C:16](=[CH:17][CH:18]=[C:19]([C:22]#[N:23])[CH:20]=3)[N:15]=[CH:14][CH:13]=2)[CH:5]=[CH:6][C:7]=1[O:8][CH3:9]
Reactant: COc1ccc(CNc2c(C(=O)O)cnc3ccc(C#N)cc23)cc1Cl
Solvent: c1ccc(Oc2ccccc2)cc1
Solvent: CCCCCC
Product: COc1ccc(CNc2ccnc3ccc(C#N)cc23)cc1Cl
Temperature: 240 °C
Yield: 75.3 %

Procedure:
To 2.16 g (5.87 mmol) 4-[[(3-chloro-4-methoxyphenyl)methyl]amino]-6-cyano-3-quinolinecarboxylic acid was added 50 mL diphenyl ether (Aldrich), and nitrogen was vigorously bubbled through this mixture for 20 minutes. The resulting mixture was then heated to 240° C. under nitrogen for 30 minutes. During the course of the reaction, the dispersed starting material slowly dissolved, and gas evolution was observed. The resulting solution was poured into 200 mL hexane, and a precipitated solid was filtered to yield 1.43 g (4.42 mmol, 75% yield) of the title compound as a off-white solid: LC/MS: M/Z 324 (M+H) observed, 96% purity; mp: decomposed 227–230° C. LC: 2.84′.
Reaction SMILES: [O:1]1[CH:5]=[N:4][N:3]=[C:2]1[C:6]1[CH:7]=[C:8]([NH:12][C:13](=[O:21])[C:14]2[CH:19]=[C:18](Br)[CH:17]=[CH:16][N:15]=2)[CH:9]=[CH:10][CH:11]=1.[CH:22]1([C:25]2[CH:30]=[CH:29][C:28](B3OC(C)(C)C(C)(C)O3)=[CH:27][N:26]=2)[CH2:24][CH2:23]1.C(=O)([O-])[O-].[K+].[K+]>C1(C)C=CC=CC=1>[O:1]1[CH:5]=[N:4][N:3]=[C:2]1[C:6]1[CH:7]=[C:8]([NH:12][C:13]([C:14]2[CH:19]=[C:18]([C:28]3[CH:27]=[N:26][C:25]([CH:22]4[CH2:24][CH2:23]4)=[CH:30][CH:29]=3)[CH:17]=[CH:16][N:15]=2)=[O:21])[CH:9]=[CH:10][CH:11]=1
Reactant: CC1(C)OB(c2ccc(C3CC3)nc2)OC1(C)C
Reactant: O=C(Nc1cccc(-c2nnco2)c1)c1cc(Br)ccn1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: Cc1ccccc1
Product: O=C(Nc1cccc(-c2nnco2)c1)c1cc(-c2ccc(C3CC3)nc2)ccn1
Temperature: 85 °C
Yield: 89.9 %

Procedure:
A suspension of N-(3-(1,3,4-oxadiazol-2-yl)phenyl)-4-bromopicolinamide (3.0 g, 8.7 mmol), 2-cyclopropyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridine (2.25 g, 9.2 mmol), dppf(Pd)Cl2 (320 mg, 5 mol %), potassium carbonate (2.4 g, 17 mmol) in degassed toluene (10 mL), degassed water (10 mL) and degassed isopropanol (10 mL) was heated at 85° C. for 4 hours. The solvent was removed under reduced pressure and the residue was suspended and sonicated in methanol (40 mL) before being filtered and washed with methanol (10 mL). The grey powder was then suspended and sonicated in water (40 mL) before being filtered and washed with water (10 mL), methanol (10 mL) and diethyl ether (10 mL) to give 6-cyclopropyl-[3,4′]bipyridinyl-2′-carboxylic acid (3-[1,3,4]oxadiazol-2-yl-phenyl)-amide (3.0 g, 90%). 384.1 (M+1).
Reaction SMILES: [C:1]([O:5][C:6]([C@@H:8]1[N:12]([CH2:13][C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[C@H:11]([CH:20]=[CH2:21])[C@H:10]([CH2:22][OH:23])[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[Si:24](Cl)([C:37]([CH3:40])([CH3:39])[CH3:38])([C:31]1[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=1)[C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1.N1C=CN=C1>ClCCl>[C:1]([O:5][C:6]([C@@H:8]1[N:12]([CH2:13][C:14]2[CH:15]=[CH:16][CH:17]=[CH:18][CH:19]=2)[C@H:11]([CH:20]=[CH2:21])[C@H:10]([CH2:22][O:23][Si:24]([C:37]([CH3:40])([CH3:39])[CH3:38])([C:31]2[CH:32]=[CH:33][CH:34]=[CH:35][CH:36]=2)[C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=2)[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: C=C[C@@H]1[C@H](CO)C[C@H](C(=O)OC(C)(C)C)N1Cc1ccccc1
Reactant: CC(C)(C)[Si](Cl)(c1ccccc1)c1ccccc1
Agent: c1c[nH]cn1
Solvent: ClCCl
Product: C=C[C@@H]1[C@H](CO[Si](c2ccccc2)(c2ccccc2)C(C)(C)C)C[C@H](C(=O)OC(C)(C)C)N1Cc1ccccc1
Yield: 98 %

Procedure:
(±)-(2R,3R,5R)-1-Benzyl-2-vinyl-3-hydroxymethyl-pyrrolidine-5-carboxylic acid t-butyl ester (30.8 g, 97.1 mmol) was reacted with t-butyldiphenylsilyl chloride (49.5 mL, 190.4 mmol) and imidazole in dichloromethane (650 mL) at 0° C. for 1 hour. The reaction was quenched methanol followed by extraction with dichloromethane (600 mL). The organic layer was dried over magnesium sulfate, filtered and concentrated in vacuo. The residue was purified by column chromatography on silica gel using 2/1: chloroform/hexane to provide the title compound (yield: 52.9 g, 98%).
Reaction SMILES: FC1C=C(F)C=CC=1C(Cl)=O.[Cl:12][C:13]1[CH:14]=[C:15]([CH:17]=[CH:18][C:19]=1[O:20][C:21]1[C:30]2[C:25](=[CH:26][C:27]([O:33][CH3:34])=[C:28]([O:31][CH3:32])[CH:29]=2)[N:24]=[CH:23][CH:22]=1)[NH2:16].[F:35][C:36]1[CH:41]=[C:40]([F:42])[CH:39]=[CH:38][C:37]=1[C:43]([N:45]=[C:46]=[S:47])=[O:44]>C1(C)C=CC=CC=1.C(O)C>[F:35][C:36]1[CH:41]=[C:40]([F:42])[CH:39]=[CH:38][C:37]=1[C:43]([N:45]=[C:46]=[S:47])=[O:44].[Cl:12][C:13]1[CH:14]=[C:15]([NH:16][C:46]([NH:45][C:43](=[O:44])[C:37]2[CH:38]=[CH:39][C:40]([F:42])=[CH:41][C:36]=2[F:35])=[S:47])[CH:17]=[CH:18][C:19]=1[O:20][C:21]1[C:30]2[C:25](=[CH:26][C:27]([O:33][CH3:34])=[C:28]([O:31][CH3:32])[CH:29]=2)[N:24]=[CH:23][CH:22]=1
Reactant: COc1cc2nccc(Oc3ccc(N)cc3Cl)c2cc1OC
Agent: O=C(Cl)c1ccc(F)cc1F
Agent: O=C(N=C=S)c1ccc(F)cc1F
Solvent: Cc1ccccc1
Solvent: CCO
Product: COc1cc2nccc(Oc3ccc(NC(=S)NC(=O)c4ccc(F)cc4F)cc3Cl)c2cc1OC
Temperature: 25 °C
Reaction time: 2 h
Yield: 63 %

Procedure:
2,4-Difluoro-1-benzenecarbonyl isothiocyanate was prepared using commercially available 2,4-difluoro-1-benzenecarbonyl chloride (80 mg) as a starting compound according to the description of the literature. 3-Chloro-4-[(6,7-dimethoxy-4-quinolyl)oxy]aniline (50 mg) was dissolved in toluene (5 ml) and ethanol (1 ml) to prepare a solution. A solution of 2,4-difluoro-1-benzenecarbonyl isothiocyanate in ethanol (1 ml) was then added to the solution, and the mixture was stirred at room temperature for 2 hr. The reaction solution was concentrated, and the residue was purified by chromatography on silica gel using chloroform/acetone for development to give the title compound (50 mg, yield 63%).
Reaction SMILES: [OH:1][N:2]=[C:3]([C:9](=[O:11])[CH3:10])[C:4]([O:6][CH2:7][CH3:8])=[O:5].C(=O)([O-])[O-].[K+].[K+].[CH2:18](Br)[CH2:19][CH2:20][CH2:21][CH2:22][CH3:23]>CN(C)C=O>[CH2:18]([O:1][N:2]=[C:3]([C:9](=[O:11])[CH3:10])[C:4]([O:6][CH2:7][CH3:8])=[O:5])[CH2:19][CH2:20][CH2:21][CH2:22][CH3:23]
Reactant: CCCCCCBr
Reactant: CCOC(=O)C(=NO)C(C)=O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CCCCCCON=C(C(C)=O)C(=O)OCC
Yield: 99.5 %

Procedure:
Ethyl 2-hydroxyimino-3-oxobutyrate (syn isomer, 40 g.), N,N-dimethylformamide (200 ml.), potassium carbonate (52 g.) and n-hexyl bromide (41.4 g.) were treated in a similar manner to that of Example F-(1) to give ethyl 2-n-hexyloxyimino-3-oxobutyrate (syn isomer, 60.7 g.), oil.
Reaction SMILES: [F:1][C:2]1[C:7]([O:8][CH3:9])=[CH:6][C:5]([O:10][CH3:11])=[C:4]([F:12])[C:3]=1[C:13]1[N:18]=[C:17]2[NH:19][N:20]=[C:21](I)[C:16]2=[CH:15][N:14]=1.[CH3:23][N:24]1[CH2:29][CH2:28][CH:27]([N:30]2[CH2:38][C:37]3[C:32](=[CH:33][CH:34]=[C:35](B4OC(C)(C)C(C)(C)O4)[CH:36]=3)[C:31]2=[O:48])[CH2:26][CH2:25]1>>[F:1][C:2]1[C:7]([O:8][CH3:9])=[CH:6][C:5]([O:10][CH3:11])=[C:4]([F:12])[C:3]=1[C:13]1[N:18]=[C:17]2[NH:19][N:20]=[C:21]([C:35]3[CH:36]=[C:37]4[C:32](=[CH:33][CH:34]=3)[C:31](=[O:48])[N:30]([CH:27]3[CH2:28][CH2:29][N:24]([CH3:23])[CH2:25][CH2:26]3)[CH2:38]4)[C:16]2=[CH:15][N:14]=1
Reactant: CN1CCC(N2Cc3cc(B4OC(C)(C)C(C)(C)O4)ccc3C2=O)CC1
Reactant: COc1cc(OC)c(F)c(-c2ncc3c(I)n[nH]c3n2)c1F
Product: COc1cc(OC)c(F)c(-c2ncc3c(-c4ccc5c(c4)CN(C4CCN(C)CC4)C5=O)n[nH]c3n2)c1F

Procedure:
This compound was prepared by using procedures analogous to those described for the synthesis of Example 4, Step 2 starting from 6-(2,6-difluoro-3,5-dimethoxyphenyl)-3-iodo-1H-pyrazolo[3,4-d]pyrimidine and 2-(1-methylpiperidin-4-yl)-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)isoindolin-1-one. LCMS (M+H)+=521.1. 1H NMR (300 MHz, DMSO-d6) δ: 14.57 (s, 1H), 9.86 (s, 1H), 8.39 (s, 1H), 8.27 (d, J=8.0 Hz, 1H), 7.82 (d, J=8.0 Hz, 1H), 7.18 (t, J=8.2 Hz, 1H), 4.58 (s, 2H), 3.94 (s, 6H), 2.92-2.84 (m, 5H), 2.21 (s, 3H), 2.08-1.66 (m, 4H).