Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl[C:2]1[CH:11]=[CH:10][C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[N:3]=1.[CH:12]([Sn](CCCC)(CCCC)CCCC)=[CH2:13]>C1(C)C=CC=CC=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>[CH:12]([C:2]1[CH:11]=[CH:10][C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[N:3]=1)=[CH2:13]
Reactant: C=C[Sn](CCCC)(CCCC)CCCC
Reactant: Clc1ccc2ccccc2n1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Solvent: Cc1ccccc1
Product: C=Cc1ccc2ccccc2n1
Yield: 99.2 %

Procedure:
A solution of 2-chloroquinoline (1 g, 6.11 mmol) and vinyl tributyl tin (2.69 mL, 9.17 mmol) in toluene (30 mL) was treated with Pd(PPh3)4 (0.706 g, 0.611 mmol) and heated to reflux for 1.5 h. The reaction mixture was concentrated and the resulting material was purified directly by gradient elution on silica gel (0 to 25% EtOAc in hexanes) to afford the title compound as a colorless oil (941 mg, 99%). All spectral data matched literature values.1 LRMS m/z (M+H) 156.1 found, 156.2 required. (1 Fakhfakh, M. A.; Franck, X.; Fournet, A.; Hocquemiller, R.; Figadère, B. Tetrahedron Lett. 2001, 42, 3847.)
Reaction SMILES: [C:1]([O:5][C:6]([N:8]([CH2:14][C:15]1[CH:27]=[CH:26][C:18]([C:19]([O:21][C:22]([CH3:25])([CH3:24])[CH3:23])=[O:20])=[CH:17][C:16]=1[N+:28]([O-])=O)[CH2:9][CH2:10][CH:11]([CH3:13])[CH3:12])=[O:7])([CH3:4])([CH3:3])[CH3:2]>C(O)C.[Pd]>[NH2:28][C:16]1[CH:17]=[C:18]([CH:26]=[CH:27][C:15]=1[CH2:14][N:8]([C:6]([O:5][C:1]([CH3:2])([CH3:3])[CH3:4])=[O:7])[CH2:9][CH2:10][CH:11]([CH3:13])[CH3:12])[C:19]([O:21][C:22]([CH3:25])([CH3:23])[CH3:24])=[O:20]
Reactant: CC(C)CCN(Cc1ccc(C(=O)OC(C)(C)C)cc1[N+](=O)[O-])C(=O)OC(C)(C)C
Agent: [Pd]
Solvent: CCO
Product: CC(C)CCN(Cc1ccc(C(=O)OC(C)(C)C)cc1N)C(=O)OC(C)(C)C
Reaction time: 0.5 h

Procedure:
A solution of t-butyl 4-[N-(t-butoxycarbonyl)-N-(isopentyl)amino-methyl]-3-nitrobenzoate (2.27 mmol) in ethanol (100 mL) containing 10% palladium on carbon (0.5 g) was hydrogenated (40 psi). After 30 min, the mixture was filtered and concentrated to give t-butyl 3-amino-4-[N-(t-butoxycarbonyl)-N-(isopentyl)-aminomethyl]benzoate.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:18])[CH2:4][C@H:5]1[CH2:10][CH2:9][C@H:8]([C:11]2[CH:16]=[CH:15][C:14]([NH2:17])=[CH:13][CH:12]=2)[CH2:7][CH2:6]1.CCN=C=NCCCN(C)C.[C:30]1([N:36]2[CH:40]=[C:39]([C:41]([NH:43][CH2:44][CH2:45][C:46](O)=[O:47])=[O:42])[C:38]([C:49]([F:52])([F:51])[F:50])=[N:37]2)[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1.C1C=CC2N(O)N=NC=2C=1.C(N(C(C)C)C(C)C)C>ClCCl.C([O-])(O)=O.[Na+]>[CH3:1][O:2][C:3](=[O:18])[CH2:4][C@H:5]1[CH2:6][CH2:7][C@H:8]([C:11]2[CH:12]=[CH:13][C:14]([NH:17][C:46](=[O:47])[CH2:45][CH2:44][NH:43][C:41]([C:39]3[C:38]([C:49]([F:52])([F:50])[F:51])=[N:37][N:36]([C:30]4[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=4)[CH:40]=3)=[O:42])=[CH:15][CH:16]=2)[CH2:9][CH2:10]1
Reactant: O=C(O)CCNC(=O)c1cn(-c2ccccc2)nc1C(F)(F)F
Reactant: COC(=O)C[C@H]1CC[C@H](c2ccc(N)cc2)CC1
Agent: CCN=C=NCCCN(C)C
Agent: O=C([O-])O
Agent: On1nnc2ccccc21
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: COC(=O)C[C@H]1CC[C@H](c2ccc(NC(=O)CCNC(=O)c3cn(-c4ccccc4)nc3C(F)(F)F)cc2)CC1
Reaction time: 24 h

Procedure:
A mixture of trans-[4-(4-aminophenyl)cyclohexyl]acetic acid methyl ester (50 mg, 0.20 mmol), EDCI (96.9 mg, 0.51 mmol), 3-[(1-phenyl-3-trifluoromethyl-1H-pyrazole-4-carbonyl)amino]propionic acid (79.4 mg, 0.24 mmol), HOBt (41 mg, 0.3 mmol) and ethyldiisopropylamine (91.7 mg, 0.71 mmol) dissolved in dichloromethane (15 mL) were stirred for 24 hours. The reaction mixture was diluted with aqueous NaHCO3 and extracted with dichloromethane. The extract was washed with brine and dried with anhydrous sodium sulfate and concentrated under vacuum. The residue was purified by silica gel column chromatography to obtain the desired compound (102 mg, 91%) as a white solid.
Reaction SMILES: [NH3:1].[Br:2][C:3]1[CH:4]=[CH:5][C:6]2[S:10][C:9]([CH2:11]Br)=[N:8][C:7]=2[CH:13]=1>CO>[Br:2][C:3]1[CH:4]=[CH:5][C:6]2[S:10][C:9]([CH2:11][NH2:1])=[N:8][C:7]=2[CH:13]=1
Reactant: BrCc1nc2cc(Br)ccc2s1
Reactant: N
Solvent: CO
Product: NCc1nc2cc(Br)ccc2s1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
Gaseous ammonia is bubbled through a solution of 5-Bromo-2-bromomethyl-benzothiazole (0.850 g, 2.768 mmol) in methanol (16 mL) for 10 minutes at 0° C. then stirred at room temperature for 3 hours. The reaction mixture is dried over magnesium sulfate, filtered and the solvent is evaporated in vacuo. The crude material is washed with n-pentane and hexane to afford the title compound (0.78 g). 1H NMR (400 MHz, DMSO-d6) δ: 4.52 (s, 2H), 7.69-7.72 (dd, J1=1.96 Hz, J2=8.68 Hz, 1H), 7.95 (d, J=8.64 Hz, 1H), 8.46 (d, J=1.96 Hz, 1H). LC-MS (m/z): [M+H]=245.0.
Reaction SMILES: [OH:1][C:2]1[CH:18]=[CH:17][C:5]([C:6]([C:8]2[S:12][C:11]([S:13]([NH2:16])(=[O:15])=[O:14])=[CH:10][CH:9]=2)=[O:7])=[CH:4][CH:3]=1.C(N(CC)CC)C.Cl[C:27]([O:29][CH2:30][CH:31]([CH3:33])[CH3:32])=[O:28]>CC(C)=O>[C:27](=[O:28])([O:1][C:2]1[CH:18]=[CH:17][C:5]([C:6]([C:8]2[S:12][C:11]([S:13](=[O:15])(=[O:14])[NH2:16])=[CH:10][CH:9]=2)=[O:7])=[CH:4][CH:3]=1)[O:29][CH2:30][CH:31]([CH3:33])[CH3:32]
Reactant: NS(=O)(=O)c1ccc(C(=O)c2ccc(O)cc2)s1
Reactant: CC(C)COC(=O)Cl
Solvent: CC(C)=O
Solvent: CCN(CC)CC
Product: CC(C)COC(=O)Oc1ccc(C(=O)c2ccc(S(N)(=O)=O)s2)cc1

Procedure:
A solution of 5-(4-hydroxybenzoyl)thiophene-2-sulfonamide (0.00783 mole) in acetone (50 ml) at 0° C. is treated with triethylamine (0.00861 mole) followed by isobutyl chloroformate (0.00861 mole) dropwise, during 30 minutes at 0°-2° C.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:25])[C:4]1[CH:9]=[CH:8][C:7]([CH3:10])=[C:6]([C:11]2[C:22](=[O:23])[N:21]([CH3:24])[C:14]3[N:15]=[C:16](SC)[N:17]=[CH:18][C:13]=3[CH:12]=2)[CH:5]=1.OOS([O-])=O.[K+].[NH2:32][CH:33]1[CH2:38][CH2:37][O:36][CH2:35][CH2:34]1>>[CH3:1][O:2][C:3](=[O:25])[C:4]1[CH:9]=[CH:8][C:7]([CH3:10])=[C:6]([C:11]2[C:22](=[O:23])[N:21]([CH3:24])[C:14]3[N:15]=[C:16]([NH:32][CH:33]4[CH2:38][CH2:37][O:36][CH2:35][CH2:34]4)[N:17]=[CH:18][C:13]=3[CH:12]=2)[CH:5]=1
Reactant: NC1CCOCC1
Reactant: COC(=O)c1ccc(C)c(-c2cc3cnc(SC)nc3n(C)c2=O)c1
Agent: O=S([O-])OO
Agent: [K+]
Product: COC(=O)c1ccc(C)c(-c2cc3cnc(NC4CCOCC4)nc3n(C)c2=O)c1

Procedure:
4-Methyl-3-(8-methyl-2-methylsulfanyl-7-oxo-7,8-dihydro-pyrido[2,3-d]pyrimidin-6-yl)-benzoic acid methyl ester was treated with OXONE™ following the procedure of step 3 of Example 1, and the resulting sulfonyl compound was treated with 4-amino-tetrahydropyran using the procedure of step 4 of Example 1, to give 4-methyl-3-[8-methyl-7-oxo-2-(tetrahydro-pyran-4-ylamino)-7,8-dihydro-pyrido[2,3-d]pyrimidin-6-yl]-benzoic acid methyl ester: MS (M+H)=409; MP=122.5-126.5° C.
Reaction SMILES: [C:1]([C:5]1[N:10]=[CH:9][C:8]([C:11]2[N:12]([C:32]([N:34]3[CH2:39][CH2:38][CH:37]([CH2:40][C:41]([OH:43])=O)[CH2:36][CH2:35]3)=[O:33])[C@@:13]([C:25]3[CH:30]=[CH:29][C:28]([Cl:31])=[CH:27][CH:26]=3)([CH3:24])[C@@:14]([C:17]3[CH:22]=[CH:21][C:20]([Cl:23])=[CH:19][CH:18]=3)([CH3:16])[N:15]=2)=[C:7]([O:44][CH2:45][CH3:46])[CH:6]=1)([CH3:4])([CH3:3])[CH3:2].[CH2:47]([O:49][CH2:50][CH2:51][NH:52][CH2:53][CH2:54][O:55][CH2:56][CH3:57])[CH3:48]>>[C:1]([C:5]1[N:10]=[CH:9][C:8]([C:11]2[N:12]([C:32]([N:34]3[CH2:35][CH2:36][CH:37]([CH2:40][C:41]([N:52]([CH2:53][CH2:54][O:55][CH2:56][CH3:57])[CH2:51][CH2:50][O:49][CH2:47][CH3:48])=[O:43])[CH2:38][CH2:39]3)=[O:33])[C@@:13]([C:25]3[CH:26]=[CH:27][C:28]([Cl:31])=[CH:29][CH:30]=3)([CH3:24])[C@@:14]([C:17]3[CH:18]=[CH:19][C:20]([Cl:23])=[CH:21][CH:22]=3)([CH3:16])[N:15]=2)=[C:7]([O:44][CH2:45][CH3:46])[CH:6]=1)([CH3:4])([CH3:2])[CH3:3]
Reactant: CCOc1cc(C(C)(C)C)ncc1C1=N[C@@](C)(c2ccc(Cl)cc2)[C@@](C)(c2ccc(Cl)cc2)N1C(=O)N1CCC(CC(=O)O)CC1
Reactant: CCOCCNCCOCC
Product: CCOCCN(CCOCC)C(=O)CC1CCN(C(=O)N2C(c3cnc(C(C)(C)C)cc3OCC)=N[C@@](C)(c3ccc(Cl)cc3)[C@@]2(C)c2ccc(Cl)cc2)CC1

Procedure:
In a manner analogous to the method described in example 163, {1-[(4S,5R)-2-(6-tert-butyl-4-ethoxy-pyridin-3-yl)-4,5-bis-(4-chloro-phenyl)-4,5-dimethyl-4,5-dihydro-imidazole-1-carbonyl]-piperidin-4-yl}-acetic acid was coupled with bis-(2-ethoxy-ethyl)-amine (TCI-US) to give the title compound. HR-MS (ES, m/z) calculated for C44H60Cl2N5O5 [(M+H)+] 808.3966, observed 808.3968.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][C@H:11]([O:14][C:15]2[CH:20]=[CH:19][CH:18]=[C:17]([NH2:21])[N:16]=2)[CH2:10][C@@H:9]1[CH3:22])=[O:7])([CH3:4])([CH3:3])[CH3:2].[Cl:23][C:24]1[CH:32]=[C:31]([F:33])[CH:30]=[CH:29][C:25]=1[C:26](Cl)=[O:27]>O1CCOCC1>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][C@H:11]([O:14][C:15]2[CH:20]=[CH:19][CH:18]=[C:17]([NH:21][C:26](=[O:27])[C:25]3[CH:29]=[CH:30][C:31]([F:33])=[CH:32][C:24]=3[Cl:23])[N:16]=2)[CH2:10][C@@H:9]1[CH3:22])=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: C[C@H]1C[C@@H](Oc2cccc(N)n2)CCN1C(=O)OC(C)(C)C
Reactant: O=C(Cl)c1ccc(F)cc1Cl
Solvent: C1COCCO1
Product: C[C@H]1C[C@@H](Oc2cccc(NC(=O)c3ccc(F)cc3Cl)n2)CCN1C(=O)OC(C)(C)C
Reaction time: 2.5 h

Procedure:
Combine 4-(6-amino-pyridin-2-yloxy)-cis-2-methyl-piperidine-1-carboxylic acid tert-butyl ester isomer 2 (preparation 64, 0.714 g) and 2-chloro-4-fluorobenzoyl chloride (0.493 g) in 1,4-dioxane (20 mL) and heat. After 2.5 hr., partition between ethyl acetate and saturated aqueous NaCl, dry over anhydrous sodium sulfate, evaporate and purify on a silica gel column eluting with dichloromethane-2M NH3 in methanol, gradient to give the title compound (0.678 g). Mass spectrum (electric spray) m/z=464 (M+1); 1H NMR (CDCl3): 8.45 (br, 1H), 7.89 (br d, 1H), 7.78 (dd, 1H), 7.68 (ddd, 1H), 7.24 (dd, 1H), 7.12 (ddd, 1H), 6.54 (d, 1H), 5.27 (m, 1H), 4.35 (m, 1H), 3.90 (m, 1H), 3.25 (m, 1H), 1.90 (m, 3H), 1.75 (m, 1H), 1.47 (s, 9H), 1.28 (d, 3H).
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][CH2:9][CH2:10][C:11]([OH:13])=[O:12])=[O:7])([CH3:4])([CH3:3])[CH3:2].[F:14][C:15]([F:25])([F:24])[O:16][C:17]1[CH:22]=[CH:21][C:20](O)=[CH:19][CH:18]=1.C(OC(NCCCC(OC1C(C)=CC=CC=1C)=O)=O)(C)(C)C>>[C:1]([O:5][C:6]([NH:8][CH2:9][CH2:10][C:11]([O:13][C:20]1[CH:19]=[CH:18][C:17]([O:16][C:15]([F:14])([F:24])[F:25])=[CH:22][CH:21]=1)=[O:12])=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)NCCC(=O)O
Reactant: Oc1ccc(OC(F)(F)F)cc1
Agent: Cc1cccc(C)c1OC(=O)CCCNC(=O)OC(C)(C)C
Product: CC(C)(C)OC(=O)NCCC(=O)Oc1ccc(OC(F)(F)F)cc1

Procedure:
The title compound was prepared from N-(tert-butoxycarbonyl)-β-alanine and 4-(trifluoromethoxy)phenol in a similar manner as described for 2,6-dimethylphenyl 4-[(tert-butoxycarbonyl)amino]butanoate. Mass Spectrum (M-tert-Bu)+H+ 293.96
Reaction SMILES: O1CCC[CH2:2]1.[OH:6][C:7]1[C:8]([CH:17]2[C:25]3[C:20](=[CH:21][CH:22]=[CH:23][CH:24]=3)[NH:19][C:18]2=[O:26])=[CH:9][C:10]2[O:15][CH2:14][CH2:13][O:12][C:11]=2[CH:16]=1.C(=O)([O-])[O-].[Cs+].[Cs+].ClCI>CN(C)C=O>[NH:19]1[C:20]2[C:25](=[CH:24][CH:23]=[CH:22][CH:21]=2)[C:17]2([C:8]3[C:7](=[CH:16][C:11]4[O:12][CH2:13][CH2:14][O:15][C:10]=4[CH:9]=3)[O:6][CH2:2]2)[C:18]1=[O:26]
Reactant: C1CCOC1
Reactant: O=C1Nc2ccccc2C1c1cc2c(cc1O)OCCO2
Agent: ClCI
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Product: O=C1Nc2ccccc2C12COc1cc3c(cc12)OCCO3
Temperature: 2.5 °C
Reaction time: 2 h
Yield: 55 %

Procedure:
A 2000 L stainless steel crystallizer was charged with N,N-dimethylformamide (113.7 kg) and tetrahydrofuran (1070.9 kg). The contents were cooled to 0-5° C. and 3-(7-hydroxy-2,3-dihydro-1,4-benzodioxin-6-yl)-1,3-dihydro-2H-indol-2-one (12.0 kg, 42.4 mol) was added, followed by cesium carbonate (30.4 kg, 93.3 mol). A solution of chloroiodomethane (9.4 kg, 53.7 mol) in N,N-dimethylformamide (16.9 kg) was added at a rate of 39.5 kg/h such that the temperature of the reaction mixture was maintained between 0 and 5° C. The reaction mixture was stirred at 0-5° C. for 2 h and heated at 20-25° C. for 18.5 h. The mixture was filtered and the filter cake was suspended in tetrahydrofuran (26.4 kg) and filtered again. The combined filtrates were combined and concentrated to a volume of 110 L under reduced pressure at a temperature <60° C. The mixture was cooled to 20-25° C. and purified water (1200.8 kg) was added at a rate of 343.1 kg/h. The mixture was cooled to 0-5° C. and filtered. The filter cake was suspended in water (310.5 kg), filtered and dried at a temperature <60° C. until the water content was 10.6% by weight by Karl-Fisher titration. A 200 L reactor was charged with tetrahydrofuran (98.0 kg). The partially-dried filter cake (˜11.0 kg) was added to the 200 L reactor by means of a solid addition funnel. The mixture was heated at reflux for 4.5 h, cooled to 10-15° C. and stirred for 3.5 h at 10-15° C. The mixture was filtered and the filter cake was washed with cold (0-5° C.) tetrahydrofuran (2×10.7 kg) and dried in a tray dryer at a temperature <55° C. to afford 2,3-dihydrospiro[furo[2,3-g][1,4]benzodioxine-8,3′-indol]-2′(1′H)-one (6.88 kg, 63%) as a pale yellow solid: purity (HPLC-UV at 210 nm) 98.3%; mp>250° C.; 1H NMR (300 MHz, DMSO-d6) δ10.58 (br s, 1H), 7.26-7.19 (m, 1H), 7.09 (d, J=7.2 Hz, 1H), 6.99-6.90 (m, 2H), 6.47 (s, 1H), 6.16 (s, 1H), 4.74, 4.60 (ABq, JAB=9.2 Hz, 2H), 4.20-4.07 (m, 4H); 13C NMR (75 MHz, DMSO-d6) δ178.4, 154.7, 144.0, 141.8, 137.8, 132.6, 128.7, 123.8, 122.3, 121.5, 111.1, 109.8, 98.7, 79.5, 64.2, 63.6, 57.7; MS (ES+) m/z 295.9 (M+1).
Reaction SMILES: [Mg].Br[C:3]1[CH:8]=[CH:7][C:6]([O:9][CH3:10])=[CH:5][CH:4]=1.[Cl:11][C:12]1[CH:13]=[C:14]2[C:18](=[CH:19][CH:20]=1)[NH:17][C:16](=[O:21])[C:15]2=[O:22]>C1COCC1>[Cl:11][C:12]1[CH:13]=[C:14]2[C:18](=[CH:19][CH:20]=1)[NH:17][C:16](=[O:21])[C:15]2([OH:22])[C:3]1[CH:8]=[CH:7][C:6]([O:9][CH3:10])=[CH:5][CH:4]=1
Reactant: COc1ccc(Br)cc1
Reactant: O=C1Nc2ccc(Cl)cc2C1=O
Agent: [Mg]
Solvent: C1CCOC1
Product: COc1ccc(C2(O)C(=O)Nc3ccc(Cl)cc32)cc1
Yield: 72.9 %

Procedure:
This compound is prepared according to the procedure described in step A of Preparation 1.3 starting with 3.5 g of magnesium, 25 g of 1-bromo-4-methoxybenzene, 50 ml of THF and a mixture of 8 g of 5-chloro-1H-indol-2,3-dione in 50 ml of THF. 9.3 g of the expected product are obtained after crystallization from hot iso ether; m.p.=202° C.
Reaction SMILES: [F:1][C:2]([F:6])([F:5])[CH2:3][SH:4].[H-].[Na+].CS(O[CH2:14][CH:15]1[CH2:20][CH2:19][N:18]([C:21]([O:23][C:24]([CH3:27])([CH3:26])[CH3:25])=[O:22])[CH2:17][CH2:16]1)(=O)=O>CN(C=O)C.CCOC(C)=O>[F:1][C:2]([F:6])([F:5])[CH2:3][S:4][CH2:14][CH:15]1[CH2:20][CH2:19][N:18]([C:21]([O:23][C:24]([CH3:25])([CH3:27])[CH3:26])=[O:22])[CH2:17][CH2:16]1
Reactant: CC(C)(C)OC(=O)N1CCC(COS(C)(=O)=O)CC1
Reactant: FC(F)(F)CS
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: CC(C)(C)OC(=O)N1CCC(CSCC(F)(F)F)CC1
Temperature: 25 °C
Reaction time: 4 h
Yield: 84.2 %

Procedure:
2,2,2-Trifluoroethane-1-thiol (0.151 mL, 1.636 mmol) was added dropwise to a suspension of sodium hydride (60% dispersion in mineral oil, 0.065 g, 1.636 mmol) in anhydrous DMF (3 mL) at 0 C. A solution of tert-butyl 4-[(methanesulfonyloxy)methyl]piperidine-1-carboxylate (Intermediate 181, 0.320 g, 1.091 mmol) in DMF (4 mL) was then added dropwise and the reaction mixture was stirred at room temperature for 4 h. The mixture was diluted with EtOAc (30 mL) and washed with a saturated aqueous solution of sodium bicarbonate (10 mL) followed by brine (10 mL). The organic layer was dried over anhydrous sodium sulfate, filtered and evaporated under reduced pressure. The crude material was purified by FCC (EtOAc: heptane, 20:80) to provide the title compound as a colourless oil (0.288 g, 82%). Method B HPLC-MS: MH+ requires m/z=313 Found: m/z=257 (M minus tert-butyl), Rt=2.28 min (97%).
Reaction SMILES: [CH:1]([C:3]1[C:11]2[C:6](=[CH:7][C:8]([Cl:13])=[CH:9][C:10]=2[Cl:12])[NH:5][C:4]=1[C:14]([O:16][CH2:17][CH3:18])=[O:15])=[O:2].[H-].[Na+].[C:21]1([S:27](Cl)(=[O:29])=[O:28])[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1.O>CN(C=O)C>[C:21]1([S:27]([N:5]2[C:6]3[C:11](=[C:10]([Cl:12])[CH:9]=[C:8]([Cl:13])[CH:7]=3)[C:3]([CH:1]=[O:2])=[C:4]2[C:14]([O:16][CH2:17][CH3:18])=[O:15])(=[O:29])=[O:28])[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1
Reactant: O=S(=O)(Cl)c1ccccc1
Reactant: CCOC(=O)c1[nH]c2cc(Cl)cc(Cl)c2c1C=O
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: CCOC(=O)c1c(C=O)c2c(Cl)cc(Cl)cc2n1S(=O)(=O)c1ccccc1
Temperature: 25 °C
Reaction time: 0.75 h

Procedure:
A solution of ethyl 3-formyl-4,6-dichloroindole-2-carboxylate (5.0 g) in dry DMF (30 ml) was added to a suspension of sodium hydride (0.629 g; 80% suspension in mineral oil) in dry DMF (10 ml) under nitrogen at 0°. The reaction was stirred at this temperature for 45 min then phenylsulfonyl chloride (2.5 ml) was added giving a yellow precipitate. The reaction was allowed to warm slowly to room temperature, stirred for a further 14 h then poured into water (250 ml). The solid was filtered, washed with water and then with ethyl acetate to give the title compound (4.493 g,) as a white solid, m.p. 225.8°-226.3°.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH2:14]O)[C:5]2[O:9][C:8]([CH3:11])([CH3:10])[C:7](=[O:12])[C:6]=2[CH:13]=1.S(Cl)([Cl:18])=O>>[Cl:1][C:2]1[CH:3]=[C:4]([CH2:14][Cl:18])[C:5]2[O:9][C:8]([CH3:11])([CH3:10])[C:7](=[O:12])[C:6]=2[CH:13]=1
Reactant: CC1(C)Oc2c(CO)cc(Cl)cc2C1=O
Reactant: O=S(Cl)Cl
Product: CC1(C)Oc2c(CCl)cc(Cl)cc2C1=O

Procedure:
A solution of 5-chloro-7-(hydroxymethyl)-2,2-dimethylbenzofuran-3(2H)-one (656) (278 mg, 1.23 mmol) in neat thionyl chloride (5 mL) was stirred at room temperature for 48 hours. The reaction was concentrated to obtain 5-chloro-7-(chloromethyl)-2,2-dimethylbenzofuran-3(2H)-one (657) as a brown/grey solid.
Reaction SMILES: [CH2:1]([N:8]1[CH2:13][CH2:12][CH:11]([NH:14][C:15]2[C:20]([C:21]([NH2:23])=[O:22])=[CH:19][N:18]=[C:17]3[N:24]([CH2:27][O:28][CH2:29][CH2:30][Si:31]([CH3:34])([CH3:33])[CH3:32])[CH:25]=[CH:26][C:16]=23)[CH2:10][CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:35](N1C=CN=C1)(N1C=CN=C1)=[O:36].[Cl-].[Na+]>CN(C)C(=O)C>[CH2:1]([N:8]1[CH2:13][CH2:12][CH:11]([N:14]2[C:15]3[C:16]4[CH:26]=[CH:25][N:24]([CH2:27][O:28][CH2:29][CH2:30][Si:31]([CH3:34])([CH3:33])[CH3:32])[C:17]=4[N:18]=[CH:19][C:20]=3[C:21](=[O:22])[NH:23][C:35]2=[O:36])[CH2:10][CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: C[Si](C)(C)CCOCn1ccc2c(NC3CCN(Cc4ccccc4)CC3)c(C(N)=O)cnc21
Reactant: O=C(n1ccnc1)n1ccnc1
Agent: [Cl-]
Agent: [Na+]
Solvent: CC(=O)N(C)C
Product: C[Si](C)(C)CCOCn1ccc2c1ncc1c(=O)[nH]c(=O)n(C3CCN(Cc4ccccc4)CC3)c12
Temperature: 25 °C
Yield: 70.5 %

Procedure:
4-[(1-Benzylpiperidin-4-yl)amino]-1-{[2-(trimethylsilyl)ethoxy]methyl}-1H-pyrrolo[2,3-b]pyridine-5-carboxamide (484 mg, 1.01 mmol) in N,N-dimethylacetamide (5 mL) was stirred with 1,1′-carbonyldiimidazole (486 mg, 3.00 mmol) at 120° C. for 3 hours. The reaction mixture was allowed to cool to room temperature and, after addition of saturated aqueous sodium chloride, extracted with ethyl acetate, and the organic layer was dried over anhydrous sodium sulfate and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (chloroform/methanol=20/1 (v/v)) to give the title compound as a colorless solid (360 mg, yield 70%).
Reaction SMILES: C([O-])(=O)C.[K+].C(Cl)Cl.CC1(C)C(C)(C)[O:13][B:12](B2OC(C)(C)C(C)(C)O2)[O:11]1.Br[C:28]1[CH:29]=[C:30]2[C:35](=[CH:36][C:37]=1[F:38])[N:34]=[C:33]([NH2:39])[C:32]([N:40]1[CH2:45][CH2:44][O:43][CH2:42][CH2:41]1)=[CH:31]2>CN(C=O)C>[NH2:39][C:33]1[C:32]([N:40]2[CH2:45][CH2:44][O:43][CH2:42][CH2:41]2)=[CH:31][C:30]2[C:35](=[CH:36][C:37]([F:38])=[C:28]([B:12]([OH:13])[OH:11])[CH:29]=2)[N:34]=1
Reactant: Nc1nc2cc(F)c(Br)cc2cc1N1CCOCC1
Reactant: CC1(C)OB(B2OC(C)(C)C(C)(C)O2)OC1(C)C
Agent: CC(=O)[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: ClCCl
Product: Nc1nc2cc(F)c(B(O)O)cc2cc1N1CCOCC1
Temperature: 125 °C

Procedure:
A microwave vessel was charged with potassium acetate (0.34 g, 3.46 mmol), [1,1′-bis(dppf)]dichloropalladium(II) complex with CH2Cl2 (0.038 g, 0.052 mmol), 4,4,4′,4′,5,5,5′,5′-octamethyl-2,2′-bi(1,3,2-dioxaborolane) (0.211 g, 0.831 mmol), 6-bromo-7-fluoro-3-morpholinoquinolin-2-amine (0.226 g, 0.693 mmol), and DMF (2.2 mL). The vessel was purged with argon, sealed, and heated by microwave radiation for 30 min at 125° C. The reaction was diluted with EtOAc (10 mL), and the suspension was filtered through celite rinsing with EtOAc. The filtrate was concentrated. The residue was purified by column chromatography on silica gel (25 mL) which had been deactivated with Et3N (2.5 mL) using 3% MeOH/DCM to afford 2-amino-7-fluoro-3-morpholinoquinolin-6-ylboronic acid.
Reaction SMILES: [C:1]([N:8]1[CH2:13][CH2:12][NH:11][CH2:10][C@H:9]1[CH3:14])([O:3][C:4]([CH3:7])([CH3:6])[CH3:5])=[O:2].C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].[CH3:29][C:30]([CH3:32])=O.C(O)(=O)C>CN(C=O)C.O>[C:1]([N:8]1[CH2:13][CH2:12][N:11]([CH:30]([CH3:32])[CH3:29])[CH2:10][C@@H:9]1[CH3:14])([O:3][C:4]([CH3:7])([CH3:6])[CH3:5])=[O:2]
Reactant: C[C@@H]1CNCCN1C(=O)OC(C)(C)C
Reactant: CC(C)=O
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: CC(=O)O
Solvent: CN(C)C=O
Solvent: O
Product: CC(C)N1CCN(C(=O)OC(C)(C)C)[C@@H](C)C1
Temperature: 60 °C

Procedure:
To (R)-1-Boc-2-methylpiperazine (200.0 mg, 0.999 mmol) and sodium triacetoxyborohydride (444.5 mg, 2.097 mmol) in DMF (5 mL) was added acetone (116 mg, 0.147 mL, 1.997 mmol) and acetic acid (90.0 mg, 86 μL, 1.498 mmol). The reaction mixture was heated at 60° C. for 1 h. The reaction mixture was diluted with water and extracted three times with diethyl ether. The combined organics were dried over sodium sulfate, filtered, concentrated, and used without further purification. LCMS-ESI+: calc'd for C13H27N2O2 (M+H+): 243.2; Found: 243.2 (M+H+).
Reaction SMILES: [F:1][C:2]([F:17])([F:16])[C:3]([O:11][Si:12]([CH3:15])([CH3:14])[CH3:13])([CH2:7][CH2:8][CH2:9][CH3:10])[CH2:4][C:5]#[CH:6].N(C(C)(C)C#N)=NC(C)(C)C#N.[CH2:30]([SnH:34]([CH2:39][CH2:40][CH2:41][CH3:42])[CH2:35][CH2:36][CH2:37][CH3:38])[CH2:31][CH2:32][CH3:33]>>[F:17][C:2]([F:1])([F:16])[C:3]([O:11][Si:12]([CH3:14])([CH3:15])[CH3:13])([CH2:7][CH2:8][CH2:9][CH3:10])[CH2:4]/[CH:5]=[CH:6]/[Sn:34]([CH2:35][CH2:36][CH2:37][CH3:38])([CH2:39][CH2:40][CH2:41][CH3:42])[CH2:30][CH2:31][CH2:32][CH3:33]
Reactant: C#CCC(CCCC)(O[Si](C)(C)C)C(F)(F)F
Reactant: CCCC[SnH](CCCC)CCCC
Agent: CC(C)(C#N)N=NC(C)(C)C#N
Product: CCCCC(C/C=C/[Sn](CCCC)(CCCC)CCCC)(O[Si](C)(C)C)C(F)(F)F

Procedure:
A stirred mixture of 6.66 g. of 4-trifluoromethyl-4-trimethylsiloxy-1-octyne and 26 mg. of azobisisobutyronitrile, under argon, is treated with 6.95 ml. of tri-n-butyl tin hydride, via a syringe. After treatment, a condenser is attached to the reaction vessel and the reaction mixture, under argon, is slowly heated to 130°-135° C. and maintained at this temperature for 1.5 hours. Subsequent fractional distillation of the reaction mixture at approximately 0.07 mm pressure gives the desired product, b.p. 125°-135° C. (containing a minor amount of the corresponding cis isomer).