Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br[CH2:2][C:3]([O:5][CH3:6])=[O:4].C(=O)([O-])[O-].[K+].[K+].[C:13]([O:17][C:18](=[O:33])[NH:19][C:20]1[CH:25]=[CH:24][C:23]([C:26]2[CH:31]=[CH:30][C:29]([OH:32])=[CH:28][CH:27]=2)=[CH:22][CH:21]=1)([CH3:16])([CH3:15])[CH3:14]>C1COCC1>[CH3:6][O:5][C:3](=[O:4])[CH2:2][O:32][C:29]1[CH:28]=[CH:27][C:26]([C:23]2[CH:24]=[CH:25][C:20]([NH:19][C:18]([O:17][C:13]([CH3:16])([CH3:15])[CH3:14])=[O:33])=[CH:21][CH:22]=2)=[CH:31][CH:30]=1
Reactant: COC(=O)CBr
Reactant: CC(C)(C)OC(=O)Nc1ccc(-c2ccc(O)cc2)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: C1CCOC1
Product: COC(=O)COc1ccc(-c2ccc(NC(=O)OC(C)(C)C)cc2)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 83.1 %

Procedure:
Methyl bromoacetate (128.5 mg, 0.84 mmol) potassium iodide (11.7 mg) and potassium carbonate (193.5 mg, 1.4 mmol) were added to a solution of (4′-hydroxy-biphenyl-4-yl)-carbamic acid tert-butyl ester (0.2 g, 0.70 mmol), prepared in the previous step, in 15 mL of THF and the reaction stirred at room temperature overnight. The solvent was removed under reduced pressure. The residue was partitioned between ethyl acetate and water. The aqueous layer was separated and extracted multiple times with ethyl acetate. The combined extracts were dried (Na2SO4) and the solvent removed under reduced pressure. Purification of the residue on silica gel using 20% ethyl acetate-hexane as the eluent gave (4′-tert-butoxycarbonylamino-biphenyl-4-yloxy)-acetic acid methyl ester (208 mg, 80%) as a white solid.
Reaction SMILES: [CH3:1][N:2]1[C:7]2[CH:8]=[CH:9][C:10]([N:12]3[CH2:16][C@H:15]([C:17]([NH2:19])=[O:18])[O:14][C:13]3=[O:20])=[CH:11][C:6]=2[O:5][CH2:4][C:3]1=[O:21].[F:22][CH2:23][CH2:24]N.Cl.C(N(CC)CC)C>CO>[F:22][CH2:23][CH2:24][NH:19][C:17]([C@@H:15]1[O:14][C:13](=[O:20])[N:12]([C:10]2[CH:9]=[CH:8][C:7]3[N:2]([CH3:1])[C:3](=[O:21])[CH2:4][O:5][C:6]=3[CH:11]=2)[CH2:16]1)=[O:18]
Reactant: NCCF
Reactant: CN1C(=O)COc2cc(N3C[C@H](C(N)=O)OC3=O)ccc21
Agent: Cl
Solvent: CO
Solvent: CCN(CC)CC
Product: CN1C(=O)COc2cc(N3C[C@H](C(=O)NCCF)OC3=O)ccc21
Temperature: 55 °C
Reaction time: 16 h
Yield: 69.8 %

Procedure:
To a stirred suspension of (5R)-3-(3,4-dihydro-4-methyl-3-oxo-2H-1,4-benzoxazin-7-yl)-2-oxo-oxazolidine-5-carboxylic acid methyl ester (EXAMPLE 59, Step 3, 200 mg, 0.65 mmol) in MeOH (7.5 mL) is added FCH2CH2NH2.HCl (325 mg, 3.25 mmol). To this resulting suspension is added triethylamine (453 μL, 3.25 mmol), and the solution is heated to 55° C. for 5 h followed by stirring for 16 h at room temperature. The reaction mixture is then concentrated to dryness under reduced pressure and the residue is purified by silica gel column chromatography (eluent: EtOAc) to give the title compound (153 mg, 63%); 1H NMR (300 MHz, DMSO) δ 8.68 (br t, 1H), 7.30 (d, 1H), 7.22-7.14 (m, 2H), 5.08 (dd, 1H), 4.65 (s, 2H), 4.54 (dd, 1H), 4.38 (t, 1H), 4.26 (t, 1H), 3.45 (s, 3H), 3.96 (dd, 1H), 3.50-3.35 (m, 5H); MS for C15H16FN3O5 m/z 338.5 (M+H)+.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[CH:4][C:3]=1[OH:9].[Cl:10][S:11](O)(=[O:13])=[O:12].O=S(Cl)Cl>>[OH:9][C:3]1[C:2]([Cl:1])=[CH:7][C:6]([Cl:8])=[CH:5][C:4]=1[S:11]([Cl:10])(=[O:13])=[O:12]
Reactant: O=S(=O)(O)Cl
Reactant: Oc1ccc(Cl)cc1Cl
Solvent: O=S(Cl)Cl
Product: O=S(=O)(Cl)c1cc(Cl)cc(Cl)c1O
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 94 %

Procedure:
Molten 2,4-dichlorophenol (82.7 g) was contacted with 166 ml of chlorosulfonic acid at 37°-40° C. over a 1 hour period. After a 15 minute hold at 40° C. the reaction was cooled to 25° C. and 73 ml of SOCl2 was added. The temperature was raised to 32° C. for 40 minutes and then allowed to cool to 25° C. over 1 hour. The reaction mixture was quenched onto ice. Filtration and drying afforded 126.7 g of 99% pure 2-hydroxy-3,5-dichlorobenzenesulfonyl chloride (C) (94% yield).
Reaction SMILES: [CH2:1]([O:8][CH2:9][C@H:10]1[N:14]([S:15]([C:18]2[CH:27]=[CH:26][C:25]3[C:20](=[CH:21][CH:22]=[CH:23][CH:24]=3)[CH:19]=2)(=[O:17])=[O:16])[CH2:13][C@@H:12](OS(C)(=O)=O)[CH2:11]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:33]([O-:36])(=[S:35])[CH3:34].[K+]>CN(C=O)C>[CH2:1]([O:8][CH2:9][C@@H:10]1[N:14]([S:15]([C:18]2[CH:27]=[CH:26][C:25]3[C:20](=[CH:21][CH:22]=[CH:23][CH:24]=3)[CH:19]=2)(=[O:17])=[O:16])[CH2:13][C@@H:12]([S:35][C:33](=[O:36])[CH3:34])[CH2:11]1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CS(=O)(=O)O[C@H]1C[C@@H](COCc2ccccc2)N(S(=O)(=O)c2ccc3ccccc3c2)C1
Reactant: CC([O-])=S
Agent: [K+]
Solvent: CN(C)C=O
Product: CC(=O)S[C@H]1C[C@H](COCc2ccccc2)N(S(=O)(=O)c2ccc3ccccc3c2)C1
Temperature: 100 °C
Reaction time: 1 h
Yield: 75.2 %

Procedure:
To a solution of (3S,5S)-methanesulfonic acid 5-benzyloxymethyl-1-(naphthalene-2-sulfonyl)-pyrrolidin-3-yl ester (3.0 g) in abs DMF (60 ml) was added potassium thioacetate (1.08 g). The reaction mixture was stirred for 1 h at 100° C. and concentrated under oil pump vacuum. The residue was treated with ice/water and extracted with EtOAc. The organic phase was washed with water and brine, dried over magnesium sulphate and concentrated. The residue was chromatographed on silica gel using EtOAc/hexane 1:3 as eluent to obtain (3S,5R)-thioacetic acid S-[5-benzyloxymethyl-1-(naphthalene-2-sulfonyl)-pyrrolidin-3-yl]ester (2.16 g) as a slightly yellow powder, MS: 334 (M−121).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]2[NH:8][C:9](=[O:40])[C:10]3([CH:15]([C:16]4[CH:21]=[C:20]([Cl:22])[CH:19]=[CH:18][C:17]=4[O:23][C:24]([C:27]([O:29][CH3:30])=[O:28])([CH3:26])[CH3:25])[CH2:14][C:13](=O)[NH:12][CH:11]3[C:32]3[CH:37]=[C:36]([F:38])[CH:35]=[CH:34][C:33]=3[CH3:39])[C:5]2=[CH:4][CH:3]=1.P12(SP3(SP(SP(S3)(S1)=S)(=S)S2)=S)=[S:42]>C1COCC1.C1(C)C=CC=CC=1>[Cl:1][C:2]1[CH:7]=[C:6]2[NH:8][C:9](=[O:40])[C:10]3([CH:15]([C:16]4[CH:21]=[C:20]([Cl:22])[CH:19]=[CH:18][C:17]=4[O:23][C:24]([C:27]([O:29][CH3:30])=[O:28])([CH3:26])[CH3:25])[CH2:14][C:13](=[S:42])[NH:12][CH:11]3[C:32]3[CH:37]=[C:36]([F:38])[CH:35]=[CH:34][C:33]=3[CH3:39])[C:5]2=[CH:4][CH:3]=1
Reactant: S=P12SP3(=S)SP(=S)(S1)SP(=S)(S2)S3
Reactant: COC(=O)C(C)(C)Oc1ccc(Cl)cc1C1CC(=O)NC(c2cc(F)ccc2C)C12C(=O)Nc1cc(Cl)ccc12
Solvent: Cc1ccccc1
Solvent: C1CCOC1
Product: COC(=O)C(C)(C)Oc1ccc(Cl)cc1C1CC(=S)NC(c2cc(F)ccc2C)C12C(=O)Nc1cc(Cl)ccc12
Temperature: 40 °C
Yield: 83.1 %

Procedure:
A mixture of chiral (2′S, 3S, 4′R)-6-chloro-4′-[5-chloro-2-(1-methoxycarbonyl-1-methyl-ethoxy)-phenyl]-2′-(5-fluoro-2-methyl-phenyl) spiro[3H-indole-3,3′-piperidine]-2,6′(1H)-dione (300 mg, 0.52 mmol) prepared in Example 6 and P2S5 (227 mg, 1.02 mmol) in THF (3 mL) was heated at 40° C. for 2 h, and then diluted with toluene (20 mL). The mixture was concentrated in vacuo and the residue was washed with DCM twice. The DCM solution was collected and purified by flash column chromatography to give the title compound as white solid (260 mg).
Reaction SMILES: [O:1]1[C@H:5]2[O:6][CH2:7][CH2:8][C@H:4]2[C@@H:3]([O:9][C:10]([NH:12][C@H:13]([C@H:28]([OH:47])[CH2:29][N:30]([S:35]([C:38]2[CH:46]=[CH:45][C:41]3[O:42][CH2:43][O:44][C:40]=3[CH:39]=2)(=[O:37])=[O:36])[CH2:31][CH:32]([CH3:34])[CH3:33])[CH2:14][C:15]2[CH:27]=[CH:26][C:18]([O:19][CH2:20][C:21]([O:23]CC)=[O:22])=[CH:17][CH:16]=2)=[O:11])[CH2:2]1.O.[OH-].[Li+]>O1CCCC1.O>[O:1]1[C@H:5]2[O:6][CH2:7][CH2:8][C@H:4]2[C@@H:3]([O:9][C:10]([NH:12][C@H:13]([C@H:28]([OH:47])[CH2:29][N:30]([S:35]([C:38]2[CH:46]=[CH:45][C:41]3[O:42][CH2:43][O:44][C:40]=3[CH:39]=2)(=[O:37])=[O:36])[CH2:31][CH:32]([CH3:33])[CH3:34])[CH2:14][C:15]2[CH:27]=[CH:26][C:18]([O:19][CH2:20][C:21]([OH:23])=[O:22])=[CH:17][CH:16]=2)=[O:11])[CH2:2]1
Reactant: CCOC(=O)COc1ccc(C[C@H](NC(=O)O[C@H]2CO[C@H]3OCC[C@H]32)[C@H](O)CN(CC(C)C)S(=O)(=O)c2ccc3c(c2)OCO3)cc1
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Product: CC(C)CN(C[C@@H](O)[C@H](Cc1ccc(OCC(=O)O)cc1)NC(=O)O[C@H]1CO[C@H]2OCC[C@H]21)S(=O)(=O)c1ccc2c(c1)OCO2
Temperature: 25 °C
Reaction time: 1 h
Yield: 74 %

Procedure:
To an ice cold solution of Ethyl (4-{(2S,3R)-2-({[(3R,3aS,6aR)-hexahydrofuro[2,3-b]furan-3-yloxy]carbonyl}amino)-4-[(1,3-benzodioxol-5-ylsulfonyl)(isobutyl)amino]-3-hydroxybutyl}phenoxy)acetate (107 mg, 0.16 mmol) in tetrahydrofuran/water (4 mL, 3:1) was added lithium hydroxide monohydrate (21 mg, 0.48 mmol). The reaction was allowed to warm to ambient temperature and stir for 1 h. The tetrahydrofuran was evaporated and the residue diluted with water (30 mL). The aqueous was then extracted with ether (30 mL), cooled in an ice bath and acidified to pH ˜2 with 1.0 N hydrochloric acid. The resulting precipitate was extracted into ethyl acetate (30 mL), washed with water (20 mL), dried (magnesium sulfate) and concentrated in vacuo to a white solid. Triturated with 10% ether in hexane and filtered to afford the title compound (77 mg) as a 2:1 mixture with the compound derived from the loss of the bis-tetrahydrofuran alcohol and subsequent ring closure at the 2-hydroxy position. The mixture was confirmed by NMR, HPLC and mass spectra. Data for major product: 1H NMR (DMSO-d6): δ 0.78 (6H, dd), 1.17-1.45 (2H, m), 1.92 (1H, m), 2.35 (1H, t), 2.64-2.78 (3H, m), 2.88-3.02 (2H, m), 3.24-3.30 (1H, m), 3.40-3.60 (4H, m), 3.70 (1H, t), 3.78-3.82 (1H, m), 4.54 (2H, s), 4.82 (1H, q), 5.00 (1H, d), 5.46 (1H, d), 6.12 (2H, s), 6.71 (2H, d), 7.00-7.30 (6H, m), 12.85 (1H, broad); MS: 651 (MH+); C30H38N2O12S (by-product MS: 521 (MH+); C24H28N2O9S).
Reaction SMILES: FC(F)(F)C(O)=O.[CH2:8]([NH:12][C:13]1[N:21]=[C:20]2[C:16]([N:17]=[C:18]([O:22][CH3:23])[NH:19]2)=[C:15]([NH2:24])[N:14]=1)[CH2:9][CH2:10][CH3:11].C(=O)([O-])[O-].[K+].[K+].CS(O[CH2:36][CH2:37][CH:38]1[CH2:43][CH2:42][CH2:41][CH2:40][O:39]1)(=O)=O>CN(C=O)C>[CH2:8]([NH:12][C:13]1[N:21]=[C:20]2[C:16]([N:17]=[C:18]([O:22][CH3:23])[N:19]2[CH2:36][CH2:37][CH:38]2[CH2:43][CH2:42][CH2:41][CH2:40][O:39]2)=[C:15]([NH2:24])[N:14]=1)[CH2:9][CH2:10][CH3:11]
Reactant: CS(=O)(=O)OCCC1CCCCO1
Reactant: CCCCNc1nc(N)c2nc(OC)[nH]c2n1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O=C(O)C(F)(F)F
Solvent: CN(C)C=O
Product: CCCCNc1nc(N)c2nc(OC)n(CCC3CCCCO3)c2n1
Temperature: 60 °C
Reaction time: 1 h
Yield: 37.7 %

Procedure:
A mixture of N2-butyl-8-methoxy-9H-purine-2,6-diamine trifluoroacetic acid salt (200 mg) and potassium carbonate (236 mg) in dry DMF (2 mL) were heated at 60° C. with stirring for 1 h. 2-(Tetrahydro-2H-pyran-2-yl)ethyl methanesulfonate (142 mg) was added and the reaction was continued for 3 h at 60° C. The mixture was quenched with water and extracted with EtOAc (×3). The combined organics were washed with water and brine, dried using a hydrophobic frit and evaporated to give crude material (250 mg). The material was purified by C18 reverse phase chromatography using water (containing 0.1% formic acid)-acetonitrile (containing 0.05% formic acid) as eluent (20-60%) and the appropriate fractions combined and evaporated to remove acetonitrile. The remaining aqueous mixture was made basic with saturated sodium hydrogen carbonate, extracted three times with dichloromethane and the combined extracts dried by passing through a phase separation cartridge then evaporated to give 75 mg of material which was recrystallised from ether/light petrol yielding the title compound as a solid, 54 mg.
Reaction SMILES: C(N(C(C)C)CC)(C)C.Cl[C:11]1[N:12]=[C:13]([S:22][CH3:23])[N:14]=[N:15][C:16]=1[C:17]([O:19][CH2:20][CH3:21])=[O:18].[S:24]1[CH:28]=[CH:27][C:26]2[C:29]([NH2:33])=[CH:30][CH:31]=[CH:32][C:25]1=2>C1COCC1>[S:24]1[CH:28]=[CH:27][C:26]2[C:29]([NH:33][C:11]3[N:12]=[C:13]([S:22][CH3:23])[N:14]=[N:15][C:16]=3[C:17]([O:19][CH2:20][CH3:21])=[O:18])=[CH:30][CH:31]=[CH:32][C:25]1=2
Reactant: CCOC(=O)c1nnc(SC)nc1Cl
Reactant: Nc1cccc2sccc12
Solvent: C1CCOC1
Solvent: CCN(C(C)C)C(C)C
Product: CCOC(=O)c1nnc(SC)nc1Nc1cccc2sccc12
Temperature: 25 °C
Reaction time: 0.58 h

Procedure:
Diisopropylethylamine (0.10 ml) was added to a solution of ethyl 5-chloro-3-(methylthio)-1,2,4-triazine-6-carboxylate (70 mg) and benzo[b]thiophen-4-amine (70 mg) in THF (1 ml), and the reaction solution was stirred at room temperature for 35 minutes. The solvent was evaporated under vacuum, and then the resultant residue was purified by column chromatography on silica gel (developing solvent:hexane/ethyl acetate) to obtain ethyl 5-(benzo[b]thiophen-4-ylamino)-3-(methylthio)-1,2,4-triazine-6-carboxylate as a white solid.
Reaction SMILES: [F:1][C:2]([F:34])([F:33])[C:3]1[CH:4]=[C:5]([CH:26]=[C:27]([C:29]([F:32])([F:31])[F:30])[CH:28]=1)[C:6]([N:8]1[CH2:25][CH2:24][C:11]2([C:15](=[O:16])[NH:14][C:13](=[O:17])[CH:12]2[C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)[CH2:10][CH2:9]1)=[O:7].O[CH2:36][CH2:37][N:38]1[CH2:42][CH2:41][CH2:40][CH2:39]1>>[F:32][C:29]([F:30])([F:31])[C:27]1[CH:26]=[C:5]([CH:4]=[C:3]([C:2]([F:1])([F:33])[F:34])[CH:28]=1)[C:6]([N:8]1[CH2:9][CH2:10][C:11]2([C:15](=[O:16])[N:14]([CH2:36][CH2:37][N:38]3[CH2:42][CH2:41][CH2:40][CH2:39]3)[C:13](=[O:17])[CH:12]2[C:18]2[CH:19]=[CH:20][CH:21]=[CH:22][CH:23]=2)[CH2:24][CH2:25]1)=[O:7]
Reactant: O=C1NC(=O)C2(CCN(C(=O)c3cc(C(F)(F)F)cc(C(F)(F)F)c3)CC2)C1c1ccccc1
Reactant: OCCN1CCCC1
Product: O=C(c1cc(C(F)(F)F)cc(C(F)(F)F)c1)N1CCC2(CC1)C(=O)N(CCN1CCCC1)C(=O)C2c1ccccc1

Procedure:
The title compound, MS: m/e=582.2 (M+H+), was prepared in accordance with the general method of example 121 from (rac)-8-(3,5-bis-trifluoromethyl-benzoyl)-4-phenyl-2,8-diaza-spiro[4.5]decane-1,3-dione and 1-(2-hydroxyethyl)-pyrrolidine.
Reaction SMILES: [CH2:1]([O:3][C:4]([N:6]1[C:15]2[C:10](=[N:11][C:12]([O:16][CH3:17])=[CH:13][CH:14]=2)[C@@H:9]([NH:18][C:19]2[N:24]=[C:23]([CH2:25][C:26]3[CH:31]=[C:30]([C:32]([F:35])([F:34])[F:33])[CH:29]=[C:28]([C:36]([F:39])([F:38])[F:37])[CH:27]=3)[C:22]([OH:40])=[CH:21][N:20]=2)[CH2:8][C@H:7]1[CH2:41][CH3:42])=[O:5])[CH3:2].[CH3:43][O:44][C:45]([C:47]1[CH:52]=[CH:51][C:50](B(O)O)=[CH:49][CH:48]=1)=[O:46].C(N(CC)CC)C>C(Cl)Cl.C([O-])(=O)C.[Cu+2].C([O-])(=O)C>[CH2:1]([O:3][C:4]([N:6]1[C:15]2[C:10](=[N:11][C:12]([O:16][CH3:17])=[CH:13][CH:14]=2)[C@@H:9]([NH:18][C:19]2[N:24]=[C:23]([CH2:25][C:26]3[CH:31]=[C:30]([C:32]([F:35])([F:34])[F:33])[CH:29]=[C:28]([C:36]([F:38])([F:39])[F:37])[CH:27]=3)[C:22]([O:40][C:50]3[CH:51]=[CH:52][C:47]([C:45]([O:44][CH3:43])=[O:46])=[CH:48][CH:49]=3)=[CH:21][N:20]=2)[CH2:8][C@H:7]1[CH2:41][CH3:42])=[O:5])[CH3:2]
Reactant: COC(=O)c1ccc(B(O)O)cc1
Reactant: CCOC(=O)N1c2ccc(OC)nc2[C@@H](Nc2ncc(O)c(Cc3cc(C(F)(F)F)cc(C(F)(F)F)c3)n2)C[C@H]1CC
Agent: [Cu+2]
Agent: CC(=O)[O-]
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CCOC(=O)N1c2ccc(OC)nc2[C@@H](Nc2ncc(Oc3ccc(C(=O)OC)cc3)c(Cc3cc(C(F)(F)F)cc(C(F)(F)F)c3)n2)C[C@H]1CC
Temperature: 25 °C
Reaction time: 8 h
Yield: 63.5 %

Procedure:
(2R,4S)-4-{[3, 5-Bis(trifluoromethyl)benzyl]-(5-hydroxypyrimidin-2-yl)}amino-2-ethyl-6-methoxy-3,4-dihydro-2H-[1,5]naphthyridine-1-carboxylic acid ethyl ester (170 mg) is dissolved in methylene chloride (3 ml), and thereto are added 4-methoxycarbonylphenylboronic acid (51 mg), copper (II) acetate (52 mg), triethylamine (79 μl) and molecular sieves 4A (170 mg). The mixture is stirred overnight at room temperature. The insoluble materials are removed by filtration and the filtrate is partitioned by adding ethyl acetate and saturated brine. The organic layer is washed with saturated brine and dried over magnesium sulfate, then concentrated under reduced pressure. The resulting residue is purified by column chromatography (silica gel; hexane:ethyl acetate=9:1→3:1) to give (2R,4S)-4-{[3,5-bis(trifluoromethyl)benzyl]-[5-(4-methoxycarbonylphenoxy)-pyrimidin-2-yl]}amino-2-ethyl-6-methoxy-3,4-dihydro-2H-[1,5]naphthyridine-1-carboxylic acid ethyl ester (132 mg). MS (m/z): 734 [M+H]+.
Reaction SMILES: [O:1]=[C:2]1[C:6]2([CH2:11][CH2:10][N:9]([S:12](Cl)(=[O:14])=[O:13])[CH2:8][CH2:7]2)[CH2:5][CH2:4][N:3]1[C:16]1[CH:21]=[CH:20][C:19]([O:22][C:23]([F:26])([F:25])[F:24])=[CH:18][CH:17]=1.[CH3:27][NH:28][C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1>>[CH3:27][N:28]([C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1)[S:12]([N:9]1[CH2:10][CH2:11][C:6]2([C:2](=[O:1])[N:3]([C:16]3[CH:21]=[CH:20][C:19]([O:22][C:23]([F:26])([F:25])[F:24])=[CH:18][CH:17]=3)[CH2:4][CH2:5]2)[CH2:7][CH2:8]1)(=[O:14])=[O:13]
Reactant: CNc1ccccc1
Reactant: O=C1N(c2ccc(OC(F)(F)F)cc2)CCC12CCN(S(=O)(=O)Cl)CC2
Product: CN(c1ccccc1)S(=O)(=O)N1CCC2(CCN(c3ccc(OC(F)(F)F)cc3)C2=O)CC1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
This material was prepared in analogy to example 285 step B) from 1-Oxo-2-(4-trifluoromethoxy-phenyl)-2,8-diaza-spiro[4.5]decane-8-sulfonyl chloride and methyl-phenyl-amine. The reaction was subjected to work-up and purification after stirring for 2 h at room temperature. MS (ESI): 484.4 (MH+).
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]([CH:10]=[CH:11][C:12]=1[OH:13])[C:5]([O:7][CH2:8][CH3:9])=[O:6].Br[CH2:15][CH2:16]Br.C([O-])([O-])=O.[K+].[K+]>CN(C=O)C>[O:13]1[CH2:16][CH2:15][O:1][C:2]2[CH:3]=[C:4]([C:5]([O:7][CH2:8][CH3:9])=[O:6])[CH:10]=[CH:11][C:12]1=2
Reactant: BrCCBr
Reactant: CCOC(=O)c1ccc(O)c(O)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CCOC(=O)c1ccc2c(c1)OCCO2
Temperature: 70 °C
Yield: 22.8 %

Procedure:
According to the procedure described in Example 6A Step 1, a mixture of ethyl 3,4-dihydroxybenzoate (5.465 g, 30 mmol), 1,2-dibromoethane (5.636 g, 30 mmol), and K2CO3 (6.219 g, 45 mmol) in DMF (100 mL) was heated at 70° C. overnight. The residue was purified by silica gel chromatography with 20-50% EtOAc/hexane as eluants to afford ethyl 2,3-dihydrobenzo[b][1,4]dioxine-6-carboxylate as an oil (1.423 g, 23%). 1H NMR (300 MHz, CDCl3) δ 7.58 (d, 1H), 7.56 (dd, 1H), 6.88 (d, 1H), 4.30 (m, 6H), 1.37 (t, 3H); LC-MS (ESI) m/z 209 (M+H)+.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[CH:8]=[C:7]([S:12]([N:15]1[CH2:20][CH2:19][N:18]([C:21](=[O:39])[C:22]3[CH:27]=[CH:26][CH:25]=[CH:24][C:23]=3[C:28]3[CH:33]=[CH:32][N:31]=[C:30]([O:34]C(C)(C)C)[N:29]=3)[CH2:17][CH2:16]1)(=[O:14])=[O:13])[CH:6]=[CH:5]2.Cl.CO>ClCCl>[ClH:1].[Cl:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[CH:8]=[C:7]([S:12]([N:15]1[CH2:16][CH2:17][N:18]([C:21](=[O:39])[C:22]3[CH:27]=[CH:26][CH:25]=[CH:24][C:23]=3[C:28]3[CH:33]=[CH:32][N:31]=[C:30]([OH:34])[N:29]=3)[CH2:19][CH2:20]1)(=[O:13])=[O:14])[CH:6]=[CH:5]2
Reactant: CC(C)(C)Oc1nccc(-c2ccccc2C(=O)N2CCN(S(=O)(=O)c3ccc4cc(Cl)ccc4c3)CC2)n1
Agent: Cl
Solvent: ClCCl
Solvent: CO
Product: O=C(c1ccccc1-c1ccnc(O)n1)N1CCN(S(=O)(=O)c2ccc3cc(Cl)ccc3c2)CC1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a solution of 1-(6-chloronaphth-2-ylsulphonyl)-4-[(2-tert-butyloxypyrimidin-4-yl)benzoyl]piperazine (120 mg, 0.213 mmol) in dichloromethane (5 ml) was added a solution of hydrogen chloride in methanol (0.24 ml of ˜4.5 M, 1.06 mmol). A precipitate formed immediately, and the reaction was stirred at ambient temperature for 1 hr. The solvent was removed in vacuo and the residue triturated with methanol. The solid was collected by filtration to give 1-(6-chloronaphth-2-ylsulphonyl)-4-[(2-hydroxypyrimidin-4-yl)benzoyl]piperazine hydrochloride as a colourless solid.
Reaction SMILES: C[Si]([C:5]#[C:6][C:7]1[CH:16]=[C:15]2[C:10]([C:11](=[O:26])[N:12]3[CH2:25][CH2:24][C:19]4([O:23][CH2:22][CH2:21][O:20]4)[CH2:18][CH2:17][C:13]3=[N:14]2)=[CH:9][CH:8]=1)(C)C.[OH-].[K+]>CO>[C:6]([C:7]1[CH:16]=[C:15]2[C:10]([C:11](=[O:26])[N:12]3[CH2:25][CH2:24][C:19]4([O:23][CH2:22][CH2:21][O:20]4)[CH2:18][CH2:17][C:13]3=[N:14]2)=[CH:9][CH:8]=1)#[CH:5]
Reactant: C[Si](C)(C)C#Cc1ccc2c(=O)n3c(nc2c1)CCC1(CC3)OCCO1
Agent: [K+]
Agent: [OH-]
Solvent: CO
Product: C#Cc1ccc2c(=O)n3c(nc2c1)CCC1(CC3)OCCO1

Procedure:
A solution of 3-((trimethylsilyl)ethynyl)-9,10-dihydro-6H-spiro[azepino[2,1-b]quinazoline-8,2′-[1,3]dioxolan]-12(7H)-one (1.5 g, 4.1 mmol, 1 equiv) and 1 N aq. KOH in methanol was stirred at rt for half an hour. The reaction mixture was quenched with water and extracted with ethyl acetate (3×100 mL). The combined organic layers were washed with brine and dried over anhydrous sodium sulfate, then concentrated under reduced pressure. The product was obtained by silica gel chromatography purification.
Reaction SMILES: [NH2:1][NH2:2].[N:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[C:9]([O:11]CC)=O>C(O)C>[N:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[C:9]([NH:1][NH2:2])=[O:11]
Reactant: CCOC(=O)c1ccccn1
Reactant: NN
Solvent: CCO
Product: NNC(=O)c1ccccn1

Procedure:
Pyridine-2-carboxylic acid hydrazide is prepared as follows: 230 g (228 mL) of anhydrous hydrazine is added, over a period of 10-15 minutes, to a stirred solution of 977.4 g of ethyl pyridine-2-carboxylate ((ethyl picolinate) in 1750 mL of anhydrous ethanol. The reaction is exothermic. The solution is stirred and refluxed for 5 hours, then stirred at room temperature overnight. The crystalline product is filtered off, washed first with anhydrous alcohol and then with anhydrous ether, and air-dried to yield pyridine-2-carboxylic acid hydrazide, m.p. 95°-100°.
Reaction SMILES: [F:1][C:2]1[CH:10]=[C:9]2[C:5]([C:6]([CH:11]3[CH2:16][CH2:15][N:14]([CH2:17][C:18]#[N:19])[CH2:13][CH2:12]3)=[N:7][NH:8]2)=[CH:4][CH:3]=1.[H-].[Al+3].[Li+].[H-].[H-].[H-]>C1COCC1>[F:1][C:2]1[CH:10]=[C:9]2[C:5]([C:6]([CH:11]3[CH2:12][CH2:13][N:14]([CH2:17][CH2:18][NH2:19])[CH2:15][CH2:16]3)=[N:7][NH:8]2)=[CH:4][CH:3]=1
Reactant: N#CCN1CCC(c2n[nH]c3cc(F)ccc23)CC1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: C1CCOC1
Product: NCCN1CCC(c2n[nH]c3cc(F)ccc23)CC1
Temperature: 0 °C
Yield: 90.5 %

Procedure:
To a solution of [4-(6-fluoro-1H-indazol-3-yl)-1-piperidinyl]-acetonitrile (6.1 g, 23.6 mmol) in dry THF (235 ml) was added (dropwise) lithium aluminum hydride (LAH) (28.4 mmol, 1.0M in THF) at room temperature, under nitrogen. Upon complete addition, the reaction mixture was warmed to reflux for 3 hours. After cooling to 0° C. in an ice bath, the reaction was carefully quenched with water (4.0 ml). The solids were removed via filtration and washed with THF. The combined filtrates were concentrated to give 5.6 g of the desired product. This material was suspended in DCM and filtered to give the product as an off-white solid, m.p. 125°-128° C.
Reaction SMILES: [CH:1]1[C:13]2[CH:12]([CH2:14][O:15][C:16]([NH:18][C:19]3([C:24]([NH:26][C@H:27]([C:31]([N:33]([CH3:50])[C@@H:34]([C@@H:46]([CH3:49])[CH2:47][CH3:48])[C@H:35]([O:44][CH3:45])[CH2:36][C:37]([O:39]C(C)(C)C)=[O:38])=[O:32])[CH:28]([CH3:30])[CH3:29])=[O:25])[CH2:23][CH2:22][CH2:21][CH2:20]3)=[O:17])[C:11]3[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=3)[C:5]=2[CH:4]=[CH:3][CH:2]=1.FC(F)(F)C(O)=O>ClCCl>[CH:10]1[C:11]2[CH:12]([CH2:14][O:15][C:16]([NH:18][C:19]3([C:24]([NH:26][C@H:27]([C:31]([N:33]([CH3:50])[C@@H:34]([C@@H:46]([CH3:49])[CH2:47][CH3:48])[C@H:35]([O:44][CH3:45])[CH2:36][C:37]([OH:39])=[O:38])=[O:32])[CH:28]([CH3:29])[CH3:30])=[O:25])[CH2:20][CH2:21][CH2:22][CH2:23]3)=[O:17])[C:13]3[C:5](=[CH:4][CH:3]=[CH:2][CH:1]=3)[C:6]=2[CH:7]=[CH:8][CH:9]=1
Reactant: CC[C@H](C)[C@@H]([C@@H](CC(=O)OC(C)(C)C)OC)N(C)C(=O)[C@@H](NC(=O)C1(NC(=O)OCC2c3ccccc3-c3ccccc32)CCCC1)C(C)C
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CC[C@H](C)[C@@H]([C@@H](CC(=O)O)OC)N(C)C(=O)[C@@H](NC(=O)C1(NC(=O)OCC2c3ccccc3-c3ccccc32)CCCC1)C(C)C
Reaction time: 18 h

Procedure:
To a solution of #27 (500 mg, 0.723 mmol) in dichloromethane (7 mL, 0.1 M) was added trifluoroacetic acid (3 mL). The reaction mixture initially became orange, then darkened over time. After stirring for 18 hours, the solvent was removed in vacuo to give #28 (460 mg, quantitative) as a dark brown glass, which was used without further purification. LC-MS: m/z 636.3 [M+H+].