Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: O=[C:2]([CH3:8])[CH2:3][C:4](OC)=[O:5].C[O-].[Na+].[CH3:12][NH:13][C:14]([NH2:16])=[S:15]>CO>[CH3:12][N:13]1[C:4](=[O:5])[CH:3]=[C:2]([CH3:8])[N:16]=[C:14]1[SH:15]
Reactant: COC(=O)CC(C)=O
Reactant: CNC(N)=S
Agent: C[O-]
Agent: [Na+]
Solvent: CO
Product: Cc1cc(=O)n(C)c(S)n1
Temperature: 25 °C
Yield: 74.7 %

Procedure:
Methyl 3-oxobutanoate (2 mL, 18.5 mmol) was added dropwise to a solution of sodium methoxide (25% wt in MeOH, 5 mL) and anhydrous MeOH (20 mL). N-methyl thiourea (1.67 g, 18.5 mmol) was added to the reaction mixture. The resulting solution was stirred at reflux for 5 hours. After cooling to room temperature, the solvent was evaporated. The residue was dissolved in water (25 mL), and the solution was acidified to pH 2-3 with concentrated HCl. The solid material was recovered by filtration, washed with water (2×20 mL) and diethyl ether (1×30 mL), and dried in vacuo, affording 3,6-dimethyl-2-sulfanyl-3,4-dihydropyrimidin-4-one (2.16 g, 73% yield). The product was used without further purification.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([O:8][CH2:9][CH:10]=[C:11]([Cl:13])[Cl:12])[CH:5]=[C:4]([Cl:14])[C:3]=1[OH:15].[O:16]([CH2:23][CH2:24][CH2:25]O)[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.CC(OC(/N=N/C(OC(C)C)=O)=O)C>O1CCCC1>[Cl:1][C:2]1[CH:7]=[C:6]([O:8][CH2:9][CH:10]=[C:11]([Cl:13])[Cl:12])[CH:5]=[C:4]([Cl:14])[C:3]=1[O:15][CH2:25][CH2:24][CH2:23][O:16][C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1
Reactant: Oc1c(Cl)cc(OCC=C(Cl)Cl)cc1Cl
Reactant: OCCCOc1ccccc1
Agent: CC(C)OC(=O)/N=N/C(=O)OC(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: ClC(Cl)=CCOc1cc(Cl)c(OCCCOc2ccccc2)c(Cl)c1
Temperature: 25 °C
Yield: 81.9 %

Procedure:
To a solution of 0.30 g of 2,6-dichloro-4-(3,3-dichloro-2-propenyloxy)phenol, 0.16 g of 3-phenoxy-1-propanol and 0.27 g of triphenylphosphine dissolved in 10 ml of tetrahydrofuran was added dropwise a solution of 0.21 g of diisopropylazodicarboxylate dissolved in 5 ml of tetrahydrofuran, while stirring at room temperature. After stirring at room temperature for 24 hours, the reaction mixture was concentrated to obtain a residue. The residue was subjected to silica gel chromatography, which afforded 0.36 g of 3,5-dichloro-1-(3,3-dichloro-2-propenyloxy)-4-(3-phenoxypropyloxy)benzene (82% yield), nD25.0 1.5762.
Reaction SMILES: S(Cl)([Cl:3])=O.[Br:5][C:6]1[CH:7]=[CH:8][C:9]([O:14][CH2:15][CH2:16][N:17]2[CH2:21][CH2:20][CH2:19][CH2:18]2)=[C:10]([CH2:12]O)[CH:11]=1.C(N(CC)CC)C.C(=O)(O)[O-].[Na+]>C1COCC1>[Br:5][C:6]1[CH:7]=[CH:8][C:9]([O:14][CH2:15][CH2:16][N:17]2[CH2:21][CH2:20][CH2:19][CH2:18]2)=[C:10]([CH2:12][Cl:3])[CH:11]=1
Reactant: O=S(Cl)Cl
Reactant: OCc1cc(Br)ccc1OCCN1CCCC1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: ClCc1cc(Br)ccc1OCCN1CCCC1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
0.16 mL (2.20 mmol) of thionyl chloride was added at −10° C. to a solution of 0.60 g (2.00 mmol) of [5-bromo-2-(2-pyrrolidin-1-ylethoxy)phenyl]methanol and 0.42 mL (3.00 mmol) of triethylamine in 30 mL of THF and the mixture was stirred for 16 hours at RT. Ice and dilute aqueous sodium bicarbonate solution was added to the reaction mixture and the phases were separated. The aqueous phase was exhaustively extracted with DCM, and the combined organic phases were washed with water, dried over magnesium sulfate, and evaporated down in vacuo. Yield: 0.39 g (62% of theoretical); C13H17BrClNO (M=318.637); calc.: molpeak (M+H)+: 318/320/322 (BrCl); found: molpeak (M+H)+: 318/320/322 (BrCl); HPLC-MS: 5.84 minutes (method A).
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[CH2:7][CH2:8][OH:9].C(N(CC)CC)C.[CH3:17][S:18](Cl)(=[O:20])=[O:19]>C1COCC1>[CH3:17][S:18]([O:9][CH2:8][CH2:7][C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][N:1]=1)(=[O:20])=[O:19]
Reactant: OCCc1ccccn1
Reactant: CS(=O)(=O)Cl
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: CS(=O)(=O)OCCc1ccccn1

Procedure:
A solution of 2-pyridin-2-yl-ethanol (Aldrich, 0.11 mL, 0.99 mmol), triethylamine (0.42 mL, 3.0 mmol), and methanesulfonyl chloride (0.12 mL, 1.5 mmol) in 5 mL THF were processed as described in Example 1C to give the crude title compound which was used directly in the next reaction.
Reaction SMILES: [NH2:1][C:2]1[N:11]=[C:10]([OH:12])[C:9]2[C:4](=[N:5][CH:6]=[C:7]([CH2:13][NH:14][C:15]3[CH:49]=[CH:48][C:18]([C:19]([NH:21][C@H:22]([C:44]([O:46]C)=[O:45])[CH2:23][CH2:24][C:25](=[O:43])[NH:26][CH2:27][CH2:28][O:29][CH2:30][CH2:31][O:32][CH2:33][CH2:34][NH:35]C(=O)OC(C)(C)C)=[O:20])=[CH:17][CH:16]=3)[N:8]=2)[N:3]=1.[OH-].[Li+].C1COCC1.O>Cl>[NH2:1][C:2]1[N:11]=[C:10]([OH:12])[C:9]2[C:4](=[N:5][CH:6]=[C:7]([CH2:13][NH:14][C:15]3[CH:16]=[CH:17][C:18]([C:19]([NH:21][C@@H:22]([CH2:23][CH2:24][C:25]([NH:26][CH2:27][CH2:28][O:29][CH2:30][CH2:31][O:32][CH2:33][CH2:34][NH2:35])=[O:43])[C:44]([OH:46])=[O:45])=[O:20])=[CH:48][CH:49]=3)[N:8]=2)[N:3]=1
Reactant: COC(=O)[C@H](CCC(=O)NCCOCCOCCNC(=O)OC(C)(C)C)NC(=O)c1ccc(NCc2cnc3nc(N)nc(O)c3n2)cc1
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Product: NCCOCCOCCNC(=O)CC[C@H](NC(=O)c1ccc(NCc2cnc3nc(N)nc(O)c3n2)cc1)C(=O)O
Temperature: 25 °C
Reaction time: 2 h
Yield: 98.1 %

Procedure:
(S)-methyl 18-(4-((2-amino-4-hydroxypteridin-6-yl)methylamino)benzamido)-2,2-dimethyl-4,15-dioxo-3,8,11-trioxa-5,14-diazanonadecan-19-oate (225 mg, 0.33 mmol, crude) in 6 M aqueous hydrochloric acid (20 mL) was stirred at ambient temperature for 2 hours. After this time, the reaction was purified by semi-preparative HPLC (0-70% H2O/CH3CN with 0.05% TFA over 25 minutes) to give a mixture of the desired acid and the methyl ester (190 mg) as a yellow solid. To this mixture lithium hydroxide (30 mg, 1.25 mmol) was added along with a 1:1 THF/H2O mixture (6 mL). This mixture was stirred at ambient temperature for 2 hours. After this time, the THF was removed under reduced pressure, and the reaction was purified by semi-preparative HPLC (0-70% H2O/CH3CN with 0.05% TFA over 25 min) to afford (S)-2-(4-((2-amino-4-hydroxypteridin-6-yl)methylamino)benzamido)-5-(2-(2-(2-aminoethoxy)ethoxy)ethylamino)-5-oxopentanoic acid (185 mg, 100%) as a yellow solid that was obtained from lyophilization: 1H NMR (500 MHz, DMSO-d6) δ 12.47 (vbs, 1H), 11.44 (vbs, 1H), 8.64 (s, 1H), 8.17 (d, J=7.5 Hz, 1H), 7.87 (t, J=5.5 Hz, 1H), 7.72 (bs, 2H), 7.65 (d, J=9.0 Hz, 2H), 6.93 (bs, 2H), 6.64 (d, J=9.0 Hz, 2H), 4.48 (s, 2H), 4.30-4.26 (m, 1H), 3.57-3.49 (m, 6H), 3.37 (t, J=6.0 Hz, 2H), 3.22-3.13 (m, 2H), 2.99-2.94 (m, 2H), 2.19 (t, J=7.5 Hz, 2H), 2.08-2.01 (m, 1H), 1.93-1.85 (m, 1H), exchangeable proton not observed (1H); ESI MS m/z=570 [M−H]−.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:29])[CH2:5][C:6]1[CH:11]=[CH:10][C:9]([O:12][CH3:13])=[C:8]([O:14][C:15]2[CH:20]=[CH:19][C:18]([NH2:21])=[CH:17][C:16]=2[CH2:22][N:23]2[CH2:27][CH2:26][O:25][C:24]2=[O:28])[CH:7]=1)[CH3:2].[CH:30]1([C:36](Cl)=[O:37])[CH2:35][CH2:34][CH2:33][CH2:32][CH2:31]1>>[CH2:1]([O:3][C:4](=[O:29])[CH2:5][C:6]1[CH:11]=[CH:10][C:9]([O:12][CH3:13])=[C:8]([O:14][C:15]2[CH:20]=[CH:19][C:18]([NH:21][C:36]([CH:30]3[CH2:35][CH2:34][CH2:33][CH2:32][CH2:31]3)=[O:37])=[CH:17][C:16]=2[CH2:22][N:23]2[CH2:27][CH2:26][O:25][C:24]2=[O:28])[CH:7]=1)[CH3:2]
Reactant: O=C(Cl)C1CCCCC1
Reactant: CCOC(=O)Cc1ccc(OC)c(Oc2ccc(N)cc2CN2CCOC2=O)c1
Product: CCOC(=O)Cc1ccc(OC)c(Oc2ccc(NC(=O)C3CCCCC3)cc2CN2CCOC2=O)c1

Procedure:
Prepared according to the procedure described in Example 100, Step 1, using the following starting materials: {3-[4-amino-2-(2-oxo-oxazolidin-3-ylmethyl)-phenoxy]-4-methoxy-phenyl}-acetic acid ethyl ester and cyclohexanecarbonyl chloride.
Reaction SMILES: [CH2:1]([N:3]1[CH2:7][CH:6]2[O:8][CH:5]2[CH2:4]1)[CH3:2].[Cl:9][C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=1[OH:16].Cl>Cl.C(Cl)Cl>[ClH:9].[Cl:9][C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=1[O:16][C@@H:6]1[CH2:7][N:3]([CH2:1][CH3:2])[CH2:4][C@H:5]1[OH:8]
Reactant: CCN1CC2OC2C1
Reactant: Oc1ccccc1Cl
Agent: Cl
Solvent: ClCCl
Product: CCN1C[C@@H](O)[C@H](Oc2ccccc2Cl)C1

Procedure:
A mixture of 17.0 g. (0.15 mole) of 1-ethyl-3,4-epoxypyrrolidine, 20.5 g. (0.16 mole) of a o-chlorophenol and 3 drops concentrated hydrochloric acid was heated on a steam both overnight. The oil was dissolved in methylene chloride and washed with three 50-ml. portions of 5% sodium hydroxide and one 50-ml. portion of water. The methylene chloride solution was dried over anhydrous sodium sulfate, concentrated and chromatographed on silica gel to give 8.9 g. (25%) of an oil as residue. The oil was converted to the hydrochloride and recrystallized from ethyl acetateacetonitrile to yield white powder, m.p. 108°-110° C.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([C:8]([C:13]([O:15][C:16]([CH3:19])([CH3:18])[CH3:17])=[O:14])([CH3:12])[C:9]([OH:11])=[O:10])[CH:5]=[CH:6][CH:7]=1.[C:20]1(C)C=CC=CC=1.[Si](C=[N+]=[N-])(C)(C)C>CO>[Br:1][C:2]1[CH:3]=[C:4]([C:8]([C:13]([O:15][C:16]([CH3:19])([CH3:18])[CH3:17])=[O:14])([CH3:12])[C:9]([O:11][CH3:20])=[O:10])[CH:5]=[CH:6][CH:7]=1
Reactant: CC(C)(C)OC(=O)C(C)(C(=O)O)c1cccc(Br)c1
Reactant: Cc1ccccc1
Agent: C[Si](C)(C)C=[N+]=[N-]
Solvent: CO
Product: COC(=O)C(C)(C(=O)OC(C)(C)C)c1cccc(Br)c1
Temperature: 25 °C
Reaction time: 16 h
Yield: 100 %

Procedure:
To a solution of 2-(3-bromophenyl)-2-(tert-butoxycarbonyl)propanoic acid (11.3 g, 32.8 mmol) in MeOH (35 mL) was added toluene (175 mL) followed by TMSCHN2 (2M in hexane, 44 mL, 98 mmol, 3 eq). The mixture was stirred at RT for 16 h. Solvents were evaporated and the residue was chromatographed on silica by eluting with EtOAc/hexanes to give 11.8 g (100%) of methyl 2-(3-bromophenyl)-2-(tert-butoxycarbonyl)propanoate as a yellow oil. 1H NMR (CDCl3) 7.59 (t, J=1.8 Hz, 1H), 7.36-7.44 (m, 2H), 7.21 (t, J=8.0 Hz, 1H), 5.92 (s, 1H), 3.70 (s, 3H), 1.97 (s, 3H), 1.36 (br s, 9H).
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:16]=[CH:15][C:14]([S:17]([CH3:20])(=[O:19])=[O:18])=[CH:13][C:10]=1[CH:11]=O)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[NH2:21][C:22]1[CH:31]=[CH:30][C:25]([C:26]([O:28][CH3:29])=[O:27])=[CH:24][CH:23]=1>C1(C)C=CC=CC=1>[CH2:1]([O:8][C:9]1[CH:16]=[CH:15][C:14]([S:17]([CH3:20])(=[O:19])=[O:18])=[CH:13][C:10]=1[CH2:11][NH:21][C:22]1[CH:23]=[CH:24][C:25]([C:26]([O:28][CH3:29])=[O:27])=[CH:30][CH:31]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: COC(=O)c1ccc(N)cc1
Reactant: CS(=O)(=O)c1ccc(OCc2ccccc2)c(C=O)c1
Solvent: Cc1ccccc1
Product: COC(=O)c1ccc(NCc2cc(S(C)(=O)=O)ccc2OCc2ccccc2)cc1
Reaction time: 1 h

Procedure:
A suspension of 2-benzyloxy-5-methanesulphonylbenzaldehyde (10 g) and methyl 4-aminobenzoate (5.2 g) in toluene (100 mL) was heated on a steam bath for 18 hours and evaporated to dryness. The residue was dissolved in a mixture of methanol (100 mL) and tetrahydrofuran (100 mL) and the first portion of sodium borohydride (1.3 g) was added. The mixture was stirred for 1 hour and the second portion of sodium borohydride (1.3 g) was added. The mixture was stirred for 30 minutes and evaporated to dryness. The residue was dissolved in dichloromethane (250 mL) and was washed with water and dried (MgSO4). The solvent was evaporated and the residue subjected to chromatography on silica eluting initially with dichloromethane and then with a mixture of ethyl acetate and dichloromethane (3/7 v/v) to give methyl 4-[N-(2-benzyloxy-5-methanesulphonylbenzyl)amino]benzoate, yield 10.2 g, mp 124° C.
Reaction SMILES: [Cl:1][C:2]1[C:3]2[S:10][CH:9]=[CH:8][C:4]=2[N:5]=[CH:6][N:7]=1.ClC1C=CN=C2C=C([CH:21]=[O:22])SC=12>>[Cl:1][C:2]1[C:3]2[S:10][C:9]([CH:21]=[O:22])=[CH:8][C:4]=2[N:5]=[CH:6][N:7]=1
Reactant: O=Cc1cc2nccc(Cl)c2s1
Reactant: Clc1ncnc2ccsc12
Product: O=Cc1cc2ncnc(Cl)c2s1
Yield: 84 %

Procedure:
Starting from 4-chloro-thieno[3,2-d]pyrimidine (20, scheme 4) and following procedure described above for the synthesis of aldehyde 14 (scheme 3, step 1, example 20), title compound 186 was obtained in 84% yield. LRMS (M+1) 199.0 (100%).
Reaction SMILES: [Cl:1][C:2]1[CH:26]=[N:25][C:5]2[NH:6][C:7]3[C:12]([C:4]=2[CH:3]=1)=[C:11]([C:13]1[CH:18]=[CH:17][CH:16]=[C:15]([S:19]([CH2:22][CH3:23])(=[O:21])=[O:20])[CH:14]=1)[CH:10]=[CH:9][C:8]=3[OH:24].C(S(C1C=C(C2C=C[C:44]([O:47][CH2:48][CH2:49]CN(C)C)=[C:43]3C=2[C:40]2C=C(C)C=N[C:41]=2[NH:42]3)C=CC=1)(=O)=O)C>>[Cl:1][C:2]1[CH:26]=[N:25][C:5]2[NH:6][C:7]3[C:12]([C:4]=2[CH:3]=1)=[C:11]([C:13]1[CH:18]=[CH:17][CH:16]=[C:15]([S:19]([CH2:22][CH3:23])(=[O:21])=[O:20])[CH:14]=1)[CH:10]=[CH:9][C:8]=3[O:24][CH2:40][CH2:41][N:42]1[CH2:43][CH2:44][O:47][CH2:48][CH2:49]1
Reactant: CCS(=O)(=O)c1cccc(-c2ccc(O)c3[nH]c4ncc(Cl)cc4c23)c1
Reactant: CCS(=O)(=O)c1cccc(-c2ccc(OCCCN(C)C)c3[nH]c4ncc(C)cc4c23)c1
Product: CCS(=O)(=O)c1cccc(-c2ccc(OCCN3CCOCC3)c3[nH]c4ncc(Cl)cc4c23)c1

Procedure:
The title compound was prepared from Compound 218 by using an analogous procedure to that outlined in the preparation of Compound 205. 1H NMR (400 MHz, Methanol-d4) δ 8.12 (s, 1H) 8.00 (m, 1H) 7.92 (m, 1H) 7.74 (t, J=7.84 Hz, 1H) 7.64 (s, 1H) 7.09 (m, 1H) 7.02 (m, 1H) 6.84 (s, 1H) 4.40 (t, J=5.0 Hz, 2H) 4.11 (br, 4H) 3.80 (br, 4H) 3.55 (t, J=5.0 Hz, 2H) 3.30 (q, J=7.32 Hz, 2H) 1.27 (t, J=7.32 Hz, 3H). [M+H] calc'd for C25H27ClN3O4S, 500; found, 500.
Reaction SMILES: [C:1]([O:5][C:6](=[O:28])[CH2:7][C@H:8]([C:18]1[O:22][N:21]=[C:20]([C:23](OCC)=[O:24])[N:19]=1)[CH2:9][CH2:10][CH2:11][CH:12]1[CH2:17][CH2:16][CH2:15][CH2:14][CH2:13]1)([CH3:4])([CH3:3])[CH3:2].[NH:29]1[CH2:34][CH2:33][CH2:32][CH2:31][CH2:30]1>C(O)C>[CH:12]1([CH2:11][CH2:10][CH2:9][C@@H:8]([C:18]2[O:22][N:21]=[C:20]([C:23]([N:29]3[CH2:34][CH2:33][CH2:32][CH2:31][CH2:30]3)=[O:24])[N:19]=2)[CH2:7][C:6]([O:5][C:1]([CH3:4])([CH3:3])[CH3:2])=[O:28])[CH2:13][CH2:14][CH2:15][CH2:16][CH2:17]1
Reactant: CCOC(=O)c1noc([C@H](CCCC2CCCCC2)CC(=O)OC(C)(C)C)n1
Reactant: C1CCNCC1
Solvent: CCO
Product: CC(C)(C)OC(=O)C[C@@H](CCCC1CCCCC1)c1nc(C(=O)N2CCCCC2)no1
Temperature: 60 °C
Yield: 101.4 %

Procedure:
A solution of ethyl 5-{(1R)-1-[2-(tert-butoxy)-2-oxoethyl]-4-cyclohexylbutyl}-1,2,4-oxadiazole-3-carboxylate (Preparation 3) (300 mg, 0.76 mmol) in ethanol (4 ml) was treated dropwise with piperidine (0.75 ml, 7.60 mmol) and the resulting mixture was heated at 60° C. under a nitrogen atmosphere for 9 hours. The mixture was cooled and the solvent removed under reduced pressure. The residue was purified by column chromatography on silica gel eluting with dichloromethane:ethyl acetate (80:20) to afford the title compound as a pale yellow oil (334 mg).
Reaction SMILES: [O:1]1[CH:5]=[C:4]([C:6](Cl)=[O:7])[CH:3]=[N:2]1.[NH:9]1[CH2:14][CH2:13][CH2:12][CH2:11][CH2:10]1>>[O:1]1[CH:5]=[C:4]([C:6]([N:9]2[CH2:14][CH2:13][CH2:12][CH2:11][CH2:10]2)=[O:7])[CH:3]=[N:2]1
Reactant: O=C(Cl)c1cnoc1
Reactant: C1CCNCC1
Product: O=C(c1cnoc1)N1CCCCC1

Procedure:
of melting point 78° to 81° C., prepared from 4-isoxazolecarboxylic acid chloride and piperidine.
Reaction SMILES: [C:1]1([NH:7][S:8]([C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=2[CH:17]=[CH:18][C:19]([OH:21])=O)(=[O:10])=[O:9])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[Cl:22]CCl>CN(C)C=O>[C:1]1([NH:7][S:8]([C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=2[CH:17]=[CH:18][C:19]([Cl:22])=[O:21])(=[O:10])=[O:9])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: ClCCl
Reactant: O=C(O)C=Cc1ccccc1S(=O)(=O)Nc1ccccc1
Solvent: CN(C)C=O
Product: O=C(Cl)C=Cc1ccccc1S(=O)(=O)Nc1ccccc1
Temperature: 40 °C
Reaction time: 1 h
Yield: 100.1 %

Procedure:
To a suspension of 3-(2-phenylsulfamoyl-phenyl)-acrylic acid (35a) (0.18 g, 0.59 mmol) in dichloromethane (3.0 ml) oxalyl chloride (0.18 ml, 2.06 mmol) and one drop of dimethylformamide were added. The reaction mixture was stirred at 40° C. for one hour and concentrated under reduced pressure to give crude title compound (0.19 g, 99%).
Reaction SMILES: CC(C)(O[N:5]([C@H:9]([CH2:39][C:40]1[CH:45]=[CH:44][CH:43]=[CH:42][CH:41]=1)[C:10]([NH:12][C:13]1[CH:18]=[C:17]([NH:19][C:20]([N:22]2[CH2:26][CH2:25][CH2:24][CH2:23]2)=[O:21])[CH:16]=[C:15]([NH:27][C:28]2[N:33]=[C:32]([O:34][CH2:35][C:36]#[CH:37])[C:31]([Br:38])=[CH:30][N:29]=2)[CH:14]=1)=[O:11])C(=O)[O-])C.S(=O)(=O)(O)O.O>O1CCOCC1>[NH2:5][C@H:9]([CH2:39][C:40]1[CH:41]=[CH:42][CH:43]=[CH:44][CH:45]=1)[C:10]([NH:12][C:13]1[CH:18]=[C:17]([NH:19][C:20]([N:22]2[CH2:26][CH2:25][CH2:24][CH2:23]2)=[O:21])[CH:16]=[C:15]([NH:27][C:28]2[N:33]=[C:32]([O:34][CH2:35][C:36]#[CH:37])[C:31]([Br:38])=[CH:30][N:29]=2)[CH:14]=1)=[O:11]
Reactant: C#CCOc1nc(Nc2cc(NC(=O)[C@@H](Cc3ccccc3)N(OC(C)(C)C)C(=O)[O-])cc(NC(=O)N3CCCC3)c2)ncc1Br
Agent: O=S(=O)(O)O
Solvent: C1COCCO1
Solvent: O
Product: C#CCOc1nc(Nc2cc(NC(=O)[C@H](N)Cc3ccccc3)cc(NC(=O)N3CCCC3)c2)ncc1Br
Yield: 86.8 %

Procedure:
1,1-Dimethylethoxy[(1R)-2-[[3-[[5-bromo-4-(prop-2-ynyloxy)pyrimidin-2-yl]amino]-5-[[(pyrrolidin-1-yl)carbonyl]amino]phenyl]amino]-2-oxo-1(phenylmethyl)ethyl]carbamate (105 mg) and sulfuric acid (0.5 ml; 2 n) were stirred in dioxane (5 ml) at 85° C. for 3.5 h. After cooling and dilution with water saturated NaHCO3-solution was added and the resulting precipitate collected by filtration yielding the title compound (76 mg).
Reaction SMILES: [CH3:1][Si](C=[N+]=[N-])(C)C.CCCCCC.[C:14]([O:18][C:19]([N:21]1[CH2:26][CH2:25][C@@H:24]([CH2:27][CH2:28][C:29]([OH:31])=[O:30])[C@@H:23]([CH:32]=[CH2:33])[CH2:22]1)=[O:20])([CH3:17])([CH3:16])[CH3:15]>CO>[C:14]([O:18][C:19]([N:21]1[CH2:26][CH2:25][C@@H:24]([CH2:27][CH2:28][C:29]([O:31][CH3:1])=[O:30])[C@@H:23]([CH:32]=[CH2:33])[CH2:22]1)=[O:20])([CH3:17])([CH3:16])[CH3:15]
Reactant: C=C[C@H]1CN(C(=O)OC(C)(C)C)CC[C@H]1CCC(=O)O
Reactant: C[Si](C)(C)C=[N+]=[N-]
Solvent: CO
Solvent: CCCCCC
Product: C=C[C@H]1CN(C(=O)OC(C)(C)C)CC[C@H]1CCC(=O)OC
Temperature: 22 °C
Reaction time: 3 h

Procedure:
50 cm3 of a solution of 2M trimethylsilyldiazomethane/hexane are added, at a temperature in the region of 15° C., under an argon atmosphere, to 5 g (17.64 mmol) of (3R,4R)-1-tert-butyloxycarbonyl-4-(2-carboxyethyl)-3-vinylpiperidine in solution in 50 cm3 of methanol. After stirring for 3 hours at a temperature in the region of 22° C., the reaction medium is concentrated to dryness under reduced pressure (2.7 kPa) to give 5.3 g of (3R,4R)-1-tert-butyloxycarbonyl-4-(2-methoxycarbonylethyl)-3-vinylpiperidine in the form of an orange oil.
Reaction SMILES: [C:1]([O:4][CH:5](P(CC)(CC)=O)[C:6]([O:8][CH3:9])=[O:7])(=[O:3])[CH3:2].[Cl-].[Li+].CN(C)C(=N)N(C)C.[CH3:26][O:27][CH2:28][N:29]1[CH:37]=[C:36]2[C:31]([C:32]([CH3:40])=[CH:33][C:34]([CH:38]=O)=[CH:35]2)=[N:30]1>O1CCCC1>[C:1]([O:4][C:5](=[CH:38][C:34]1[CH:33]=[C:32]([CH3:40])[C:31]2[C:36](=[CH:37][N:29]([CH2:28][O:27][CH3:26])[N:30]=2)[CH:35]=1)[C:6]([O:8][CH3:9])=[O:7])(=[O:3])[CH3:2]
Reactant: CCP(=O)(CC)C(OC(C)=O)C(=O)OC
Reactant: COCn1cc2cc(C=O)cc(C)c2n1
Agent: CN(C)C(=N)N(C)C
Agent: [Cl-]
Agent: [Li+]
Solvent: C1CCOC1
Product: COCn1cc2cc(C=C(OC(C)=O)C(=O)OC)cc(C)c2n1
Temperature: -78 °C
Reaction time: 0.17 h

Procedure:
To a solution of methyl 2-acetoxy-2-(diethylphosphoryl)acetate (4.89 g, 18.2 mmol) in tetrahydrofuran (25 mL) was added lithium chloride (0.74 g, 17.5 mmol). The reaction was stirred until dissolution was complete. The reaction was cooled to −78° C., and treated with tetramethylguanidine (2.20 mL, 17.5 mmol) to give a white suspension which was stirred for 10 min. To this was added 2-(methoxymethyl)-7-methyl-2H-indazole-5-carbaldehyde (3.10 g, 15.2 mmol) in one portion. After 10 min, the ice bath was concentrated and the reaction stirred overnight. The reaction was poured onto water/diethyl ether, and the layers separated. The ethereal was washed with water, then brine, dried over magnesium sulfate, and concentrated. Column chromatography gave recovered 2-(methoxymethyl)-7-methyl-2H-indazole-5-carbaldehyde (0.57 g, 18%) and the title compound (2.86 g, 59%) as a colorless oil. NMR shows a 3:2 ratio of Z and E isomers which were not separated. Major (Z isomer): 1H-NMR (CDCl3, 500 MHz) δ 2.25 (s, 3H), 2.62 (s, 3H), 3.40 (s, 3H), 3.71 (s, 3H), 5.69 (s, 2H), 6.88 (s, 1H), 7.09 (s, 1H), 7.72 (s, 1H), 8.10 (s, 1H). Mass spec.: 319.18 (MH)+. Minor (E isomer): 1H-NMR (CDCl3, 500 MHz) δ 2.35 (s, 3H), 2.62 (s, 3H), 3.40 (s, 3H), 3.85 (s, 3H), 5.69 (s, 2H), 7.32 (s, 1H), 7.38 (s, 1H), 7.78 (s, 1H), 8.14 (s, 1H). Mass spec.: 319.18 (MH)+.
Reaction SMILES: Cl.[I:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][CH:12]=1)[N:9]([CH:13]1[CH2:18][CH2:17][CH2:16][NH:15][CH2:14]1)[CH:8]=[C:7]([C:19]([O:21][CH2:22][CH3:23])=[O:20])[C:6]2=[O:24].[N:25]1[CH:30]=[CH:29][C:28]([CH:31]=O)=[CH:27][CH:26]=1.C([BH3-])#N.[Na+].O>CO>[I:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][CH:12]=1)[N:9]([CH:13]1[CH2:18][CH2:17][CH2:16][N:15]([CH2:31][C:28]3[CH:29]=[CH:30][N:25]=[CH:26][CH:27]=3)[CH2:14]1)[CH:8]=[C:7]([C:19]([O:21][CH2:22][CH3:23])=[O:20])[C:6]2=[O:24]
Reactant: CCOC(=O)c1cn(C2CCCNC2)c2ccc(I)cc2c1=O
Reactant: O=Cc1ccncc1
Agent: Cl
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CO
Solvent: O
Product: CCOC(=O)c1cn(C2CCCN(Cc3ccncc3)C2)c2ccc(I)cc2c1=O
Temperature: 23 °C
Reaction time: 16 h
Yield: 82.3 %

Procedure:
Ethyl 6-iodo-4-oxo-1-(piperidin-3-yl)-1,4-dihydroquinoline-3-carboxylate hydrochloride (Intermediate 132, 500 mg, 1.08 mmol) was suspended in methanol (15 mL) then 4-pyridinecarboxaldehyde (520 μl, 5.4 mmol) and sodium cyanoborohydride (612 mg, 9.7 mmol) were added. The reaction was stirred at 23° C. for 16 h. The volume of the reaction was reduced by half and water (25 mL) was added. The suspension was extracted with 2:1 ethyl acetate: tetrahydrofuran (3×, 10 mL). The organic phases were combined, dried over sodium sulfate, and the solvent was removed in vacuo. The residue was passed through a plug of silica gel (2 g) eluting with 10% methanol in dichloromethane to remove any remaining borohydride. The solid was then dried in a vacuum oven at 50° C. for 18 h to give 460 mg (82% yield) of ethyl 6-iodo-4-oxo-1-(1-(pyridin-4-ylmethyl)piperidin-3-yl)-1,4-dihydroquinoline-3-carboxylate as an off white solid.
Reaction SMILES: [CH3:1][N:2]([S:26]([C:29]1[CH:34]=[CH:33][C:32]([CH3:35])=[CH:31][CH:30]=1)(=[O:28])=[O:27])[C:3]1[C:12]2[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=2)[C:6]([N:13]2[CH2:18][CH2:17][N:16](C(OC(C)(C)C)=O)[CH2:15][CH2:14]2)=[CH:5][CH:4]=1.[ClH:36]>CO.CCOCC>[ClH:36].[CH3:1][N:2]([C:3]1[C:12]2[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=2)[C:6]([N:13]2[CH2:14][CH2:15][NH:16][CH2:17][CH2:18]2)=[CH:5][CH:4]=1)[S:26]([C:29]1[CH:34]=[CH:33][C:32]([CH3:35])=[CH:31][CH:30]=1)(=[O:27])=[O:28]
Reactant: Cc1ccc(S(=O)(=O)N(C)c2ccc(N3CCN(C(=O)OC(C)(C)C)CC3)c3ccccc23)cc1
Agent: Cl
Solvent: CCOCC
Solvent: CO
Product: Cc1ccc(S(=O)(=O)N(C)c2ccc(N3CCNCC3)c3ccccc23)cc1
Reaction time: 8 h

Procedure:
1-tert-Butyl 4-(4-{methyl[(4-methylphenyl)sulfonyl]amino}-1-naphthyl)-1-piperazinecarboxylate (intermediate 14 after reduction according to Method A) (75 mg, 0.15 mmol) was dissolved in methanol (5 mL) and treated with 1N HCl in ether (20 mL). After stirring overnight, the product precipitated and was collected by filtration, washed with ether and dried. Yield 60 mg (92%) of an off white solid.