Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([O:21][CH3:22])[C:6]2[CH2:12][CH2:11][N:10](C(OC(C)(C)C)=O)[CH2:9][CH2:8][C:7]=2[N:20]=1>Cl>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([O:21][CH3:22])[C:6]2[CH2:12][CH2:11][NH:10][CH2:9][CH2:8][C:7]=2[N:20]=1
Reactant: COc1cc(OC)c2c(n1)CCN(C(=O)OC(C)(C)C)CC2
Agent: Cl
Product: COc1cc(OC)c2c(n1)CCNCC2
Temperature: 25 °C
Reaction time: 16 h

Procedure:
Ag2CO3 (1.63 mmol, 449 mg) was added to a solution of tert-butyl 4-hydroxy-2-oxo-1,2,5,6,8,9-hexahydro-7H-pyrido[2,3-d]azepine-7-carboxylate (91.0 mg, 0.325 mmol) in DCM (1.5 ml) at room temperature. After 10 min of stirring, MeI (1.63 mmol, 106 μl) was added. After 15 h of stirring, sat. aq. NH4Cl was added and the mixture was extracted with DCM. The organic layer was washed with water, dried over Na2SO4 and concentrated under reduced pressure. The crude product was purified by column chromatography to provide 72 mg (72%) of tert-butyl 2,4-dimethoxy-5,6,8,9-tetrahydro-7H-pyrido[2,3-d]azepine-7-carboxylate. 1H-NMR (CDCl3) δ 6.02 (1H), 3.85 (3H), 3.76 (3H), 3.55 (2H), 3.48 (2H), 2.98 (2H), 2.81 (2H), 1.45 (9H) ppm. tert-Butyl 2,4-dimethoxy-5,6,8,9-tetrahydro-7H-pyrido[2,3-d]azepine-7-carboxylate (72 mg, 0.23 mmol) was dissolved in HCl (2 N in Et2O, 3 ml) and stirred for 16 h at room temperature. The hydrochloric salt of 2,4-dimethoxy-6,7,8,9-tetrahydro-5H-pyrido[2,3-d]azepine was obtained in quantitative yield. 1H-NMR (CDCl3) δ 9.98 (br s, 2H), 6.32 (s, 1H), 3.73 (s, 3H), 3.65 (s, 3H), 3.25 (m, 2H), 2.88 (m, 2H), 2.86 (m, 2H), 2.78 (m, 2H) ppm.
Reaction SMILES: Br[C:2]1[N:6]2[CH2:7][C:8]3([C:15]4[CH:20]=[CH:19][C:18]([O:21][CH3:22])=[CH:17][CH:16]=4)[NH:14][CH2:13][CH2:12][N:9]3[C:10](=[O:11])[C:5]2=[CH:4][CH:3]=1.C(N(CC)CC)C.[CH3:30][Si:31]([C:34]#[CH:35])([CH3:33])[CH3:32]>Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.[Cu]I>[CH3:22][O:21][C:18]1[CH:19]=[CH:20][C:15]([C:8]23[NH:14][CH2:13][CH2:12][N:9]2[C:10](=[O:11])[C:5]2[N:6]([C:2]([C:35]#[C:34][Si:31]([CH3:33])([CH3:32])[CH3:30])=[CH:3][CH:4]=2)[CH2:7]3)=[CH:16][CH:17]=1
Reactant: C#C[Si](C)(C)C
Reactant: COc1ccc(C23Cn4c(Br)ccc4C(=O)N2CCN3)cc1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Cu]I
Solvent: CCN(CC)CC
Product: COc1ccc(C23Cn4c(C#C[Si](C)(C)C)ccc4C(=O)N2CCN3)cc1
Temperature: 80 °C
Yield: 67.1 %

Procedure:
8-bromo-10a-(4-methoxyphenyl)-2,3,10,10a-tetrahydro-1H,5H-imidazo[1,2-a]pyrrolo[1,2-d]pyrazin-5-one (120 mg, 0.33 mmol), Pd(PPh3)2Cl2 (23 mg, 0.033 mmol) and copper(I) iodide (15 mg, 0.079 mmol) were added to a 10 mL round bottom flask that was then evacuated and then filled back with argon twice. Dry DMF (5 mL) was added and the solution degassed with argon for 10 minutes. Triethylamine (0.24 mL, 1.7 mmol) and trimethylsilylacetylene (0.24 mL, 1.7 mmol) were added and the resulting brown solution was degassed with argon for a further minute. The reaction flask was sealed and heated at 80° C. until full consumption of the starting material (4 hours; monitored by LCMS). The solution was diluted with ethyl acetate (50 mL) and washed with brine (3×15 mL). The organic layer was dried (Na2SO4), filtered and concentrated in vacuo to give a material that was purified by flash chromatography (2× Biotage SP4, 12 g cartridge, CH2Cl2 3 CV, gradient 0-10% MeOH in CH2Cl2 15 CV, hold for 5 CV) and (Biotage SP4, 12 g cartridge, gradient 50-100% EtOAc in hexanes 10 CV, hold for 15 CV) to give 10a-(4-methoxyphenyl)-8-[(trimethylsilyl)ethynyl]-2,3,10,10a-tetrahydro-1H,5H-imidazo[1,2-a]pyrrolo[1,2-d]pyrazin-5-one as a yellow solid (84 mg, yield 62%). ESI-MI m/z [M+H]+ 380.0.
Reaction SMILES: [CH:1]([C:3]1[CH:15]=[C:14]([C:16]2[S:17][CH:18]=[CH:19][CH:20]=2)[C:13]([O:21][CH3:22])=[CH:12][C:4]=1[O:5][CH2:6][C:7]([N:9]([CH3:11])[CH3:10])=[O:8])=O.[C:23]([C:26]1[CH:34]=[CH:33][C:29]([C:30]([OH:32])=[O:31])=[CH:28][CH:27]=1)(=[O:25])[CH3:24]>>[CH3:10][N:9]([CH3:11])[C:7]([CH2:6][O:5][C:4]1[CH:12]=[C:13]([O:21][CH3:22])[C:14]([C:16]2[S:17][CH:18]=[CH:19][CH:20]=2)=[CH:15][C:3]=1/[CH:1]=[CH:24]/[C:23]([C:26]1[CH:34]=[CH:33][C:29]([C:30]([OH:32])=[O:31])=[CH:28][CH:27]=1)=[O:25])=[O:8]
Reactant: COc1cc(OCC(=O)N(C)C)c(C=O)cc1-c1cccs1
Reactant: CC(=O)c1ccc(C(=O)O)cc1
Product: COc1cc(OCC(=O)N(C)C)c(/C=C/C(=O)c2ccc(C(=O)O)cc2)cc1-c1cccs1
Yield: 75 %

Procedure:
The title compound was prepared by condensing 2-(2-formyl-5-methoxy-4-thiophen-2-yl-phenoxy)-N,N-dimethyl-acetamide (Ex-67A) and 4-acetylbenzoic acid in a similar manner as described in Ex-3. Yellow solid, mp 228–229° C., 75% yield. 1H-NMR (300 MHz, DMSO-d6) δ 8.31 (d, 2H, J=9.3 Hz), 8.22 (d, 2H, J=13.3 Hz), 8.08 (d, 2H, J=9.3 Hz), 7.95 (s, 1H), 7.65 (d, 1H, J=2.7 Hz), 7.52 (d, 1H, J=5.1 Hz), 7.13 (dd, 1H, J=5.1, 2.7 Hz), 6.85 (s, 1H), 5.11 (s, 2H), 3.99 (s, 3H), 3.06 (s, 3H), 2.93 (s, 3H). MS (EI) m/z=465 ([M]+, 100%). HRMS (EI) Calcd. for C25H23NO6S: 465.1246. Found: 465.1246.
Reaction SMILES: [CH2:1]([O:3][C:4]1[CH:18]=[C:17]([CH2:19][N:20]2[CH2:24][CH2:23][CH:22]([C:25]3[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=3)[CH2:21]2)[CH:16]=[CH:15][C:5]=1[O:6][C:7]1[CH:14]=[CH:13][C:10]([C:11]#[N:12])=[CH:9][N:8]=1)[CH3:2].C(=O)([O-])[O-:32].[K+].[K+].OO>CS(C)=O>[CH2:1]([O:3][C:4]1[CH:18]=[C:17]([CH2:19][N:20]2[CH2:24][CH2:23][CH:22]([C:25]3[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=3)[CH2:21]2)[CH:16]=[CH:15][C:5]=1[O:6][C:7]1[CH:14]=[CH:13][C:10]([C:11]([NH2:12])=[O:32])=[CH:9][N:8]=1)[CH3:2]
Reactant: O=C([O-])[O-]
Reactant: CCOc1cc(CN2CCC(c3ccccc3)C2)ccc1Oc1ccc(C#N)cn1
Agent: OO
Agent: [K+]
Solvent: CS(C)=O
Product: CCOc1cc(CN2CCC(c3ccccc3)C2)ccc1Oc1ccc(C(N)=O)cn1

Procedure:
Using a method similar to Example 371, and using (±)-6-[2-Ethoxy-4-(3-phenyl-pyrrolidin-1-ylmethyl)-phenoxy]-nicotinonitrile (step 2 above), potassium carbonate (approx. 0.5 equivalent), and 30% hydrogen peroxide solution (aq) (approx. 3 mole equivalents) in dimethylsulfoxide provides the title compound.
Reaction SMILES: Cl[C:2]1[S:3][C:4]2[CH:10]=[CH:9][CH:8]=[CH:7][C:5]=2[N:6]=1.C[Sn](C)(C)[C:13]1[CH:14]=[CH:15][C:16]([C:19]([NH2:21])=[O:20])=[N:17][CH:18]=1>O1CCOCC1.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>[S:3]1[C:4]2[CH:10]=[CH:9][CH:8]=[CH:7][C:5]=2[N:6]=[C:2]1[C:13]1[CH:14]=[CH:15][C:16]([C:19]([NH2:21])=[O:20])=[N:17][CH:18]=1
Reactant: C[Sn](C)(C)c1ccc(C(N)=O)nc1
Reactant: Clc1nc2ccccc2s1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Solvent: C1COCCO1
Product: NC(=O)c1ccc(-c2nc3ccccc3s2)cn1
Temperature: 160 °C
Yield: 29.1 %

Procedure:
A mixture of 2-chloro-1,3-benzothiazole (38 μL, 0.31 mmol), 5-(trimethylstannyl)pyridine-2-carboxamide (97 mg, 0.34 mmol) and Pd(PPh3)4 (35 mg, 0.03 mmol) in dry dioxane (2 mL) was heated under argon to 160° C. for 30 min in a microwave reactor. The precipitate was filtered off. Flash chromatography (DCM/MeOH 99:1→DCM/Acetone 1:1) gave the title compound (23 mg) as a white solid. 1H NMR δ 9.31 (dd, 1H) 8.63 (dd, 1H) 8.27 (br s, 1H) 8.26-8.19 (m, 2H) 8.16 (d, 1H) 7.83 (br s, 1H) 7.64-7.59 (m, 1H) 7.57-7.52 (m, 1H); MS m/z (M+H) 256.
Reaction SMILES: [F:1][C:2]([F:7])([F:6])[C:3]([OH:5])=[O:4].[F:8][C:9]([F:14])([F:13])[C:10]([OH:12])=[O:11].FC(F)(F)C(O)=O.[Cl:22][C:23]1[CH:24]=[N:25][C:26]2[NH:27][C:28]3[CH:29]=[N:30][CH:31]=[C:32]([CH:54]=3)[CH2:33][CH2:34][C:35]3[CH:43]=[C:39]([NH:40][C:41]=1[N:42]=2)[CH:38]=[CH:37][C:36]=3[NH:44][C:45](=[O:53])[CH2:46][CH:47]1[CH2:52][CH2:51][NH:50][CH2:49][CH2:48]1.[CH3:55][O:56][C:57]1[CH:58]=[C:59]([S:63](Cl)(=[O:65])=[O:64])[CH:60]=[CH:61][CH:62]=1>>[F:1][C:2]([F:7])([F:6])[C:3]([OH:5])=[O:4].[F:8][C:9]([F:14])([F:13])[C:10]([OH:12])=[O:11].[Cl:22][C:23]1[CH:24]=[N:25][C:26]2[NH:27][C:28]3[CH:29]=[N:30][CH:31]=[C:32]([CH:54]=3)[CH2:33][CH2:34][C:35]3[CH:43]=[C:39]([NH:40][C:41]=1[N:42]=2)[CH:38]=[CH:37][C:36]=3[NH:44][C:45](=[O:53])[CH2:46][CH:47]1[CH2:52][CH2:51][N:50]([S:63]([C:59]2[CH:60]=[CH:61][CH:62]=[C:57]([O:56][CH3:55])[CH:58]=2)(=[O:65])=[O:64])[CH2:49][CH2:48]1
Reactant: O=C(CC1CCNCC1)Nc1ccc2cc1CCc1cncc(c1)Nc1ncc(Cl)c(n1)N2
Reactant: COc1cccc(S(=O)(=O)Cl)c1
Solvent: O=C(O)C(F)(F)F
Product: COc1cccc(S(=O)(=O)N2CCC(CC(=O)Nc3ccc4cc3CCc3cncc(c3)Nc3ncc(Cl)c(n3)N4)CC2)c1
Yield: 28 %

Procedure:
The desired compound was prepared according to the procedure of Example A42 using N-[6-chloro-2,4,8,18,22-pentaazatetracyclo[14.3.1.1(3,7).1(9,13)]docosa-1(20),3(22),4,6,9(21),10,12,16,18-nonaen-12-yl]-2-piperidin-4-ylacetamide tris(trifluoroacetate) and 3-methoxybenzenesulfonyl chloride as starting materials in 28% yield. LCMS for C31H33ClN7O4S (M+H)+: m/z=634.2.
Reaction SMILES: C([O:4][CH2:5][CH:6]1[N:11]([C:12]([O:14][C:15]([CH3:18])([CH3:17])[CH3:16])=[O:13])[CH2:10][C:9]2[C:19]3[CH:25]=[C:24]([S:26]([C:29]4[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=4)(=[O:28])=[O:27])[CH:23]=[C:22]([Cl:35])[C:20]=3[O:21][C:8]=2[CH2:7]1)(=O)C.O.[OH-].[Li+]>CO.O>[Cl:35][C:22]1[C:20]2[O:21][C:8]3[CH2:7][CH:6]([CH2:5][OH:4])[N:11]([C:12]([O:14][C:15]([CH3:18])([CH3:17])[CH3:16])=[O:13])[CH2:10][C:9]=3[C:19]=2[CH:25]=[C:24]([S:26]([C:29]2[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=2)(=[O:28])=[O:27])[CH:23]=1
Reactant: CC(=O)OCC1Cc2oc3c(Cl)cc(S(=O)(=O)c4ccccc4)cc3c2CN1C(=O)OC(C)(C)C
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: CO
Product: CC(C)(C)OC(=O)N1Cc2c(oc3c(Cl)cc(S(=O)(=O)c4ccccc4)cc23)CC1CO
Temperature: 25 °C
Reaction time: 2 h
Yield: 80.8 %

Procedure:
To the crude product of step K (110 mg, 0.22 mmol) in methanol (5 mL) and water (5 mL) at 0° C. was added lithium hydroxide monohydrate (92 mg, 2.2 mmol). The solution was stirred at ambient temperature for 2 h then concentrated in vacuo. Water (10 mL) was added and the mixture extracted with ethyl acetate (3×10 mL). The combined organic extracts were dried over Na2SO4, filtered, and concentrated in vacuo to give the crude product. Purification by flash column chromatography (SiO2, 9:1 to 7:3, hexanes/ethyl acetate) afforded tert-butyl 6-chloro-3-(hydroxymethyl)-8-(phenylsulfonyl)-3,4-dihydrobenzofuro[3,2-c]pyridine-2(1H)-carboxylate (85 mg, 80%) as a colorless oil: 1H NMR (CDCl3, 300 MHz) δ 7.98-7.95 (m, 3H), 7.84 (d, J=1.5 Hz, 1H), 7.56-7.51 (m, 3H), 4.93 (br s, 2H), 4.13-4.10 (m, 1H), 3.64-3.61 (m, 2H), 3.17-3.08 (m, 1H), 2.88 (d, J=17.4 Hz, 1H), 1.85 (br s, 1H), 1.53 (s, 9H).
Reaction SMILES: C([O:3][C:4]([CH2:6][N:7]1[C:11]2[CH:12]=[CH:13][C:14]([N:16]([S:22]([CH3:25])(=[O:24])=[O:23])[CH2:17][CH2:18][N:19]([CH3:21])[CH3:20])=[CH:15][C:10]=2[N:9]=[C:8]1[CH2:26][O:27][C:28]1[CH:33]=[CH:32][C:31]([C:34](=[NH:36])[NH2:35])=[CH:30][CH:29]=1)=[O:5])C.[OH-].[Na+]>>[OH:5][C:4]([CH2:6][N:7]1[C:11]2[CH:12]=[CH:13][C:14]([N:16]([S:22]([CH3:25])(=[O:23])=[O:24])[CH2:17][CH2:18][N:19]([CH3:21])[CH3:20])=[CH:15][C:10]=2[N:9]=[C:8]1[CH2:26][O:27][C:28]1[CH:33]=[CH:32][C:31]([C:34](=[NH:35])[NH2:36])=[CH:30][CH:29]=1)=[O:3]
Reactant: CCOC(=O)Cn1c(COc2ccc(C(=N)N)cc2)nc2cc(N(CCN(C)C)S(C)(=O)=O)ccc21
Agent: [Na+]
Agent: [OH-]
Product: CN(C)CCN(c1ccc2c(c1)nc(COc1ccc(C(=N)N)cc1)n2CC(=O)O)S(C)(=O)=O

Procedure:
Prepared analogously to Example 3 from 1-ethoxycarbonylmethyl-2-[(4-amidinophenyl)-oxymethyl]-5-[N-(2-dimethylaminoethyl)-methanesulphonylamino]-benzimidazole and sodium hydroxide solution.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]([CH2:43][C:44]([S:47][C:48]([C:61]1[CH:66]=[CH:65][CH:64]=[CH:63][CH:62]=1)([C:55]1[CH:60]=[CH:59][CH:58]=[CH:57][CH:56]=1)[C:49]1[CH:54]=[CH:53][CH:52]=[CH:51][CH:50]=1)([CH3:46])[CH3:45])[CH2:9][CH2:10][N:11]([CH2:19][C:20]([CH3:42])([S:22][C:23]([C:36]1[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=1)([C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1)[C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1)[CH3:21])[CH2:12][CH2:13][CH2:14][CH2:15][C:16](O)=[O:17])=[O:7])([CH3:4])([CH3:3])[CH3:2].C([N:70]=C=NC(C)C)(C)C.ON1C(=O)CCC1=O.NCCN(CCN)CCN>C(Cl)Cl>[C:1]([O:5][C:6]([N:8]([CH2:43][C:44]([S:47][C:48]([C:55]1[CH:56]=[CH:57][CH:58]=[CH:59][CH:60]=1)([C:49]1[CH:50]=[CH:51][CH:52]=[CH:53][CH:54]=1)[C:61]1[CH:62]=[CH:63][CH:64]=[CH:65][CH:66]=1)([CH3:45])[CH3:46])[CH2:9][CH2:10][N:11]([CH2:19][C:20]([CH3:42])([S:22][C:23]([C:30]1[CH:31]=[CH:32][CH:33]=[CH:34][CH:35]=1)([C:36]1[CH:37]=[CH:38][CH:39]=[CH:40][CH:41]=1)[C:24]1[CH:25]=[CH:26][CH:27]=[CH:28][CH:29]=1)[CH3:21])[CH2:12][CH2:13][CH2:14][CH2:15][C:16]([NH2:70])=[O:17])=[O:7])([CH3:2])([CH3:3])[CH3:4]
Reactant: CC(C)N=C=NC(C)C
Reactant: CC(C)(C)OC(=O)N(CCN(CCCCC(=O)O)CC(C)(C)SC(c1ccccc1)(c1ccccc1)c1ccccc1)CC(C)(C)SC(c1ccccc1)(c1ccccc1)c1ccccc1
Agent: NCCN(CCN)CCN
Agent: O=C1CCC(=O)N1O
Solvent: ClCCl
Product: CC(C)(C)OC(=O)N(CCN(CCCCC(N)=O)CC(C)(C)SC(c1ccccc1)(c1ccccc1)c1ccccc1)CC(C)(C)SC(c1ccccc1)(c1ccccc1)c1ccccc1
Temperature: 25 °C
Reaction time: 4 h

Procedure:
BAT-BM was prepared as follows. BAT acid (N9 -(t-butoxycarbonyl)-N6,N9 -bis(2-methyl-2-triphenylmethylthiopropyl)-6,9-diazanonanoic acid) (10.03 g, 10.89 mmol) and 75 mL of dry methylene chloride (CH2Cl2) were added to a 250 mL round-bottomed flask equipped with magnetic stir bar and argon balloon. To this solution was added diisopropylcarbodiimide (3.40 mL, 21.7 mmol, 199 mole %), followed by N-hydroxysuccinimide (3.12g, 27.1 mmol, 249 mole %). This solution was observed to become cloudy within 1 h, and was further incubated with stirring for a total of 4 h at room temperature. A solution of tris(2-aminoethyl)amine (30 mL, 200 mmol, 1840 mole %) in 30 mL methylene chloride was then added and stirring continued overnight. The reaction mixture was then concentrated under reduced pressure, and the residue partitioned between ethylacetate (150 mL) and 0.5M potassium carbonate (K2CO3 ; 150 mL). The organic layer was separated, washed with brine and concentrated to give the crude product N-[2-N',N'-bis(2-aminoethyl)aminoethyl)]-N9 -(t-butoxycarbonyl)-N6,N9 -bis(2-methyl-2-triphenylmethylthiopropyl)-6,9-diazanonanamide as a foam/oil.
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C@@H:9]1[CH2:14][CH2:13][C@@H:12]([S:15][C:16](=[O:23])[C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[C@H:11]([OH:24])[CH2:10]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].CC(OI1(OC(C)=O)(OC(C)=O)OC(=O)C2C1=CC=CC=2)=O.C1(C)C=CC=CC=1.C(OCC)(=O)C>ClCCl>[C:1]([O:5][C:6]([NH:8][CH:9]1[CH2:14][CH2:13][CH:12]([S:15][C:16](=[O:23])[C:17]2[CH:18]=[CH:19][CH:20]=[CH:21][CH:22]=2)[C:11](=[O:24])[CH2:10]1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)N[C@@H]1CC[C@@H](SC(=O)c2ccccc2)[C@H](O)C1
Agent: CC(=O)OI1(OC(C)=O)(OC(C)=O)OC(=O)c2ccccc21
Solvent: Cc1ccccc1
Solvent: CCOC(C)=O
Solvent: ClCCl
Product: CC(C)(C)OC(=O)NC1CCC(SC(=O)c2ccccc2)C(=O)C1
Temperature: 5 °C
Reaction time: 1 h
Yield: 84 %

Procedure:
A mixture of thiobenzoic acid S-((1R, 2R, 4R)-4-tert-butoxycarbonylamino-2-hydroxy-cyclohexyl)ester+(1S, 2S, 4S)diasteromer (5 g, 14.2 mmol), 4 Å-molecular sieve (3 g) 1,1-dihydro-1,1,1-triacetoxy-1,2-benziodoxol-3(1H)-one (6.33 g, 15 mmol) in 100 ml of dichloromethane was stirred under argon at 5° C. for 1 hour and 1 hour at room temperature. The mixture was filtered over celite, dried and concentrated under vacuum to give the crude product. After chromatography of the mixture (silica, toluene/ethyl acetate=7/1) the title compound (toluene/ethyl acetate=3/1, Rf=0.48, 4.18 g, 84% yield) was obtained as a white solid.
Reaction SMILES: [Cl:1][C:2]1[CH:9]=[N:8][CH:7]=[C:6]([C:10]2[CH:15]=[CH:14][C:13]([OH:16])=[CH:12][CH:11]=2)[C:3]=1[C:4]#[N:5].[CH3:17][O:18][C:19]1[CH:24]=[CH:23][C:22](B(O)O)=[CH:21][CH:20]=1.N1C=CC=CC=1>ClCCl.C([O-])(=O)C.[Cu+2].C([O-])(=O)C>[Cl:1][C:2]1[CH:9]=[N:8][CH:7]=[C:6]([C:10]2[CH:15]=[CH:14][C:13]([O:16][C:22]3[CH:23]=[CH:24][C:19]([O:18][CH3:17])=[CH:20][CH:21]=3)=[CH:12][CH:11]=2)[C:3]=1[C:4]#[N:5]
Reactant: N#Cc1c(Cl)cncc1-c1ccc(O)cc1
Reactant: COc1ccc(B(O)O)cc1
Agent: [Cu+2]
Agent: CC(=O)[O-]
Solvent: ClCCl
Solvent: c1ccncc1
Product: COc1ccc(Oc2ccc(-c3cncc(Cl)c3C#N)cc2)cc1
Temperature: 25 °C
Reaction time: 96 h
Yield: 68 %

Procedure:
A mixture of 3-chloro-5-(4-hydroxyphenyl)isonicotinonitrile (50 mg, 0.217 mmol), 4-methoxyphenylboronic acid (132 mg, 0.867 mmol), copper(II) acetate (47.2 mg, 0.260 mmol), pyridine (0.140 mL, 1.734 mmol) and 4 A molecular sieves (300 mg) in dichloromethane (6 mL) was stirred under air at room temperature for 4 days. The mixture was filtered through a CELITE® pad to remove molecular sieves (rinsed with dichloromethane), quenched with saturated ammonium chloride (20 mL) and ammonium hydroxide (2 mL) and extracted with dichloromethane (3×10 mL). The combined extracts were dried (MgSO4) and concentrated. Silica gel chromatography, loading with toluene and eluting with 5-30% ethyl acetate in hexanes, gave 3-chloro-5-(4-(4-methoxyphenoxy)phenyl)isonicotinonitrile as a white solid (49.7 mg, 67% yield). 1H NMR (400 MHz, CDCl3) δ ppm 8.72 (1H, s), 8.68 (1H, s), 7.45-7.59 (2H, m), 6.99-7.14 (4H, m), 6.88-6.99 (2H, m), 3.83 (3H, s); MS (ES+) m/z: 337 (M+H); LC retention time: 4.321 min (analytical HPLC Method A).
Reaction SMILES: [CH3:1][O:2]/[N:3]=[C:4](/[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)\[CH2:5][O:6][C:7]1[CH:12]=[CH:11][C:10]([CH2:13][OH:14])=[CH:9][CH:8]=1.O[C:22]1[CH:27]=[CH:26][C:25]([CH2:28][CH2:29][C:30]([O:32]CC)=[O:31])=[C:24]([O:35][CH:36]([CH3:38])[CH3:37])[CH:23]=1>>[CH3:1][O:2]/[N:3]=[C:4](/[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)\[CH2:5][O:6][C:7]1[CH:12]=[CH:11][C:10]([CH2:13][O:14][C:22]2[CH:27]=[CH:26][C:25]([CH2:28][CH2:29][C:30]([OH:32])=[O:31])=[C:24]([O:35][CH:36]([CH3:38])[CH3:37])[CH:23]=2)=[CH:9][CH:8]=1
Reactant: CCOC(=O)CCc1ccc(O)cc1OC(C)C
Reactant: CO/N=C(\COc1ccc(CO)cc1)c1ccccc1
Product: CO/N=C(\COc1ccc(COc2ccc(CCC(=O)O)c(OC(C)C)c2)cc1)c1ccccc1
Yield: 13.73 %

Procedure:
Compound 60 was synthesized from (1Z)-2-[4-(hydroxymethyl)phenoxy]-1-phenylethanone O-methyloxime (0.268 g, 0.99 mmol) and ethyl 3-(4-hydroxy-2-isopropoxyphenyl)propanoate (0.25 g, 0.99 mmol) by following the procedure described in scheme 15 (0.04 g, yield: 13.73%); Purity: 97.21%.
Reaction SMILES: [CH2:1]([O:8][C:9]1[C:14](=[O:15])[N:13]([CH3:16])[C:12](S(C)(=O)=O)=[N:11][C:10]=1[C:21]([O:23][CH3:24])=[O:22])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.CC#[N:27]>>[CH3:24][O:23][C:21]([C:10]1[N:11]=[C:12]([NH2:27])[N:13]([CH3:16])[C:14](=[O:15])[C:9]=1[O:8][CH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1)=[O:22]
Reactant: CC#N
Reactant: COC(=O)c1nc(S(C)(=O)=O)n(C)c(=O)c1OCc1ccccc1
Product: COC(=O)c1nc(N)n(C)c(=O)c1OCc1ccccc1

Procedure:
In a round-bottomed flask, methyl 5-(benzyloxy)-1-methyl-2-(methylsulfonyl)-6-oxo-1,6-dihydropyrimidine-4-carboxylate (3.65 g, 10.4 mmol) was combined with CH3CN (50 ml) to give a colorless solution. Gaseous ammonia was bubbled at 25° C. for 20 min. The crude material was purified by flash chromatography (silica gel, 30% to 50% EtOAc in hexanes) and then through a second column (5% MeOH/DCM) to give the title product as a white solid. LCMS: m/z=290 (MH+).
Reaction SMILES: [Cl:1][C:2]1[N:3]=[C:4]([C:9]([NH:11][C@H:12]2[CH2:17][CH2:16][N:15]([C:18]3[S:19][C:20]([C:26]([O:28][CH2:29][CH3:30])=[O:27])=[C:21]([C:23](O)=[O:24])[N:22]=3)[CH2:14][C@H:13]2[O:31][CH3:32])=[O:10])[NH:5][C:6]=1[CH2:7][CH3:8].[CH3:33][N:34]([CH3:38])[CH2:35][CH2:36][NH2:37].CCN=C=NCCCN(C)C.Cl.C1C=CC2N(O)N=NC=2C=1>>[Cl:1][C:2]1[N:3]=[C:4]([C:9]([NH:11][C@H:12]2[CH2:17][CH2:16][N:15]([C:18]3[S:19][C:20]([C:26]([O:28][CH2:29][CH3:30])=[O:27])=[C:21]([C:23](=[O:24])[NH:37][CH2:36][CH2:35][N:34]([CH3:38])[CH3:33])[N:22]=3)[CH2:14][C@H:13]2[O:31][CH3:32])=[O:10])[NH:5][C:6]=1[CH2:7][CH3:8]
Reactant: CN(C)CCN
Reactant: CCOC(=O)c1sc(N2CC[C@H](NC(=O)c3nc(Cl)c(CC)[nH]3)[C@H](OC)C2)nc1C(=O)O
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Product: CCOC(=O)c1sc(N2CC[C@H](NC(=O)c3nc(Cl)c(CC)[nH]3)[C@H](OC)C2)nc1C(=O)NCCN(C)C
Yield: 83 %

Procedure:
The same operation as in Example (1g) was performed using cis(±)-2-(4-{[(4-chloro-5-ethyl-1H-imidazol-2-yl)carbonyl]amino}-3-methoxypiperidin-1-yl)-5-(ethoxycarbonyl)-1,3-thiazole-4-carboxylic acid obtained by the method described in Example (50a) (65 mg, 0.13 mmol), N,N-dimethylethylenediamine (35 μL, 0.27 mmol), WSC hydrochloride (80 mg, 0.42 mmol) and HOBT (18 mg, 0.13 mmol), to obtain 61.5 mg of the title compound as a white solid (83%).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][N:11]2[C:14]([CH:19]3[CH2:24][CH2:23][N:22]([C:25]([O:27][CH2:28][C:29]4[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=4)=[O:26])[CH2:21][CH2:20]3)=[CH:15][C:16]([C:17]#[N:18])=[C:10]2[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].C(O[C:40]([N:42]1CCN2C(C3CCN(C(OCC4C=CC=CC=4)=O)CC3)=C(C#N)C=C2C1)=O)(C)(C)C>>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][N:11]2[C:14]([CH:19]3[CH2:20][CH2:21][N:22]([C:25]([O:27][CH2:28][C:29]4[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=4)=[O:26])[CH2:23][CH2:24]3)=[C:15]([C:40]#[N:42])[C:16]([C:17]#[N:18])=[C:10]2[CH2:9]1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)N1CCn2c(cc(C#N)c2C2CCN(C(=O)OCc3ccccc3)CC2)C1
Reactant: CC(C)(C)OC(=O)N1CCn2c(C3CCN(C(=O)OCc4ccccc4)CC3)cc(C#N)c2C1
Product: CC(C)(C)OC(=O)N1CCn2c(c(C#N)c(C#N)c2C2CCN(C(=O)OCc3ccccc3)CC2)C1

Procedure:
By proceeding in a similar manner to that described in Reference Example 8 but using a mixture of 6-(1-benzyloxycarbonylpiperidin-4-yl)-8-cyano-3,4-dihydro-1H-pyrrolo[1,2-a]pyrazine-2-carboxylic acid tert-butyl ester and 6-(1-benzyloxycarbonylpiperidin-4-yl)-7-cyano-3,4-dihydro-1H-pyrrolo[1,2-a]pyrazine-2-carboxylic acid tert-butyl ester (5.00 g, Reference Example 15) the title compound (4.71 g) was prepared as a yellow oil, MS: 490 [MH]+. 1H NMR [(CDCl3]: δ 7.42–7.30 (m, 5H), 5.15 (s, 2H), 4.71 (s, 2H), 4.50–4.28 (bs, 2H), 3.92 (t, 2H), 3.86 (t, 2H), 2.93–2.72 (m, 3H), 2.20–1.93 (bs, 2H), 1.80 (d, 2H) and 1.51 (s, 9H).
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[CH:9][C:8]([S:11](Cl)(=[O:13])=[O:12])=[CH:7][C:3]=1[C:4]([OH:6])=[O:5].[Cl:15][C:16]1[CH:22]=[C:21]([Cl:23])[CH:20]=[CH:19][C:17]=1[NH2:18].C1(C)C=CC=CC=1>[OH-].[Na+]>[Cl:1][C:2]1[CH:10]=[CH:9][C:8]([S:11](=[O:13])(=[O:12])[NH:18][C:17]2[CH:19]=[CH:20][C:21]([Cl:23])=[CH:22][C:16]=2[Cl:15])=[CH:7][C:3]=1[C:4]([OH:6])=[O:5]
Reactant: Nc1ccc(Cl)cc1Cl
Reactant: O=C(O)c1cc(S(=O)(=O)Cl)ccc1Cl
Agent: [Na+]
Agent: [OH-]
Solvent: Cc1ccccc1
Product: O=C(O)c1cc(S(=O)(=O)Nc2ccc(Cl)cc2Cl)ccc1Cl
Reaction time: 6 h

Procedure:
602 Parts of 2-chloro-5-chlorosulfonylbenzoic acid are added to a solution of 830 parts of 2,4-dichloroaniline in 600 parts of toluene at 60° and the mixture is stirred for 6 hours at the same temperature. Insoluble material is then dissolved in dilute sodium hydroxide solution, the aqueous layer is separated off and acidified with dilute hydrochloric acid and the product is filtered off and washed with water. After redissolving in sodium hydroxide solution, reprecipitation with hydrochloric acid and drying, 592 parts of 2-chloro-5-[2,4-dichlorophenyl-sulfamoyl]-benzoic acid are obtained as a colorless powder of melting point 174° C.