Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH:1]([N:5]=[C:6]=[N:7][C:8]1[CH:9]=[N:10][CH:11]=[CH:12][CH:13]=1)([CH2:3][CH3:4])[CH3:2].C([N:18]=[C:19]=[N:20]C1C=NC=CC=1)(C)(C)C>>[CH:1]([NH:5][C:6]([NH:7][C:8]1[CH:9]=[N:10][CH:11]=[CH:12][CH:13]=1)=[N:20][C:19]#[N:18])([CH2:3][CH3:4])[CH3:2]
Reactant: CC(C)(C)N=C=Nc1cccnc1
Reactant: CCC(C)N=C=Nc1cccnc1
Product: CCC(C)NC(=NC#N)Nc1cccnc1

Procedure:
By following the procedure of Example 1, but substituting N-sec-butyl-N'-3-pyridylcarbodiimide for the N-tert-butyl-N'-3-pyridylcarbodiimide, the desired compound was obtained with a melting point of 133.5°-135.0° C.
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]([CH3:35])([O:8][C:9]1[CH:14]=[CH:13][C:12]([CH2:15][CH2:16][CH2:17][C:18]([NH:20][N:21]([CH2:26][C:27]2[CH:32]=[CH:31][C:30]([CH3:33])=[C:29]([CH3:34])[CH:28]=2)[C:22]([NH:24]C)=[O:23])=O)=[CH:11][CH:10]=1)[CH3:7])=[O:5])[CH3:2].C12(CS(O)(=O)=O)C(C)(C)C(CC1)CC2=O>C(OCC)(=O)C>[CH2:1]([O:3][C:4](=[O:5])[C:6]([O:8][C:9]1[CH:14]=[CH:13][C:12]([CH2:15][CH2:16][CH2:17][C:18]2[NH:24][C:22](=[O:23])[N:21]([CH2:26][C:27]3[CH:32]=[CH:31][C:30]([CH3:33])=[C:29]([CH3:34])[CH:28]=3)[N:20]=2)=[CH:11][CH:10]=1)([CH3:35])[CH3:7])[CH3:2]
Reactant: CCOC(=O)C(C)(C)Oc1ccc(CCCC(=O)NN(Cc2ccc(C)c(C)c2)C(=O)NC)cc1
Agent: CC1(C)C2CCC1(CS(=O)(=O)O)C(=O)C2
Solvent: CCOC(C)=O
Product: CCOC(=O)C(C)(C)Oc1ccc(CCCc2nn(Cc3ccc(C)c(C)c3)c(=O)[nH]2)cc1
Temperature: 25 °C

Procedure:
1-[4-[4-(1-Ethoxycarbonyl-1-methylethoxy)phenyl]butyryl]-2-(3,4-dimethylphenylmethyl)-4-methylsemicarbazide (1.20 g, 2.47 mmol) was dissolved in ethyl acetate (10 mL). Camphorsulfonic acid (0.64 g, 2.72 mmol) was added in one portion and the solution was heated to reflux for 1 h. The solution was cooled to rt and washed with sat'd aq. NaHCO3 (2×8 mL) followed by 1H HCl (2×8 mL ). The organic phase was dried (MgSO4) and concentrated to afford the title compound as a clear, colorless oil (1.08 g, 94%). 1H NMR (DMSO-d6) δ 7.04 (m, 3H), 7.03 (s, 1H), 6.93 (d, 1H, J=2 Hz), 6.68 (d, 2H, J=7 Hz), 4.72 (s, 2H), 4.13 (q, 2H, J=7 Hz), 3.08 (s, 3H), 2.53 (t, 2H, J=8 Hz), 2.47 (t, 2H, J=8 Hz), 1.80 (quint, 2H, J=7 Hz), 1.47 (s, 6H), 1.14 (t, 3H, J=7 Hz); 13C NMR (DMSO-d6) δ 174.0, 154.1, 147.1, 136.8, 135.9, 135.6, 135.3, 130.1, 129.8, 129.4, 125.7, 119.5, 79.2, 61.6, 48.4, 34.1, 27.7, 27.6, 25.7, 25.0, 20.0, 19.7, 14.6; IR (CHCl3) 2941, 1729, 1509, 1238, 1143 cm−1; Anal. Calcd. for C27H35N3O4: C, 69.65; H, 7.58; N, 9.03. Found: C, 69.25; H, 7.47; N, 8.88.
Reaction SMILES: F[C:2]1[CH:12]=[CH:11][C:5]([C:6]([O:8][CH2:9][CH3:10])=[O:7])=[CH:4][CH:3]=1.[CH:13]([S:16][Na])([CH3:15])[CH3:14]>CN(C=O)C.C(OCC)(=O)C>[CH:13]([S:16][C:2]1[CH:12]=[CH:11][C:5]([C:6]([O:8][CH2:9][CH3:10])=[O:7])=[CH:4][CH:3]=1)([CH3:15])[CH3:14]
Reactant: CC(C)S[Na]
Reactant: CCOC(=O)c1ccc(F)cc1
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: CCOC(=O)c1ccc(SC(C)C)cc1
Temperature: 80 °C
Yield: 67.3 %

Procedure:
A mixture of ethyl 4-fluorobenzoate (390 mg, 2.32 mmol) and isopropylsulfanylsodium (273 mg, 2.78 mmol) in DMF (2.5 mL) was heated at 80° C. for 36 h. The reaction mixture was diluted with ethyl acetate before being washed with 1N NaOH and then brine. The organic layer was dried over sodium sulfate and evaporated. The residue was purified by column chromatography eluting with 50-100% ethyl acetate in hexanes to give ethyl 4-isopropylsulfanylbenzoate (350 mg).
Reaction SMILES: [CH3:1][C:2]([NH:11][CH:12]=[O:13])([CH3:10])[CH2:3][C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1.[Cl-].[Al+3].[Cl-].[Cl-].[Br:18]Br>C(Cl)Cl>[Br:18][C:7]1[CH:6]=[CH:5][C:4]([CH2:3][C:2]([NH:11][CH:12]=[O:13])([CH3:1])[CH3:10])=[CH:9][CH:8]=1
Reactant: BrBr
Reactant: CC(C)(Cc1ccccc1)NC=O
Agent: [Al+3]
Agent: [Cl-]
Solvent: ClCCl
Product: CC(C)(Cc1ccc(Br)cc1)NC=O
Temperature: -5 °C

Procedure:
1.00 g (5.64 mmol) N-(1,1-dimethyl-2-phenyl-ethyl)-formamide (I34) is added to 8 mL DCM and cooled down to −5° C. Then 1.50 g (11.3 mmol) aluminium chloride is added by several portions, stirred for 5 min, before 0.9 g (5.64) bromine is added over a period of 1 min. Having finished the addition, the mixture is stirred for two more minutes at 0° C., poured onto ice water and extracted with DCM. The organic layer is dried with MgSO4 and the solvent is removed in vacuo.
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:14]=[CH:13][C:12]([C:15](=[O:17])[CH3:16])=[CH:11][C:10]=1[O:18][CH3:19])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[N+:20]([O-])([OH:22])=[O:21].S(=O)(=O)(O)O>ClCCl>[CH2:1]([O:8][C:9]1[C:10]([O:18][CH3:19])=[CH:11][C:12]([C:15](=[O:17])[CH3:16])=[C:13]([N+:20]([O-:22])=[O:21])[CH:14]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: COc1cc(C(C)=O)ccc1OCc1ccccc1
Reactant: O=[N+]([O-])O
Agent: O=S(=O)(O)O
Solvent: ClCCl
Product: COc1cc(C(C)=O)c([N+](=O)[O-])cc1OCc1ccccc1
Yield: 59.7 %

Procedure:
A stirred solution of 1-(4-benzyloxy-3-methoxyphenyl)ethanone (51.3 g, 200 mmol) in dichloromethane (750 mL) was cooled to 0° C. Nitric acid (90%, 14 mL, 300 mmol) was added dropwise to the cooled solution over 20 min. Sulfuric acid (96.2%, 16.3 mL, 300 mmol) was then added dropwise over 40 min at 0° C. Additional nitric acid (9.4 mL, 200 mmol) was added dropwise over 20 min. The reaction mixture was washed with water (3×200 mL), and saturated sodium bicarbonate (4×200 mL, or until neutral). The organic layer was dried over Na2SO4 and concentrated. The crude mixture was recrystallized from DMF to give 1-(4-benzyloxy-5-methoxy-2-nitrophenyl)ethanone (36 g, 60%). 1H NMR (400 MHz, CDCl3): δ 7.65 (s, 1H), 7.45-7.33 (m, 5H), 6.74 (s, 1H), 5.21 (s, 2H), 3.97 (s, 3H), 2.49 (s, 3H).
Reaction SMILES: [Br:1][C:2]1[C:15]2[C:14](=[O:16])[C:13]3[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=3)[C:7](=[O:17])[C:6]=2[C:5]([NH:18][C:19](=[O:21])[CH3:20])=[CH:4][CH:3]=1.[OH-].[K+].[CH3:24]OS(=O)(=O)OC>[Br-].C([N+](CCCC)(CCCC)CCCC)CCC.C(O)(=O)C.ClC1C=CC=CC=1.O>[Br:1][C:2]1[C:15]2[C:14](=[O:16])[C:13]3[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=3)[C:7](=[O:17])[C:6]=2[C:5]([N:18]([CH3:24])[C:19](=[O:21])[CH3:20])=[CH:4][CH:3]=1
Reactant: CC(=O)Nc1ccc(Br)c2c1C(=O)c1ccccc1C2=O
Reactant: COS(=O)(=O)OC
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [Br-]
Agent: [K+]
Solvent: CC(=O)O
Solvent: O
Solvent: Clc1ccccc1
Product: CC(=O)N(C)c1ccc(Br)c2c1C(=O)c1ccccc1C2=O
Temperature: 30 °C
Reaction time: 1 h
Yield: 95.8 %

Procedure:
A mixture of 4-bromo-1-acetylaminoanthraquinone (purity 98%, 35.1 g), monochlorobenzene (420 g), tetra-n-butyl ammonium bromide (0.3 g) and 96% potassium hydroxide (12.0 g) was stirred for one hour while being maintained at 30° C. Dimethylsulfuric acid (25.2 g) was dropped at 30° C. over 2 hours. The mixture was stirred at 30° C. for 30 minutes, 40° C. for 2 hours and 50° C. for 4 hours, successively. After water (200 g) was added, the solution was stirred for 1 hour while being maintained at 50° C. pH of the aqueous phase was 10 or higher. After acetic acid (0.5 g) was added for neutralization (pH of the aqueous phase being 7), monochlorobenzene was recovered by heating. After being cooled down to 50° C., the solution was filtered. A solid material was washed and dried to obtain 4-bromo-N-acetyl-1-methylaminoanthraquinone (35.0 g, purity 94.0%, yield 91.9%).
Reaction SMILES: Cl.Cl.Cl.[NH2:4][C@@H:5]([C:11]([N:13]1[CH2:18][CH2:17][N:16]([CH:19]2[CH2:24][CH2:23][N:22]([CH3:25])[CH2:21][CH2:20]2)[CH2:15][CH2:14]1)=[O:12])[CH2:6][CH2:7][C:8](=[O:10])[OH:9].[Cl:26][C:27]1[CH:28]=[CH:29][C:30]2[CH:34]=[C:33]([C:35](O)=[O:36])[S:32][C:31]=2[CH:38]=1>>[Cl:26][C:27]1[CH:28]=[CH:29][C:30]2[CH:34]=[C:33]([C:35]([NH:4][C@@H:5]([C:11]([N:13]3[CH2:14][CH2:15][N:16]([CH:19]4[CH2:24][CH2:23][N:22]([CH3:25])[CH2:21][CH2:20]4)[CH2:17][CH2:18]3)=[O:12])[CH2:6][CH2:7][C:8](=[O:9])[OH:10])=[O:36])[S:32][C:31]=2[CH:38]=1
Reactant: O=C(O)c1cc2ccc(Cl)cc2s1
Reactant: CN1CCC(N2CCN(C(=O)[C@H](N)CCC(=O)O)CC2)CC1
Agent: Cl
Product: CN1CCC(N2CCN(C(=O)[C@@H](CCC(=O)O)NC(=O)c3cc4ccc(Cl)cc4s3)CC2)CC1

Procedure:
Using methods substantially equivalent to those described in Method D-1, the subtitled compound was prepared from 1-(D-glutamyl)-4-(1-methylpiperidin-4-yl)piperazine trihydrochloride and 6-chlorobenzo[b]thiophene-2-carboxylic acid (41%).
Reaction SMILES: [CH2:1]([C:3]1[N:8]=[C:7]([NH:9][C:10]2[S:11][C:12]([C:15]#[N:16])=[CH:13][N:14]=2)[CH:6]=[C:5]([CH2:17]O)[CH:4]=1)[CH3:2].CN(C)C=O.P(Cl)(Cl)([Cl:26])=O>C(Cl)Cl>[Cl:26][CH2:17][C:5]1[CH:4]=[C:3]([CH2:1][CH3:2])[N:8]=[C:7]([NH:9][C:10]2[S:11][C:12]([C:15]#[N:16])=[CH:13][N:14]=2)[CH:6]=1
Reactant: O=P(Cl)(Cl)Cl
Reactant: CCc1cc(CO)cc(Nc2ncc(C#N)s2)n1
Solvent: CN(C)C=O
Solvent: ClCCl
Product: CCc1cc(CCl)cc(Nc2ncc(C#N)s2)n1
Reaction time: 2.5 h

Procedure:
2-{[6-Ethyl-4-(hydroxymethyl)pyridin-2-yl]amino}-1,3-thiazole-5-carbonitrile (12-3, 0.146 g, 0.56 mmol) was stirred in anhydrous CH2Cl2 (2.5 mL) under N2. N,N-Dimethylformamide (0.043 mL, 0.56 mmol) was added followed by phosphorous oxychloride (0.209 mL, 2.24 mmol). After 2.5 hours, the reaction was concentrated and quenched by the addition of saturated NaHCO3 (aq). A precipitate formed which was filtered and washed with water to afford 2-{[4-(chloromethyl)-6-ethylpyridin-2-yl]amino}-1,3-thiazole-5-carbonitrile as an orange solid. 1H NMR (DMSO-d6) δ 12.32 (s, 1H), 8.28 (s, 1H), 7.00 (d, 2H, J=3.66 Hz), 4.77 (s, 2H), 2.83 (q, 2H, J=7.63 Hz), 1.34 (t, 3H, J=7.63 Hz).
Reaction SMILES: [NH:1]1[CH:9]=[C:7]([CH3:8])[C:5](=[O:6])[NH:4][C:2]1=[O:3].[CH3:10][O:11][C:12](=[O:18])[CH2:13][S:14][CH2:15][CH2:16]Br.C(OC(C)C)(C)C>>[CH3:10][O:11][C:12](=[O:18])[CH2:13][S:14][CH2:15][CH2:16][N:1]1[CH:9]=[C:7]([CH3:8])[C:5](=[O:6])[NH:4][C:2]1=[O:3]
Reactant: COC(=O)CSCCBr
Reactant: Cc1c[nH]c(=O)[nH]c1=O
Solvent: CC(C)OC(C)C
Product: COC(=O)CSCCn1cc(C)c(=O)[nH]c1=O

Procedure:
(I-7, Compound of Formula I, Where R1 is [2-[5-methyl-2,4-1H,3H-pyrimidinedione-1-yl]ethyl]thio) p A] [[2-[5-Methyl-2,4-(1H,3H)-pyrimidinedione-1-yl]ethyl]thio]acetic acid methyl ester was synthesized from thymine and [[2-bromoethyl]thio]acetic acid methyl ester as described in example 6A. Mp: 75° C. (diisopropyl ether).
Reaction SMILES: [N+:1]([O-:4])(O)=[O:2].[C:5]([N:8]1[CH2:13][CH2:12][C:11]2([CH2:17][C:16]3[CH:18]=[CH:19][CH:20]=[CH:21][C:15]=3[O:14]2)[CH2:10][CH2:9]1)(=[O:7])[CH3:6].O>C(O)(=O)C>[C:5]([N:8]1[CH2:13][CH2:12][C:11]2([CH2:17][C:16]3[CH:18]=[C:19]([N+:1]([O-:4])=[O:2])[CH:20]=[CH:21][C:15]=3[O:14]2)[CH2:10][CH2:9]1)(=[O:7])[CH3:6]
Reactant: CC(=O)N1CCC2(CC1)Cc1ccccc1O2
Reactant: O=[N+]([O-])O
Solvent: O
Solvent: CC(=O)O
Product: CC(=O)N1CCC2(CC1)Cc1cc([N+](=O)[O-])ccc1O2
Temperature: 100 °C

Procedure:
3.8 g of nitric acid (sp gr 1.42) in 30 ml of glacial acetic acid are added dropwise to a stirred solution of 4.7 g of 2,3-dihydro-1'-acetylspiro[benzofuran-2,4'-piperidine], Example 16, in 65 ml of glacial acetic acid. After total addition, the reaction mixture is slowly heated to 100° C. over a 2 hour span and then cooled and poured into 500 ml of water. The diluted mixture is extracted with chloroform and the chloroform extracts are washed sequentially with a saturated sodium bicarbonate solution, a saturated sodium chloride solution and then dried. The chloroform is removed under reduced pressure. The residue is triturated with ether, causing an orange precipitate which is collected and recrystallized first from an ethyl alcohol-ether mixture and then from ethyl alcohol to provide the product, 2,3-dihydro-1'-acetyl-5-nitrospiro[benzofuran-2,4'-piperidine], mp 149°-150° C.
Reaction SMILES: [CH:1]1[CH:10]=[C:9]2[C:11]([O:13][C:14](=[O:15])[C:7]3=[C:8]2[C:3](=[C:4]([Br:16])[CH:5]=[CH:6]3)[CH:2]=1)=O.[CH2:17]([NH2:23])[CH2:18][CH2:19][CH2:20][CH2:21][CH3:22].C1(C)C=CC=CC=1.C(Cl)(Cl)Cl>C(O)(=O)C>[Br:16][C:4]1[CH:5]=[CH:6][C:7]2[C:14](=[O:15])[N:23]([CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH3:22])[C:11](=[O:13])[C:9]3[C:8]=2[C:3]=1[CH:2]=[CH:1][CH:10]=3
Reactant: CCCCCCN
Reactant: O=C1OC(=O)c2ccc(Br)c3cccc1c23
Solvent: CC(=O)O
Solvent: Cc1ccccc1
Solvent: ClC(Cl)Cl
Product: CCCCCCN1C(=O)c2cccc3c(Br)ccc(c23)C1=O
Reaction time: 1 h
Yield: 74.3 %

Procedure:
A mixture of 4-bromo-1,8-naphthalic anhydride (21.40 g, 77.2 mmol), n-hexylamine (13.1 mL, 100 mmol), toluene (200 mL), and chloroform (200 mL) was heated to boil for 1 hour. Precipitate formed making stirring difficult. The mixture was acidified with acetic acid, and heating was continued at 90° C. with distillation of chloroform. After all precipitate dissolved, the reaction mixture was poured onto crushed ice (300 g) and acidified with concentrated HCl to pH 1. After the ice melted, the solid was filtered off and dried. The crude product was purified by column chromatography (silica gel, hexane/ethyl acetate 2:1) to give 6-bromo-2-hexyl-1H-benzo[de]isoquinoline-1,3(2H)-dione (20.66 g, 74%).
Reaction SMILES: [N:1]1([C@:4]23[CH2:39][CH2:38][C@@H:37]([C:40]([CH3:42])=[CH2:41])[C@@H:5]2[C@@H:6]2[C@@:19]([CH3:22])([CH2:20][CH2:21]3)[C@@:18]3([CH3:23])[C@@H:9]([C@:10]4([CH3:36])[C@@H:15]([CH2:16][CH2:17]3)[C:14]([CH3:25])([CH3:24])[C:13]([C:26]3[CH:35]=[CH:34][C:29]([C:30]([O:32][CH3:33])=[O:31])=[CH:28][CH:27]=3)=[CH:12][CH2:11]4)[CH2:8][CH2:7]2)[CH2:3][CH2:2]1.[C@H:43]12[CH2:56][C@H:47]([N:48]1[C:49]([O:51][C:52]([CH3:55])([CH3:54])[CH3:53])=[O:50])[CH2:46][NH:45][CH2:44]2.C(N(CC)C(C)C)(C)C>C1COCC1>[CH3:33][O:32][C:30]([C:29]1[CH:28]=[CH:27][C:26]([C:13]2[C:14]([CH3:24])([CH3:25])[C@H:15]3[C@:10]([CH3:36])([CH2:11][CH:12]=2)[C@@H:9]2[C@:18]([CH3:23])([C@@:19]4([CH3:22])[C@H:6]([CH2:7][CH2:8]2)[C@H:5]2[C@H:37]([C:40]([CH3:42])=[CH2:41])[CH2:38][CH2:39][C@:4]2([NH:1][CH2:2][CH2:3][N:45]2[CH2:44][C@@H:43]5[CH2:56][C@@H:47]([N:48]5[C:49]([O:51][C:52]([CH3:53])([CH3:55])[CH3:54])=[O:50])[CH2:46]2)[CH2:21][CH2:20]4)[CH2:17][CH2:16]3)=[CH:35][CH:34]=1)=[O:31]
Reactant: CC(C)(C)OC(=O)N1[C@@H]2CNC[C@H]1C2
Reactant: C=C(C)[C@@H]1CC[C@]2(N3CC3)CC[C@]3(C)[C@H](CC[C@@H]4[C@@]5(C)CC=C(c6ccc(C(=O)OC)cc6)C(C)(C)[C@@H]5CC[C@]43C)[C@@H]12
Solvent: CCN(C(C)C)C(C)C
Solvent: C1CCOC1
Product: C=C(C)[C@@H]1CC[C@]2(NCCN3C[C@H]4C[C@@H](C3)N4C(=O)OC(C)(C)C)CC[C@]3(C)[C@H](CC[C@@H]4[C@@]5(C)CC=C(c6ccc(C(=O)OC)cc6)C(C)(C)[C@@H]5CC[C@]43C)[C@@H]12
Temperature: 100 °C
Reaction time: 112 h
Yield: 28.9 %

Procedure:
Methyl 4-((1R,3aS,5aR,5bR,7aR,11aS,11bR,13aR,13bR)-3a-(aziridin-1-yl)-5a,5b,8,8,11a-pentamethyl-1-(prop-1-en-2-yl)-2,3,3a,4,5,5a,5b,6,7,7a,8,11,11a,11b,12,13,13a,13b-octadecahydro-1H-cyclopenta[a]chrysen-9-yl)benzoate (250 mg, 0.439 mmol) and (1R,5S)-tert-butyl 3,6-diazabicyclo[3.1.1]heptane-6-carboxylate (435 mg, 2.194 mmol) were combined in a 20 mL scintillation vial, dissolved in THF (5 mL) and treated with N,N-di-iso-propylethylamine (0.764 mL, 4.39 mmol). The reaction mixture was heated to 100° C. After 112 h, the reaction mixture was cooled to rt, purified by reverse phase HPLC using prep-HPLC method 13 and dried under vacuum to give the title compound (126.6 mg, 0.127 mmol, 29.0% yield) as a white solid. LC/MS: m/e 768.5 (M+H)+, 2.41 min (method 7). 1H NMR (400 MHz, CHLOROFORM-d) δ 7.94 (d, J=8.6 Hz, 2H), 7.20 (d, J=8.3 Hz, 2H), 5.30 (d, J=4.4 Hz, 1H), 4.79 (s, 1H), 4.70 (s, 1H), 4.17 (d, J=5.9 Hz, 2H), 3.92 (s, 3H), 3.62 (d, J=11.7 Hz, 1H), 3.56-3.44 (m, 3H), 3.43-3.31 (m, 5H), 2.85-2.72 (m, 1H), 2.66-2.56 (m, 1H), 2.12 (dd, J=17.0, 6.5 Hz, 2H), 2.07-1.89 (m, 5H), 1.75 (d, J=11.5 Hz, 1H), 1.70 (s, 3H), 1.65 (br. s., 1H), 1.60-1.50 (m, 5H), 1.48 (s, 9H), 1.46-1.34 (m, 5H), 1.26-1.19 (m, 1H), 1.13 (s, 3H), 1.05 (s, 3H), 1.00 (s, 3H), 0.94 (s, 3H), 0.94 (br. s., 3H). 13C NMR (101 MHz, CHLOROFORM-d) δ 167.2, 154.9, 148.6, 146.9, 146.3, 130.0, 128.5, 128.0, 123.9, 111.8, 81.7, 77.2, 72.4, 58.3, 53.9, 52.8, 52.0, 49.4, 49.0, 45.3, 42.1, 41.8, 40.7, 37.9, 37.5, 37.2, 36.2, 33.5, 32.6, 29.4, 28.3, 28.3, 27.8, 26.3, 25.4, 25.1, 21.0, 20.9, 19.6, 19.1, 16.5, 15.8, 14.6.
Reaction SMILES: CS(O)(=O)=O.O[C:7]1([C:13]2[CH:20]=[CH:19][C:16]([C:17]#[N:18])=[CH:15][CH:14]=2)[CH2:12][CH2:11][O:10][CH2:9][CH2:8]1.[BH4-].[Na+].[OH-].[Na+]>C(Cl)Cl>[O:10]1[CH2:9][CH:8]=[C:7]([C:13]2[CH:20]=[CH:19][C:16]([C:17]#[N:18])=[CH:15][CH:14]=2)[CH2:12][CH2:11]1
Reactant: N#Cc1ccc(C2(O)CCOCC2)cc1
Agent: CS(=O)(=O)O
Agent: [BH4-]
Agent: [Na+]
Solvent: ClCCl
Product: N#Cc1ccc(C2=CCOCC2)cc1
Reaction time: 1 h

Procedure:
12.65 ml (195 mmol) MeSO3H in 10 ml CH2Cl2 was slowly added to a mixture of 611 mg (3.0 mmol) 4-(4-hydroxytetrahydro-2H-pyran-4-yl)benzonitrile and 1.13 g (30 mmol) NaBH4 in 15 ml CH2Cl2 at 0° C. Stirred for 1 h. 2M NaOH was added until pH>10. The mixture was extracted with CH2Cl2. The organic phase was dried (MgSO4) and concentrated. The crude product (450 mg, 81%) was used directly in the next step.
Reaction SMILES: [Na+].[C:2]([S:5][CH2:6][CH:7]([CH2:20][C:21]1[CH:26]=[CH:25][C:24]([F:27])=[CH:23][CH:22]=1)[C:8]([NH:10][C:11]1[CH:12]=[C:13]([CH:17]=[CH:18][CH:19]=1)[C:14]([O-:16])=[O:15])=[O:9])(=[O:4])[CH3:3].Cl>O>[C:2]([S:5][CH2:6][CH:7]([CH2:20][C:21]1[CH:22]=[CH:23][C:24]([F:27])=[CH:25][CH:26]=1)[C:8]([NH:10][C:11]1[CH:12]=[C:13]([CH:17]=[CH:18][CH:19]=1)[C:14]([OH:16])=[O:15])=[O:9])(=[O:4])[CH3:3]
Reactant: CC(=O)SCC(Cc1ccc(F)cc1)C(=O)Nc1cccc(C(=O)[O-])c1
Agent: Cl
Agent: [Na+]
Solvent: O
Product: CC(=O)SCC(Cc1ccc(F)cc1)C(=O)Nc1cccc(C(=O)O)c1
Yield: 84.7 %

Procedure:
3-[[2-Acetylthiomethyl-3-(4-fluorophenyl)-propionyl]amino]benzoic acid sodium salt (compound of Example 40) (0.5 g) is dissolved in water (10 ml), and the mixture is adjusted to pH 2.5 with 1 N hydrochloric acid with stirring under ice cooling, and the mixture is extracted with ethyl acetate (20 ml). The extract is washed with water and dried over anhydrous magnesium sulfate, and then ethyl acetate is distilled off to give the title compound (0.4 g).
Reaction SMILES: [NH2:1][C:2]1[N:7]=[C:6](OS(C2C(C)=CC(C)=CC=2C)(=O)=O)[C:5]([CH2:21][C:22]2[CH:40]=[CH:39][C:25]([CH2:26][N:27]([CH2:34][C:35]([F:38])([F:37])[F:36])[CH2:28][C:29]([O:31][CH2:32][CH3:33])=[O:30])=[CH:24][C:23]=2[O:41][CH3:42])=[C:4]([CH3:43])[N:3]=1.[NH2:44][C@@H:45]([CH2:49][CH2:50][CH3:51])[CH2:46][CH2:47][OH:48]>>[NH2:1][C:2]1[N:7]=[C:6]([NH:44][C@@H:45]([CH2:49][CH2:50][CH3:51])[CH2:46][CH2:47][OH:48])[C:5]([CH2:21][C:22]2[CH:40]=[CH:39][C:25]([CH2:26][N:27]([CH2:34][C:35]([F:36])([F:37])[F:38])[CH2:28][C:29]([O:31][CH2:32][CH3:33])=[O:30])=[CH:24][C:23]=2[O:41][CH3:42])=[C:4]([CH3:43])[N:3]=1
Reactant: CCOC(=O)CN(Cc1ccc(Cc2c(C)nc(N)nc2OS(=O)(=O)c2c(C)cc(C)cc2C)c(OC)c1)CC(F)(F)F
Reactant: CCC[C@H](N)CCO
Product: CCC[C@@H](CCO)Nc1nc(N)nc(C)c1Cc1ccc(CN(CC(=O)OCC)CC(F)(F)F)cc1OC
Yield: 45.4 %

Procedure:
The sub-title compound was synthesized by the method of example 1 step (viii) from the product of step (ii) (61 mg) and (S)-3-aminohexan-1-ol (34 mg). The sub-title compound (24 mg) was obtained as a pale yellow gum; 1H NMR (CDCl3); 6.93 (1H, s), 6.89 (1H, d), 6.76 (1H, d), 4.62-4.59 (3H, m), 4.15 (2H, q), 4.10-4.04 (1H, m), 3.91 (2H, s), 3.87 (3H, s), 3.66 (2H, s), 3.44 (2H, s), 3.37-3.20 (4H, m), 2.33 (3H, s), 1.82-1.69 (1H, m), 1.42-1.32 (3H, m), 1.24 (3H, t), 1.09-0.98 (2H, m), 0.73 (3H, t).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[CH:8]([OH:10])[CH3:9].O1CCCC1.[H-].[Na+].[C:18]([O:22][C:23]([N:25]1[CH2:30][CH2:29][N:28]([C:31]2[N:36]=[C:35](Cl)[CH:34]=[CH:33][N:32]=2)[CH2:27][CH2:26]1)=[O:24])([CH3:21])([CH3:20])[CH3:19]>O>[C:18]([O:22][C:23]([N:25]1[CH2:30][CH2:29][N:28]([C:31]2[N:32]=[C:33]([O:10][CH:8]([C:3]3[CH:4]=[CH:5][CH:6]=[CH:7][C:2]=3[Cl:1])[CH3:9])[CH:34]=[CH:35][N:36]=2)[CH2:27][CH2:26]1)=[O:24])([CH3:21])([CH3:19])[CH3:20]
Reactant: CC(C)(C)OC(=O)N1CCN(c2nccc(Cl)n2)CC1
Reactant: CC(O)c1ccccc1Cl
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: C1CCOC1
Product: CC(Oc1ccnc(N2CCN(C(=O)OC(C)(C)C)CC2)n1)c1ccccc1Cl
Temperature: 25 °C
Reaction time: 1 h
Yield: 90.3 %

Procedure:
1-(2-Chloro-phenyl)-ethanol (31.4 mg, 0.20 mmol) was dissolved into 1.7 mL of anhydrous tetrahydrofuran and treated with sodium hydride (8.0 mg, 60% dispersion in mineral oil, 0.20 mmol). This was stirred under nitrogen for 1 hour at ambient temperature, then the reaction was treated with 4-(4-chloro-pyrimidin-2-yl)-piperazine-1-carboxylic acid tert-butyl ester (I-2a) (50 mg, 0.17 mmol) in one portion. The resultant mixture was refluxed under nitrogen for 4 hours. After cooling to room temperature, the reaction was poured into water (20 mL) and extracted with ethyl acetate (2×25 mL). The combined organic extracts were washed with brine (20 mL), then dried over sodium sulfate, filtered, and concentrated. The residue was purified by preparative TLC (7:13 ethyl acetate:hexanes) to afford 64.3 mg of the title product (I-2b).
Reaction SMILES: [C:1]([C:3]([C:7]1[CH:8]=[CH:9][C:10]([O:15][CH3:16])=[C:11]([CH:14]=1)[CH:12]=O)([C:5]#[N:6])[CH3:4])#[N:2].[ClH:17].Cl.[C:19]1([C@H:25]2[C@@H:30]([NH2:31])[CH2:29][CH2:28][CH2:27][NH:26]2)[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1.Cl.Cl.C(C1(C2C=CC(OC)=C(C=2)CN[C@H]2CCCN[C@H]2C2C=CC=CC=2)CC1)#N>>[ClH:17].[ClH:17].[C:1]([C:3]([C:7]1[CH:8]=[CH:9][C:10]([O:15][CH3:16])=[C:11]([CH:14]=1)[CH2:12][NH:31][C@H:30]1[CH2:29][CH2:28][CH2:27][NH:26][C@H:25]1[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1)([C:5]#[N:6])[CH3:4])#[N:2]
Reactant: N[C@H]1CCCN[C@H]1c1ccccc1
Reactant: COc1ccc(C(C)(C#N)C#N)cc1C=O
Agent: COc1ccc(C2(C#N)CC2)cc1CN[C@H]1CCCN[C@H]1c1ccccc1
Agent: Cl
Product: COc1ccc(C(C)(C#N)C#N)cc1CN[C@H]1CCCN[C@H]1c1ccccc1

Procedure:
This compound was prepared from Compound 37 and Compound 3 in the same manner of Compound 5.
Reaction SMILES: [NH2:1][CH:2]([CH3:5])[CH2:3][OH:4].[NH:6]1[C:14]2[C:9](=[CH:10][C:11]([NH:15][C:16]3[C:17]4[S:24][C:23]([C:25]5[CH:32]=[CH:31][C:28]([CH:29]=O)=[CH:27][CH:26]=5)=[CH:22][C:18]=4[N:19]=[CH:20][N:21]=3)=[CH:12][CH:13]=2)[CH:8]=[CH:7]1>>[NH:6]1[C:14]2[C:9](=[CH:10][C:11]([NH:15][C:16]3[C:17]4[S:24][C:23]([C:25]5[CH:32]=[CH:31][C:28]([CH2:29][NH:1][CH:2]([CH3:5])[CH2:3][OH:4])=[CH:27][CH:26]=5)=[CH:22][C:18]=4[N:19]=[CH:20][N:21]=3)=[CH:12][CH:13]=2)[CH:8]=[CH:7]1
Reactant: O=Cc1ccc(-c2cc3ncnc(Nc4ccc5[nH]ccc5c4)c3s2)cc1
Reactant: CC(N)CO
Product: CC(CO)NCc1ccc(-c2cc3ncnc(Nc4ccc5[nH]ccc5c4)c3s2)cc1

Procedure:
The title compound was prepared from 2-amino-propan-1-ol and 4-[4-(1H-indol-5-ylamino)-thieno[3,2-d]pyrimidin-6-yl]-benzaldehyde by a procedure analogous to example 17. M.P. 160-175° C.; LC-MS: 444 (MH+); HPLC RT: 3.90 minutes.
Reaction SMILES: [NH2:1][CH:2]([C:11]1[C:16]([O:17][CH3:18])=[CH:15][CH:14]=[CH:13][C:12]=1[O:19][CH3:20])[CH2:3][CH2:4][CH2:5][CH2:6][C:7]([O:9]C)=O.[N:21]1[CH:26]=[CH:25][C:24]([C:27]2[CH:28]=[C:29]([CH:32]=[CH:33][CH:34]=2)[CH:30]=O)=[CH:23][CH:22]=1>>[CH3:20][O:19][C:12]1[CH:13]=[CH:14][CH:15]=[C:16]([O:17][CH3:18])[C:11]=1[CH:2]1[N:1]([CH2:30][C:29]2[CH:32]=[CH:33][CH:34]=[C:27]([C:24]3[CH:23]=[CH:22][N:21]=[CH:26][CH:25]=3)[CH:28]=2)[C:7](=[O:9])[CH2:6][CH2:5][CH2:4][CH2:3]1
Reactant: COC(=O)CCCCC(N)c1c(OC)cccc1OC
Reactant: O=Cc1cccc(-c2ccncc2)c1
Product: COc1cccc(OC)c1C1CCCCC(=O)N1Cc1cccc(-c2ccncc2)c1

Procedure:
Prepared according to the described general procedure 1 (GP1) by reaction of methyl 6-amino-6-(2,6-dimethoxyphenyl)hexanoate with commercially available 3-(pyridin-4-yl)benzaldehyde. Subsequent purification by preparative HPLC afforded the target compound. LC-MS (conditions A): tR=0.65 min.; [M+H]+: 417.01 g/mol.