Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[N:7]=[C:6]([N:8]2[C:12]([CH3:14])([CH3:13])[CH2:11][CH:10]([N:15]([CH3:17])[CH3:16])[CH2:9]2)[C:5]([F:18])=[C:4]([NH:19][NH2:20])[N:3]=1.[CH:21]1([CH2:26][C@H:27]([CH2:31][N:32]([CH:41]=[O:42])[O:33][CH2:34][C:35]2[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=2)[C:28](O)=[O:29])[CH2:25][CH2:24][CH2:23][CH2:22]1.CN1CCOCC1.ON1C2N=CC=CC=2N=N1.C(Cl)CCl>CN(C=O)C.CCOCC>[Cl:1][C:2]1[N:3]=[C:4]([NH:19][NH:20][C:28](=[O:29])[C@H:27]([CH2:26][CH:21]2[CH2:22][CH2:23][CH2:24][CH2:25]2)[CH2:31][N:32]([O:33][CH2:34][C:35]2[CH:36]=[CH:37][CH:38]=[CH:39][CH:40]=2)[CH:41]=[O:42])[C:5]([F:18])=[C:6]([N:8]2[CH2:9][CH:10]([N:15]([CH3:16])[CH3:17])[CH2:11][C:12]2([CH3:14])[CH3:13])[N:7]=1
Reactant: O=CN(C[C@@H](CC1CCCC1)C(=O)O)OCc1ccccc1
Reactant: CN(C)C1CN(c2nc(Cl)nc(NN)c2F)C(C)(C)C1
Agent: On1nnc2cccnc21
Solvent: CN1CCOCC1
Solvent: ClCCCl
Solvent: CN(C)C=O
Product: CN(C)C1CN(c2nc(Cl)nc(NNC(=O)[C@H](CC3CCCC3)CN(C=O)OCc3ccccc3)c2F)C(C)(C)C1
Reaction time: 8 h
Yield: 85 %

Procedure:
To a solution of 1-(2-chloro-5-fluoro-6-hydrazino-4-pyrimidinyl)-N,N,5,5-tetramethyl-3-pyrrolidinamine (1.0502 g, 3.469 mmol) in DMF (16 mL) was added (2R)-3-cyclopentyl-2-({formyl[(phenylmethyl)oxy]amino}methyl)propanoic acid (1.0075 g, 3.299 mmol), N-methylmorpholine (1.8 mL, 16.37 mmol), 1-hydroxy-7-azabenzotriazole (0.540 g, 3.968 mmol), and EDC (0.760 g, 3.964 mmol). The solution was stirred overnight and then diluted with Et2O (100 mL). The mixture was washed with water (3×50 mL), and the combined aqueous phase was extracted with a fresh portion of Et2O (50 mL). This organic phase was washed with a fresh portion of water (25 mL), and the combined organic phase was dried over anhydrous Na2SO4, filtered, and concentrated in vacuo. The residue was dissolved in DCM (150 mL), dried over anhydrous Na2SO4, filtered, and concentrated in vacuo to provide crude [(2R)-3-(2-{2-chloro-6-[4-(dimethylamino)-2,2-dimethyl-1-pyrrolidinyl]-5-fluoro-4-pyrimidinyl}hydrazino)-2-(cyclopentylmethyl)-3-oxopropyl][(phenylmethyl)oxy]formamide (1.6539 g, 85% crude yield) as a dark red foam. LCMS: (M+H)+: 590.2.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([NH:13][C:14]([NH2:16])=[O:15])[CH:6]=[C:7]([O:11][CH3:12])[C:8]=1[O:9][CH3:10].C([O:19][C:20](=[O:26])[CH2:21][C:22]([CH2:24]Cl)=O)C>O1CCOCC1>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([NH:13][C:14](=[O:15])[NH:16][C:22]2[CH2:24][O:19][C:20](=[O:26])[CH:21]=2)[CH:6]=[C:7]([O:11][CH3:12])[C:8]=1[O:9][CH3:10]
Reactant: CCOC(=O)CC(=O)CCl
Reactant: COc1cc(NC(N)=O)cc(OC)c1OC
Solvent: C1COCCO1
Product: COc1cc(NC(=O)NC2=CC(=O)OC2)cc(OC)c1OC
Yield: 38.5 %

Procedure:
A mixture of 3,4,5-trimethoxyphenylurea (400 mg) and ethyl-4-chloroacetoacetate (350 mg) in dioxane (0.8 ml) is heated at reflux for 4 hours. After one hour at 25° C. the precipitate is recovered by filtration and recrystallized from methanol (3 ml), to give 210 mg of product.
Reaction SMILES: [CH3:1][C:2]1[CH:6]=[C:5]([CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][O:14][C:15]2[CH:16]=[C:17]([C:20]([O:22]C)=[O:21])[S:18][CH:19]=2)[O:4][N:3]=1.[OH-].[K+]>C(O)C.O>[CH3:1][C:2]1[CH:6]=[C:5]([CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][O:14][C:15]2[CH:16]=[C:17]([C:20]([OH:22])=[O:21])[S:18][CH:19]=2)[O:4][N:3]=1
Reactant: COC(=O)c1cc(OCCCCCCCc2cc(C)no2)cs1
Agent: [K+]
Agent: [OH-]
Solvent: CCO
Solvent: O
Product: Cc1cc(CCCCCCCOc2csc(C(=O)O)c2)on1

Procedure:
11.34 g (33.61 mmol) of methyl 4-(7-(3-methyl-5-isoxazolyl)-heptyloxy)-2-thiophenecarboxylate are heated under reflux in 95 ml of ethanol and 45 ml of water, and 2.18 g (38.9 mmol) of KOH, dissolved in 70 ml of water and 46 ml of ethanol, are added dropwise to this solution. After the mixture has been heated under reflux for 3 hours, it is cooled and concentrated, the residue is partitioned between water and ether and the aqueous phase, after acidification to pH 1 with 2N HCl, is extracted several times with ether. The combined organic phases are dried over sodium sulfate/active charcoal and evaporated.
Reaction SMILES: [NH2:1][C:2]1[N:3]=[C:4]([C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)[C:5]([C:10]2[CH:11]=[CH:12][C:13](=[O:19])[N:14]([CH:16]([CH3:18])[CH3:17])[CH:15]=2)=[N:6][C:7]=1[O:8]C.Cl>O1CCOCC1>[NH2:1][C:2]1[N:3]=[C:4]([C:20]2[CH:21]=[CH:22][CH:23]=[CH:24][CH:25]=2)[C:5]([C:10]2[CH:11]=[CH:12][C:13](=[O:19])[N:14]([CH:16]([CH3:18])[CH3:17])[CH:15]=2)=[N:6][C:7]=1[OH:8]
Reactant: COc1nc(-c2ccc(=O)n(C(C)C)c2)c(-c2ccccc2)nc1N
Agent: Cl
Solvent: C1COCCO1
Product: CC(C)n1cc(-c2nc(O)c(N)nc2-c2ccccc2)ccc1=O
Temperature: 100 °C
Reaction time: 3 h
Yield: 47 %

Procedure:
A mixture of 5-(5-amino-6-methoxy-3-phenyl-2-pyrazinyl)-1-isopropyl-2(1H)-pyridone (80 mg), conc. HCl (0.8 ml), and dioxane (1.6 ml) was heated with stirring at 100° C. for 3 hours. After cooling, the pH of the mixture was adjusted to 8 and a generated precipitate was isolated by filtration and dired in vacuo to give 5-(5-amino-6-hydroxy-3-phenyl-2-pyrazinyl)-1-isopropyl-2(1H)-pyridone (36 mg).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([N+]([O-])=O)[CH:5]=[CH:4][N:3]=1.[CH3:11][O:12][C:13]1[CH:18]=[CH:17][C:16]([CH2:19][SH:20])=[CH:15][CH:14]=1.CN(C=O)C.C(=O)([O-])[O-].[Cs+].[Cs+]>ClCCl>[CH3:11][O:12][C:13]1[CH:18]=[CH:17][C:16]([CH2:19][S:20][C:6]2[CH:5]=[CH:4][N:3]=[C:2]([Cl:1])[CH:7]=2)=[CH:15][CH:14]=1
Reactant: COc1ccc(CS)cc1
Reactant: O=[N+]([O-])c1ccnc(Cl)c1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Solvent: ClCCl
Product: COc1ccc(CSc2ccnc(Cl)c2)cc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 84.7 %

Procedure:
A flask was charged with 2-chloro-4-nitropyridine (12.75 g, 80.4 mmol), (4-methoxyphenyl)methanethiol (12.40 g, 80.4 mmol) and DMF (100 mL). Cesium carbonate (31.43 g, 96.48 mmol) was added in portions, and the mixture was stirred for 2 hours at ambient temperature. The solution was diluted with dichloromethane (250 mL) and washed with diluted sodium bicarbonate solution, dried over magnesium sulfate, filtered and evaporated. The resulting yellowish residue was triturated with hexanes and the solid was filtered to obtain the desired product (18.1 g, 85%) as a pale yellow powder.
Reaction SMILES: [Cl:1][C:2]1[CH:19]=[CH:18][C:5]([C:6]([NH:8][C:9]2[S:10][CH:11]=[C:12]([CH2:14][C:15]([OH:17])=O)[N:13]=2)=[O:7])=[CH:4][CH:3]=1.[C:20]([NH:24][S:25]([C:28]1[C:29]([C:34]2[CH:39]=[CH:38][C:37]([NH2:40])=[C:36]([F:41])[CH:35]=2)=[CH:30][CH:31]=[CH:32][CH:33]=1)(=[O:27])=[O:26])([CH3:23])([CH3:22])[CH3:21]>>[C:20]([NH:24][S:25]([C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][C:29]=1[C:34]1[CH:39]=[CH:38][C:37]([NH:40][C:15]([CH2:14][C:12]2[N:13]=[C:9]([NH:8][C:6](=[O:7])[C:5]3[CH:4]=[CH:3][C:2]([Cl:1])=[CH:19][CH:18]=3)[S:10][CH:11]=2)=[O:17])=[C:36]([F:41])[CH:35]=1)(=[O:27])=[O:26])([CH3:23])([CH3:21])[CH3:22]
Reactant: CC(C)(C)NS(=O)(=O)c1ccccc1-c1ccc(N)c(F)c1
Reactant: O=C(O)Cc1csc(NC(=O)c2ccc(Cl)cc2)n1
Product: CC(C)(C)NS(=O)(=O)c1ccccc1-c1ccc(NC(=O)Cc2csc(NC(=O)c3ccc(Cl)cc3)n2)c(F)c1

Procedure:
In analogy to example 1.3, [2-(4-chloro-benzoylamino)-thiazol-4-yl]-acetic acid (example 1.2) was coupled with 4′-amino-3′-fluoro-biphenyl-2-sulfonic acid tert-butylamide (CAS 209919-51-7, prepared according to B.-Y. Zhu et al., patent application WO 2000071515) to give N-{4-[(2′-tert-butylsulfamoyl-3-fluoro-biphenyl-4-ylcarbamoyl)-methyl]-thiazol-2-yl}-4-chloro-benzamide, using general procedure C. White amorphous solid. MS 601.3 ([M+H]+)
Reaction SMILES: [Br:1][C:2]1[CH:12]=[N:11][C:5]2[N:6]=[C:7](O)[N:8]=[CH:9][C:4]=2[CH:3]=1.C(N(C(C)C)CC)(C)C.P(Cl)(Cl)([Cl:24])=O>>[Br:1][C:2]1[CH:12]=[N:11][C:5]2[N:6]=[C:7]([Cl:24])[N:8]=[CH:9][C:4]=2[CH:3]=1
Reactant: O=P(Cl)(Cl)Cl
Reactant: Oc1ncc2cc(Br)cnc2n1
Solvent: CCN(C(C)C)C(C)C
Product: Clc1ncc2cc(Br)cnc2n1
Temperature: 120 °C
Reaction time: 12 h
Yield: 67 %

Procedure:
To a stirred mixture of 6-bromopyrido[2,3-d]pyrimidin-2-ol (1.1 g, 4.9 mmol) in 30 mL of phosphoryl trichloride was added diisopropylethylamine (1.6 g, 12.2 mmol) at room temperature, and the reaction mixture was then stirred at 120° C. for 12 hours. Most of phosphoryl trichloride was removed under reduced pressure. The residue was diluted with ethyl acetate (200 mL) and added to saturated sodium bicarbonate solution (300 mL) at 0° C. The mixture was extracted with ethyl acetate (200 mL×3). The combined organic layers were dried over anhydrous sodium sulfate, filtered and concentrated to afford the title compound (800 mg, 67%) as a yellow solid. MS (ES+) C7H3BrClN3 requires: 243, 245, found: 244, 246 [M+H]+.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[CH2:13][CH2:12][N:11](C(OC(C)(C)C)=O)[CH2:10][CH2:9]2)=[CH:4][C:3]=1[NH:21][S:22]([C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1)(=[O:24])=[O:23].[C:31]1([CH3:43])[CH:36]=[C:35]([CH3:37])[CH:34]=[C:33]([CH3:38])[C:32]=1[S:39](Cl)(=[O:41])=[O:40]>>[CH3:43][C:31]1[CH:36]=[C:35]([CH3:37])[CH:34]=[C:33]([CH3:38])[C:32]=1[S:39]([NH:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[CH2:13][CH2:12][NH:11][CH2:10][CH2:9]2)=[CH:4][C:3]=1[NH:21][S:22]([C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1)(=[O:24])=[O:23])(=[O:41])=[O:40]
Reactant: Cc1cc(C)c(S(=O)(=O)Cl)c(C)c1
Reactant: CC(C)(C)OC(=O)N1CCN(c2ccc(N)c(NS(=O)(=O)c3ccccc3)c2)CC1
Product: Cc1cc(C)c(S(=O)(=O)Nc2ccc(N3CCNCC3)cc2NS(=O)(=O)c2ccccc2)c(C)c1

Procedure:
2,4,6-Trimethyl-N-[2-[(phenylsulfonyl)amino]-4-(1-piperazinyl)phenyl]benzenesulfonamide was synthesized from N-{2-amino-5-(4-t-butyloxycarbonyl-piperazinyl)-phenyl}benzenesulfonamide and 2-mesitylenesulfonylchloride (52 mg, 0.239 mmol) according to general method 3 to give 50 mg of a purple solid. MS (posES-FIA) m/z=Found: 515.3; Calcd 515.17; 1H-NMR δ 7.74 (d, 2H); 7.63-7.46 (m, 3H), 6.92 (s, 2H), 6.74-6.55 (m, 3H), 3.27-3.20 (m, 8H), 2.35 (s, 6H), 2.25 (s, 3H).
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:32])[CH2:5][CH:6]([N:10]1[C:18]2[C:13](=[CH:14][C:15]([CH2:19][CH2:20][CH2:21][C:22]3[CH:31]=[CH:30][C:29]4[C:24](=[N:25][CH:26]=[CH:27][CH:28]=4)[N:23]=3)=[CH:16][CH:17]=2)[CH:12]=[CH:11]1)[CH2:7][CH2:8][CH3:9])[CH3:2]>[Pd].CO>[CH2:1]([O:3][C:4](=[O:32])[CH2:5][CH:6]([N:10]1[C:18]2[C:13](=[CH:14][C:15]([CH2:19][CH2:20][CH2:21][C:22]3[CH:31]=[CH:30][C:29]4[CH2:28][CH2:27][CH2:26][NH:25][C:24]=4[N:23]=3)=[CH:16][CH:17]=2)[CH:12]=[CH:11]1)[CH2:7][CH2:8][CH3:9])[CH3:2]
Reactant: CCCC(CC(=O)OCC)n1ccc2cc(CCCc3ccc4cccnc4n3)ccc21
Agent: [Pd]
Solvent: CO
Product: CCCC(CC(=O)OCC)n1ccc2cc(CCCc3ccc4c(n3)NCCC4)ccc21
Reaction time: 48 h
Yield: 80 %

Procedure:
A mixture of 3-[5-(3-[1,8]naphthyridin-2-yl-propyl)-indol-1-yl]-hexanoic acid ethyl ester (100 mg, 0.665 mmol) and 10% palladium on carbon (30 mg) in methanol (5 mL) was stirred under hydrogen for 2 days. The reaction solution was filtered through celite and dried to give the crude product, which was purified via column chromatography eluting with hexane/ethyl acetate (4/1), to give the title compound (80% yield). 1H NMR (CDCl3) δ 7.39 (d, J=0.9 Hz, 1H), 7.31 (d, J=8.5 Hz, 1H), 7.02-7.10 (m, 3H), 6.44 (dd, J=3.6, 6.3 Hz, 1H), 6.33 (d, J=7.3 Hz, 1H), 5.60 (br, 1H), 4.82 (m, 1H), 3.97 (q, 2H), 3.35 (t, 2H), 2.60-2.80 (m, 8H), 1.80-2.10 (m, 6H), 1.20 (m, 2H), 1.11 (m, 3H), 0.87 (m, 3H). Mass Spectrum (LCMS, ESI) calculated for C27H36N3O2 434.3 (M+H); found 434.4.
Reaction SMILES: Cl[C:2]1[N:12]=[C:11]2[C:5]([N:6]([CH3:18])[C:7](=[O:17])[CH2:8][CH2:9][N:10]2[CH2:13][CH:14]([CH3:16])[CH3:15])=[CH:4][N:3]=1.[NH2:19][C:20]1[CH:35]=[CH:34][C:23]([C:24]([NH:26][CH:27]2[CH2:32][CH2:31][N:30]([CH3:33])[CH2:29][CH2:28]2)=[O:25])=[CH:22][C:21]=1[O:36][CH3:37].C1(C)C=CC(S(O)(=O)=O)=CC=1>CC(C)CC(O)C.CO.O>[CH3:37][O:36][C:21]1[CH:22]=[C:23]([CH:34]=[CH:35][C:20]=1[NH:19][C:2]1[N:12]=[C:11]2[C:5](=[CH:4][N:3]=1)[N:6]([CH3:18])[C:7](=[O:17])[CH2:8][CH2:9][N:10]2[CH2:13][CH:14]([CH3:16])[CH3:15])[C:24]([NH:26][CH:27]1[CH2:32][CH2:31][N:30]([CH3:33])[CH2:29][CH2:28]1)=[O:25]
Reactant: COc1cc(C(=O)NC2CCN(C)CC2)ccc1N
Reactant: CC(C)CN1CCC(=O)N(C)c2cnc(Cl)nc21
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: CO
Solvent: CC(C)CC(C)O
Solvent: O
Product: COc1cc(C(=O)NC2CCN(C)CC2)ccc1Nc1ncc2c(n1)N(CC(C)C)CCC(=O)N2C
Temperature: 160 °C

Procedure:
10-chloro-6-methyl-2-(2-methylpropyl)-2,6,9,11-tetrazabicyclo[5.4.0]undeca-7,9,11-trien-5-one (Intermediate 84; 65 mg, 0.24 mmol), 4-amino-3-methoxy-N-(1-methyl-4-piperidyl)benzamide (WO06/018220, 57 mg, 0.24 mmol) and p-toluene sulphonic acid (110 mg, 0.58 mmol) were taken up in 4-methyl-2-pentanol (1 mL) and heated to 160° C. by microwave irradiation for 1 hour. The reaction mixture was diluted with methanol (5 mL) and water (2 mL) and resultant solution poured onto an SCX-3 cartridge (2 g). The cartridge was washed with methanol (˜30 mL) before eluting products with 2M ammonia methanol (20 mL). The Ammoniacal fraction was evaporated to give an amber gum which was purified by reverse phase HPLC to yield the title compound as a colourless glass (scratches down to a white solid) (80 mg, 75%).
Reaction SMILES: [CH3:1][C@:2]1([C:8]([OH:10])=[O:9])[CH2:7][CH2:6][CH2:5][CH2:4][NH:3]1.[F:11][C:12]([F:22])([F:21])[C:13]1[CH:20]=[CH:19][C:16]([CH2:17]Br)=[CH:15][CH:14]=1.C([O-])([O-])=O.[Na+].[Na+]>>[CH3:1][C@:2]1([C:8]([O:10][CH2:17][C:16]2[CH:15]=[CH:14][C:13]([C:12]([F:11])([F:21])[F:22])=[CH:20][CH:19]=2)=[O:9])[CH2:7][CH2:6][CH2:5][CH2:4][N:3]1[CH2:17][C:16]1[CH:19]=[CH:20][C:13]([C:12]([F:22])([F:21])[F:11])=[CH:14][CH:15]=1
Reactant: C[C@]1(C(=O)O)CCCCN1
Reactant: FC(F)(F)c1ccc(CBr)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Product: C[C@]1(C(=O)OCc2ccc(C(F)(F)F)cc2)CCCCN1Cc1ccc(C(F)(F)F)cc1

Procedure:
The title compound (D79) (70 mg) was prepared according to the general procedure for substituted benzyl amines preparation starting from (R)-2-methylpiperidine-2-carboxylic acid (D47) (60 mg) and 4-(Trifluoromethyl)benzyl bromide (0.126 ml). (Na2CO3: 8 eq; reaction time 48 hrs; 68° C.)
Reaction SMILES: O[CH2:2][CH2:3][C@H:4]1[C:13]([CH3:15])([CH3:14])[C:12]2[C:7](=[CH:8][CH:9]=[C:10]([CH3:16])[CH:11]=2)[C:6]([CH3:18])([CH3:17])[CH2:5]1.N1C=CC=CC=1.S(Cl)([Cl:27])=O>C1(C)C=CC=CC=1>[Cl:27][CH2:2][CH2:3][C@H:4]1[C:13]([CH3:15])([CH3:14])[C:12]2[C:7](=[CH:8][CH:9]=[C:10]([CH3:16])[CH:11]=2)[C:6]([CH3:18])([CH3:17])[CH2:5]1
Reactant: O=S(Cl)Cl
Reactant: Cc1ccc2c(c1)C(C)(C)[C@H](CCO)CC2(C)C
Solvent: c1ccncc1
Solvent: Cc1ccccc1
Product: Cc1ccc2c(c1)C(C)(C)[C@H](CCCl)CC2(C)C
Temperature: 0 °C
Yield: 61.3 %

Procedure:
(S)-3-(2-Hydroxyethyl)-1,1,4,4,6-pentamethyl-1,2,3,4-tetrahydronaphthalene ([α]546 -8.1° (C=0.62 in ethanol)) (70.5 g; 0.287 mol) was dissolved in toluene (700 g), and pyridine (25.0 g; 0.316 mol) was added thereto. The resulting mixture was cooled to 0° C., and thionyl chloride (41.0 g; 0.345 mol) was added dropwise thereto. After the addition was completed, the resultant mixture was heated at 60° C. for 5 hours. The reaction mixture was cooled, washed with dilute hydrochloric acid, saturated sodium carbonate solution and saturated sodium chloride solution in order, dried over anhydrous sodium sulfate and concentrated to give (S)-3-(2-chloroethyl)-1,1,4,4,6-pentamethyl-1,2,3,4-tetrahydronaphthalene (46.5 g; 0.176 mol; 61%). B.P., 106°-107° C./0.13 mmHg. [α]546 -33.4° (C=1.2 in ethanol).
Reaction SMILES: [OH:1][C:2]([C:5]1[N:6]=[C:7]([S:52][CH3:53])[N:8]([CH2:15][C:16]2[CH:21]=[CH:20][C:19]([C:22]3[CH:27]=[CH:26][CH:25]=[CH:24][C:23]=3[C:28]3[N:32](C(C4C=CC=CC=4)(C4C=CC=CC=4)C4C=CC=CC=4)[N:31]=[N:30][N:29]=3)=[CH:18][CH:17]=2)[C:9]=1[C:10]([O:12][CH2:13][CH3:14])=[O:11])([CH3:4])[CH3:3]>C(O)(=O)C>[OH:1][C:2]([C:5]1[N:6]=[C:7]([S:52][CH3:53])[N:8]([CH2:15][C:16]2[CH:21]=[CH:20][C:19]([C:22]3[CH:27]=[CH:26][CH:25]=[CH:24][C:23]=3[C:28]3[NH:32][N:31]=[N:30][N:29]=3)=[CH:18][CH:17]=2)[C:9]=1[C:10]([O:12][CH2:13][CH3:14])=[O:11])([CH3:3])[CH3:4]
Reactant: CCOC(=O)c1c(C(C)(C)O)nc(SC)n1Cc1ccc(-c2ccccc2-c2nnnn2C(c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Solvent: CC(=O)O
Product: CCOC(=O)c1c(C(C)(C)O)nc(SC)n1Cc1ccc(-c2ccccc2-c2nnn[nH]2)cc1
Temperature: 60 °C
Reaction time: 1 h
Yield: 88.5 %

Procedure:
900 mg of ethyl 4-(1-hydroxy-1-methylethyl)-2-methylthio-1-{4-[2-(trityltetrazol-5-yl)phenyl]phenyl}metylimidazole-5-carboxylate [prepared as described in step (a) above] were added to 10 ml of a 25% v/v aqueous solution of acetic acid, and the mixture was stirred at 60° C. for 1 hour. At the end of this time, the reaction mixture was cooled, and the crystals of trityl alcohol which appeared were filtered off. These crystals were washed with a 50% v/v aqueous solution of acetic acid, and the filtrate and the washings were mixed. The resulting mixture was concentrated by evaporation under reduced pressure, and the resulting residue was crystallized from ethyl acetate, to give 529 mg of the title compound as crystals, melting at 209°-210° C.
Reaction SMILES: CC(C1C=C(C(C)C)C(C2C(P(C3CCCCC3)C3CCCCC3)=C(OC)C=CC=2OC)=C(C(C)C)C=1)C.CC([O-])(C)C.[Na+].Cl[C:46]1[N:47]=[CH:48][CH:49]=[C:50]2[CH:54]=[CH:53][N:52]([CH3:55])[C:51]=12.[NH2:56][C@@H:57]1[CH2:62][CH2:61][CH2:60][N:59]([C:63]([O:65][C:66]([CH3:69])([CH3:68])[CH3:67])=[O:64])[CH2:58]1>C1(C)C=CC=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd].O>[CH3:55][N:52]1[C:51]2=[C:46]([NH:56][C@@H:57]3[CH2:62][CH2:61][CH2:60][N:59]([C:63]([O:65][C:66]([CH3:69])([CH3:68])[CH3:67])=[O:64])[CH2:58]3)[N:47]=[CH:48][CH:49]=[C:50]2[CH:54]=[CH:53]1
Reactant: CC(C)(C)OC(=O)N1CCC[C@@H](N)C1
Reactant: Cn1ccc2ccnc(Cl)c21
Agent: [Pd]
Agent: CC(C)(C)[O-]
Agent: COc1ccc(OC)c(P(C2CCCCC2)C2CCCCC2)c1-c1c(C(C)C)cc(C(C)C)cc1C(C)C
Solvent: O
Solvent: Cc1ccccc1
Product: Cn1ccc2ccnc(N[C@@H]3CCCN(C(=O)OC(C)(C)C)C3)c21
Temperature: 105 °C
Reaction time: 3 h
Yield: 94 %

Procedure:
A solution of Pd2(dba)3 (1.53 g, 1.68 mmol), BrettPhos (1.86 g, 3.36 mmol) in toluene (40 mL) under N2 atmosphere was stirred for 20 min. NaOtBu (3.23 g, 33.6 mmol), the compound from Step 1 7-chloro-1-methyl-1H-pyrrolo[2,3-c]pyridine (2.80 g, 16.8 mmmol) and tert-butyl (3R)-3-aminopiperidine-1-carboxylate (4.04 g, 20.2 mmol) were added. The reaction was stirred at 105° C. for 3 h. The reaction mixture was poured into water (20 mL) and extracted with EtOAc (3×20 mL). The organic layers were dried over Na2SO4, filtered and the filtrate was concentrated in vacuo. The residue was purified by silica gel column chromatography, eluting with a gradient of 17-50% EtOAc/petroleum ether to give the title compound as a brown solid (5.2 g, 94%).
Reaction SMILES: [C:1]1([CH:11]=[N:12][OH:13])[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][CH:2]=1.ClN1C(=O)CCC1=O.[CH:22]([P:24]([CH3:28])(=[O:27])[O:25][CH3:26])=[CH2:23].C(N(CC)CC)C>>[C:1]1([C:11]2[CH2:23][CH:22]([P:24]([CH3:28])(=[O:27])[O:25][CH3:26])[O:13][N:12]=2)[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][CH:2]=1
Reactant: C=CP(C)(=O)OC
Reactant: ON=Cc1cccc2ccccc12
Agent: O=C1CCC(=O)N1Cl
Solvent: CCN(CC)CC
Product: COP(C)(=O)C1CC(c2cccc3ccccc23)=NO1
Yield: 96.8 %

Procedure:
39.1 g (0.25 mol) of naphthaldoxime, 36.7 g (0.275 mol) of N-chlorosuccinimide, 33 g (0.275 mol) of methyl vinyl(P-methyl)phosphinate and 38.2 ml (0.275 mol) of triethylamine are reacted as in Example 1 to give 70 g of oily product.
Reaction SMILES: [O:1]=[C:2]([C:8]1[CH:9]=[C:10]2[C:14](=[CH:15][CH:16]=1)[N:13]([CH3:17])[CH:12]1[N:18]([CH3:21])[CH2:19][CH2:20][C:11]21[CH3:22])[C:3]([O:5][CH2:6][CH3:7])=[O:4]>C(O)CCCCC.[Ti]>[O:1]=[C:2]([C:8]1[CH:9]=[C:10]2[C:14](=[CH:15][CH:16]=1)[N:13]([CH3:17])[CH:12]1[N:18]([CH3:21])[CH2:19][CH2:20][C:11]21[CH3:22])[C:3]([O:5][CH2:6][CH2:7][CH2:3][CH2:2][CH2:8][CH3:16])=[O:4]
Reactant: CCOC(=O)C(=O)c1ccc2c(c1)C1(C)CCN(C)C1N2C
Agent: [Ti]
Solvent: CCCCCCO
Product: CCCCCCOC(=O)C(=O)c1ccc2c(c1)C1(C)CCN(C)C1N2C
Temperature: 25 °C
Yield: 164.8 %

Procedure:
To a stirred solution of 1,2,3,3a,8,8a-hexahydro-α-oxo-1,3a,8-trimethyl-5-pyrrolo[2,3-b]indole acetic acid, ethyl ester (3.0 g) in n-hexyl alcohol (73.6 ml) was added at 0° C. under a nitrogen atmosphere, titanium IV ethoxide (0.83 ml). The mixture was warmed to room temperature and heated for 2 hours keeping the temperature between 60°-80° C. The excess n-hexyl alcohol was removed by distillation under high vacuum. The residue was taken up in ethyl acetate, washed twice with 100 ml portions of saturated aqueous NH4Cl solution, twice with 100 ml portions of saturated aqueous NaHCO3 solution and once with 100 ml of brine. The organic phase was dried (NaSO4), filtered, and concentrated to afford an oil which was purified using preparative HPLC (silica gel, 3% methanol in dichloromethane as the loading solvent and eluent). The appropriate fractions were combined and the solvents removed under reduced pressure yielding 2.93 g of 1,2,3,3a,8,8a-hexahydro-α-oxo-1,3a,8 -trimethyl-5-pyrrolo[2,3-b]indole acetic acid, n-hexyl ester, as an oil.
Reaction SMILES: [NH2:1][C:2]1[S:3][CH:4]=[CH:5][C:6]=1[C:7]([O:9][CH3:10])=[O:8].N[C:12]1[CH:16]=CS[C:13]=1[C:17](OC)=O>>[CH2:16]([NH:1][C:2]1[S:3][CH:4]=[CH:5][C:6]=1[C:7]([O:9][CH3:10])=[O:8])[CH2:12][CH2:13][CH3:17]
Reactant: COC(=O)c1ccsc1N
Reactant: COC(=O)c1sccc1N
Product: CCCCNc1sccc1C(=O)OC
Yield: 40.7 %

Procedure:
In the same manner as in Reference Example 1-1), methyl 2-aminothiophene-3-carboxylate [Chem. Ber. 98, 3571 (1965)]was used in place of methyl 3-aminothiophene-2-carboxylate to obtain 8.69 g (40.7%) of Compound (g-1).
Reaction SMILES: C([O:5][C:6](=[O:47])[C:7]([CH2:43][C:44]#[C:45][CH3:46])([S:12]([C:15]1[CH:20]=[CH:19][C:18]([N:21]2[CH2:26][CH2:25][CH:24]([NH:27][CH2:28][C@H:29]([OH:42])[C:30]3[CH:35]=[CH:34][C:33]([OH:36])=[C:32]([NH:37][S:38]([CH3:41])(=[O:40])=[O:39])[CH:31]=3)[CH2:23][CH2:22]2)=[CH:17][CH:16]=1)(=[O:14])=[O:13])[CH2:8][C:9]#[C:10][CH3:11])(C)(C)C.FC(F)(F)C(O)=O>ClCCl>[CH2:8]([C:7]([S:12]([C:15]1[CH:16]=[CH:17][C:18]([N:21]2[CH2:26][CH2:25][CH:24]([NH:27][CH2:28][C@H:29]([OH:42])[C:30]3[CH:35]=[CH:34][C:33]([OH:36])=[C:32]([NH:37][S:38]([CH3:41])(=[O:39])=[O:40])[CH:31]=3)[CH2:23][CH2:22]2)=[CH:19][CH:20]=1)(=[O:13])=[O:14])([CH2:43][C:44]#[C:45][CH3:46])[C:6]([OH:47])=[O:5])[C:9]#[C:10][CH3:11]
Reactant: CC#CCC(CC#CC)(C(=O)OC(C)(C)C)S(=O)(=O)c1ccc(N2CCC(NC[C@H](O)c3ccc(O)c(NS(C)(=O)=O)c3)CC2)cc1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CC#CCC(CC#CC)(C(=O)O)S(=O)(=O)c1ccc(N2CCC(NC[C@H](O)c3ccc(O)c(NS(C)(=O)=O)c3)CC2)cc1
Temperature: 25 °C
Reaction time: 48 h
Yield: 44.8 %

Procedure:
To a solution of 2-(2-butynyl)-2-[(4-{4-[((2R)-2-hydroxy-2-(4-hydroxy-3-[(methylsulfonyl)amino]-phenyl}ethyl)amino]-1-piperidinyl)phenyl)sulfonyl]-4-hexynoicacid tert-butyl ester 0.21 g (0.3 mmol) in dichloromethane (3 ml) was added trifluoroacetic acid (0.23 ml, 3 mmol), and the mixture was stirred at room temperature for 2 days. It was then evaporated and treated with 10% sodium bicarbonate solution until pH 6. The resulting suspension was filtered and the precipitate washed with water, and dried in vacuo to give 85 mg of a beige solid; m.p. 175-177° C.; MS (ES) m/z 630.6 (M−H—); HRMS (EI) Calcd. for C30H36N3O8S2 (M−H−): 630.1949, Found: 630.1943.