Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH:1]1[CH:2]=[CH:3][C:4]([C:7]2[N:8]=[C:9]([NH2:14])[N:10]=[C:11]([NH2:13])[N:12]=2)=[CH:5][CH:6]=1.[C:15]1(=[O:25])[O:20][C:18](=[O:19])[C:17]2=[CH:21][CH:22]=[CH:23][CH:24]=[C:16]12.[OH2:26]>>[CH:1]1[CH:6]=[CH:5][C:4]([C:7]2[N:8]=[C:9]([NH2:14])[N:10]=[C:11]([NH2:13])[N:12]=2)=[CH:3][CH:2]=1.[C:15]([O-:20])(=[O:25])[C:16]1[C:17](=[CH:21][CH:22]=[CH:23][CH:24]=1)[C:18]([O-:26])=[O:19]
Reactant: O
Reactant: O=C1OC(=O)c2ccccc21
Agent: Nc1nc(N)nc(-c2ccccc2)n1
Product: O=C([O-])c1ccccc1C(=O)[O-]

Procedure:
187 g of benzoguanamine, 148 g of phthalic anhydride and 5 L of water were placed into the a flask provided with a stirrer and a reflux tube, and were continuously refluxed for 5 hours to form a crystal, which was then filtered out and dried to obtain benzoguanamine phthalate.
Reaction SMILES: C(N)C1C=CC=CC=1.O1CC1COC1C2C3C(=CC=CC=3)NC=2C=CC=1.[CH3:27][O:28][C:29]1[C:34]([O:35][CH2:36][CH2:37][N:38]([CH2:46][CH:47]([OH:63])[CH2:48][O:49][C:50]2[C:55]3[C:56]4[C:61]([NH:62][C:54]=3[CH:53]=[CH:52][CH:51]=2)=[CH:60][CH:59]=[CH:58][CH:57]=4)CC2C=CC=CC=2)=[CH:33][CH:32]=[CH:31][CH:30]=1>[Cl-].[Cl-].[Zn+2].C(COC)OC>[CH3:27][O:28][C:29]1[CH:30]=[CH:31][CH:32]=[CH:33][C:34]=1[O:35][CH2:36][CH2:37][NH:38][CH2:46][CH:47]([OH:63])[CH2:48][O:49][C:50]1[CH:51]=[CH:52][CH:53]=[C:54]2[NH:62][C:61]3[CH:60]=[CH:59][CH:58]=[CH:57][C:56]=3[C:55]=12
Reactant: COc1ccccc1OCCN(Cc1ccccc1)CC(O)COc1cccc2[nH]c3ccccc3c12
Agent: [Cl-]
Agent: [Zn+2]
Agent: c1ccc2c(c1)[nH]c1cccc(OCC3CO3)c12
Solvent: NCc1ccccc1
Solvent: COCCOC
Product: COc1ccccc1OCCNCC(O)COc1cccc2[nH]c3ccccc3c12
Reaction time: 10 h

Procedure:
To 250 ml dimethoxyethane, 70 g (0.27 moles) of anhydrous N-2-[2-(methoxy)-phenoxy]-ethyl]-benzylamine, 10.25 g (0.075 moles) of anhydrous ZnCl2 and 50 g (0.21 moles) of 4-(oxiranylmethoxy)-9H-carbazole are added and the reaction mixture is heated to 70-75° C. for 2.5 hrs (TLC control for checking conversion to N-benzyl carvedilol). Dimethoxyethane is distilled off from the reaction mixture and to the concentrated mass is added 400 ml ethylacetate, followed by 100 ml of ˜12-15% aqueous ammonia. The aqueous layer separated, and the product enriched organic layer is washed with water till neutral pH. The organic layer is charcoalised, filtered. To this solution of N-benzyl carvedilol in ethylacetate, (7 g) of wet Pd/C catalyst (5% Pd content and 50% moisture content) is added. The reaction mixture is hydrogenated at 3.5-4.5 Kg/cm2 at temperature of 60-70° C. for a period of about 10 hours. The reaction mixture is filtered and filtrate concentrated to remove ethylacetate. To the resultant syrupy mass n-butanol (100 ml) is added and the solution is stirred for about 10 hours, the crystals separated by filtration, washed successively with n-butanol (50 ml) and toluene (50 ml) to obtain carvedilol (50 g). The product is recrystallized from 3 volumes of ethyl acetate to obtain carvedilol (45 g).
Reaction SMILES: FC1C=CC(S(CCC)(=O)=O)=CC=1C#C[Si](C)(C)C.[C:20]([O:24][C:25](=[O:37])[CH2:26][O:27][C:28]1[CH:33]=[CH:32][C:31]([Cl:34])=[CH:30][C:29]=1[C:35]#[CH:36])([CH3:23])([CH3:22])[CH3:21].Br[C:39]1[CH:44]=[C:43]([S:45]([CH2:48][CH2:49][CH3:50])(=[O:47])=[O:46])[CH:42]=[CH:41][C:40]=1[Cl:51]>>[C:20]([O:24][C:25](=[O:37])[CH2:26][O:27][C:28]1[CH:33]=[CH:32][C:31]([Cl:34])=[CH:30][C:29]=1[C:35]#[C:36][C:41]1[CH:42]=[C:43]([S:45]([CH2:48][CH2:49][CH3:50])(=[O:46])=[O:47])[CH:44]=[CH:39][C:40]=1[Cl:51])([CH3:23])([CH3:22])[CH3:21]
Reactant: C#Cc1cc(Cl)ccc1OCC(=O)OC(C)(C)C
Reactant: CCCS(=O)(=O)c1ccc(Cl)c(Br)c1
Agent: CCCS(=O)(=O)c1ccc(F)c(C#C[Si](C)(C)C)c1
Product: CCCS(=O)(=O)c1ccc(Cl)c(C#Cc2cc(Cl)ccc2OCC(=O)OC(C)(C)C)c1

Procedure:
Following the general method as outlined in Intermediate 107, starting from (4-chloro-2-ethynyl-phenoxy)-acetic acid tert-butyl ester (Intermediate 3) and 2-bromo-1-chloro-4-(propylsulfonyl)benzene (Intermediate 126), the title compound was obtained as a colorless oil after purification by flash column chromatography (silica), eluting with cyclohexane containing increasing amounts of EtOAc.
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[CH2:9][CH2:10][C:11]1[N:12]([CH2:22][C:23](O)=[O:24])[C:13]2[C:18]([C:19](=[O:21])[N:20]=1)=[CH:17][CH:16]=[CH:15][CH:14]=2.[CH3:26][C:27]([N:34]1[CH2:39][CH2:38][CH:37]([NH:40][CH2:41][C:42]2[CH:47]=[CH:46][C:45]([C:48]3[CH:53]=[CH:52][C:51]([O:54][C:55]([F:58])([F:57])[F:56])=[CH:50][CH:49]=3)=[CH:44][CH:43]=2)[CH2:36][CH2:35]1)([CH3:33])[C:28]([O:30][CH2:31][CH3:32])=[O:29].CCN(C(C)C)C(C)C.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F>CN(C=O)C>[F:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[CH2:9][CH2:10][C:11]1[N:12]([CH2:22][C:23]([N:40]([CH2:41][C:42]2[CH:47]=[CH:46][C:45]([C:48]3[CH:49]=[CH:50][C:51]([O:54][C:55]([F:57])([F:56])[F:58])=[CH:52][CH:53]=3)=[CH:44][CH:43]=2)[CH:37]2[CH2:36][CH2:35][N:34]([C:27]([CH3:26])([CH3:33])[C:28]([O:30][CH2:31][CH3:32])=[O:29])[CH2:39][CH2:38]2)=[O:24])[C:13]2[C:18]([C:19](=[O:21])[N:20]=1)=[CH:17][CH:16]=[CH:15][CH:14]=2
Reactant: O=C(O)Cn1c(CCc2ccc(F)cc2F)nc(=O)c2ccccc21
Reactant: CCOC(=O)C(C)(C)N1CCC(NCc2ccc(-c3ccc(OC(F)(F)F)cc3)cc2)CC1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: CCOC(=O)C(C)(C)N1CCC(N(Cc2ccc(-c3ccc(OC(F)(F)F)cc3)cc2)C(=O)Cn2c(CCc3ccc(F)cc3F)nc(=O)c3ccccc32)CC1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 63 %

Procedure:
A mixture of [2-[2-(2,4-difluorophenyl)ethyl]-4-oxo-1(4H)-quinazolinyl]acetic acid (Int. C3) (114 mg, 1.1 equiv), ethyl 2-methyl-2-{4-[({4′-[(trifluoromethyl)oxy]-4-biphenylyl}methyl)amino]-1-piperidinyl}propanoate (Int. B3) (139 mg, 1 equiv), DMF (1.2 ml) and DIPEA (0.16 ml, 3 equiv) was shaken at room temperature, then HATU (176 mg, 1.5 equiv) was added with vigorous agitation and shaking continued for 30 min. A further portion of Intermediate D5 (21 mg, 0.2 equiv) was added, followed 1 h later by further HATU (23 mg, 0.2 equiv), then shaking was continued for 18 h. Reverse phase HPLC (Preparative Method B) gave ethyl 2-{4-[{[2-[2-(2,4-difluorophenyl)ethyl]-4-oxo-1(4H)-quinazolinyl]acetyl}({4′-[(trifluoromethyl)oxy]-4-biphenylyl}methyl)amino]-1-piperidinyl}-2-methylpropanoate as a white solid (149 mg).
Reaction SMILES: N[C:2]1[CH:3]=[CH:4][C:5]2[N:9]=[C:8]3[CH2:10][CH2:11][CH2:12][N:7]3[C:6]=2[CH:13]=1.N([O-])=O.[Na+].[ClH:18]>O>[Cl:18][C:2]1[CH:3]=[CH:4][C:5]2[N:9]=[C:8]3[CH2:10][CH2:11][CH2:12][N:7]3[C:6]=2[CH:13]=1
Reactant: Cl
Reactant: Nc1ccc2nc3n(c2c1)CCC3
Agent: O=N[O-]
Agent: [Na+]
Solvent: O
Product: Clc1ccc2nc3n(c2c1)CCC3

Procedure:
A suspension of 17.3 g of 7-amino-2,3-dihydro-1H-pyrrolo [1,2-a]benzimidazole prepared according to W. Reppe, Ann. 596, 209 (1955) in 200 cm3 of 5 N hydrochloric acid is diazotized with a solution of 7.2 g of sodium nitrite in 30 cm3 of water. The obtained solution is added to a solution of 8 g of cuprous chloride in 35 cm3 of concentrated hydrochloric acid at 50°-60°C. After cooling the precipitate is sucked off, washed with water and suspended in water. By adding to this suspension a 25 % aqueous solution of ammonia the heterocyclic base is set free and sucked off. After drying, recrystallization from benzene yields 4.1 g of 7-chloro-2,3-dihydro-1H-pyrrolo[1,2-a]benzimidazole. Melting point: 136°C.
Reaction SMILES: [C:1](=O)([O-])[O-].[K+].[K+].[CH:7]1([CH2:10][N:11]2[C:17](=[O:18])[C@@H:16]([NH:19][C:20]([N:22]3[CH2:27][CH2:26][CH:25]([N:28]4[CH:32]=[C:31]([C:33]5[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=5)[NH:30][C:29]4=[O:39])[CH2:24][CH2:23]3)=[O:21])[CH2:15][NH:14][C@H:13]([C:40]3[CH:45]=[CH:44][CH:43]=[CH:42][CH:41]=3)[CH2:12]2)[CH2:9][CH2:8]1.IC>CC(C)=O>[CH:7]1([CH2:10][N:11]2[C:17](=[O:18])[C@H:16]([NH:19][C:20]([N:22]3[CH2:27][CH2:26][CH:25]([N:28]4[CH:32]=[C:31]([C:33]5[CH:34]=[CH:35][CH:36]=[CH:37][CH:38]=5)[NH:30][C:29]4=[O:39])[CH2:24][CH2:23]3)=[O:21])[CH2:15][N:14]([CH3:1])[C@@H:13]([C:40]3[CH:45]=[CH:44][CH:43]=[CH:42][CH:41]=3)[CH2:12]2)[CH2:9][CH2:8]1
Reactant: O=C([O-])[O-]
Reactant: O=C(N[C@H]1CN[C@H](c2ccccc2)CN(CC2CC2)C1=O)N1CCC(n2cc(-c3ccccc3)[nH]c2=O)CC1
Agent: [K+]
Solvent: CC(C)=O
Solvent: CI
Product: CN1C[C@@H](NC(=O)N2CCC(n3cc(-c4ccccc4)[nH]c3=O)CC2)C(=O)N(CC2CC2)C[C@@H]1c1ccccc1
Reaction time: 18 h
Yield: 35.1 %

Procedure:
Potassium carbonate (5.8 mg, 0.040 mmol) was added to a solution of N-[(3R,6S)-1-(cyclopropylmethyl)-7-oxo-3-phenyl-1,4-diazepan-6-yl]-4-(2-oxo-4-phenyl-2,3-dihydro-1H-imidazol-1-yl)piperidine-1-carboxamide (11.0 mg, 0.021 mmol) and iodomethane (3 □L, 0.040 mmol) in acetone (0.5 mL). After 18 h, the mixture was concentrated. Purification by silica gel chromatography (1% methanol/dichloromethane→5% methanol/dichloromethane) gave the title compound (4 mg). MS 543.3 (M+1).
Reaction SMILES: [F:1][C:2]([F:33])([F:32])[C:3]1[CH:31]=[CH:30][C:6]([CH2:7][N:8]2[C@@H:13]([C:14]([NH:16][C:17]3([C:20]4[CH:29]=[CH:28][C:23]([C:24]([O:26]C)=[O:25])=[CH:22][CH:21]=4)[CH2:19][CH2:18]3)=[O:15])[CH2:12][CH:11]3[CH:9]2[CH2:10]3)=[CH:5][CH:4]=1.O[Li].O>>[F:33][C:2]([F:1])([F:32])[C:3]1[CH:31]=[CH:30][C:6]([CH2:7][N:8]2[C@@H:13]([C:14]([NH:16][C:17]3([C:20]4[CH:29]=[CH:28][C:23]([C:24]([OH:26])=[O:25])=[CH:22][CH:21]=4)[CH2:18][CH2:19]3)=[O:15])[CH2:12][CH:11]3[CH:9]2[CH2:10]3)=[CH:5][CH:4]=1
Reactant: COC(=O)c1ccc(C2(NC(=O)[C@H]3CC4CC4N3Cc3ccc(C(F)(F)F)cc3)CC2)cc1
Agent: [Li]O
Solvent: O
Product: O=C(O)c1ccc(C2(NC(=O)[C@H]3CC4CC4N3Cc3ccc(C(F)(F)F)cc3)CC2)cc1
Yield: 47.5 %

Procedure:
The title compound (E31) (46 mg) was prepared according to the general procedure for esters hydrolysis (Method C) starting from methyl 4-(1-((3R)-2-(4-(trifluoromethyl)benzyl)-2-azabicyclo[3.1.0]hexane-3-carboxamido)cyclopropyl)benzoate (diastereoisomer 2) (D148) (100 mg). (LiOH H2O: 4 eq; reaction time: 18 hrs)
Reaction SMILES: [C:1]([CH2:3][NH:4][C:5](=[O:26])[CH:6]([C:11]1[CH:16]=[CH:15][CH:14]=[C:13](B2OC(C)(C)C(C)(C)O2)[CH:12]=1)[CH2:7][CH:8]([CH3:10])[CH3:9])#[N:2].Br[C:28]1[CH:42]=[CH:41][C:31]([CH2:32][NH:33][C:34](=[O:40])[O:35][C:36]([CH3:39])([CH3:38])[CH3:37])=[CH:30][CH:29]=1.C(=O)(O)[O-].[Na+].CN(C=O)C>O.[Pd](Cl)Cl>[C:1]([CH2:3][NH:4][C:5]([CH:6]([C:11]1[CH:12]=[C:13]([C:28]2[CH:29]=[CH:30][C:31]([CH2:32][NH:33][C:34](=[O:40])[O:35][C:36]([CH3:38])([CH3:37])[CH3:39])=[CH:41][CH:42]=2)[CH:14]=[CH:15][CH:16]=1)[CH2:7][CH:8]([CH3:9])[CH3:10])=[O:26])#[N:2]
Reactant: CC(C)CC(C(=O)NCC#N)c1cccc(B2OC(C)(C)C(C)(C)O2)c1
Reactant: CC(C)(C)OC(=O)NCc1ccc(Br)cc1
Agent: Cl[Pd]Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: CC(C)CC(C(=O)NCC#N)c1cccc(-c2ccc(CNC(=O)OC(C)(C)C)cc2)c1
Temperature: 82.5 °C
Yield: 82.1 %

Procedure:
A mixture comprised of N-cyanomethyl-4-methyl-2-[3-(4,4,5,5-tetramethyl[1,3,2]dioxaborolan-2-yl)phenyl]pentanamide (250 mg, 0.702 mmol), tert-butyl 4-bromobenzylcarbamate (303 mg, 1.053 mmol), sodium bicarbonate (1.1 mL, 2.11 mmol), palladium(II) chloride (18 mg, 0.0211 mmol) and DMF (15.8 mL) was stirred under nitrogen at between 80-85° C. until the reaction was complete. The mixture was diluted with water and the product was extracted with diethyl ether (3×). The combined extracts were washed with brine, dried (MgSO4) and then concentrated in vacuo. The product was purified from the residue by flash chromatography over silica gel (ethyl acetate/hexanes) to provide tert-butyl 3′-(1-cyanomethylcarbamoyl-3-methylbutyl)biphenyl-4-ylmethylcarbamate (252 mg, 0.576 mmol). 1H NMR (400 MHz, d6-DMSO): δ 8.79 (br s, 1H), 7.58-7.26 (m, 9H), 4.16 (d, J=5.2 Hz, 2H), 4.11 (br s, 2H), 3.67 (dd, J=7.2, 7.2 Hz, 1H), 1.95-1.91 (m, 1H), 1.57-1.53 (m, 1H), 1.40-1.33 (m, 10H), 0.88 (dd, J=6.7, 6.7 Hz, 6H); MS (−ESI) m/z 434.6 (M−H)−.
Reaction SMILES: [Cl-].[Al+3].[Cl-].[Cl-].[C:5]([N:8]1[C:17]2[C:12](=[CH:13][C:14]([Br:18])=[CH:15][CH:16]=2)[C@H:11]([NH:19]C(=O)OC(C)C)[CH2:10][C@@H:9]1[CH3:26])(=[O:7])[CH3:6].C(N(CC)CC)C.CO>C(Cl)Cl.C(OCC)(=O)C>[NH2:19][C@H:11]1[C:12]2[C:17](=[CH:16][CH:15]=[C:14]([Br:18])[CH:13]=2)[N:8]([C:5](=[O:7])[CH3:6])[C@@H:9]([CH3:26])[CH2:10]1
Reactant: CC(=O)N1c2ccc(Br)cc2[C@H](NC(=O)OC(C)C)C[C@@H]1C
Agent: [Al+3]
Agent: [Cl-]
Solvent: ClCCl
Solvent: CO
Solvent: CCN(CC)CC
Product: CC(=O)N1c2ccc(Br)cc2[C@H](N)C[C@@H]1C
Reaction time: 0.5 h
Yield: 85.4 %

Procedure:
A suspension of aluminium chloride (41.2 g, 309 mmol) in DCM (480 mL) at 0° C. under nitrogen was treated with a solution of isopropyl ((2S,4R)-1-acetyl-6-bromo-2-methyl-1,2,3,4-tetrahydroquinolin-4-yl)carbamate (30 g, 81 mmol) in DCM (80 ml) via cannula and the resulting mixture was stirred at this temperature for 30 minutes. The reaction mixture was then slowly treated with a mixture of triethylamine (136 mL, 975 mmol) and methanol (48 mL) via cannula. The resulting cake formed was stirred in ethyl acetate (800 mL), isolated by filtration and subsequently partitioned between DCM (800 mL) and saturated aqueous NaHCO3 solution (800 mL). Sodium potassium tartrate (300 g) was added and the resulting mixture was stirred vigorously for 2 h. The layers were separated and the DCM layer was filtered through a sinter funnel. The filtrate was dried (MgSO4) and concentrated in vacuo to give a first crop of 1-((2S,4R)-4-amino-6-bromo-2-methyl-3,4-dihydroquinolin-1(2H)-yl)ethanone (19.6 g, 69.2 mmol, 85% yield) as a yellow foam. The aqueous phase was treated further with DCM (800 mL) and the biphasic mixture stirred overnight. The layers were then separated and the organic layer was dried over (MgSO4) and concentrated in vacuo to give a second crop of 1-((2S,4R)-4-amino-6-bromo-2-methyl-3,4-dihydroquinolin-1(2H)-yl)ethanone (3.4 g, 12.01 mmol, 14.78% yield). LCMS (HpH, 2 min), Rt=0.77 min, MH+=283 (1 Br).
Reaction SMILES: [CH:1]([CH:4]([CH:10]=[CH:11][C:12]1[CH:17]=[CH:16][C:15]([O:18][CH3:19])=[CH:14][CH:13]=1)[C:5]([O:7]CC)=[O:6])([CH3:3])[CH3:2].[OH-].[K+]>CO.O>[CH:1]([CH:4]([CH:10]=[CH:11][C:12]1[CH:13]=[CH:14][C:15]([O:18][CH3:19])=[CH:16][CH:17]=1)[C:5]([OH:7])=[O:6])([CH3:3])[CH3:2]
Reactant: CCOC(=O)C(C=Cc1ccc(OC)cc1)C(C)C
Agent: [K+]
Agent: [OH-]
Solvent: CO
Solvent: O
Product: COc1ccc(C=CC(C(=O)O)C(C)C)cc1

Procedure:
The thus-prepared ester is hydrolyzed by treatment with potassium hydroxide in methanol/water to give 2-isopropyl-4-(4-methoxyphenyl)-3-butenoic acid, which is reacted with m-phenoxybenzyl bromide using the procedure of Example 1 to give m-phenoxybenzyl 2-isopropyl-4-(4-methoxyphenyl)-3-butenoate, MS m/e 416 (M+).
Reaction SMILES: [C:1]([C:5]1[NH:6][S:7](=[O:20])(=[O:19])[C:8]2[C:14]3[CH:15]=[CH:16][CH:17]=[CH:18][C:13]=3[S:12][C:9]=2[C:10]=1[OH:11])([O:3][CH3:4])=[O:2].[H-].[Na+].[CH3:23][O:24][C:25]1[CH:32]=[CH:31][C:28]([CH2:29]Br)=[CH:27][CH:26]=1.Cl>CN(C)C=O>[C:1]([C:5]1[N:6]([CH2:29][C:28]2[CH:31]=[CH:32][C:25]([O:24][CH3:23])=[CH:26][CH:27]=2)[S:7](=[O:20])(=[O:19])[C:8]2[C:14]3[CH:15]=[CH:16][CH:17]=[CH:18][C:13]=3[S:12][C:9]=2[C:10]=1[OH:11])([O:3][CH3:4])=[O:2]
Reactant: COc1ccc(CBr)cc1
Reactant: COC(=O)C1=C(O)c2sc3ccccc3c2S(=O)(=O)N1
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: COC(=O)C1=C(O)c2sc3ccccc3c2S(=O)(=O)N1Cc1ccc(OC)cc1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
935 mg. of 3-carbomethoxy-4-hydroxy-2H-[1]benzothieno[2,3-e]-1,2-thiazine 1,1-dioxide are dissolved in 10 ml. of absolute dimethylformamide and 290 mg. of a 55% sodium hydride dispersion in paraffin are added. The suspension is stirred at room temperature for 1 hour. Then, a solution of 730 mg. of 4-methoxybenzyl bromide in 5 ml. of absolute dimethylformamide is added dropwise within 30 minutes, the mixture is stirred at room temperature for a further 3 hours and then poured into 100 ml. of ice-cold water while stirring. The mixture is then acidified to pH 2 with concentrated hydrochloric acid. The precipitate which results is filtered off under suction and dissolved in methylene chloride. The solution is dried over sodium sulfate, filtered and evaporated. The residue crystallizes from methylene chloride after the addition of petroleum ether. The 3-carbomethoxy-4-hydroxy-2-(4-methoxybenzyl)-2H-[1]benzothieno[2,3-e]-1,2-thiazine 1,1-dioxide obtained melts at 163°-164° C.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:17]3[C:12](=[N:13][C:14]([C:18]([F:21])([F:20])[F:19])=[CH:15][CH:16]=3)[N:11]=[CH:10][CH:9]=2)=[CH:4][C:3]=1[OH:22].Cl[CH2:24][C:25]([N:27]([CH3:29])[CH3:28])=[O:26]>>[F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:17]3[C:12](=[N:13][C:14]([C:18]([F:19])([F:20])[F:21])=[CH:15][CH:16]=3)[N:11]=[CH:10][CH:9]=2)=[CH:4][C:3]=1[O:22][CH2:24][C:25]([N:27]([CH3:29])[CH3:28])=[O:26]
Reactant: Oc1cc(-c2ccnc3nc(C(F)(F)F)ccc23)ccc1F
Reactant: CN(C)C(=O)CCl
Product: CN(C)C(=O)COc1cc(-c2ccnc3nc(C(F)(F)F)ccc23)ccc1F
Yield: 58.5 %

Procedure:
2-Fluoro-5-(7-trifluoromethyl[1,8]naphthyridin-4-yl)phenol (50.0 mg, 0.16 mmol) was alkylated with 2-chloro-N,N-dimethylacetamide (20.1 μL, 23.7 mg, 0.20 mmol) as described in Example 47, affording 2-[2-fluoro-5-(7-trifluoromethyl[1,8]naphthyridin-4-yl)phenoxy]-N,N-dimethylacetamide (36.8 mg, 58%). δH (360 MHz, CDCl3) 2.99 (3H, s), 3.10 (3H, s), 4.85 (2H, s), 7.05-7.09 (1H, m), 7.18 (1H, dd, J 2.1 and 8.1), 7.31 (1H, dd, J 8.1 and 10.9), 7.54 (1H, d, J 4.2), 7.82 (1H, d, J 8.4), 8.53 (1H, d, J 8.4), 9.25 (1H, d, J 4.6). m/z (ES+) 394 [MH]+.
Reaction SMILES: [C:1]1([C:7]2[CH:8]=[N:9][N:10]([CH2:12][CH2:13][C@@:14]([CH3:22])([S:18]([CH3:21])(=[O:20])=[O:19])[C:15]([OH:17])=O)[CH:11]=2)[CH2:6][CH2:5][CH2:4][CH2:3][CH:2]=1.CCN(C(C)C)C(C)C.O.ON1C2C=CC=CC=2N=N1.[O:43]1[CH2:48][CH2:47][CH2:46][CH2:45][CH:44]1[O:49][NH2:50].Cl.CN(CCCN=C=NCC)C>ClCCl>[C:1]1([C:7]2[CH:8]=[N:9][N:10]([CH2:12][CH2:13][C@@:14]([CH3:22])([S:18]([CH3:21])(=[O:20])=[O:19])[C:15]([NH:50][O:49][CH:44]3[CH2:45][CH2:46][CH2:47][CH2:48][O:43]3)=[O:17])[CH:11]=2)[CH2:6][CH2:5][CH2:4][CH2:3][CH:2]=1
Reactant: NOC1CCCCO1
Reactant: C[C@@](CCn1cc(C2=CCCCC2)cn1)(C(=O)O)S(C)(=O)=O
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: O
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: C[C@@](CCn1cc(C2=CCCCC2)cn1)(C(=O)NOC1CCCCO1)S(C)(=O)=O
Reaction time: 0.5 h
Yield: 52 %

Procedure:
To a solution of (2R)-4-[4-(cyclohex-1-en-1-yl)-1H-pyrazol-1-yl]-2-methyl-2-(methylsulfonyl)butanoic acid (339 mg, 1.04 mmol, 1.0 eq) in dichloromethane (10 mL) under nitrogen, was added DIPEA (285 mg, 2.20 mmol, 0.384 mL, 2.12 eq) followed by the addition of 1-hydroxybenzotriazole monohydrate (307 mg, 2.00 mmol, 1.93 eq). The solution was allowed to stir for 30 minutes before being treated with O-tetrahydro-2H-pyran-2-yl-hydroxylamine (163 mg, 1.39 mmol, 1.34 eq) and then dimethylaminopropyl-3-ethylcarbodiimide hydrochloride (285 mg 1.49 mmol, 1.43 eq). The mixture was then allowed to stir for 3 hours at RT. The mixture was then absorbed onto silica gel and purified by flash chromatography eluting with 5-100% EtOAc/Hpt to give (2R)-4-[4-(cyclohex-1-en-1-yl)-1H-pyrazol-1-yl]-2-methyl-2-(methylsulfonyl)-N-(tetrahydro-2H-pyran-2-yloxy)butanamide (230 mg, 52% yield). LC-MS M+H+426.1.
Reaction SMILES: [I:1][C:2]1[C:3]([S:11][C:12]2[NH:13][C:14]3[C:19]([N:20]=2)=[C:18]([NH2:21])[N:17]=[CH:16][N:15]=3)=[CH:4][C:5]2[O:9][CH2:8][O:7][C:6]=2[CH:10]=1.C([O-])([O-])=O.[Cs+].[Cs+].Br[CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][C:34]([NH2:36])=[O:35]>CN(C=O)C>[NH2:21][C:18]1[N:17]=[CH:16][N:15]=[C:14]2[C:19]=1[N:20]=[C:12]([S:11][C:3]1[C:2]([I:1])=[CH:10][C:6]3[O:7][CH2:8][O:9][C:5]=3[CH:4]=1)[N:13]2[CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][C:34]([NH2:36])=[O:35]
Reactant: Nc1ncnc2[nH]c(Sc3cc4c(cc3I)OCO4)nc12
Reactant: NC(=O)CCCCCBr
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Product: NC(=O)CCCCCn1c(Sc2cc3c(cc2I)OCO3)nc2c(N)ncnc21
Temperature: 25 °C
Reaction time: 2 h

Procedure:
50 mg (0.121 mmol) of 8-(6-iodobenzo[d][1,3]dioxol-5-ylthio)-9H-purin-6-amine (S13-1) was dissolved in DMF (2 mL). 47 mg (0.145 mmol) of Cs2CO3 and 117.4 mg (0.605 mmol) of 6-bromohexanamide (S13-2) were added and the mixture was stirred at rt for 2 h. Solvent was removed under reduced pressure and the resulting residue was purified by preparatory TLC (CH2Cl2:MeOH—NH3 (7N), 10:1) to give 12.7 mg (20%) of DZ5-49-N9. 1H NMR (500 MHz, CDCl3/MeOH-d4): δ 8.13 (s, 1H), 7.31 (s, 1H), 6.97 (s, 1H), 5.98 (s, 2H), 4.13 (t, J=7.6 Hz, 2H), 2.14 (t, J=7.6 Hz, 2H), 1.71-1.80 (m, 2H), 1.55-1.65 (m, 2H), 1.28-1.39 (m, 2H); HRMS (ESI) m/z [M+H]+ calcd. for C18H20IN6O3S, 527.0362. found 527.0364.
Reaction SMILES: Br[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][Br:7].[C:8]1([CH2:14][CH2:15][OH:16])[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1>>[Br:7][CH2:6][CH2:5][CH2:4][CH2:3][CH2:2][O:16][CH2:15][CH2:14][C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1
Reactant: BrCCCCCBr
Reactant: OCCc1ccccc1
Product: BrCCCCCOCCc1ccccc1

Procedure:
(3.8 g), T.l.c. [K] Rf 0.46 from 1,5-dibromopentane (11.3 g) and benzeneethanol (2 g).
Reaction SMILES: Cl[P:2]([CH2:7][CH2:8][CH2:9][CH2:10][C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1)(=[O:6])[O:3][CH2:4][CH3:5].[NH2:17][CH:18]1[C:24](=[O:25])[N:23]([CH2:26][C:27]([O:29][CH2:30][CH3:31])=[O:28])[C:22]2[CH:32]=[CH:33][CH:34]=[CH:35][C:21]=2[S:20][CH2:19]1.C(N(CC)CC)C>O1CCCC1>[CH2:4]([O:3][P:2]([NH:17][CH:18]1[C:24](=[O:25])[N:23]([CH2:26][C:27]([O:29][CH2:30][CH3:31])=[O:28])[CH:22]2[CH2:32][CH:33]=[CH:34][CH:35]=[C:21]2[S:20][CH2:19]1)([CH2:7][CH2:8][CH2:9][CH2:10][C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1)=[O:6])[CH3:5]
Reactant: CCOP(=O)(Cl)CCCCc1ccccc1
Reactant: CCOC(=O)CN1C(=O)C(N)CSc2ccccc21
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: CCOC(=O)CN1C(=O)C(NP(=O)(CCCCc2ccccc2)OCC)CSC2=CC=CCC21
Reaction time: 0.33 h

Procedure:
A mixture of crude chloro (4-phenylbutyl)phosphinic acid, ethyl ester (2.44 mmole), dry tetrahydrofuran (10 ml.), and (±)-3-amino-3,4-dihydro-4-oxo-1,5-benzothiazepine-5(2H)-acetic acid, ethyl ester (0.65 g., 2.05 mmole) at 0° (ice bath) in an argon atmosphere is treated dropwise with triethylamine (0.86 ml., 3.0 eq.) in tetrahydrofuran (5 ml.) over 1 minute. After standing at 0° for 20 minutes the ice bath is removed and the reaction mixture is stirred for 16 hours. The reaction mixture is diluted with ethyl acetate and washed successively with saturated sodium bicarbonate, 5% potassium bisulfate and brine, dried (MgSO4), and evaporated. The residue (1.2 g.) is chromatographed on silica (60 g.) eluting with acetone/hexane (1:1) to give 0.8 g. of (±)-dihydro-3-[[ethoxy(4-phenylbutyl)phosphinyl]amino]-4-oxo-1,5-benzothiazepine-5(2H)-acetic acid, ethyl ester as an oil after evaporation. TLC (acetone/hexane; 2:1) two spots at Rf =0.59,0.65(isomers at phosphorus).
Reaction SMILES: [CH2:1]([NH:5][C:6]1[CH:11]=[C:10]2[O:12][CH2:13][O:14][C:9]2=[CH:8][C:7]=1[N+:15]([O-:17])=[O:16])[CH2:2][CH2:3][CH3:4].C[O-].[Na+]>CO>[CH3:13][O:12][C:10]1[CH:11]=[C:6]([NH:5][CH2:1][CH2:2][CH2:3][CH3:4])[C:7]([N+:15]([O-:17])=[O:16])=[CH:8][C:9]=1[OH:14]
Reactant: CCCCNc1cc2c(cc1[N+](=O)[O-])OCO2
Agent: C[O-]
Agent: [Na+]
Solvent: CO
Product: CCCCNc1cc(OC)c(O)cc1[N+](=O)[O-]

Procedure:
A solution of 0.03 mol (6.9 g) of 2-n-butylamino-4,5-methylenedioxy-1-nitrobenzene, prepared according to Example 4, in 45 ml of a 30% strength solution of sodium methylate in methanol is brought for 15 minutes to the refluxing temperature of the methanol.
Reaction SMILES: [C:1]1(=[CH:9][C:10](OCC)=[O:11])[CH2:8][CH2:7][CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1>C(O)C.[C].[Pd]>[CH:1]1([CH2:9][CH2:10][OH:11])[CH2:8][CH2:7][CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: CCOC(=O)C=C1CCCCCCC1
Agent: [Pd]
Solvent: CCO
Product: OCCC1CCCCCCC1
Temperature: 25 °C
Reaction time: 64 h
Yield: 88.1 %

Procedure:
To a solution of ethyl cyclooctylideneacetate (969 mg) in ethanol (40 mL) was added 10% palladium-carbon (60 mg). The solution was stirred under hydrogen atmosphere at room temperature for 64 hours. The catalyst was filtered off and the filtrate was concentrated under reduced pressure. To a solution of the resulting residue (920 mg) in diethyl ether (40 mL) was added lithium aluminum hydride (132 mg) under ice cooling. The solution was stirred under ice cooling for 30 minutes and then water (0.13 mL), and a 15% aqueous sodium hydroxide solution (0.13 mL) were successively added thereto. The solution was stirred at room temperature for 15 minutes, to which water (0.39 mL) was then added. The solution was stirred for additional 30 minutes, dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The resulting residue was purified by chromatography (silica gel, hexane:ethyl acetate=2:1) to give the title compound (680 mg).