Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: OC(C(F)(F)F)=O.[N:8]1([C:15]([C:17]2[CH:18]=[C:19]([CH:32]=[CH:33][C:34]=2[F:35])[CH2:20][C:21]2[C:30]3[C:25](=[CH:26][CH:27]=[CH:28][CH:29]=3)[C:24](=[O:31])[NH:23][N:22]=2)=[O:16])[CH2:14][CH2:13][CH2:12][NH:11][CH2:10][CH2:9]1.[O:36]=[C:37]([C:41]1[CH:46]=[CH:45][CH:44]=[CH:43][CH:42]=1)[C:38](O)=[O:39].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:35][C:34]1[CH:33]=[CH:32][C:19]([CH2:20][C:21]2[C:30]3[C:25](=[CH:26][CH:27]=[CH:28][CH:29]=3)[C:24](=[O:31])[NH:23][N:22]=2)=[CH:18][C:17]=1[C:15]([N:8]1[CH2:14][CH2:13][CH2:12][N:11]([C:38](=[O:39])[C:37]([C:41]2[CH:46]=[CH:45][CH:44]=[CH:43][CH:42]=2)=[O:36])[CH2:10][CH2:9]1)=[O:16]
Reactant: O=C(O)C(=O)c1ccccc1
Reactant: O=C(c1cc(Cc2n[nH]c(=O)c3ccccc23)ccc1F)N1CCCNCC1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Solvent: O=C(O)C(F)(F)F
Product: O=C(C(=O)N1CCCN(C(=O)c2cc(Cc3n[nH]c(=O)c4ccccc34)ccc2F)CC1)c1ccccc1
Temperature: 25 °C
Reaction time: 85 h
Yield: 42 %

Procedure:
4-(3-(1,4-diazepane-1-carbonyl)-4-fluorobenzyl)phthalazin-1(2H)-one TFA salt (320 mg, 0.65 mmol), 2-oxo-2-phenylacetic acid (1.4 g, 9.32 mmol), DIPEA (3 ml, 17.4 mmol), and HATU (1.8 g, 4.72 mmol) were mixed in DMF (50 ml). After the resulting reaction mixture was stirred at room temperature for 85 h, the reaction mixture was partition between DCM and water (100 ml each). The aqueous phase was extracted with DCM (100 ml), and the combined organic phase was washed with water, sat. aqueous sodium bicarbonate, and brine, dried over sodium sulphate, filtered, and concentrated to yield the crude product. Then the crude product was purified by preparative TLC (Petroleum ether:Ethyl Acetate=1:1 to 1:2) to afford the desired product (140 mg, 41%) as a light yellow solid.
Reaction SMILES: Cl.[NH2:2][CH2:3][CH2:4][CH2:5][C:6]([O:8][CH2:9][CH3:10])=[O:7].CO[CH:13]1[CH2:17][CH2:16][CH:15](OC)O1>C(O)(=O)C>[N:2]1([CH2:3][CH2:4][CH2:5][C:6]([O:8][CH2:9][CH3:10])=[O:7])[CH:13]=[CH:17][CH:16]=[CH:15]1
Reactant: COC1CCC(OC)O1
Reactant: CCOC(=O)CCCN
Agent: Cl
Solvent: CC(=O)O
Product: CCOC(=O)CCCn1cccc1

Procedure:
Ethyl 4-aminobutanoate hydrochloride (0.2 mole) is added to 300 ml glacial acetic acid containing (0.3 mole) sodium acetate. The mixture is heated until the solution becomes clear and then 2,5-dimethoxy tetrahydrofuran (about 0.2 mole) is added as quickly as possible. The solution is refluxed for an additional two minutes and the acetic acid is flash evaporated. The residue is distilled to give ethyl 4-(1-pyrryl)butanoate. The acid is obtained by hydrolyzing the ester in alcoholic sodium hydroxide followed by neutralization with hydrochloric acid.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([C@@H:9]([NH2:11])[CH3:10])[CH:6]=[CH:7][CH:8]=1.[Cl:12][C:13]1[N:18]=[C:17](Cl)[C:16]([Cl:20])=[CH:15][N:14]=1.C(=O)([O-])[O-].[K+].[K+]>CN(C)C=O>[Cl:12][C:13]1[N:18]=[C:17]([NH:11][C@H:9]([C:5]2[CH:6]=[CH:7][CH:8]=[C:3]([O:2][CH3:1])[CH:4]=2)[CH3:10])[C:16]([Cl:20])=[CH:15][N:14]=1
Reactant: Clc1ncc(Cl)c(Cl)n1
Reactant: COc1cccc([C@H](C)N)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: COc1cccc([C@H](C)Nc2nc(Cl)ncc2Cl)c1
Yield: 91.6 %

Procedure:
To a solution of (1S)-1-(3-methoxyphenyl)ethanamine (1.50 g, 9.92 mol) (S-isomer, >99% ee purity) and 2,4,5-trichloropyrimidine (1.19 mL, 10.4 mmol) in N,N-dimethylformamide (30 mL) was added potassium carbonate (4.1 g, 30 mmol). The resultant mixture was stirred overnight at room temperature. The reaction was quenched with water. Then EtOAc was added and the layers were separated. The aqueous layer was extracted with EtOAc twice. The combined organic layers were washed with water and then dried (Na2SO4), filtered, and concentrated to give the desired product as a light yellow thick oil (2.84 g, 96%). LCMS for C13H14Cl2N3O (M+H)+: m/z=298.0, 300.0, 302.0 (9:6:1).
Reaction SMILES: [C:1]([C:3]1[CH:8]=[CH:7][C:6]([S:9]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)(=[O:11])=[O:10])=[CH:5][CH:4]=1)#[CH:2].I[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1.C(N(CC)CC)C.O>C1(C)C=CC=CC=1.[Cu]I.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>[C:19]1([C:2]#[C:1][C:3]2[CH:4]=[CH:5][C:6]([S:9]([C:12]3[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=3)(=[O:10])=[O:11])=[CH:7][CH:8]=2)[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1
Reactant: C#Cc1ccc(S(=O)(=O)c2ccccc2)cc1
Reactant: Ic1ccccc1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Cu]I
Solvent: Cc1ccccc1
Solvent: O
Solvent: CCN(CC)CC
Product: O=S(=O)(c1ccccc1)c1ccc(C#Cc2ccccc2)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 27.5 %

Procedure:
A mixture of 1-ethynyl-4-(phenylsulfonyl)benzene (100 mg, 0.4 mmol), iodobenzene (0.05 mL, 0.44 mmol) and triethylamine (1 mL) in toluene (1 mL) was degassed. Copper(I) iodide (3 mg, 0.004 mmol) and dichlorobis(triphenylphosphine)-palladium(II) (3 mg, 0.004 mmol) were added and the reaction stirred at room temperature overnight. The mixture was poured into water and extracted with ethyl acetate. The organic layer was dried and concentrated in vacuo. The residue was purified by preparative HPLC to give the title compound (35 mg, 28%). δH (500 MHz, d6 DMSO): 7.97 (4H, dd, J=2.6, 8.4 Hz), 7.77–7.69 (3H, m), 7.64–7.56 (4H, m), 7.43–7.41 (3H, m).
Reaction SMILES: Cl.[NH2:2][CH2:3][C:4]1[C:9]([CH2:10][CH3:11])=[N:8][C:7]2[N:12]([CH2:15][CH3:16])[N:13]=[CH:14][C:6]=2[C:5]=1[NH:17][CH:18]1[CH2:23][CH2:22][O:21][CH2:20][CH2:19]1.[C:24]([O:31][CH3:32])(=[O:30])[CH2:25][CH2:26][C:27]([O-])=[O:28].CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(CC)CC>C(Cl)Cl>[CH2:15]([N:12]1[C:7]2=[N:8][C:9]([CH2:10][CH3:11])=[C:4]([CH2:3][NH:2][C:27](=[O:28])[CH2:26][CH2:25][C:24]([O:31][CH3:32])=[O:30])[C:5]([NH:17][CH:18]3[CH2:19][CH2:20][O:21][CH2:22][CH2:23]3)=[C:6]2[CH:14]=[N:13]1)[CH3:16]
Reactant: CCc1nc2c(cnn2CC)c(NC2CCOCC2)c1CN
Reactant: COC(=O)CCC(=O)[O-]
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CCc1nc2c(cnn2CC)c(NC2CCOCC2)c1CNC(=O)CCC(=O)OC
Temperature: 25 °C
Yield: 105.6 %

Procedure:
A mixture of 5-(aminomethyl)-1,6-diethyl-N-(tetrahydro-2H-pyran-4-yl)-1H-pyrazolo[3,4-b]pyridin-4-amine hydrochloride (400 mg, 1.18 mmol), mono-methyl succinate (156 mg, 1.18 mmol), HBTU (536 mg, 1.41 mmol) and Et3N (0.82 mL, 5.89 mmol) in DCM (8 mL) was stirred at room temperature over the weekend. It was quenched with saturated NaHCO3 and extracted with DCM twice. The combined organic layers were washed with water followed by a brine wash. The organic layer was dried over sodium sulfate, filtered, concentrated and purified with CombiFlash eluting with 70% ethyl acetate in hexane. The product fractions were combined and concentrated to give methyl 4-({[1,6-diethyl-4-(tetrahydro-2H-pyran-4-ylamino)-1H-pyrazolo[3,4-b]pyridin-5-yl]methyl}amino)-4-oxobutanoate as an oil (520 mg, 105%). LC-MS m/z 418 (M+H)+.
Reaction SMILES: [H-].[Na+].[C:3]([CH:5]([CH2:10][C:11]1[O:12][CH:13]=[CH:14][CH:15]=1)[C:6]([O:8][CH3:9])=[O:7])#[N:4].[NH2:16][C:17]1[NH:22][C:21](=[O:23])[C:20]([N+:24]([O-:26])=[O:25])=[C:19](Cl)[N:18]=1.Cl.[CH3:29]N(C=O)C>O>[NH2:16][C:17]1[NH:22][C:21](=[O:23])[C:20]([N+:24]([O-:26])=[O:25])=[C:19]([C:5]([C:3]#[N:4])([CH2:10][C:11]2[O:12][CH:13]=[CH:14][CH:15]=2)[C:6]([O:8][CH2:9][CH3:29])=[O:7])[N:18]=1
Reactant: COC(=O)C(C#N)Cc1ccco1
Reactant: CN(C)C=O
Reactant: Nc1nc(Cl)c([N+](=O)[O-])c(=O)[nH]1
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: O
Product: CCOC(=O)C(C#N)(Cc1ccco1)c1nc(N)[nH]c(=O)c1[N+](=O)[O-]
Temperature: 65 °C

Procedure:
Sodium hydride (8.4 g, 60% suspension in oil, washed with hexane) is suspended in dry DMF (100 mL) under an atmosphere of dry N2 and a solution of methyl 2-cyano-3-(2-furanyl)propionate (U.S. Pat. No. 4,279,903) (37.6 g) in DMF (100 mL) is added dropwise. When the addition is complete, a clear red solution is formed. 2-Amino-6-chloro-5-nitro-4(3H)-pyrimidinone (recrystallized from methanol) (13.34 g) is added as a solid. The reaction mixture is heated at 100° C. for 1 h and at 65° C. overnight. The reaction mixture is cooled in an ice bath, acidified with 10% aq HCl and diluted with enough water to precipitate out the product 2-Amino-α-cyano-α-(2-furanylmethyl)-1,6-dihydro-5-nitro-6-oxo-4-pyrimidineacetic acid, ethyl ester. The product is collected by filtration and rinsed with water and ether (18.5 g). ##STR21##
Reaction SMILES: [NH2:1][CH2:2][C:3]1([OH:8])[CH2:7][CH2:6][CH2:5][CH2:4]1.[CH3:9][C:10]([CH3:15])([CH3:14])[CH2:11][CH:12]=O.[S-:16][C:17]#[N:18].[K+].II>C(#N)C>[C:10]([C:11]1[S:16][C:17](=[NH:18])[N:1]([CH2:2][C:3]2([OH:8])[CH2:7][CH2:6][CH2:5][CH2:4]2)[CH:12]=1)([CH3:15])([CH3:14])[CH3:9]
Reactant: CC(C)(C)CC=O
Reactant: N#C[S-]
Reactant: NCC1(O)CCCC1
Agent: II
Agent: [K+]
Solvent: CC#N
Product: CC(C)(C)c1cn(CC2(O)CCCC2)c(=N)s1
Yield: 73.3 %

Procedure:
A mixture of 1-(aminomethyl)cyclopentanol (prepared from cyclopentanone as described in WO 2006/100208) (3.5 g, 30 mmol), 3,3-dimethylbutanal (3.4 g, 33 mmol), 4 Å molecular sieves (4 g, 8-12 mesh beads), potassium thiocyanate (3.9 g, 40 mmol) and iodine (7.7 g, 30 mmol) in acetonitrile (50 mL) were processed as described in Example 18A to provide the title compound (5.6 g, 22 mmol, 72% yield). MS (DCI/NH3) m/z 255 (M+H)+.
Reaction SMILES: [CH2:1]([O:4][C:5]([N:7]1[CH2:11][C@H:10]([O:12][S:13]([CH3:16])(=[O:15])=[O:14])[CH2:9][C@H:8]1[CH2:17][CH2:18]OS(C)(=O)=O)=[O:6])[CH:2]=[CH2:3].[Si:24]([O:31][CH2:32][C:33]1[N:34]=[CH:35][NH:36][CH:37]=1)([C:27]([CH3:30])([CH3:29])[CH3:28])([CH3:26])[CH3:25].CC(C)([O-])C.[K+]>>[CH2:1]([O:4][C:5]([N:7]1[CH2:11][C@H:10]([O:12][S:13]([CH3:16])(=[O:14])=[O:15])[CH2:9][C@H:8]1[CH2:17][CH2:18][N:36]1[CH:37]=[C:33]([CH2:32][O:31][Si:24]([C:27]([CH3:30])([CH3:29])[CH3:28])([CH3:25])[CH3:26])[N:34]=[CH:35]1)=[O:6])[CH:2]=[CH2:3]
Reactant: CC(C)(C)[Si](C)(C)OCc1c[nH]cn1
Reactant: C=CCOC(=O)N1C[C@H](OS(C)(=O)=O)C[C@H]1CCOS(C)(=O)=O
Agent: CC(C)(C)[O-]
Agent: [K+]
Product: C=CCOC(=O)N1C[C@H](OS(C)(=O)=O)C[C@H]1CCn1cnc(CO[Si](C)(C)C(C)(C)C)c1
Yield: 136.7 %

Procedure:
(2R,4R)-1-Allyloxycarbonyl-4-methanesulfonyloxy-2-(2-methanesulfonyloxyethyl)pyrrolidine (13.2 g) was reacted with 4-(t-butyldimethylsilyloxymethyl)imidazol (8.30 g) and potassium t-butoxide (4.39 g) in substantially the same manner as Preparation 10-3) to give (2R,4R)-1-allyloxycarbonyl-2-[2-{4-(t-butyldimethylsilyloxymethyl)-imidazol-1-yl}ethyl]-4-methanesulfonyloxypyrrolidine (23.7 g) as a brown paste.
Reaction SMILES: [Cl:1][C:2]1[C:7]2[O:8][C:9]3[CH2:14][CH2:13][N:12]([C:15]([O:17][C:18]([CH3:21])([CH3:20])[CH3:19])=[O:16])[CH2:11][C:10]=3[C:6]=2[CH:5]=[C:4]([S:22](Cl)(=[O:24])=[O:23])[CH:3]=1.[NH:26]1[C:34]2[C:29](=[CH:30][CH:31]=[CH:32][CH:33]=2)[CH:28]=[CH:27]1>>[N:26]1([S:22]([C:4]2[CH:3]=[C:2]([Cl:1])[C:7]3[O:8][C:9]4[CH2:14][CH2:13][N:12]([C:15]([O:17][C:18]([CH3:21])([CH3:20])[CH3:19])=[O:16])[CH2:11][C:10]=4[C:6]=3[CH:5]=2)(=[O:24])=[O:23])[C:34]2[C:29](=[CH:30][CH:31]=[CH:32][CH:33]=2)[CH:28]=[CH:27]1
Reactant: c1ccc2[nH]ccc2c1
Reactant: CC(C)(C)OC(=O)N1CCc2oc3c(Cl)cc(S(=O)(=O)Cl)cc3c2C1
Product: CC(C)(C)OC(=O)N1CCc2oc3c(Cl)cc(S(=O)(=O)n4ccc5ccccc54)cc3c2C1
Yield: 45 %

Procedure:
The product of step B and indole were reacted using the procedure of Example 41, step C to provide tert-butyl 8-(1H-indol-1-ylsulfonyl)-6-chloro-3,4-dihydrobenzofuro[3,2-c]pyridine-2(1H)-carboxylate (35 mg, 45%) as an off-white solid: 1H NMR (CDCl3, 300 MHz) δ 8.00 (d, J=8.1 Hz, 1H), 7.89 (s, 1H), 7.73 (d, J=1.5 Hz, 1H), 7.58 (d, J=3.6 Hz, 1H), 7.52 (d, J=7.8 Hz, 1H), 7.36-7.30 (m, 1H), 7.25-7.20 (m, 1H), 6.69-6.68 (m, 1H), 4.52 (s, 2H), 3.80 (t, J=5.4 Hz, 2H), 2.88 (t, J=5.1 Hz, 2H), 1.50 (s, 9H).
Reaction SMILES: Br[C:2]1[CH:3]=[CH:4][C:5]2[O:11][CH2:10][CH2:9][C:8]([C:12]([O:14][CH3:15])=[O:13])=[CH:7][C:6]=2[CH:16]=1.B([O-])([O-])O[C:19]1[S:20][C:21]([CH3:24])=[CH:22][CH:23]=1.C(=O)([O-])[O-].[K+].[K+]>C1(C)C=CC=CC=1.C(O)C.O>[CH3:24][C:21]1[S:20][C:19]([C:2]2[CH:3]=[CH:4][C:5]3[O:11][CH2:10][CH2:9][C:8]([C:12]([O:14][CH3:15])=[O:13])=[CH:7][C:6]=3[CH:16]=2)=[CH:23][CH:22]=1
Reactant: COC(=O)C1=Cc2cc(Br)ccc2OCC1
Reactant: Cc1ccc(OB([O-])[O-])s1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CCO
Solvent: Cc1ccccc1
Product: COC(=O)C1=Cc2cc(-c3ccc(C)s3)ccc2OCC1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 58.1 %

Procedure:
In toluene/ethanol/water (10/1/1) (24 ml) was dissolved methyl 7-bromo-2,3-dihydro-1-benzoxepine-4-carboxylate (560 mg), and to the mixture were added 5-methyl-2-thienyl borate (875 mg) and potassium carbonate (1.56 g). The mixture was stirred at room temperature for 30 minutes. To the mixture was added tetrakistriphenylphosphine palladium (260 mg), and the mixture was stirred at 100° C. for 24 hours and cooled to room temperature. The mixture was extracted with ethyl acetate, washed with saturated brine and dried with magnesium sulfate. Under reduced pressure, the solvent was removed, and the resulting residue was purified with silica gel column chromatography (hexane/acetone=12/1) to give methyl 7-(5-methyl-2-thienyl)-2,3-dihydro-1-benzoxepine-4-carboxylate (345 mg).
Reaction SMILES: C(N1C=C(C(=O)C=C(O)C(OC)=O)C(=O)N(CC2C=CC=CC=2)C1=O)C1C=CC=CC=1.[F:32][C:33]1[CH:64]=[CH:63][C:36]([CH2:37][N:38]2[CH:43]=[C:42]([C:44](=[O:52])[CH:45]=[C:46]([OH:51])[C:47]([O:49]C)=[O:48])[C:41](=[O:53])[N:40]([CH2:54][C:55]3[CH:60]=[CH:59][C:58]([F:61])=[CH:57][CH:56]=3)[C:39]2=[O:62])=[CH:35][CH:34]=1>>[F:32][C:33]1[CH:34]=[CH:35][C:36]([CH2:37][N:38]2[CH:43]=[C:42]([C:44](=[O:52])[CH:45]=[C:46]([OH:51])[C:47]([OH:49])=[O:48])[C:41](=[O:53])[N:40]([CH2:54][C:55]3[CH:56]=[CH:57][C:58]([F:61])=[CH:59][CH:60]=3)[C:39]2=[O:62])=[CH:63][CH:64]=1
Reactant: COC(=O)C(O)=CC(=O)c1cn(Cc2ccc(F)cc2)c(=O)n(Cc2ccc(F)cc2)c1=O
Agent: COC(=O)C(O)=CC(=O)c1cn(Cc2ccccc2)c(=O)n(Cc2ccccc2)c1=O
Product: O=C(O)C(O)=CC(=O)c1cn(Cc2ccc(F)cc2)c(=O)n(Cc2ccc(F)cc2)c1=O
Yield: 49.7 %

Procedure:
The title compound was synthesized using a similar procedure to that described in Example 2, except that methyl 4-(1,3-dibenzyl-1,2,3,4-tetrahydro-2,4-dioxopyrimidin-5-yl)-2-hydroxy-4-oxobut-2-enoate was replaced with methyl 4-[1,3-bis(4-fluorobenzyl)-1,2,3,4-tetrahydro-2,4-dioxopyrimidin-5-yl]-2-hydroxy-4-oxobut-2-enoate (3c). The title compound was crystallized from hexane and ethyl acetate (3:1). The yield was 49.7%. Mp. 186-188° C. 1HNMR (DMSO-d6): 15.07 (br, s, 1H), 14.02 (br, s, 1H), 8.90 (s, 1H), 7.56 (s, 1H), 7.34-7.46 (m, 4H), 7.10-7.21 (m, 4H), 5.13 (s, 2H), 4.98 (s, 2H). 13CNMR (DMSO-d6): 185.8, 169.2, 163.1, 161.8 (d, J=244.1 Hz), 161.3 (d, J=243.2 Hz), 159.7, 150.8, 150.1, 132.6 (d, J=2.9 Hz), 131.8 (d, J=3.4 Hz), 130.2 (d, J=8.2 Hz), 129.9 (d, J=8.2 Hz), 115.4 (d, J=21.6 Hz), 115.0 (d, J=21.0 Hz), 107.7, 100.7, 52.1, 43.5. FAB-HRMS: [M+H]+ Calcd. for C22H17F2N2O6 443.1055. Found 443.1044.
Reaction SMILES: [O:1]=[C:2]1[C:23]2[C:9]3[CH2:10][CH2:11][C:12]4[CH:18]=[CH:17][C:16]([C:19]([O:21]C)=[O:20])=[CH:15][C:13]=4[S:14][C:8]=3[CH:7]=[CH:6][C:5]=2[CH2:4][CH2:3]1.[O:24]=C1C2C3SC4=CCCC=C4C=C(C(OC)=O)C=3C=CC=2CC1>>[O:24]=[S:14]1[C:8]2[CH:7]=[CH:6][C:5]3[CH2:4][CH2:3][C:2](=[O:1])[C:23]=3[C:9]=2[CH2:10][CH2:11][C:12]2[CH:18]=[CH:17][C:16]([C:19]([OH:21])=[O:20])=[CH:15][C:13]1=2
Reactant: COC(=O)C1=CC2=CCCC=C2Sc2c1ccc1c2C(=O)CC1
Reactant: COC(=O)c1ccc2c(c1)Sc1ccc3c(c1CC2)C(=O)CC3
Product: O=C(O)c1ccc2c(c1)S(=O)c1ccc3c(c1CC2)C(=O)CC3

Procedure:
Substituting an equivalent amount of methyl 1-oxo-2,3,11,12-tetrahydro-1H-benzo[b]indeno[4,5-f]-thiepin-8-carboxylate in Example 38, Step A, in place of methyl 1-oxo-2,3,9,10-tetrahydro-1H-benzo[b]-indeno[5,4-f]thiepin-6-carboxylate and taking the product through Step B of this example provided the title compound.
Reaction SMILES: C([O:8][C:9]1[CH:17]=[C:16]([CH3:18])[CH:15]=[C:14]2[C:10]=1[CH:11]=[C:12]([C:19]([N:21]([CH3:23])[CH3:22])=[O:20])[NH:13]2)C1C=CC=CC=1>CO.COCCOC.[Pd]>[OH:8][C:9]1[CH:17]=[C:16]([CH3:18])[CH:15]=[C:14]2[C:10]=1[CH:11]=[C:12]([C:19]([N:21]([CH3:22])[CH3:23])=[O:20])[NH:13]2
Reactant: Cc1cc(OCc2ccccc2)c2cc(C(=O)N(C)C)[nH]c2c1
Agent: [Pd]
Solvent: COCCOC
Solvent: CO
Product: Cc1cc(O)c2cc(C(=O)N(C)C)[nH]c2c1
Yield: 98 %

Procedure:
10.7 g of the thus prepared 4-benzyloxy-2-dimethylaminocarbonyl-6-methyl indole are suspended in a mixture of 100 ml methanol and 100 ml ethylene glycol dimethyl ether and hydrogenated after the addition of 1.0 g 10% Pd/C. The catalyst is aspirated and the filtrate is evaporated. There is obtained 7.6 g (~98% of theory) 4-hydroxy-2-dimethylaminocarbonyl-6-methylindole as a brownish solid body, which is further processed without purification.
Reaction SMILES: [C:1](Cl)(=O)[C:2]([Cl:4])=[O:3].[CH2:7]([C:11]1[O:12][C:13]2[CH:22]=[CH:21][CH:20]=[CH:19][C:14]=2C=1C(O)=O)[CH2:8][CH2:9][CH3:10].CN(C=O)C>C(Cl)Cl.C1C=CC=CC=1>[CH2:7]([C:11]1[O:12][C:13]2[CH:22]=[CH:21][CH:20]=[CH:19][C:14]=2[C:1]=1[C:2]([Cl:4])=[O:3])[CH2:8][CH2:9][CH3:10]
Reactant: CCCCc1oc2ccccc2c1C(=O)O
Reactant: O=C(Cl)C(=O)Cl
Solvent: CN(C)C=O
Solvent: ClCCl
Solvent: c1ccccc1
Product: CCCCc1oc2ccccc2c1C(=O)Cl
Temperature: 25 °C
Reaction time: 1.5 h

Procedure:
Oxalyl Chloride (460 μL, 5.27 mmol) was added under nitrogen at room temperature to a solution of 2-butyl-benzofuran-3-carboxylic acid (230 mg, 1.05 mmol), prepared in the previous step, in 10 mL of methylene chloride. After the addition a catalytic amount of DMF was added and the reaction stirred at room temperature for 1.5 h. The solvent was removed under reduced pressure to give a brown oil. The oil was dissolved in benzene and the solvent removed under reduced pressure to give 2-butyl-benzofuran-3-carbonyl chloride as a brown oil. The material was immediately used in the following reaction with out additional purification.
Reaction SMILES: [F:1][C:2]1[CH:11]=[CH:10][C:9]([NH2:12])=[C:8]2[C:3]=1[CH:4]=[CH:5][CH:6]=[N:7]2.[C:13]1([S:19](Cl)(=[O:21])=[O:20])[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1>CN(C1C=CN=CC=1)C.C(Cl)Cl>[F:1][C:2]1[CH:11]=[CH:10][C:9]([NH:12][S:19]([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)(=[O:21])=[O:20])=[C:8]2[C:3]=1[CH:4]=[CH:5][CH:6]=[N:7]2
Reactant: O=S(=O)(Cl)c1ccccc1
Reactant: Nc1ccc(F)c2cccnc12
Agent: CN(C)c1ccncc1
Solvent: ClCCl
Product: O=S(=O)(Nc1ccc(F)c2cccnc12)c1ccccc1
Yield: 60.5 %

Procedure:
In a similar fashion using route 14 general procedure 27, 5-fluoroquinolin-8-amine (Intermediate 50) (150 mg, 0.93 mmol), benzenesulfonyl chloride (196 mg, 1.11 mmol) and DMAP (cat) gave the title compound (170 mg, 61%) after column chromatography with DCM eluent.
Reaction SMILES: [ClH:1].[NH2:2][CH2:3][C:4]1([CH2:11][C:12]([OH:14])=[O:13])[CH2:10][CH2:9][CH2:8][CH2:7][CH2:6][CH2:5]1.Cl.[CH3:16]O>>[NH2:2][CH2:3][C:4]1([CH2:11][C:12]([O:14][CH3:16])=[O:13])[CH2:10][CH2:9][CH2:8][CH2:7][CH2:6][CH2:5]1.[ClH:1]
Reactant: NCC1(CC(=O)O)CCCCCC1
Reactant: CO
Agent: Cl
Product: COC(=O)CC1(CN)CCCCCC1

Procedure:
In an anologous manner as described in Example 2 1-aminomethyl-1-cycloheptane acetic acid hydrochloride is esterified with methanol in the presence of hydrogen chloride. After working up and crystallisation from isopropanol/ether/hexane, methyl 1-aminomethyl-1-cycloheptane-acetate is obtained as hydrochloride in the form of colourless crystals having a melting point of 115° - 116° C.
Reaction SMILES: [Na].[CH:2]1([SH:8])[CH2:7][CH2:6][CH2:5][CH2:4][CH2:3]1.F[C:10]1[CH:17]=[CH:16][C:13]([C:14]#[N:15])=[CH:12][CH:11]=1.Cl>C(O)C>[CH:2]1([S:8][C:10]2[CH:17]=[CH:16][C:13]([C:14]#[N:15])=[CH:12][CH:11]=2)[CH2:7][CH2:6][CH2:5][CH2:4][CH2:3]1
Reactant: N#Cc1ccc(F)cc1
Reactant: SC1CCCCC1
Agent: Cl
Agent: [Na]
Solvent: CCO
Product: N#Cc1ccc(SC2CCCCC2)cc1
Yield: 67.9 %

Procedure:
Dissolve sodium metal (343 mg, 14.9 mmoles) in anhydrous ethanol (20 mL) at room temperature under nitrogen atmosphere. Then add cyclohexyl mercaptan (2 mL, 16.37 mmoles) and stir at room temperature for 30 min. Add then neat 4-fluoro-benzonitrile (1.8 g, 14.9 mmol) and heat the resulting solution at 80° C. overnight. Cool the reaction to room temperature and quench the reaction by adding 1N aqueous HCl (100 mL). Concentrate the mixture in vacuo and take up the residue with EtOAc (100 mL). Wash the organic layer with saturated aqueous NaHCO3 (100 mL) and brine (100 mL). Dry the organic phase over MgSO4 and concentrate in vacuo. Purify the crude mixture by chromatography on silica gel (120 g, pre-packed cartridge) eluting with cyclohexane/EtOAc (98:2 to 80:20 gradient) to afford the desired intermediate (2.2 g, 68%). GC-MS m/z: 217 (M+).
Reaction SMILES: [CH3:1][C:2]1[C:8](=[O:9])[NH:7][C:5](=[O:6])[N:4]([C@@H:10]2[O:14][C@H:13]([CH2:15][OH:16])[C@@H:12]([N:17]=[N+:18]=[N-:19])[CH2:11]2)[CH:3]=1.Br[CH2:21][CH2:22][N:23]1[C:27](=[O:28])[C:26]2=[CH:29][CH:30]=[CH:31][CH:32]=[C:25]2[C:24]1=[O:33]>>[C:24]1(=[O:33])[N:23]([CH2:22][CH2:21][N:7]2[C:8](=[O:9])[C:2]([CH3:1])=[CH:3][N:4]([C@@H:10]3[O:14][C@H:13]([CH2:15][OH:16])[C@@H:12]([N:17]=[N+:18]=[N-:19])[CH2:11]3)[C:5]2=[O:6])[C:27](=[O:28])[C:26]2=[CH:29][CH:30]=[CH:31][CH:32]=[C:25]12
Reactant: O=C1c2ccccc2C(=O)N1CCBr
Reactant: Cc1cn([C@H]2C[C@H](N=[N+]=[N-])[C@@H](CO)O2)c(=O)[nH]c1=O
Product: Cc1cn([C@H]2C[C@H](N=[N+]=[N-])[C@@H](CO)O2)c(=O)n(CCN2C(=O)c3ccccc3C2=O)c1=O

Procedure:
AZT is reacted with N-(2-bromoethyl)-phthalimide (Reaction B) to provide 3-(2-phthalimidoethyl)-3'-azido-3'-deoxythymidine (3-PHT-E-AZT) (Example 25).
Reaction SMILES: [C:1]([O:5][C:6](=[O:20])[CH2:7][O:8][C:9]1[CH:14]=[CH:13][C:12]([S:15][CH2:16][C:17]#[CH:18])=[CH:11][C:10]=1[CH3:19])([CH3:4])([CH3:3])[CH3:2].[Cl:21][C:22]1[CH:27]=[CH:26][C:25](I)=[CH:24][CH:23]=1>>[C:1]([O:5][C:6](=[O:20])[CH2:7][O:8][C:9]1[CH:14]=[CH:13][C:12]([S:15][CH2:16][C:17]#[C:18][C:25]2[CH:26]=[CH:27][C:22]([Cl:21])=[CH:23][CH:24]=2)=[CH:11][C:10]=1[CH3:19])([CH3:4])([CH3:3])[CH3:2]
Reactant: C#CCSc1ccc(OCC(=O)OC(C)(C)C)c(C)c1
Reactant: Clc1ccc(I)cc1
Product: Cc1cc(SCC#Cc2ccc(Cl)cc2)ccc1OCC(=O)OC(C)(C)C

Procedure:
In analogy to the procedure described in example 5B], (2-methyl-4-prop-2-ynylsulfanyl-phenoxy)-acetic acid tert-butyl ester (example 5A]) and 1-chloro-4-iodo-benzene gave the title compound as a light yellow oil.
Reaction SMILES: [S:1]1[CH:5]=[CH:4][C:3]2[CH:6]=[C:7]([C:10]3[CH:17]=[CH:16][CH:15]=[CH:14][C:11]=3[CH:12]=[O:13])[CH:8]=[CH:9][C:2]1=2.[BH4-].[Na+]>CO>[S:1]1[CH:5]=[CH:4][C:3]2[CH:6]=[C:7]([C:10]3[CH:17]=[CH:16][CH:15]=[CH:14][C:11]=3[CH2:12][OH:13])[CH:8]=[CH:9][C:2]1=2
Reactant: O=Cc1ccccc1-c1ccc2sccc2c1
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Product: OCc1ccccc1-c1ccc2sccc2c1
Temperature: 25 °C
Reaction time: 2 h
Yield: 93.7 %

Procedure:
To a suspension of 2-Benzo[b]thiophene-5-yl-benzaldehyde (compound PRE14) (3.31 g, 13.9 mmole) in methanol (30 mL) was added at 0-5° C. portionwise NaBH4 (0.528 g, 13.9 mmole). At the end of the addition, the cooling bath was removed and the reaction mixture was stirred at room temperature for 2 h. After concentration, the residue was diluted with water and diethyl ether, the organic layer dried over Na2SO4 and concentrated to give 3.13 g of compound O7 as an orange brown oil (Yield=94%).
Reaction SMILES: [Na].[NH2:2][C:3]([NH2:5])=[S:4].[CH3:6][CH:7]([C:13](=O)[CH:14]([CH3:16])[CH3:15])[C:8](OCC)=[O:9]>C(O)C>[CH:14]([C:13]1[NH:5][C:3](=[S:4])[NH:2][C:8](=[O:9])[C:7]=1[CH3:6])([CH3:16])[CH3:15]
Reactant: NC(N)=S
Reactant: CCOC(=O)C(C)C(=O)C(C)C
Agent: [Na]
Solvent: CCO
Product: Cc1c(C(C)C)[nH]c(=S)[nH]c1=O
Yield: 77.5 %

Procedure:
To anhydrous ethanol (110 mL) was added sodium metal (1.16 g, 50.4 mmol) and the mixture was stirred until dissolution was complete. To this solution was added thiourea (1.79 g, 23.5 mmol) and ethyl 2,4-dimethyl-3-oxopentanoate (2.89 g, 16.8 mmol). The reaction mixture was stirred at 85° C. for 20 h then cooled and concentrated. The residue was diluted with water, the pH adjusted to 4 with 1 N hydrochloric acid then extracted with ethyl acetate (3×80 mL). The combined organic layers were washed with brine, dried over anhydrous sodium sulfate, filtered and concentrated to provide 6-isopropyl-5-methyl-2-thioxo-2,3-dihydropyrimidin-4(1H)-one (2.40 g, 78% yield) as a tan solid that was used without further purification. C8H12N2OS: 185 (MH+).