Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: FC(F)(F)C(O)=O.[NH:8]1[CH2:12][CH2:11][C@@H:10]([S:13][C:14]2[CH:19]=[CH:18][C:17]([OH:20])=[CH:16][CH:15]=2)[CH2:9]1.[C:21]1([CH2:27][CH2:28][CH2:29][CH:30]=O)[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1>C(Cl)(Cl)Cl>[C:21]1([CH2:27][CH2:28][CH2:29][CH2:30][N:8]2[CH2:12][CH2:11][C@@H:10]([S:13][C:14]3[CH:19]=[CH:18][C:17]([OH:20])=[CH:16][CH:15]=3)[CH2:9]2)[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1
Reactant: O=CCCCc1ccccc1
Reactant: Oc1ccc(S[C@@H]2CCNC2)cc1
Solvent: ClC(Cl)Cl
Solvent: O=C(O)C(F)(F)F
Product: Oc1ccc(S[C@@H]2CCN(CCCCc3ccccc3)C2)cc1

Procedure:
The title compound, MS: m/e=328.3 (M+H+) and [α]D20 +10.15° (c=0.56, chloroform) was prepared from (R)-4-(pyrrolidin-3-yl-sulfanyl)-phenol trifluoroacetic acid salt and 4-phenyl-butyraldehyde.
Reaction SMILES: C[O:2][C:3](=[O:17])[C:4]1[CH:9]=[C:8]([C:10]2[CH:11]=[N:12][CH:13]=[CH:14][CH:15]=2)[CH:7]=[C:6]([Br:16])[CH:5]=1.[OH-].[Na+]>CO>[Br:16][C:6]1[CH:5]=[C:4]([CH:9]=[C:8]([C:10]2[CH:11]=[N:12][CH:13]=[CH:14][CH:15]=2)[CH:7]=1)[C:3]([OH:17])=[O:2]
Reactant: COC(=O)c1cc(Br)cc(-c2cccnc2)c1
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: O=C(O)c1cc(Br)cc(-c2cccnc2)c1
Temperature: 25 °C
Yield: 136.2 %

Procedure:
In a 100 ml round bottom flask equipped with stir bar added Methyl-3-bromo-5-(3-pyridyl)benzoate (1.16 g, 3.96 mmol), methanol (15 ml) and sodium hydroxide (5.94 ml, 5.94 mmol, 1N aqueous). Stirred the resulting mixture at 50° C. for 2 h. The reaction mixture was cooled to room temperature, concentrated in-vacuo and the residue was dissolved in methanol (20 ml). To this mixture added hydrochloric acid (1N diethyl ether) dropwise and stirred at room temperature for 10 min. The reaction mixture was concentrated in-vacuo and the residue was triturated with diethyl ether to provide the crude hydrochloride salt of title compound (1.50 g) as a white solid.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([C:8]2[N:13]=[C:12]([C:14]3[CH:19]=[CH:18][C:17]([C:20]([F:23])([F:22])[F:21])=[CH:16][C:15]=3[F:24])[CH:11]=[C:10]([C:25]([F:28])([F:27])[F:26])[N:9]=2)[CH:5]=[CH:6][CH:7]=1.[C:29]([NH:33][S:34]([C:37]1[S:38][C:39](B2OC(C)(C)C(C)(C)O2)=[CH:40][CH:41]=1)(=[O:36])=[O:35])([CH3:32])([CH3:31])[CH3:30]>>[C:29]([NH:33][S:34]([C:37]1[S:38][C:39]([C:2]2[CH:7]=[CH:6][CH:5]=[C:4]([C:8]3[N:9]=[C:10]([C:25]([F:27])([F:28])[F:26])[CH:11]=[C:12]([C:14]4[CH:19]=[CH:18][C:17]([C:20]([F:22])([F:23])[F:21])=[CH:16][C:15]=4[F:24])[N:13]=3)[CH:3]=2)=[CH:40][CH:41]=1)(=[O:35])=[O:36])([CH3:30])([CH3:31])[CH3:32]
Reactant: Fc1cc(C(F)(F)F)ccc1-c1cc(C(F)(F)F)nc(-c2cccc(Br)c2)n1
Reactant: CC(C)(C)NS(=O)(=O)c1ccc(B2OC(C)(C)C(C)(C)O2)s1
Product: CC(C)(C)NS(=O)(=O)c1ccc(-c2cccc(-c3nc(-c4ccc(C(F)(F)F)cc4F)cc(C(F)(F)F)n3)c2)s1

Procedure:
N-tert-Butyl-5-{3-[6-(2-fluoro-4-trifluoromethyl-phenyl)-4-trifluoromethyl-pyrimidin-2-yl]-phenyl}-thiophene-2-sulfonic acid amide was prepared from 2-(3-bromophenyl)-4-(2-fluoro-4-trifluoromethyl-phenyl)-6-trifluoromethyl-pyrimidine (example E.105) (0.465 g, 1.0 mmol) and N-tert-butyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)thiophene-2-sulfonamide (example F.1) (0.414 g, 1.2 mmol) according to the general procedure VI. Obtained as an off-white solid (0.43 g), which was subsequently deprotected.
Reaction SMILES: [OH:1][C:2]1[CH:11]=[CH:10][CH:9]=[C:8]2[C:3]=1[CH2:4][CH2:5][NH:6][C:7]2=[O:12].C(=O)([O-])[O-].[K+].[K+].Br[CH:20](O)[CH2:21][CH2:22][Cl:23]>C(O)C>[Cl:23][CH2:22][CH2:21][CH2:20][O:1][C:2]1[CH:11]=[CH:10][CH:9]=[C:8]2[C:3]=1[CH2:4][CH2:5][NH:6][C:7]2=[O:12]
Reactant: O=C1NCCc2c(O)cccc21
Reactant: OC(Br)CCCl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCO
Product: O=C1NCCc2c(OCCCCl)cccc21
Reaction time: 5 h
Yield: 84.4 %

Procedure:
A mixture of 3.0 g (22.0 mmol) of 3,4-dihydro-5-hydroxy-1(2H)-isoquinolinone and 6.7 g (48.5 mmol) of potassium carbonate in 100 ml of ethanol was refluxed for one hour. Then 10.9 ml (100 mmol) of 1-bromo-3-chloropropanol was added and refluxing continued for five hours. The solution was cooled and concentrated. The residue was dissolved in chloroform, filtered and concentrated to provide 4.45 g (85%) of 5-(3-chloropropoxy)-3,4-dihydro-1(2H)-isoquinolinone; mp 131.5°-133°.
Reaction SMILES: Br[C:2]1[CH:11]=[C:10]2[C:5]([N:6]=[CH:7][C:8](=[O:12])[NH:9]2)=[CH:4][CH:3]=1.[CH3:13][S-:14].[Na+]>CN1CCCC1=O>[CH3:13][S:14][C:2]1[CH:11]=[C:10]2[C:5]([N:6]=[CH:7][C:8](=[O:12])[NH:9]2)=[CH:4][CH:3]=1
Reactant: C[S-]
Reactant: O=c1cnc2ccc(Br)cc2[nH]1
Agent: [Na+]
Solvent: CN1CCCC1=O
Product: CSc1ccc2ncc(=O)[nH]c2c1
Yield: 90.1 %

Procedure:
A solution of 7-bromo-1H-quinoxalin-2-one (12.0 g, 53.3 mmol, 1.0 eq) and sodium methanethiolate (9.44 g, 133.3 mmol, 2.5 eq) in N-methylpyrrolidone is stirred at 160° C. for 1 hour. Then solvent is evaporated and the residue is dissolved in water, acidified to pH=5 with 20% hydrochloric acid aqueous solution at 0° C., and the resulting precipitate is collected by filtration, washed with water and ethyl acetate to afford 7-methylsulfanyl-1H-quinoxalin-2-one as a yellow solid (9.23 g, 54% yield).
Reaction SMILES: [CH2:1]([O:3][C:4]1[CH:9]=[CH:8][C:7]([C:10]2[CH:15]=[CH:14][C:13]([C:16](O)([OH:21])[C:17]([F:20])([F:19])[F:18])=[CH:12][CH:11]=2)=[CH:6][C:5]=1[CH2:23][NH:24][CH:25]1[CH2:30][CH2:29][CH:28]([N:31]([CH3:39])[C:32](=[O:38])[O:33][C:34]([CH3:37])([CH3:36])[CH3:35])[CH2:27][CH2:26]1)[CH3:2].[Cl:40][C:41]1[C:42]2[C:52]([F:53])=[CH:51][CH:50]=[C:49]([F:54])[C:43]=2[S:44][C:45]=1[C:46](Cl)=[O:47]>>[Cl:40][C:41]1[C:42]2[C:52]([F:53])=[CH:51][CH:50]=[C:49]([F:54])[C:43]=2[S:44][C:45]=1[C:46]([N:24]([CH2:23][C:5]1[CH:6]=[C:7]([C:10]2[CH:15]=[CH:14][C:13]([C:16](=[O:21])[C:17]([F:20])([F:18])[F:19])=[CH:12][CH:11]=2)[CH:8]=[CH:9][C:4]=1[O:3][CH2:1][CH3:2])[CH:25]1[CH2:30][CH2:29][CH:28]([N:31]([CH3:39])[C:32](=[O:38])[O:33][C:34]([CH3:35])([CH3:37])[CH3:36])[CH2:27][CH2:26]1)=[O:47]
Reactant: CCOc1ccc(-c2ccc(C(O)(O)C(F)(F)F)cc2)cc1CNC1CCC(N(C)C(=O)OC(C)(C)C)CC1
Reactant: O=C(Cl)c1sc2c(F)ccc(F)c2c1Cl
Product: CCOc1ccc(-c2ccc(C(=O)C(F)(F)F)cc2)cc1CN(C(=O)c1sc2c(F)ccc(F)c2c1Cl)C1CCC(N(C)C(=O)OC(C)(C)C)CC1

Procedure:
Biaryl amine 119 (487 mg, 0.88 mmol) is treated with acid chloride 8 (235 mg, 0.88 mmol) using Method D to give the title compound.
Reaction SMILES: Cl[C:2]1[CH:9]=[CH:8][C:5]([C:6]#[N:7])=[CH:4][N:3]=1.[CH2:10]([Sn](CCCC)(CCCC)C=C)[CH2:11]CC>C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.C1(C)C=CC=CC=1>[CH:10]([C:2]1[CH:9]=[CH:8][C:5]([C:6]#[N:7])=[CH:4][N:3]=1)=[CH2:11]
Reactant: C=C[Sn](CCCC)(CCCC)CCCC
Reactant: N#Cc1ccc(Cl)nc1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: Cc1ccccc1
Product: C=Cc1ccc(C#N)cn1
Temperature: 25 °C
Yield: 113.9 %

Procedure:
A 100 mL round bottom flask equipped with a condenser was charged with 6-Chloro-nicotinonitrile (500 mg, 3.61 mmol), Pd(PPh3)4 (42 mg, 0.036 mmol), PPh3 (28.4 mg, 0.11 mmol), toluene (20 mL) and tributyl-vinyl-stannane (1.37 g, 4.33 mmol) under argon. The mixture was heated to reflux for three hours, then cooled to RT, quenched with water (12 mL), and extracted with EtOAc (30 mL) three times. The organic layer was combined and dried over MgSO4, filtered, and concentrated in vacuo. The residue was purified by silica gel chromatography (5% EtOAc/Hexane) to afford compound 384A as a light yellow oil (535 mg). HPLC retention time=1.43 min. (condition A), M+=131.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5]2[O:9][CH:8]([CH3:10])[C:7](=O)[C:6]=2[CH:12]=1.[CH2:13]([O:15][C:16](=[O:37])[CH:17]=P(C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[CH3:14]>C1(C)C=CC=CC=1.Cl.C(O)C>[CH2:13]([O:15][C:16](=[O:37])[CH2:17][C:7]1[C:6]2[CH:12]=[C:2]([Br:1])[CH:3]=[CH:4][C:5]=2[O:9][C:8]=1[CH3:10])[CH3:14]
Reactant: CCOC(=O)C=P(c1ccccc1)(c1ccccc1)c1ccccc1
Reactant: CC1Oc2ccc(Br)cc2C1=O
Agent: Cl
Solvent: CCO
Solvent: Cc1ccccc1
Product: CCOC(=O)Cc1c(C)oc2ccc(Br)cc12
Temperature: 120 °C
Yield: 77.6 %

Procedure:
A mixture of 5-bromo-2-methyl-benzofuran-3-one (6.8 g, 29.9 mmol) and (triphenyl-phosphanylidene)-acetic acid ethyl ester (17.4 g, 44.9 mmol) in anhydrous toluene is heated for 40 h at 120° C. under an argon atmosphere. After cooling to room temperature the volatiles are removed by rotary evaporation. The residue is purified by flash column chromatography (silica gel, gradient of cyclohexane/EtOAc 100:0 to 90:10) to afford a mixture of two regioisomeric products. The product mixture (7.1 g, 31.3 mmol) is dissolved in a 1.25 M solution of HCl in ethanol and heated at reflux for 1 h. After cooling to room temperature the solvent is removed by rotary evaporation to yield the title compound as a pale yellow oil (6.9 g, 23.2 mmol, 78%). 1H NMR (400 MHz, CDCl3, 298 K): δ=7.59 (d, J=2.0 Hz, 1H), 7.31-7.22 (m, 2H), 4.15 (q, J=7.1 Hz, 2H), 3.54 (s, 2H), 2.42 (s, 3H), 1.25 (t, J=7.1 Hz, 3H). MS (ES+): 297 (M(C13H1379BrO3)+H)+.
Reaction SMILES: [CH3:1][C:2]([CH3:36])([CH2:5][C@@:6]1([C:30]2[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=2)[O:11][C:10](=[O:12])[N:9]([C@H:13]([C:15]2[CH:20]=[CH:19][C:18](B3OC(C)(C)C(C)(C)O3)=[CH:17][CH:16]=2)[CH3:14])[CH2:8][CH2:7]1)[C:3]#[N:4].Br[C:38]1[S:39][C:40]([C:43]([NH:45][CH:46]2[CH2:48][CH2:47]2)=[O:44])=[CH:41][N:42]=1>>[C:3]([C:2]([CH3:36])([CH3:1])[CH2:5][C@@:6]1([C:30]2[CH:31]=[CH:32][CH:33]=[CH:34][CH:35]=2)[O:11][C:10](=[O:12])[N:9]([C@H:13]([C:15]2[CH:16]=[CH:17][C:18]([C:38]3[S:39][C:40]([C:43]([NH:45][CH:46]4[CH2:47][CH2:48]4)=[O:44])=[CH:41][N:42]=3)=[CH:19][CH:20]=2)[CH3:14])[CH2:8][CH2:7]1)#[N:4]
Reactant: O=C(NC1CC1)c1cnc(Br)s1
Reactant: C[C@@H](c1ccc(B2OC(C)(C)C(C)(C)O2)cc1)N1CC[C@](CC(C)(C)C#N)(c2ccccc2)OC1=O
Product: C[C@@H](c1ccc(-c2ncc(C(=O)NC3CC3)s2)cc1)N1CC[C@](CC(C)(C)C#N)(c2ccccc2)OC1=O

Procedure:
The title compound was prepared from 2,2-dimethyl-3-((R)-2-oxo-6-phenyl-3-((S)-1-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)ethyl)-1,3-oxazinan-6-yl)propanenitrile and 2-bromo-N-cyclopropylthiazole-5-carboxamide following a procedure analogous to that described in Example 1 Step 2. LC-MS Method 2 tR=1.262 min, m/z=529.3; 1H NMR (CDCl3) 0.63 (m, 2H), 0.86 (m, 2H), 1.30 (s, 3H), 1.43 (s, 3H), 1.52 (d, 3H), 2.02 (s, 2H), 2.29 (m, 1H), 2.81-2.99 (m, 2H), 5.62 (m, 1H), 6.50 (s, 1H), 6.89 (d, 2H), 7.37 (m, 5H), 7.60 (m, 2H), 8.14 (s, 1H)
Reaction SMILES: [F:1][C:2]1[CH:3]=[CH:4][C:5]([OH:26])=[C:6]([C@H:8]2[CH2:12][CH:11]([OH:13])[CH2:10][N:9]2[C:14]2[CH:19]=[CH:18][N:17]3[N:20]=[CH:21][C:22]([C:23](O)=[O:24])=[C:16]3[N:15]=2)[CH:7]=1.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.Cl.[NH2:52][CH2:53][C@H:54]([OH:57])[CH2:55][Cl:56].C(N(CC)C(C)C)(C)C>CN(C=O)C.CCOC(C)=O>[Cl:56][CH2:55][C@@H:54]([OH:57])[CH2:53][NH:52][C:23]([C:22]1[CH:21]=[N:20][N:17]2[CH:18]=[CH:19][C:14]([N:9]3[CH2:10][CH:11]([OH:13])[CH2:12][C@@H:8]3[C:6]3[CH:7]=[C:2]([F:1])[CH:3]=[CH:4][C:5]=3[OH:26])=[N:15][C:16]=12)=[O:24]
Reactant: NC[C@H](O)CCl
Reactant: O=C(O)c1cnn2ccc(N3CC(O)C[C@@H]3c3cc(F)ccc3O)nc12
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Solvent: CCOC(C)=O
Product: O=C(NC[C@H](O)CCl)c1cnn2ccc(N3CC(O)C[C@@H]3c3cc(F)ccc3O)nc12
Temperature: 25 °C
Reaction time: 18 h
Yield: 82.2 %

Procedure:
To a suspension of (R)-5-(2-(5-fluoro-2-hydroxyphenyl)-4-hydroxypyrrolidin-1-yl)pyrazolo[1,5-a]pyrimidine-3-carboxylic acid (Preparation D; 0.0339 g, 0.0946 mmol) and HATU (0.0540 g, 0.142 mmol) in DMF (0.5 mL) at 0° C. was added (S)-1-amino-3-chloropropan-2-ol hydrochloride (Example 19, Step A; 0.0155 g, 0.142 mmol; prepared according to the method described in Org. Process Res. Dev. 2003, vol. 7, p. 533) and N,N-diisopropylethylamine (0.0494 mL, 0.284 mmol). The resulting mixture was warmed to ambient temperature and stirred for 18 hours. The reaction mixture was diluted with EtOAc (10 mL), washed with brine, dried over MgSO4, filtered, and concentrated under reduced pressure to give the crude material which was purified by silica column chromatography, eluting with 0-20% MeOH/DCM to afford N-((S)-3-chloro-2-hydroxypropyl)-5-((R)-2-(5-fluoro-2-hydroxyphenyl)-4-hydroxypyrrolidin-1-yl)pyrazolo[1,5-a]pyrimidine-3-carboxamide (as a mixture of cis and trans isomers, 0.0407 g, 82.2% yield, 86% purity). LC/MS (ES+APCI) m/z=448.1 (M−H).
Reaction SMILES: Cl.Cl.[O:3]1[C:8]2=[CH:9][CH:10]=[CH:11][C:7]2=[CH:6][C:5]([CH:12]2[CH2:17][CH2:16][CH2:15][CH2:14][N:13]2[CH2:18][CH2:19][C@H:20]2[CH2:25][CH2:24][C@H:23]([NH2:26])[CH2:22][CH2:21]2)=[CH:4]1.[C:27](O)(=[O:31])[CH:28]([CH3:30])[CH3:29]>>[O:3]1[C:8]2=[CH:9][CH:10]=[CH:11][C:7]2=[CH:6][C:5]([CH:12]2[CH2:17][CH2:16][CH2:15][CH2:14][N:13]2[CH2:18][CH2:19][C@H:20]2[CH2:21][CH2:22][C@H:23]([NH:26][C:27](=[O:31])[CH:28]([CH3:30])[CH3:29])[CH2:24][CH2:25]2)=[CH:4]1
Reactant: N[C@H]1CC[C@H](CCN2CCCCC2c2coc3cccc-3c2)CC1
Reactant: CC(C)C(=O)O
Agent: Cl
Product: CC(C)C(=O)N[C@H]1CC[C@H](CCN2CCCCC2c2coc3cccc-3c2)CC1

Procedure:
The title compound, off-white solid (70 mg, 70%), MS (ISP) m/z=397.3 [(M+H)+], mp 173° C., was prepared in accordance with the general method of example 1 from trans-4-[2-(4-benzofuran-3-yl-piperidin-1-yl)-ethyl]-cyclohexylamine dihydrochloride (intermediate A) (100 mg, 0.25 mmol) and isobutyric acid.
Reaction SMILES: [Br:1][C:2]1[C:3]([OH:23])=[C:4]([C:9]([CH2:12][S:13]([C:16]2[CH:21]=[CH:20][CH:19]=[C:18](Cl)[CH:17]=2)(=[O:15])=[O:14])=[CH:10][CH:11]=1)[C:5]([O:7][CH3:8])=[O:6].C1(S(CC2C(C(OC)=O)=C(OC)C(Br)=CC=2)(=O)=O)C=CC=CC=1>>[C:16]1([S:13]([CH2:12][C:9]2[C:4]([C:5]([O:7][CH3:8])=[O:6])=[C:3]([OH:23])[C:2]([Br:1])=[CH:11][CH:10]=2)(=[O:15])=[O:14])[CH:17]=[CH:18][CH:19]=[CH:20][CH:21]=1
Reactant: COC(=O)c1c(CS(=O)(=O)c2cccc(Cl)c2)ccc(Br)c1O
Agent: COC(=O)c1c(CS(=O)(=O)c2ccccc2)ccc(Br)c1OC
Product: COC(=O)c1c(CS(=O)(=O)c2ccccc2)ccc(Br)c1O

Procedure:
Prepared by proceeding in a similar manner to Intermediate 54, starting from methyl 6-(benzenesulphonylmethyl)-3-bromo-2-methoxybenzoate (Intermediate 65).
Reaction SMILES: O[CH:2]1[C:8]2[CH:9]=[CH:10][CH:11]=[CH:12][C:7]=2[CH2:6][O:5][C:4]2[CH:13]=[CH:14][C:15]([O:17][CH2:18][C:19]3[CH:28]=[CH:27][C:26]4[C:21](=[CH:22][CH:23]=[CH:24][CH:25]=4)[N:20]=3)=[CH:16][C:3]1=2.[SH:29][CH:30]([CH3:34])[C:31]([OH:33])=[O:32]>>[C:31]([CH:30]([S:29][CH:2]1[C:8]2[CH:9]=[CH:10][CH:11]=[CH:12][C:7]=2[CH2:6][O:5][C:4]2[CH:13]=[CH:14][C:15]([O:17][CH2:18][C:19]3[CH:28]=[CH:27][C:26]4[C:21](=[CH:22][CH:23]=[CH:24][CH:25]=4)[N:20]=3)=[CH:16][C:3]1=2)[CH3:34])([OH:33])=[O:32]
Reactant: CC(S)C(=O)O
Reactant: OC1c2ccccc2COc2ccc(OCc3ccc4ccccc4n3)cc21
Product: CC(SC1c2ccccc2COc2ccc(OCc3ccc4ccccc4n3)cc21)C(=O)O

Procedure:
11-Hydroxy-2-(quinolin-2-yl)methoxy-6,11-dihydrodibenz[b,e]oxepine and 2-mercaptopropionic acid were used and reacted in the same manner as in Example 1 to obtain the title compound.
Reaction SMILES: [O:1]1[CH:5]=[C:4]([C:6]2[CH:11]=[CH:10][N:9]=[C:8]([S:12][CH3:13])[N:7]=2)[CH:3]=[N:2]1.[OH-].[Na+].C(O)(=O)CC(CC(O)=O)(C(O)=O)O>O.CO>[CH3:13][S:12][C:8]1[N:7]=[C:6]([CH:4]([CH:5]=[O:1])[C:3]#[N:2])[CH:11]=[CH:10][N:9]=1
Reactant: CSc1nccc(-c2cnoc2)n1
Agent: O=C(O)CC(O)(CC(=O)O)C(=O)O
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: O
Product: CSc1nccc(C(C#N)C=O)n1
Temperature: 70 °C
Reaction time: 6 h
Yield: 89.2 %

Procedure:
A mixture of 4-(isoxazol-4-yl)-2-(methylthio)pyrimidine (4) (112.0 g, 0.58 mol) and NaOH (23.2 g) in water/MeOH (350 mL/350 mL) was stirred at 70° C. for 6 h. The reaction mixture was allowed to cool to room temperature and adjusted to pH 3.5 with citric acid. The resulting precipitate was filtered, washed with water (500 mL×3) and ethyl ether (500 mL×3). Then the precipitate was dried in vacuum to give 2-(2-(methylthio)pyrimidin-4-yl)-3-oxopropanenitrile (5) (100 g, 89.3%) as a yellow solid.
Reaction SMILES: [NH2:1][C:2]1[CH:10]=[CH:9][CH:8]=[C:7]2[C:3]=1[CH:4]=[CH:5][N:6]2[C:11]([C:18]1[CH:23]=[CH:22][C:21]([Cl:24])=[CH:20][CH:19]=1)([CH2:16][CH3:17])[C:12]([O:14][CH3:15])=[O:13].[CH3:25][C:26](=O)[CH2:27][CH2:28][C:29](=O)[CH3:30].CC1C=CC(S(O)(=O)=O)=CC=1>C1(C)C=CC=CC=1>[Cl:24][C:21]1[CH:20]=[CH:19][C:18]([C:11]([N:6]2[C:7]3[C:3](=[C:2]([N:1]4[C:29]([CH3:30])=[CH:28][CH:27]=[C:26]4[CH3:25])[CH:10]=[CH:9][CH:8]=3)[CH:4]=[CH:5]2)([CH2:16][CH3:17])[C:12]([O:14][CH3:15])=[O:13])=[CH:23][CH:22]=1
Reactant: CC(=O)CCC(C)=O
Reactant: CCC(C(=O)OC)(c1ccc(Cl)cc1)n1ccc2c(N)cccc21
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: Cc1ccccc1
Product: CCC(C(=O)OC)(c1ccc(Cl)cc1)n1ccc2c(-n3c(C)ccc3C)cccc21

Procedure:
A mixture of methyl 2-(4-amino-1H-indol-1-yl)-2-(4-chlorophenyl)butanoate (140 mg), hexane-2,5-dione (166 mg) and 4-methylbenzenesulfonic acid (3 mg) in toluene (5 mL) was stirred under reflux for 30 min. Concentrated, the residue was purified by chromatography on silica gel column (5-15% ethyl acetate in hexanes) to give the title compound as a yellow solid. LC/MS m/z=421.2 [M+H]+.
Reaction SMILES: [F:1][C:2]1([F:29])[CH2:7][CH2:6][N:5]([C:8]([C:10]2[NH:28][C:13]3=[N:14][CH:15]=[C:16]([O:18][CH:19]4[CH2:24][CH2:23][N:22]([CH:25]([CH3:27])[CH3:26])[CH2:21][CH2:20]4)[CH:17]=[C:12]3[CH:11]=2)=[O:9])[CH2:4][CH2:3]1.[H-].[Na+].[CH3:32][O:33][CH2:34][CH2:35]Br>>[F:29][C:2]1([F:1])[CH2:7][CH2:6][N:5]([C:8]([C:10]2[N:28]([CH2:35][CH2:34][O:33][CH3:32])[C:13]3=[N:14][CH:15]=[C:16]([O:18][CH:19]4[CH2:20][CH2:21][N:22]([CH:25]([CH3:27])[CH3:26])[CH2:23][CH2:24]4)[CH:17]=[C:12]3[CH:11]=2)=[O:9])[CH2:4][CH2:3]1
Reactant: CC(C)N1CCC(Oc2cnc3[nH]c(C(=O)N4CCC(F)(F)CC4)cc3c2)CC1
Reactant: COCCBr
Agent: [H-]
Agent: [Na+]
Product: COCCn1c(C(=O)N2CCC(F)(F)CC2)cc2cc(OC3CCN(C(C)C)CC3)cnc21
Yield: 49 %

Procedure:
The title compound was synthesized in analogy to example 18 from (4,4-difluoro-piperidin-1-yl)-[5-(1-isopropyl-piperidin-4-yloxy)-1H-pyrrolo[2,3-b]pyridin-2-yl]-methanone (example 13), sodium hydride and 2-bromoethyl methyl ether to give the desired product as light yellow oil (49%).
Reaction SMILES: C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.FC1C=CC(Br)=CC=1.[F:28][C:29]1[CH:37]=[CH:36][C:32]([CH2:33][CH2:34]O)=[CH:31][CH:30]=1.[Br-].FC1C=CC(CC[P+](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.[CH2:67]([CH:72]1[CH2:77][CH2:76][CH:75]([CH2:78][CH:79]=O)[CH2:74][CH2:73]1)[CH2:68][CH2:69][CH2:70][CH3:71]>CCOCC.O1CCCC1.C1(C)C(C)=CC=CC=1>[F:28][C:29]1[CH:37]=[CH:36][C:32](/[CH:33]=[CH:34]\[CH2:79][CH2:78][CH:75]2[CH2:76][CH2:77][CH:72]([CH2:67][CH2:68][CH2:69][CH2:70][CH3:71])[CH2:73][CH2:74]2)=[CH:31][CH:30]=1
Reactant: OCCc1ccc(F)cc1
Reactant: CCCCCC1CCC(CC=O)CC1
Agent: Fc1ccc(Br)cc1
Agent: Fc1ccc(CC[P+](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: [Br-]
Solvent: Cc1ccccc1C
Solvent: C1CCOC1
Solvent: CCOCC
Product: CCCCCC1CCC(CC/C=C\c2ccc(F)cc2)CC1

Procedure:
Into a flask, were placed triphenylphosphine (2.9 g, 11 mmol) and 4-fluorophenyl bromide (2.2 g, 11 mmol) prepared from 4-fluorophenethyl alcohol, followed by adding and dissolving xylene (5 ml), heating under reflux for 10 hours, depositing and filtering off white crystals (4.6 g, 10 mmol) of 4-fluorophenethyltriphenylphosphonium bromide. After drying, the white crystals were dissolved in tetrahydrofuran (THF, 10 ml), followed by stirring under ice cooling, adding a hexane solution (1.6M, 6.1 ml) of n-butyl lithium dropwise; stirring at room temperature for 2 hours, adding THF (5 ml) solution of 4-pentylcyclohexylacetaldehyde (2.1 g, 11 mmol), further stirring for 5 hours, adding ether after the completion of reaction. After separating the deposited white crystals by filtration, the filtrate was concentrated under reduced pressure, purifying the resulting oily substance by means of silica gel column chromatography, to obtain a mixture (2.2 g, 7.3 mmol) of 1-(4-fluorophenyl)-4-(4pentylcyclohexyl)-2Z-butene with its E-isomer.
Reaction SMILES: C([O:8][C@H:9]1[CH2:26][CH2:25][C@@:24]2([CH3:27])[C:11](=[CH:12][CH2:13][C@@H:14]3[C@@H:23]2[CH2:22][CH2:21][C@@:19]2([CH3:20])[C@H:15]3[CH2:16][CH2:17][C:18]2=[O:28])[CH2:10]1)C1C=CC=CC=1.C(N([CH2:38][CH3:39])C(F)(F)C(Cl)F)C>>[OH:8][C@H:9]1[CH2:26][CH2:25][C@@:24]2([CH3:27])[C:11](=[CH:12][C@H:13]([CH:38]=[CH2:39])[C@@H:14]3[C@@H:23]2[CH2:22][CH2:21][C@@:19]2([CH3:20])[C@H:15]3[CH2:16][CH2:17][C:18]2=[O:28])[CH2:10]1
Reactant: CCN(CC)C(F)(F)C(F)Cl
Reactant: C[C@]12CC[C@H](OCc3ccccc3)CC1=CC[C@@H]1[C@@H]2CC[C@]2(C)C(=O)CC[C@@H]12
Product: C=C[C@H]1C=C2C[C@@H](O)CC[C@]2(C)[C@H]2CC[C@]3(C)C(=O)CC[C@H]3[C@H]12

Procedure:
Reaction of 3β,16α-dihydroxyandrost-5-en-17-one 3β-acetate 1 with a fluorinating agent such as diethyl (2-chloro-1,1,2-trifluoroethyl)amine affords 16α-fluoro-3β-hydroxyandrost-5-en-17-one 3-acetate 3. Hydrolysis of the ester with aqueous acid yields 16α-fluoro-3β-hydroxyandrost-5-en-17-one, 2a. ##STR47##
Reaction SMILES: C(=O)([O-])[O-].[Cs+].[Cs+].Br[C:8]1[CH:16]=[C:15]2[C:11]([CH2:12][CH2:13][C:14]2=[O:17])=[CH:10][CH:9]=1.[F:18][C:19]1[CH:20]=[C:21](B(O)O)[CH:22]=[CH:23][CH:24]=1.C1(C)C=CC=CC=1>C(OCC)(=O)C.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[F:18][C:19]1[CH:24]=[C:23]([C:8]2[CH:16]=[C:15]3[C:11]([CH2:12][CH2:13][C:14]3=[O:17])=[CH:10][CH:9]=2)[CH:22]=[CH:21][CH:20]=1
Reactant: OB(O)c1cccc(F)c1
Reactant: O=C1CCc2ccc(Br)cc21
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CCOC(C)=O
Solvent: Cc1ccccc1
Product: O=C1CCc2ccc(-c3cccc(F)c3)cc21
Temperature: 80 °C
Yield: 81.1 %

Procedure:
Cesium carbonate (618 mg, 1.90 mmol) was added to a solution of 6-bromo-2,3-dihydro-1H-inden-1-one (200 mg, 0.948 mmol), (3-fluorophenyl)boronic acid (265 mg, 1.90 mmol) and toluene (20 mL) in a 50 mL Schlenk tube at room temperature. A nitrogen atmosphere was established by evacuating and refilling with nitrogen (3×), then tetrakis(triphenylphosphine)palladium (0) (11 mg, 0.001 mmol) was added to the reaction. The flask was sealed and heated in a 80° C. oil bath overnight. The resulting mixture was cooled to room temperature. The reaction was then diluted with ethyl acetate and filtered through celite. Ethyl acetate (30 mL) was used to wash the flask and the combined organic filtrate was concentrated in vacuo. The resulting crude residue was purified on a Teledyne-Isco combiflash machine (40 g column, hexanes→100% ethyl acetate/hexanes, gradient) to afford 174 mg (81%) of 6-(3-fluorophenyl)-2,3-dihydro-1H-inden-1-one.
Reaction SMILES: [NH:1]1[CH:9]=[C:7]([CH3:8])[C:5](=[O:6])[NH:4][C:2]1=[O:3].[H-].[Na+].Br[CH2:13][C@@H:14]1O[C@@H](P(OCC)=O)CC1>CN(C=O)C>[CH2:13]([N:1]1[CH:9]=[C:7]([CH3:8])[C:5](=[O:6])[NH:4][C:2]1=[O:3])[CH3:14]
Reactant: Cc1c[nH]c(=O)[nH]c1=O
Reactant: CCO[PH](=O)[C@H]1CC[C@H](CBr)O1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CCn1cc(C)c(=O)[nH]c1=O
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 25.8 %

Procedure:
To a stirring suspension of thymine (536 mg, 4.18 mmol) in dry DMF (5 mL) was added sodium hydride (60% oil dispersion, 167 mg, 4.18 mmol). After stirring the mixture for 30 min at room temperature, a solution of trans-5-bromomethyl-2-ethoxyphosphinoyl-tetrahydrofuran (example 66) (630 mg, 2.09 mmol) in DMF (3 mL) was added via cannula. The mixture was then stirred at 90° C. for 18 h after which the mixture was cooled and quenched with saturated ammonium chloride (5 mL). The volatiles were removed under vacuo and the residue was dissolved in a mixture of dichloromethane (20 mL) and water (10 mL). The mixture was filtered and the aqueous layer was collected and extracted with dichloromethane (2×20 mL). The combined extracts were then washed with brine (20 mL), dried (MgSO4) and concentrated to dryness. Purification by chromatography eluting with EtAc, 5% MeOH in EtAc then 10% MeOH in EtAc yielded first N1 -ethyl thymine (83 mg, 26%) and then the title compound as an oil (186 mg, 26%).