Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl.[CH2:2]([N:4]1[CH:8]=[C:7]([CH2:9][N:10]2[C:15]3[CH:16]=[C:17]([C:19]4[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=4)[S:18][C:14]=3[C:13](=[O:25])[N:12]([CH:26]3[CH2:31][CH2:30][NH:29][CH2:28][CH2:27]3)[C:11]2=[O:32])[CH:6]=[N:5]1)[CH3:3].[CH2:33]([O:35][C:36]1[C:45]([O:46][CH3:47])=[CH:44][C:43]2[C:42]([C:48]3[CH:56]=[CH:55][C:51]([C:52](O)=[O:53])=[CH:50][CH:49]=3)=[N:41][C@@H:40]3[CH2:57][CH2:58][S:59][CH2:60][C@@H:39]3[C:38]=2[CH:37]=1)[CH3:34].CCN=C=NCCCN(C)C.C1C=C2N=NN(O)C2=CC=1.O.S([O-])(O)(=O)=O.[K+]>C(Cl)Cl.O>[CH2:33]([O:35][C:36]1[C:45]([O:46][CH3:47])=[CH:44][C:43]2[C:42]([C:48]3[CH:49]=[CH:50][C:51]([C:52]([N:29]4[CH2:30][CH2:31][CH:26]([N:12]5[C:13](=[O:25])[C:14]6[S:18][C:17]([C:19]7[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=7)=[CH:16][C:15]=6[N:10]([CH2:9][C:7]6[CH:6]=[N:5][N:4]([CH2:2][CH3:3])[CH:8]=6)[C:11]5=[O:32])[CH2:27][CH2:28]4)=[O:53])=[CH:55][CH:56]=3)=[N:41][C@@H:40]3[CH2:57][CH2:58][S:59][CH2:60][C@@H:39]3[C:38]=2[CH:37]=1)[CH3:34]
Reactant: CCOc1cc2c(cc1OC)C(c1ccc(C(=O)O)cc1)=N[C@@H]1CCSC[C@H]21
Reactant: CCn1cc(Cn2c(=O)n(C3CCNCC3)c(=O)c3sc(-c4ccccc4)cc32)cn1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: O=S(=O)([O-])O
Solvent: ClCCl
Solvent: O
Product: CCOc1cc2c(cc1OC)C(c1ccc(C(=O)N3CCC(n4c(=O)c5sc(-c6ccccc6)cc5n(Cc5cnn(CC)c5)c4=O)CC3)cc1)=N[C@@H]1CCSC[C@H]21
Temperature: 25 °C
Reaction time: 14 h

Procedure:
To a suspension of 1-[(1-ethyl-1H-pyrazol-4-yl)methyl]-6-phenyl-3-(piperidin-4-yl)thieno[3,2-d]pyrimidine-2,4(1H,3H)-dione hydrochloride (300 mg; compound B42), 4-[(4aR,10bR)-9-ethoxy-8-methoxy-3,4,4a,10b-tetrahydro-1H-thiopyrano[4,3-c]isoquinolin-6-yl]benzoic acid (253 mg; compound C10), EDCI (122 mg) and HOBT hydrate (86 mg) in DCM (10 ml) DIPEA (0.28 ml) is added. After 45 min additional 4-[(4aR,10bR)-9-ethoxy-8-methoxy-3,4,4a,10b-tetrahydro-1H-thiopyrano[4,3-c]isoquinolin-6-yl]benzoic acid (126 mg; compound C10) is added and the reaction mixture is stirred for 14 h at RT. Water and aqueous potassium hydrogen sulfate solution (10% w/w) are added and the mixture is extracted with DCM. The combined organic layers are dried (sodium sulfate) and concentrated under reduced pressure. The residue is purified by flash column chromatography [silica gel, eluation gradient: DCM/MeOH, 1/0 to 1/1 (v/v)] and preparative HPLC to afford the title compound as a solid.
Reaction SMILES: COC(C1CC2C(=CC=C(S)C=2)C1)=O.[CH3:15][O:16][C:17](=[O:47])[CH2:18][N:19]1[C:28]2[C:23](=[CH:24][C:25]([S:29]CC3SC(C4C=CC(C(F)(F)F)=CC=4)=NC=3C)=[CH:26][CH:27]=2)[CH2:22][CH2:21][CH2:20]1>>[CH3:15][O:16][C:17](=[O:47])[CH2:18][N:19]1[C:28]2[C:23](=[CH:24][C:25]([SH:29])=[CH:26][CH:27]=2)[CH2:22][CH2:21][CH2:20]1
Reactant: COC(=O)CN1CCCc2cc(SCc3sc(-c4ccc(C(F)(F)F)cc4)nc3C)ccc21
Agent: COC(=O)C1Cc2ccc(S)cc2C1
Product: COC(=O)CN1CCCc2cc(S)ccc21

Procedure:
11C was prepared analogously to compound 1C. Used as unpurified oil. MS: 238 (M+1)+. Preparation of {6-[4-Methyl-2-(4-trifluoromethyl-phenyl)-thiazol-5-ylmethylsulfanyl]-3,4-dihydro-2H-quinolin-1-yl}-acetic acid methyl ester (Compound 11D)
Reaction SMILES: CN(C)CCO.C([Li])CCC.[C:12]1([C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][N:19]=2)[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1.C(Br)(Br)(Br)[Br:25]>CCCCCCC.O>[Br:25][C:20]1[CH:21]=[CH:22][CH:23]=[C:18]([C:12]2[CH:13]=[CH:14][CH:15]=[CH:16][CH:17]=2)[N:19]=1
Reactant: c1ccc(-c2ccccn2)cc1
Reactant: BrC(Br)(Br)Br
Agent: CN(C)CCO
Agent: [Li]CCCC
Solvent: CCCCCCC
Solvent: O
Product: Brc1cccc(-c2ccccc2)n1
Temperature: -78 °C
Reaction time: 0.5 h

Procedure:
To N,N-dimethylethanolamine (0.8 mL, 8.00 mmol) in heptane (10 mL) cooled externally to 0° C. was added dropwise a 2.5 M n-butyllithium solution (6.40 mL) and the reaction mixture stirred for 30 minutes. 2-Phenylpyridine (12) (412 mg, 2.66 mmol) in heptane (5 mL) was then added and the reaction mixture stirred for a further 1 hour. The reaction was then cooled and carbon tetrabromide (3.18 g, 9.60 mmol) was added whilst maintaining the temperature at −78° C. The reaction was kept at −78° C. for 1 hour and then allowed to warm to ambient temperature. Water was cautiously added and extracted with TBME (×2), dried (Na2SO4) and the solvent concentrated in vacuo. The crude product was purified by column chromatography eluting with 5% EtOAc in heptane to give the title compound. Yield: 300 mg, 48%; LC-MS tr 1.63 min; HPLC Purity: 97%; MS (ES+) m/z 234, 236 (M+H)
Reaction SMILES: [S:1]1C2C=CC(C(C3C4C(=C(CSC)C=CC=4)NC=3)(C3CC3)C)=CC=2[CH:3]=[CH:2]1.Cl[C:28]1[CH:33]=[CH:32][C:31]([C:34]([C:39]2[C:47]3[C:42](=[C:43]([CH2:48][S:49]([CH3:52])(=[O:51])=[O:50])[CH:44]=[CH:45][CH:46]=3)[NH:41][CH:40]=2)([CH:36]2[CH2:38][CH2:37]2)[CH3:35])=[CH:30][CH:29]=1>>[S:1]1[C:28]2[CH:29]=[CH:30][C:31]([C:34]([C:39]3[C:47]4[C:42](=[C:43]([CH2:48][S:49]([CH3:52])(=[O:51])=[O:50])[CH:44]=[CH:45][CH:46]=4)[NH:41][CH:40]=3)([CH:36]3[CH2:37][CH2:38]3)[CH3:35])=[CH:32][C:33]=2[CH:3]=[CH:2]1
Reactant: CSCc1cccc2c(C(C)(c3ccc4sccc4c3)C3CC3)c[nH]c12
Reactant: CC(c1ccc(Cl)cc1)(c1c[nH]c2c(CS(C)(=O)=O)cccc12)C1CC1
Product: CC(c1ccc2sccc2c1)(c1c[nH]c2c(CS(C)(=O)=O)cccc12)C1CC1

Procedure:
The title compound was prepared starting from 237 mg (0.63 mmol) of the compound from Example 187 in analogy to the synthesis of the compound from Example 209. 144 mg (56% of theory) of the target compound were obtained.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C@H:8]([NH2:10])[CH3:9])=[CH:4][CH:3]=1.[O-:11][C:12]#[N:13].[K+]>Cl>[F:1][C:2]1[CH:7]=[CH:6][C:5]([C@H:8]([NH:10][C:12]([NH2:13])=[O:11])[CH3:9])=[CH:4][CH:3]=1
Reactant: C[C@@H](N)c1ccc(F)cc1
Reactant: N#C[O-]
Agent: Cl
Agent: [K+]
Product: C[C@@H](NC(N)=O)c1ccc(F)cc1
Temperature: 80 °C
Reaction time: 3 h

Procedure:
(R)-1-(4-Fluorophenyl)ethanamine (5.15 g, 37.0 mmol) was taken up in HCl (2N, 40 mL) and potassium cyanate (15.01 g, 185 mmol) was added. The mixture was stirred at 80° C. for 3 h. Upon cooling to room temperature, a precipitate formed which was collected by filtration and washed with water. The solid was partitioned between water and EtOAc, and the aqueous phase extracted once more with EtOAc. The combined organic extracts were dried over Na2SO4, filtered, and concentrated in vacuo to give (R)-1-(1-(4-fluorophenyl)ethyl)urea), without further purification. MS ESI calc'd. for C9H11FN2O [M+1]+ 183. found 183.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[C:6]3[C:11]([CH:12]([CH3:25])[N:13]([C:16]([C:18]4[CH:19]=[C:20]([OH:24])[CH:21]=[CH:22][CH:23]=4)=[O:17])[C:14]=2[CH:15]=1)=[CH:10][CH:9]=[CH:8][CH:7]=3>C(Cl)(Cl)Cl>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[C:6]3[C:11]([C@@H:12]([CH3:25])[N:13]([C:16]([C:18]4[CH:19]=[C:20]([OH:24])[CH:21]=[CH:22][CH:23]=4)=[O:17])[C:14]=2[CH:15]=1)=[CH:10][CH:9]=[CH:8][CH:7]=3
Reactant: CC1c2ccccc2-c2ccc(Cl)cc2N1C(=O)c1cccc(O)c1
Solvent: ClC(Cl)Cl
Product: C[C@@H]1c2ccccc2-c2ccc(Cl)cc2N1C(=O)c1cccc(O)c1

Procedure:
The enantiomers of 3-[(3-chloro-6-methylphenanthridin-5(6H)-yl)carbonyl]phenol (367 mg, 1.05 mmol) were separated by automated, preparative, normal phase, chiral chromatography on a Chiralpak AD (20 mm×250 mm) column eluting with 100% ethanol at a flow rate of 10 mL/min. After combination of fractions and evaporation of the solvent in vacuo, one peak with a retention time of 3.801 minutes was isolated as a white solid (144 mg, 79% based upon a 1:1 ratio of enantiomers with a theoretical maximum amount of 183.5 mg). [α]D25=−398° (c=0.010 g/mL, CHCl3); 1H NMR (400 MHz, DMSO-d6) δ ppm 1.21 (d, J=6.73 Hz, 3 H) 5.65 (d, J=6.47 Hz, 1 H) 6.70 (d, J=7.50 Hz, 1 H) 6.73 (s, 1 H) 6.84 (ddd, J=8.15, 2.46, 0.78 Hz, 1 H) 6.92 (s, 1H) 7.17 (t, J=7.89 Hz, 1 H) 7.28 (dd, J=8.41, 2.20 Hz, 1 H) 7.39 (m, 2 H) 7.45 (m, 1H) 7.98 (d, J=8.54 Hz, 2 H) 9.68 (s, 1 H); MS (ESI) m/z 350/352 ([M+H]+); MS (ESI) m/z 348/350 ([M−H]−); HRMS: calcd for C21H16ClNO2, 349.0870 (M), 350.09424 ([M+H]+); found (ESI+), 350.09353.
Reaction SMILES: [C:1]([C:4]1[CH:5]=[C:6]([C@@H:10]([NH:12][C:13]2[N:18]=[C:17]([N:19]3[C:23]4[CH:24]=[CH:25][CH:26]=[CH:27][C:22]=4[N:21]=[CH:20]3)[CH:16]=[CH:15][N:14]=2)[CH3:11])[CH:7]=[CH:8][CH:9]=1)(O)=[O:2].C(N(CC)CC)C.[C:35]1([C@@H:41]([NH2:43])[CH3:42])[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=1.Cl.CN(C)CCCN=C=NCC>C(Cl)Cl.CN(C)C1C=CN=CC=1>[C:35]1([C@@H:41]([NH:43][C:1]([C:4]2[CH:5]=[C:6]([C@@H:10]([NH:12][C:13]3[N:18]=[C:17]([N:19]4[C:23]5[CH:24]=[CH:25][CH:26]=[CH:27][C:22]=5[N:21]=[CH:20]4)[CH:16]=[CH:15][N:14]=3)[CH3:11])[CH:7]=[CH:8][CH:9]=2)=[O:2])[CH3:42])[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=1
Reactant: C[C@H](N)c1ccccc1
Reactant: C[C@H](Nc1nccc(-n2cnc3ccccc32)n1)c1cccc(C(=O)O)c1
Agent: CCN=C=NCCCN(C)C
Agent: CN(C)c1ccncc1
Agent: Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: C[C@H](NC(=O)c1cccc([C@H](C)Nc2nccc(-n3cnc4ccccc43)n2)c1)c1ccccc1
Temperature: 25 °C
Reaction time: 17 h

Procedure:
2-[(S)-1-(3-carboxyphenyl)ethylamino]-4-[benzimidazol-1-yl]pyrimidine (15.5 mg) was dissolved in CH2Cl2 (2 mL), then triethylamine (30 μL) was added followed by (S)-1-phenylethylamine (17 μL), 1-(3-dimethylaminopropyl)-3-ethylcarbodimide hydrochloride (32.7 mg) and 4-dimethylaminopyridine (˜1 mg). The mixture was stirred at room temperature for 17 h then purified directly by silica gel column (60:40 hexanes:acetone) then on one 250 μm silica gel plate (90:10 CH2Cl2:MeOH) to yield 6.9 mg of the title compound. 1H NMR (500 MHz, CDCl3, partial): δ 8.48 (br s, 1H); 8.37 (d, J=5.5 Hz, 1H); 7.95 (s, 1H); 7.82 (d, J=7.5 Hz, 1H); 7.64 (d, J=7.8 Hz, 1H); 7.59 (d, J=7.5 Hz, 1H); 6.79 (d, J=5.5 Hz, 1H); 6.33 (d, J=7.8 Hz, 1H); 5.80 (br s, 1H); 5.36 (m, 1H); 5.24 (br s, 1H); 1.65 (d, J=6.9 Hz, 3H); 1.61 (d, J=6.9 Hz, 3H). Mass Spectrum (ESI): m/e 463.2 (M+1).
Reaction SMILES: ClC1C=C(C=CC=1)C(OO)=[O:6].[CH3:12][S:13][C:14]1[C:22]2[C:17](=[CH:18][C:19]([C:23]([N:25]3[CH2:30][C@@H:29]4[CH2:31][C@H:26]3[CH2:27][N:28]4[C:32]([O:34][C:35]([CH3:38])([CH3:37])[CH3:36])=[O:33])=[O:24])=[CH:20][CH:21]=2)[N:16]([C:39]2[N:44]=[CH:43][C:42]([C:45]3[CH:50]=[CH:49][CH:48]=[CH:47][N:46]=3)=[CH:41][N:40]=2)[CH:15]=1>ClCCl>[CH3:12][S:13]([C:14]1[C:22]2[C:17](=[CH:18][C:19]([C:23]([N:25]3[CH2:30][C@@H:29]4[CH2:31][C@H:26]3[CH2:27][N:28]4[C:32]([O:34][C:35]([CH3:38])([CH3:36])[CH3:37])=[O:33])=[O:24])=[CH:20][CH:21]=2)[N:16]([C:39]2[N:44]=[CH:43][C:42]([C:45]3[CH:50]=[CH:49][CH:48]=[CH:47][N:46]=3)=[CH:41][N:40]=2)[CH:15]=1)=[O:6]
Reactant: O=C(OO)c1cccc(Cl)c1
Reactant: CSc1cn(-c2ncc(-c3ccccn3)cn2)c2cc(C(=O)N3C[C@@H]4C[C@H]3CN4C(=O)OC(C)(C)C)ccc12
Solvent: ClCCl
Product: CS(=O)c1cn(-c2ncc(-c3ccccn3)cn2)c2cc(C(=O)N3C[C@@H]4C[C@H]3CN4C(=O)OC(C)(C)C)ccc12
Temperature: 25 °C
Reaction time: 3 h

Procedure:
m-Chloroperoxybenzoic acid (0.114 g, 0.66 mmol, 0.9 eq) was added at 0° C. to a stirred solution of 244c) (0.400 g, 0.61 mmol, 1 eq) in dichloromethane (30 mL). The reaction mixture was stirred for 3 h at room temperature, then diluted with dichloromethane (50 mL) and successively washed with saturated sodium hydrogen carbonate solution (2×30 mL) and brine (30 mL). The organic layer wasdried over sodium sulfate and concentrated under reduced pressure. The residue was purified by column chromatography [230-400 mesh silica gel, dichloromethane/methanol=95:5]. White solid. Yield: 0.290 g (71% of theory)
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][C:7]([N:10]2[CH2:14][CH2:13][CH:12]([NH:15]C(=O)C)[CH2:11]2)=[CH:6][CH:5]=1)([O-:3])=[O:2].Cl.[OH-].[Na+]>O>[N+:1]([C:4]1[CH:9]=[CH:8][C:7]([N:10]2[CH2:14][CH2:13][CH:12]([NH2:15])[CH2:11]2)=[CH:6][CH:5]=1)([O-:3])=[O:2]
Reactant: CC(=O)NC1CCN(c2ccc([N+](=O)[O-])cc2)C1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: NC1CCN(c2ccc([N+](=O)[O-])cc2)C1
Temperature: 90 °C
Yield: 89.3 %

Procedure:
100 g (0.4 mol) of N-[1-(4-nitrophenyl)-pyrrolidin-3-yl]acetamide (1) are introduced as a suspension into a solution containing 300 ml of 37% hydrochloric acid and 660 ml of water in a 2 l three-necked flask. The reaction medium is heated at 90° C. for 7 hours 45 minutes. After cooling, the medium is neutralized carefully with 300 ml of aqueous 35% sodium hydroxide (pH=approximately 8). The resulting solid is then filtered off, after which it is washed with water (until the washing waters are neutral). The product is then dried under vacuum over P2O5. 74 g (89%) of 1-(4-nitrophenyl)pyrrolidin-3-ylamine (2) are thus obtained in the form of a yellow solid.
Reaction SMILES: [NH2:1][C:2]1[CH:21]=[CH:20][C:5]([O:6][C:7]2[C:16]3[C:11](=[CH:12][C:13]([OH:19])=[C:14]([C:17]#[N:18])[CH:15]=3)[N:10]=[CH:9][CH:8]=2)=[CH:4][C:3]=1[Cl:22].CC1C=CC(S(O[CH2:34][C@H:35]2[CH2:37][O:36]2)(=O)=O)=CC=1>>[NH2:1][C:2]1[CH:21]=[CH:20][C:5]([O:6][C:7]2[C:16]3[C:11](=[CH:12][C:13]([O:19][CH2:34][C@H:35]4[CH2:37][O:36]4)=[C:14]([C:17]#[N:18])[CH:15]=3)[N:10]=[CH:9][CH:8]=2)=[CH:4][C:3]=1[Cl:22]
Reactant: Cc1ccc(S(=O)(=O)OC[C@H]2CO2)cc1
Reactant: N#Cc1cc2c(Oc3ccc(N)c(Cl)c3)ccnc2cc1O
Product: N#Cc1cc2c(Oc3ccc(N)c(Cl)c3)ccnc2cc1OC[C@H]1CO1
Yield: 16.8 %

Procedure:
The title compound (198 mg, 0.538 mmol, 16.8%) was obtained as light brown crystals from an 4-(4-amino-3-chlorophenoxy)-6-cyano-7-hydroxyquinoline crude product (1.00 g, 3.21 mmol) and (2R)-oxiran-2-ylmethyl 4-methyl-1-benzenesulfonate, by the same procedure as in Example 7.
Reaction SMILES: Br[CH2:2][CH2:3][CH2:4][C:5]([C:11]1[CH:12]=[C:13]([CH:18]=[CH:19][CH:20]=1)[C:14]([O:16][CH3:17])=[O:15])([C:9]#[N:10])[CH:6]([CH3:8])[CH3:7].[CH3:21][NH:22][CH2:23][CH2:24][C:25]1[CH:34]=[CH:33][C:28]([C:29]([O:31][CH3:32])=[O:30])=[CH:27][CH:26]=1>>[C:9]([C:5]([C:11]1[CH:12]=[C:13]([CH:18]=[CH:19][CH:20]=1)[C:14]([O:16][CH3:17])=[O:15])([CH2:4][CH2:3][CH2:2][N:22]([CH2:23][CH2:24][C:25]1[CH:34]=[CH:33][C:28]([C:29]([O:31][CH3:32])=[O:30])=[CH:27][CH:26]=1)[CH3:21])[CH:6]([CH3:8])[CH3:7])#[N:10]
Reactant: COC(=O)c1cccc(C(C#N)(CCCBr)C(C)C)c1
Reactant: CNCCc1ccc(C(=O)OC)cc1
Product: COC(=O)c1ccc(CCN(C)CCCC(C#N)(c2cccc(C(=O)OC)c2)C(C)C)cc1

Procedure:
Reaction of 1r with 2b produced 3am. MS found M+H=451. The oxalate salt of 3am was recrystallized from methanol/ether; mp 108-112° C.
Reaction SMILES: [C:1]([N:12]1[C@@H:16]([CH3:17])[C:15](=[O:18])OC1=O)(=[O:11])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH3:10].[C:20]1([CH3:29])[CH:25]=[CH:24][C:23]([C@@H:26]([NH2:28])[CH3:27])=[CH:22][CH:21]=1.CN1CCOCC1>O1CCCC1>[C:20]1([CH3:29])[CH:25]=[CH:24][C:23]([C@@H:26]([NH:28][C:15](=[O:18])[C@H:16]([CH3:17])[NH:12][C:1](=[O:11])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH3:10])[CH3:27])=[CH:22][CH:21]=1
Reactant: Cc1ccc([C@H](C)N)cc1
Reactant: CCCCCCCCCC(=O)N1C(=O)OC(=O)[C@@H]1C
Solvent: CN1CCOCC1
Solvent: C1CCOC1
Product: CCCCCCCCCC(=O)N[C@@H](C)C(=O)N[C@@H](C)c1ccc(C)cc1
Reaction time: 0.5 h
Yield: 79.4 %

Procedure:
(S)-3-Decanoyl-4-methyl-2,5-oxazolidinedione (N-decanoyl-L-alanine-NCA) (100 mg, 0.37 mmol) was dissolved in tetrahydrofuran (3 mL), and at 0° C., (S)-1-(p-tolyl)ethylamine (49 mg, 0.36 mmol) and N-methylmorpholine (37 mg, 0.36 mmol) were added, followed by stirring for 30 minutes. The reaction mixture was treated in a similar manner as in Example 19 to afford the title compound (103 mg, 77%) as white crystals.
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4]([C:8]2[CH:13]=[CH:12][C:11](/[C:14](/[CH3:18])=[CH:15]/[CH2:16][OH:17])=[CH:10][CH:9]=2)[CH:5]=[CH:6][CH:7]=1.[CH2:19]([O:21][C@@H:22]([CH2:28][C:29]1[CH:34]=[CH:33][C:32](O)=[CH:31][CH:30]=1)[C:23]([O:25][CH2:26][CH3:27])=[O:24])[CH3:20]>>[CH2:19]([O:21][C@@H:22]([CH2:28][C:29]1[CH:30]=[CH:31][C:32]([O:17][CH2:16]/[CH:15]=[C:14](/[C:11]2[CH:12]=[CH:13][C:8]([C:4]3[CH:5]=[CH:6][CH:7]=[C:2]([CH3:1])[CH:3]=3)=[CH:9][CH:10]=2)\[CH3:18])=[CH:33][CH:34]=1)[C:23]([O:25][CH2:26][CH3:27])=[O:24])[CH3:20]
Reactant: CCOC(=O)[C@H](Cc1ccc(O)cc1)OCC
Reactant: C/C(=C\CO)c1ccc(-c2cccc(C)c2)cc1
Product: CCOC(=O)[C@H](Cc1ccc(OC/C=C(\C)c2ccc(-c3cccc(C)c3)cc2)cc1)OCC
Yield: 79.6 %

Procedure:
The title compound (0.365 g, 78% yield) was prepared from (E)-3-(3′-methyl-biphenyl-4-yl)-but-2-en-1-ol (0.238 g, 1.0 mmol) and (S)-ethyl 2-ethoxy-3-(4-hydroxyphenyl)-propionate (0.25 g, 1.05 mmol) by a procedure analogous to that described in example 52c.
Reaction SMILES: [Sn](Cl)Cl.[Br:4][C:5]1[CH:6]=[CH:7][C:8]([N+:17]([O-])=O)=[C:9]([NH:11][CH2:12][CH2:13][CH2:14][O:15][CH3:16])[CH:10]=1>C(O)C>[Br:4][C:5]1[CH:10]=[C:9]([NH:11][CH2:12][CH2:13][CH2:14][O:15][CH3:16])[C:8]([NH2:17])=[CH:7][CH:6]=1
Reactant: COCCCNc1cc(Br)ccc1[N+](=O)[O-]
Agent: Cl[Sn]Cl
Solvent: CCO
Product: COCCCNc1cc(Br)ccc1N
Temperature: 25 °C

Procedure:
78.57 g of tin(II) chloride are added to a solution of 21.01 g of (5-bromo-2-nitrophenyl)-(3-methoxypropyl)amine in 950 ml of ethanol. The reaction mixture is heated to reflux for 12 hours. The mixture is cooled to room temperature and concentrated by evaporation. The residue is treated with 2M NaOH until a pH of 11 is obtained. The mixture is extracted with tert-butyl methyl ether (3×). The combined organic phases are dried over sodium sulphate and concentrated by evaporation. The title compound is obtained as an orange oil from the residue. Rf=0.31 (1:1 EtOAc-heptane). Rt=3.06 (gradient I).
Reaction SMILES: [Cl:1][C:2]1[CH:11]=[C:10]2[C:5]([CH:6]=[C:7]([N:13]([C:15]3[CH:20]=[CH:19][C:18]([OH:21])=[CH:17][CH:16]=3)[CH3:14])[N:8]=[C:9]2O)=[CH:4][CH:3]=1.P(Cl)(Cl)([Cl:24])=O>>[Cl:24][C:9]1[C:10]2[C:5](=[CH:4][CH:3]=[C:2]([Cl:1])[CH:11]=2)[CH:6]=[C:7]([N:13]([C:15]2[CH:20]=[CH:19][C:18]([OH:21])=[CH:17][CH:16]=2)[CH3:14])[N:8]=1
Reactant: O=P(Cl)(Cl)Cl
Reactant: CN(c1ccc(O)cc1)c1cc2ccc(Cl)cc2c(O)n1
Product: CN(c1ccc(O)cc1)c1cc2ccc(Cl)cc2c(Cl)n1
Temperature: 0 °C

Procedure:
A mixture of 4-[N-(7-chloro-1-hydroxyisoquinolin-3-yl)-N-methylamino]phenol (4.0 g) and phosphorus oxychloride was heated under reflux for approximately 10 minutes at which stage a clear solution had been obtained. The mixture was cooled and poured into ice-water. The precipitated solid was collected and purified by column chromatography over silica gel (eluant dichloromethane/ethyl acetate; 90:10) to give 4-[N-(1,7-dichloroisoquinolin-3-yl)-N-methylamino]phenol (2.57 g) as a yellow crystalline solid mp 124° C.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[NH:11][C:10]3[CH:12]=[CH:13][CH:14]=[CH:15][C:9]=3[C:8](=O)[NH:7][C:6]=2[CH:17]=1.[C:18]1([CH:24]2[CH2:29][NH:28][CH2:27][CH2:26][NH:25]2)[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1>>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[NH:11][C:10]3[CH:12]=[CH:13][CH:14]=[CH:15][C:9]=3[C:8]([N:28]3[CH2:27][CH2:26][NH:25][CH:24]([C:18]4[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=4)[CH2:29]3)=[N:7][C:6]=2[CH:17]=1
Reactant: c1ccc(C2CNCCN2)cc1
Reactant: O=C1Nc2cc(Cl)ccc2Nc2ccccc21
Product: Clc1ccc2c(c1)N=C(N1CCNC(c3ccccc3)C1)c1ccccc1N2
Yield: 69.4 %

Procedure:
8-Chloro-5,10-dihydro-dibenzo[b,e][1,4]diazepine-11-one (25 mg, 0.1 mmol) and 2-phenylpiperazine (162 mg, 1.0 mmol) were reacted according to GP4 to give 27 mg of the title compound (160FE45). MS (ESI) 389 (MH+). Purity for MH+ (UV/MS) 100/89.
Reaction SMILES: [F:1][C:2]([F:17])([F:16])[C:3]([C:9]1[CH:14]=[CH:13]C(C)=[CH:11][CH:10]=1)([OH:8])[C:4]([F:7])([F:6])[F:5].S(=O)(=O)(O)O.[C:23]([O:26][C:27](=[O:29])[CH3:28])(=[O:25])[CH3:24]>O.[O-2].[O-2].[O-2].[Cr+6]>[C:23]([O:26][CH:27]([O:29][C:27](=[O:26])[CH3:28])[C:28]1[CH:11]=[CH:10][C:9]([C:3]([O:8][C:23](=[O:25])[CH3:24])([C:2]([F:1])([F:16])[F:17])[C:4]([F:5])([F:6])[F:7])=[CH:14][CH:13]=1)(=[O:25])[CH3:24]
Reactant: CC(=O)OC(C)=O
Reactant: Cc1ccc(C(O)(C(F)(F)F)C(F)(F)F)cc1
Agent: [Cr+6]
Agent: O=S(=O)(O)O
Agent: [O-2]
Solvent: O
Product: CC(=O)OC(OC(C)=O)c1ccc(C(OC(C)=O)(C(F)(F)F)C(F)(F)F)cc1
Temperature: 0 °C
Reaction time: 2 h

Procedure:
To a solution of 156 g (0.60 mole) of 4-[2,2,2-trifluoro-1-hydroxy-1-(trifluoromethyl)ethyl]toluene in 675 ml of acetic anhydride is added 135 ml of concentrated sulfuric acid at 0°. To the solution stirred at 0° is added a soluton of 168 g (1.68 mole) of chromium trioxide in 750 ml of acetic anhydride dropwise over a two-hour period. After stirring is continued for an additional two hours, the resulting reaction mixture is poured into five liters of ice and is diluted with five liters of water to obtain an aqueous mixture which is allowed to stand for 18 hours. An oily solid with water above it is obtained. Water is decanted from the oily solid. The solid is dissolved in ether to obtain a solution which is washed with water and sodium bicarbonate solution, dried with anhydrous magnesium sulfate, filtered and evaporated at reduced pressure to give an oily solid. The solid is triturated with ether, filtered and recrystallized from chlorobutane to give 60 g of α,α -bis-acetyloxy-4-[1-(acetyloxy)-2,2,2-trifluoro-1-(trifluoromethyl)ethyl]toluene, m.p. 93°-94.6°.
Reaction SMILES: [Cl:1][C:2]1[CH:12]=[CH:11][CH:10]=[C:9]([F:13])[C:3]=1[C:4]([N:6]=[C:7]=[O:8])=[O:5].[CH3:14][O:15][C:16]1[CH:21]=[CH:20][C:19]([NH:22][NH:23][C:24]([O:26][C:27]([CH3:30])([CH3:29])[CH3:28])=[O:25])=[CH:18][C:17]=1[C:31]([O:33][CH3:34])=[O:32]>C(Cl)Cl>[Cl:1][C:2]1[CH:12]=[CH:11][CH:10]=[C:9]([F:13])[C:3]=1[C:4]([NH:6][C:7]([N:22]([C:19]1[CH:20]=[CH:21][C:16]([O:15][CH3:14])=[C:17]([C:31]([O:33][CH3:34])=[O:32])[CH:18]=1)[NH:23][C:24]([O:26][C:27]([CH3:30])([CH3:29])[CH3:28])=[O:25])=[O:8])=[O:5]
Reactant: O=C=NC(=O)c1c(F)cccc1Cl
Reactant: COC(=O)c1cc(NNC(=O)OC(C)(C)C)ccc1OC
Solvent: ClCCl
Product: COC(=O)c1cc(N(NC(=O)OC(C)(C)C)C(=O)NC(=O)c2c(F)cccc2Cl)ccc1OC
Yield: 89.6 %

Procedure:
The title compound was prepared according to the procedure described in step-1 of Intermediate-9 by using 2-chloro-6-fluorobenzoyl isocyanate (Intermediate-8, 2.0 g, 6.75 mmol), tert-butyl 2-[4-methoxy-3-(methoxycarbonyl)phenyl]hydrazinecarboxylate (Intermediate-10, 1.61 g, 8.18 mmol) and DCM (30 mL) to afford 3.0 g of desired product. 1H NMR (300 MHz, DMSO d6): δ 1.40 (s, 9H), 3.81 (s, 6H), 7.13-7.83 (m, 6H), 9.6 (br s, 1H), 11.13 (br s, 1H); MS (m/z): 494.05 (M−H)−.
Reaction SMILES: Cl[C:2]1[N:3]=[C:4]([N:24]2[CH2:29][CH2:28][O:27][CH2:26][CH2:25]2)[C:5]2[S:10][C:9]([C:11]3[CH:12]=[C:13]([CH:21]=[CH:22][CH:23]=3)[C:14]([NH:16][CH2:17][C@@H:18]([OH:20])[CH3:19])=[O:15])=[CH:8][C:6]=2[N:7]=1.CC1(C)C(C)(C)OB([C:38]2[CH:46]=[CH:45][CH:44]=[C:43]3[C:39]=2[CH:40]=[N:41][NH:42]3)O1>>[NH:42]1[C:43]2[C:39](=[C:38]([C:2]3[N:3]=[C:4]([N:24]4[CH2:29][CH2:28][O:27][CH2:26][CH2:25]4)[C:5]4[S:10][C:9]([C:11]5[CH:12]=[C:13]([CH:21]=[CH:22][CH:23]=5)[C:14]([NH:16][CH2:17][C@@H:18]([OH:20])[CH3:19])=[O:15])=[CH:8][C:6]=4[N:7]=3)[CH:46]=[CH:45][CH:44]=2)[CH:40]=[N:41]1
Reactant: C[C@H](O)CNC(=O)c1cccc(-c2cc3nc(Cl)nc(N4CCOCC4)c3s2)c1
Reactant: CC1(C)OB(c2cccc3[nH]ncc23)OC1(C)C
Product: C[C@H](O)CNC(=O)c1cccc(-c2cc3nc(-c4cccc5[nH]ncc45)nc(N4CCOCC4)c3s2)c1

Procedure:
3-(2-Chloro-4-morpholinothieno[3,2-d]pyrimidin-6-yl)benzoic acid (49 mg) was reacted with (S)-(+)-1-amino-2-propanol via General Procedure B to yield 3-(2-chloro-4-morpholinothieno[3,2-d]pyrimidin-6-yl)-N-((S)-2-hydroxypropyl)benzamide. 3-(2-Chloro-4-morpholinothieno[3,2-d]pyrimidin-6-yl)-N-((S)-2-hydroxypropyl)benzamide (56 mg) was coupled to 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-indazole 7 via General Procedure A to yield 24.8 mg of 336. MS (Q1) 515.2 (M)+
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[S:25][C:11]3[N:12]([CH3:24])[C:13](=[O:23])[N:14]([CH2:17][CH2:18][C:19](OC)=[O:20])[C:15](=[O:16])[C:10]=3[C:9]=2[CH3:26])=[CH:4][CH:3]=1.[BH4-].[Na+]>CCO>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[S:25][C:11]3[N:12]([CH3:24])[C:13](=[O:23])[N:14]([CH2:17][CH2:18][CH2:19][OH:20])[C:15](=[O:16])[C:10]=3[C:9]=2[CH3:26])=[CH:4][CH:3]=1
Reactant: COC(=O)CCn1c(=O)c2c(C)c(-c3ccc(Cl)cc3)sc2n(C)c1=O
Agent: [BH4-]
Agent: [Na+]
Solvent: CCO
Product: Cc1c(-c2ccc(Cl)cc2)sc2c1c(=O)n(CCCO)c(=O)n2C
Temperature: 50 °C
Reaction time: 18 h
Yield: 42.8 %

Procedure:
To a solution of methyl 3-(6-(4-chlorophenyl)-1,5-dimethyl-2,4-dioxo-1,2-dihydrothieno[2,3-d]pyrimidin-3(4H)-yl)propanoate (See Compound 24, Step 3, 25 mg, 0.064 mmol) in EtOH (1 mL) was added NaBH4 (7.2 mg, 0.19 mmol). The reaction was stirred at 50° C. for 18 h, cooled to RT, quenched with diluted HCl (0.1N, 2 mL) then concentrated to a residue which was purified by Prep HPLC to give 6-(4-chlorophenyl)-3-(3-hydroxypropyl)-1,5-dimethylthieno[2,3-d]pyrimidine-2,4(1H,3H)-dione (10 mg, 43.0% yield) as a white solid. 1H NMR (CD3OD) δ: 7.46-7.45 (m, 4H), 4.10 (t, J=6.8 Hz, 2H), 3.62 (t, J=6.0 Hz, 2H), 3.55 (s, 3H), 2.49 (s, 3H), 1.89-1.86 (m, 2H). LCMS: MH+ 365 and TR=2.742 min.