Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]1([S:7](Cl)(=[O:9])=[O:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[F:11][C:12]([F:21])([F:20])[C:13]1[CH:19]=[CH:18][CH:17]=[CH:16][C:14]=1[NH2:15].N1C=CC=CC=1>ClCCl.CN(C1C=CN=CC=1)C>[F:11][C:12]([F:20])([F:21])[C:13]1[CH:19]=[CH:18][CH:17]=[CH:16][C:14]=1[NH:15][S:7]([C:1]1[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1)(=[O:9])=[O:8]
Reactant: Nc1ccccc1C(F)(F)F
Reactant: O=S(=O)(Cl)c1ccccc1
Agent: CN(C)c1ccncc1
Solvent: ClCCl
Solvent: c1ccncc1
Product: O=S(=O)(Nc1ccccc1C(F)(F)F)c1ccccc1
Temperature: 25 °C
Reaction time: 72 h

Procedure:
Benzenesulfonyl chloride (400 g, 2.26 moles) was dissolved in dichloromethane (2 L). To this was added o-trifluoromethylaniline (250 mL, 320 g, 1.99 mol), pyridine (222 mL), and DMAP (7.5 g). The resulting solution was stirred at room temperature for 3 days (72 h), then heated to reflux for 1 hour. The cooled solution was then concentrated on the rotary evaporator, with the bath temperature gradually raised to 70° C. The residue was taken up in ether (3 L) and 1N HCl (1.5 L). The ether layer was separated, washed 2×500 mL with 1N HCl, 1×1 L with brine, 1×1 L with saturated sodium bicarbonate, and once more with 1 L of brine. It was then dried over magnesium sulfate, filtered with suction, and concentrated on the rotary evaporator without heat. The product formed fine crystals as the ether evaporated, and when most of the ether was gone, the crystals were slurried with hexane (2 L), collected with suction and dried. Yield 571 g, 84%.
Reaction SMILES: [CH3:1][C:2]1([CH3:15])[C@@H:4](/[CH:5]=[C:6](/[Br:11])\[C:7](=[O:10])[O:8][CH3:9])[C@H:3]1[C:12]([OH:14])=[O:13].[C:16]([C@@H:18](O)[C:19]1[CH:24]=[CH:23][CH:22]=[C:21]([O:25][C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=2)[CH:20]=1)#[N:17]>C(Cl)(Cl)Cl>[CH3:1][C:2]1([CH3:15])[C@@H:4](/[CH:5]=[C:6](/[Br:11])\[C:7](=[O:10])[O:8][CH3:9])[C@H:3]1[C:12]([O:14][C@H:18]([C:16]#[N:17])[C:19]1[CH:24]=[CH:23][CH:22]=[C:21]([O:25][C:26]2[CH:27]=[CH:28][CH:29]=[CH:30][CH:31]=2)[CH:20]=1)=[O:13]
Reactant: COC(=O)/C(Br)=C\[C@H]1[C@@H](C(=O)O)C1(C)C
Reactant: N#C[C@@H](O)c1cccc(Oc2ccccc2)c1
Solvent: ClC(Cl)Cl
Product: COC(=O)/C(Br)=C\[C@H]1[C@@H](C(=O)O[C@H](C#N)c2cccc(Oc3ccccc3)c2)C1(C)C

Procedure:
Using the procedure of Example 1, the product of Step B and (S)α-cyano-3-phenoxy-benzyl alcohol were reacted to obtain (S)α-cyano-3-phenoxy-benzyl (1R,cis) 2,2-dimethyl-3(E)-[2-bromo-3-oxo-3-methoxy-propenyl]-cyclopropane-1-carboxylate with a specific rotation of [α]D20 =+9.5°±2.5° (c=0.3% in chloroform).
Reaction SMILES: [NH2:1][C:2]1[C:3]([F:26])=[CH:4][C:5]([F:25])=[C:6]([N:8]2[C:17]3[C:12](=[CH:13][C:14]([F:20])=[C:15](F)[C:16]=3[CH3:18])[C:11](=[O:21])[C:10]([C:22]([OH:24])=[O:23])=[CH:9]2)[CH:7]=1.[NH2:27][CH2:28][CH2:29][CH2:30][OH:31].CN1CCCC1.N1C=CC=CC=1>CN(C)C=O>[NH2:1][C:2]1[C:3]([F:26])=[CH:4][C:5]([F:25])=[C:6]([N:8]2[C:17]3[C:12](=[CH:13][C:14]([F:20])=[C:15]([NH:27][CH2:28][CH2:29][CH2:30][OH:31])[C:16]=3[CH3:18])[C:11](=[O:21])[C:10]([C:22]([OH:24])=[O:23])=[CH:9]2)[CH:7]=1
Reactant: Cc1c(F)c(F)cc2c(=O)c(C(=O)O)cn(-c3cc(N)c(F)cc3F)c12
Reactant: NCCCO
Agent: CN1CCCC1
Solvent: c1ccncc1
Solvent: CN(C)C=O
Product: Cc1c(NCCCO)c(F)cc2c(=O)c(C(=O)O)cn(-c3cc(N)c(F)cc3F)c12
Temperature: 70 °C
Reaction time: 15 h
Yield: 26.9 %

Procedure:
1-(5-Amino-2,4-difluorophenyl)-8-methyl-6,7-difluoro-4-oxo-1,4-dihydroquinoline-3-carboxylic acid (500 mg), 3-amino-1-propanol (400 mg) and N-methylpyrrolidine (170 mg) were added to pyridine (1,500 mg), and the mixture was stirred at 70° C. for 15 hours. Since the raw material were not dissolved, N,N-dimethylformamide (1 ml) was added to the mixture, followed by stirring at 70° C. for 43 hours. The reaction mixture was concentrated under reduced pressure. A process of adding distilled water (1 ml) to the residue and then concentrating the mixture under reduced pressure was conducted 3 times repeatedly. Another process of adding toluene (1.5 ml) to the resultant residue and then concentrating the mixture under reduced pressure was conducted 3 times repeatedly. A further process of adding ethanol (1.5 ml) to the resultant residue and then concentrating the mixture under reduced pressure was conducted 3 times repeatedly. Ethanol (1 ml) was added to the resultant residue, and the mixture was heated under reflux for 5 minutes and allowed to cool. Deposits were collected by filtration and washed with ethanol and diisopropyl ether in that order to obtain the title compound (155 mg) as a colorless powder.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]=[CH:7][C:6]([C:12]([CH:14]1[CH2:16][CH2:15]1)=[O:13])=[C:5]2[NH:17][C:18]1[CH:19]=[N:20][N:21]([CH:23]2[CH2:28][CH2:27][N:26]([CH3:29])[CH2:25][CH2:24]2)[CH:22]=1.[Cl:30][C:31]1[CH:36]=[C:35](B2OC(C)(C)C(C)(C)O2)[CH:34]=[C:33]([F:46])[C:32]=1[OH:47]>>[Cl:30][C:31]1[CH:36]=[C:35]([C:2]2[CH:3]=[C:4]3[C:9](=[CH:10][CH:11]=2)[N:8]=[CH:7][C:6]([C:12]([CH:14]2[CH2:15][CH2:16]2)=[O:13])=[C:5]3[NH:17][C:18]2[CH:19]=[N:20][N:21]([CH:23]3[CH2:24][CH2:25][N:26]([CH3:29])[CH2:27][CH2:28]3)[CH:22]=2)[CH:34]=[C:33]([F:46])[C:32]=1[OH:47]
Reactant: CN1CCC(n2cc(Nc3c(C(=O)C4CC4)cnc4ccc(Br)cc34)cn2)CC1
Reactant: CC1(C)OB(c2cc(F)c(O)c(Cl)c2)OC1(C)C
Product: CN1CCC(n2cc(Nc3c(C(=O)C4CC4)cnc4ccc(-c5cc(F)c(O)c(Cl)c5)cc34)cn2)CC1
Yield: 61.2 %

Procedure:
Following general procedure D, (6-bromo-4-(1-(1-methylpiperidin-4-yl)-1H-pyrazol-4-ylamino)quinolin-3-yl)(cyclopropyl)methanone (50 mg, 0.11 mmol) was reacted with 2-chloro-6-fluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenol (47 mg, 0.17 mmol) to afford the desired product (35 mg, 59%) as a yellow-green solid: 1H NMR (500 MHz, CD3OD+TFA-d) δ 9.94 (s, 1H), 8.24 (m, 1H), 8.02 (m, 2H), 7.68 (s, 1H), 7.22 (s, 2H), 4.62 (t, J=5.3 Hz, 1H), 3.69 (d, J=12.7 Hz, 2H), 3.50 (s, 1H), 3.25 (m, 2H), 2.95 (s, 3H), 2.39 (m, 4H), 1.24 (m, 4H); ESI MS m/z 520 [C28H27ClFN5O2+H]+; HPLC 99.5% (AUC), tR=10.37 min.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][CH:6]=[C:5]2[CH2:11][CH2:12][N:13]1[CH2:17][CH2:16][CH2:15][CH2:14]1.C[Si](C)(C)[N-][Si](C)(C)C.[Na+].[Si:28](Cl)([C:31]([CH3:34])([CH3:33])[CH3:32])([CH3:30])[CH3:29]>>[Br:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[N:7]([Si:28]([C:31]([CH3:34])([CH3:33])[CH3:32])([CH3:30])[CH3:29])[CH:6]=[C:5]2[CH2:11][C@@H:12]1[CH2:15][CH2:16][CH2:17][N:13]1[CH3:14]
Reactant: Brc1ccc2[nH]cc(CCN3CCCC3)c2c1
Reactant: CC(C)(C)[Si](C)(C)Cl
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Na+]
Product: CN1CCC[C@H]1Cc1cn([Si](C)(C)C(C)(C)C)c2ccc(Br)cc12

Procedure:
5-Bromo-1-(t-butyldimethylsilyl)-3-(2-pyrrolidin lethyl)indole: (1.02 g, 73%) as a brown oil from 5-bromo-3-(2-pyrrolidinylethyl)-1H-indole (Example 3b, 1.00 g, 3.4 mmol), sodium hexamethyldisilazide (82 mL, 6.82 mmol) and t-butyidimethylsilyl chloride (6.82 mL. 6.82 mmol). 13C NMR (CDCl3): 140.1, 132.9, 129.4, 124.1, 121.5, 116.3, 115.2, 112.7, 6.9, 54.3, 26.3, 25.1, 23.5, 19.5, −3.98.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:16]=[CH:15][CH:14]=[C:13]3[C:9]=2[CH2:10][C:11](=[O:17])[NH:12]3)=[CH:4][CH:3]=1.[CH3:18][N:19]([CH3:35])[C@H:20]1[CH2:24][CH2:23][N:22]([C:25]([C:27]2[CH:31]=[C:30]([CH3:32])[NH:29][C:28]=2[CH:33]=O)=[O:26])[CH2:21]1>C(O)C.N1CCCCC1>[CH3:18][N:19]([CH3:35])[C@H:20]1[CH2:24][CH2:23][N:22]([C:25]([C:27]2[CH:31]=[C:30]([CH3:32])[NH:29][C:28]=2[CH:33]=[C:10]2[C:9]3[C:13](=[CH:14][CH:15]=[CH:16][C:8]=3[C:5]3[CH:4]=[CH:3][C:2]([F:1])=[CH:7][CH:6]=3)[NH:12][C:11]2=[O:17])=[O:26])[CH2:21]1
Reactant: O=C1Cc2c(cccc2-c2ccc(F)cc2)N1
Reactant: Cc1cc(C(=O)N2CC[C@H](N(C)C)C2)c(C=O)[nH]1
Solvent: CCO
Solvent: C1CCNCC1
Product: Cc1cc(C(=O)N2CC[C@H](N(C)C)C2)c(C=C2C(=O)Nc3cccc(-c4ccc(F)cc4)c32)[nH]1
Temperature: 25 °C
Reaction time: 72 h
Yield: 56.2 %

Procedure:
To a solution of 4-(4-fluoro-phenyl)-1,3-dihydro-indol-2-one (56.8 mg, 0.25 mmol) and 3-[3-(3S)-dimethylamino-pyrrolidine-1-carbonyl]-5-methyl-1H-pyrrole-2-carbaldehyde (64.8 mg, 0.26 mmol) in ethanol (2 mL) was added piperidine (3 drops). The reaction mixture was stirred at room temperature for three days. A yellow solid product was precipitated out, filtered, washed by ethanol for three times, and dried under high vacuum to provide pure product 3-[3-[3-(3S)-dimethylamino-pyrrolidine-1-carbonyl]-5-methyl-1H-pyrrol-2-ylmethylene]-4-(4-fluoro-phenyl)-1,3-dihydro-indol-2-one as a yellow solid (64.4 mg, 56%).
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][CH:9]([CH2:13][C:14]1[N:15]=[CH:16][N:17]([C:19]([C:32]2[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=2)([C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=2)[C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)[CH:18]=1)[C:10]([OH:12])=O)=[O:7])([CH3:4])([CH3:3])[CH3:2].CCN(C(C)C)C(C)C.F[P-](F)(F)(F)(F)F.N1(O[P+](N(C)C)(N(C)C)N(C)C)C2C=CC=CC=2N=N1.Cl.[CH3:75][NH:76][O:77][CH3:78]>CN(C=O)C>[C:1]([O:5][C:6](=[O:7])[NH:8][CH:9]([C:10](=[O:12])[N:76]([O:77][CH3:78])[CH3:75])[CH2:13][C:14]1[N:15]=[CH:16][N:17]([C:19]([C:20]2[CH:21]=[CH:22][CH:23]=[CH:24][CH:25]=2)([C:26]2[CH:27]=[CH:28][CH:29]=[CH:30][CH:31]=2)[C:32]2[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=2)[CH:18]=1)([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)OC(=O)NC(Cc1cn(C(c2ccccc2)(c2ccccc2)c2ccccc2)cn1)C(=O)O
Reactant: CNOC
Agent: CN(C)[P+](On1nnc2ccccc21)(N(C)C)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
Product: CON(C)C(=O)C(Cc1cn(C(c2ccccc2)(c2ccccc2)c2ccccc2)cn1)NC(=O)OC(C)(C)C
Yield: 90.2 %

Procedure:
2-tert-Butoxycarbonylamino-3-(1-trityl-1H-imidazol-4-yl)-propionic acid (4.56 g, 9.18 mmol), DIPEA (3.55 g, 4.79 mL, 27.53 mmol), BOP (4.26 g, 9.63 mmol) and N,O-dimethylhydroxylamine hydrochloride (940 mg, 9.63 mmol) in DMF (100 mL) were stirred overnight. The DMF was removed and CH2Cl2 added. The solution was washed with dilute aqueous HCl (1M, 4X), water and brine. The solution was dried, filtered and the solvent removed. The product was chromatographed (silica gel, EA/PE, Rf 0.38 EA) to afford the title compound (4.475 g, 90.4%). ESMS 541 (M+H+) 1H NMR (500 MHz, CDCl3) δ 1.39 (9H, s), 2.92 (1H, dd, J=6.13, 14.45), 2.98 (1H, dd, J=5.63, 14.45), 3.13 (3H, s), 3.73 (3H, s), 4.87 (1H, m), 5.61 (1H, d, J=6.95 Hz), 6.57 (1H, s), 7.11 (6H, m), 7.32 (9H, m), 7.46 (1H, s). 13C NMR (CDCl3) 28.19, 30.34, 31.02, 50.55, 61.49, 75.62, 79.34, 119.74, 127.98, 129.59, 135.19, 137.95, 141.77, 155.19, 171.77.
Reaction SMILES: FC(F)(F)[C:3]1C=C[C:6]([C:9]2([OH:22])[C:17]3[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=3)[C:11]3=[N:18][CH2:19][CH2:20][CH2:21][N:10]23)=[CH:5][CH:4]=1.FC(F)(F)C1C=CC=CC=1C1([OH:46])C2C(=CC=CC=2)C2=NCCCN12>>[O:46]1[CH:3]=[CH:4][CH:5]=[C:6]1[C:9]1([OH:22])[C:17]2[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=2)[C:11]2=[N:18][CH2:19][CH2:20][CH2:21][N:10]12
Reactant: OC1(c2ccccc2C(F)(F)F)c2ccccc2C2=NCCCN21
Reactant: OC1(c2ccc(C(F)(F)F)cc2)c2ccccc2C2=NCCCN21
Product: OC1(c2ccco2)c2ccccc2C2=NCCCN21

Procedure:
In a similar manner, 6-(4-trifluoromethylphenyl)-2,3,4,6-tetrahydropyrimido[2,1-a]isoindol-6-ol; 6-(2-trifluoromethylphenyl)-2,3,4,6-tetrahydropyrimido[2,1-a]isoindol-6-ol; and 6-furyl-2,3,4,6-tetrahydropyrimido[2,1-a]isoindol-6-ol are produced.
Reaction SMILES: C([O:3][C:4](=[O:26])[CH2:5][C:6]1([CH2:23][CH2:24][CH3:25])[C:11]2[NH:12][C:13]3[C:18]([C:10]=2[CH2:9][CH2:8][O:7]1)=[C:17]([C:19]#[N:20])[C:16]([F:21])=[CH:15][C:14]=3[CH3:22])C.[OH-].[Na+]>C1COCC1.CO>[C:19]([C:17]1[C:16]([F:21])=[CH:15][C:14]([CH3:22])=[C:13]2[C:18]=1[C:10]1[CH2:9][CH2:8][O:7][C:6]([CH2:23][CH2:24][CH3:25])([CH2:5][C:4]([OH:26])=[O:3])[C:11]=1[NH:12]2)#[N:20]
Reactant: CCCC1(CC(=O)OCC)OCCc2c1[nH]c1c(C)cc(F)c(C#N)c21
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: C1CCOC1
Product: CCCC1(CC(=O)O)OCCc2c1[nH]c1c(C)cc(F)c(C#N)c21
Temperature: 25 °C
Reaction time: 8 h
Yield: 91.3 %

Procedure:
To a solution of 5-cyano-6-fluoro-8-methyl-1-propyl-1,3,4,9-tetrahydropyrano[3,4-b]indole-1-acetic acid ethyl ester (404 mg, 1.13 mmol) in THF/MeOH (2.5 mL/5 mL) was added 1 N NaOH (2.26 mL, 2.26 mmol). The reaction mixture was stirred at ambient temperature overnight. Most of THF/MeOH was removed under reduced pressure and the resulting mixture was acidified with 1 N HCl. The mixture was extracted with EtOAc (3×10 mL). The combined organic phase was washed with brine (20 mL), dried over Na2SO4 and concentrated to provide 341 mg (91%) of title compound as a white solid. 1H NMR (DMSO): 300 MHz δ 12.02 (bs, 1H), 11.33 (bs, 1H), 7.00 (d, J=9.00 Hz, 1H), 3.96 (m, 2H), 2.95 (d, J=10.3 Hz, 1H), 2.83 (t, J=3.9 Hz, 1H), 2.72 (d, J=10.3 Hz, 1H), 2.54 (s, 3H), 1.99 (m, 2H), 1.28 (m, 1H), 0.85 (m, 1H), 0.79 (t, J=5.41 Hz, 3H).
Reaction SMILES: [C:1]([C:3]1[CH:12]=[CH:11][C:10]2[C:5](=[CH:6][CH:7]=[C:8]([N+:13]([O-])=O)[CH:9]=2)[N:4]=1)#[N:2]>CCOC(C)=O.CO.[H][H].[Pd]>[C:1]([C:3]1[CH:12]=[CH:11][C:10]2[C:5](=[CH:6][CH:7]=[C:8]([NH2:13])[CH:9]=2)[N:4]=1)#[N:2]
Reactant: N#Cc1ccc2cc([N+](=O)[O-])ccc2n1
Reactant: [H][H]
Agent: [Pd]
Solvent: CCOC(C)=O
Solvent: CO
Product: N#Cc1ccc2cc(N)ccc2n1
Yield: 76.3 %

Procedure:
Compound 45B (212 mg, 1.1 mmol) was dissolved in 30 mL of a 1:2 mixture of EtOAc and MeOH and hydrogenated at 1 atmosphere of hydrogen in the presence of 10% Pd/C (42 mg, 20 wt. %) for 1 h. The reaction was filtered, concentrated and purified by silica gel flash chromatography eluting with 2-3% MeOH—CH2Cl2 to give the title compound (142 mg, 79%) as a light yellow solid. LC/MS m/z 170 [M+H]+.
Reaction SMILES: [CH3:1][N:2]([CH3:7])[S:3](Cl)(=[O:5])=[O:4].[CH3:8][O:9][C:10]1[CH:11]=[C:12]([CH3:31])[CH:13]=[C:14]2[C:18]=1[CH:17]([NH:19][C:20]1[CH:29]=[CH:28][C:27]3[C:22](=[CH:23][CH:24]=[C:25]([NH2:30])[CH:26]=3)[N:21]=1)[CH2:16][CH2:15]2>>[CH3:8][O:9][C:10]1[CH:11]=[C:12]([CH3:31])[CH:13]=[C:14]2[C:18]=1[CH:17]([NH:19][C:20]1[CH:29]=[CH:28][C:27]3[C:22](=[CH:23][CH:24]=[C:25]([NH:30][S:3]([N:2]([CH3:7])[CH3:1])(=[O:5])=[O:4])[CH:26]=3)[N:21]=1)[CH2:16][CH2:15]2
Reactant: COc1cc(C)cc2c1C(Nc1ccc3cc(N)ccc3n1)CC2
Reactant: CN(C)S(=O)(=O)Cl
Product: COc1cc(C)cc2c1C(Nc1ccc3cc(NS(=O)(=O)N(C)C)ccc3n1)CC2

Procedure:
The title compound was prepared in accordance with the general method described in example 66 from dimethylsulfamoylchloride and rac-N2-(7-methoxy-5-methyl-indan-1-yl)-quinoline-2,6-diamine; MS: m/e=427.6 (M+H+).
Reaction SMILES: [Cl:1][C:2]1[N:7]=[CH:6][N:5]=[C:4]([O:8][C:9]2[CH:14]=[CH:13][C:12]([NH2:15])=[CH:11][CH:10]=2)[CH:3]=1.[C:16]1([N:22]=[C:23]=[O:24])[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1.O>CN(C)C=O>[Cl:1][C:2]1[N:7]=[CH:6][N:5]=[C:4]([O:8][C:9]2[CH:14]=[CH:13][C:12]([NH:15][C:23]([NH:22][C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=3)=[O:24])=[CH:11][CH:10]=2)[CH:3]=1
Reactant: O=C=Nc1ccccc1
Reactant: Nc1ccc(Oc2cc(Cl)ncn2)cc1
Solvent: CN(C)C=O
Solvent: O
Product: O=C(Nc1ccccc1)Nc1ccc(Oc2cc(Cl)ncn2)cc1
Yield: 97 %

Procedure:
4-(6-Chloropyrimidin-4-yloxy)phenylamine (663 mg, 3.00 mmol) and phenyl isocyanate (393 mg, 3.30 mmol) were stirred in dimethylformamide (5 ml) at room temperature for 18 hours. The reaction solution was poured into water and the precipitated crystals were filtered out, washed with water and ethanol and blow-dried to obtain the title compound (988 mg, 2.91 mmol, 97%) as colorless crystals.
Reaction SMILES: C([O:5][C@H:6]1[CH2:15][CH2:14][CH2:13][C@@H:12]2[C@:7]1([CH3:20])[CH2:8][CH2:9][CH2:10][C@@H:11]2[O:16][C:17](=[O:19])[CH3:18])(C)(C)C.CO>C(Cl)(Cl)(Cl)Cl>[OH:5][C@H:6]1[CH2:15][CH2:14][CH2:13][C@@H:12]2[C@:7]1([CH3:20])[CH2:8][CH2:9][CH2:10][C@@H:11]2[O:16][C:17](=[O:19])[CH3:18]
Reactant: CC(=O)O[C@H]1CCC[C@]2(C)[C@@H](OC(C)(C)C)CCC[C@@H]12
Solvent: ClC(Cl)(Cl)Cl
Solvent: CO
Product: CC(=O)O[C@H]1CCC[C@]2(C)[C@@H](O)CCC[C@@H]12
Reaction time: 0.25 h
Yield: 88.1 %

Procedure:
A solution of 4.08 g (14.45 mMol) of acetic acid (1S,4aS,5S,8aR)-5-tert-Butoxy-4a-methyl-decahydronaphtalen-1-yl ester in 7.25 ml of carbon tetrachloride is treated dropwise under stirring and argon atmosphere with 2.56 ml (18.8 mMol) of trimethylsilyljodide by keeping room temperature. After completed addition the reaction mixture is stirred for another 30 minutes, then 1.79 ml of methanol are added and the reaction kept for 15 minutes. The reaction mixture is evaporated in vacuo to dryness to yield 5.52 g. The residue is chromatographed over 500 g of silicagel with hexane/ethylacetate 4/1 to give 2.88 g (88%) of pure acetic acid (1S,4aS,5S,8aR)-5-hydroxy-4a-methyl-decahydronaphtalen-1-yl ester.
Reaction SMILES: [OH-].[Na+].[CH2:3]([OH:21])[CH2:4][O:5][CH2:6][CH2:7][O:8][CH2:9][CH2:10][O:11][CH2:12][CH2:13][O:14][CH2:15][CH2:16][O:17][CH2:18][CH2:19][OH:20].[CH2:22](Cl)[C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1>O.[Cl-].[Na+].O>[CH2:22]([O:20][CH2:19][CH2:18][O:17][CH2:16][CH2:15][O:14][CH2:13][CH2:12][O:11][CH2:10][CH2:9][O:8][CH2:7][CH2:6][O:5][CH2:4][CH2:3][OH:21])[C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1
Reactant: OCCOCCOCCOCCOCCOCCO
Reactant: ClCc1ccccc1
Agent: [Cl-]
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: OCCOCCOCCOCCOCCOCCOCc1ccccc1
Temperature: 100 °C
Reaction time: 18 h
Yield: 70.6 %

Procedure:
An aqueous sodium hydroxide solution prepared by dissolving 3.99 g (100 mmol) NaOH in 4 ml water was added slowly to monodispersed hexaethylene glycol (28.175 g, 25 ml, 100 mmol). Benzyl chloride (3.9 g, 30.8 mmol, 3.54 ml) was added and the reaction mixture was heated with stirring to 100° C. for 18 hours. The reaction mixture was then cooled, diluted with brine (250 ml) and extracted with methylene chloride (200 ml×2). The combined organic layers were washed with brine once, dried over Na2SO4, filtered and concentrated in vacuo to a dark brown oil. The crude product mixture was purified via flash chromatography (silica gel, gradient elution: ethyl acetate to 9/1 ethyl acetate/methanol) to yield 8.099 g (70%) of monodispersed compound 1 as a yellow oil.
Reaction SMILES: [C:1]([NH:4][C:5]1[CH:14]=[CH:13][C:12](N)=[C:11]2[C:6]=1[C:7](=[O:16])[CH2:8][CH2:9][S:10]2)(=[O:3])[CH3:2].N([O-])=O.[Na+].[ClH:21]>O.[Cu]Cl>[C:1]([NH:4][C:5]1[CH:14]=[CH:13][C:12]([Cl:21])=[C:11]2[C:6]=1[C:7](=[O:16])[CH2:8][CH2:9][S:10]2)(=[O:3])[CH3:2]
Reactant: CC(=O)Nc1ccc(N)c2c1C(=O)CCS2
Reactant: Cl
Agent: Cl[Cu]
Agent: O=N[O-]
Agent: [Na+]
Solvent: O
Product: CC(=O)Nc1ccc(Cl)c2c1C(=O)CCS2
Temperature: 0 °C
Reaction time: 8 h

Procedure:
Into a solution of 500 mg of 5-acetylamino-8-amino-4-thiochromanone (described in Japanese Patent Laid-open (ko-kai) 279891/1989) suspended in a mixed solvent of 12 ml of concentrated hydrochloric acid and 3 ml of water cooled to 0° C. was slowly dropped a solution of 153 mg of sodium nitrite in 2 ml of water. The mixture was stirred for 5 minutes, whereupon a solution of copper (I) chloride in 3 ml of concentrated hydrochloric acid was added to it at 0° C. The mixture was allowed to stand at room temperature overnight and stirred for 20 minutes at 70° C. The reaction mixture was extracted with chloroform, the extract was dried over anhydrous magnesium sulfate. After concentration, the residue was subjected to silica gel column chromatography using chloroform as an eluant to obtain fractions containing the target compound. The fractions were concentrated to produce 478 mg of the title compound.
Reaction SMILES: [C:1]([O:5][C:6](=[O:12])[C@@H:7]1[CH2:11][CH2:10][CH2:9][NH:8]1)([CH3:4])([CH3:3])[CH3:2].C(N(C(C)C)CC)(C)C.[CH2:22]([O:29][C:30](Cl)=[O:31])[C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1>C1COCC1>[C:1]([O:5][C:6](=[O:12])[C@@H:7]1[CH2:11][CH2:10][CH2:9][N:8]1[C:30]([O:29][CH2:22][C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1)=[O:31])([CH3:4])([CH3:2])[CH3:3]
Reactant: O=C(Cl)OCc1ccccc1
Reactant: CC(C)(C)OC(=O)[C@@H]1CCCN1
Solvent: C1CCOC1
Solvent: CCN(C(C)C)C(C)C
Product: CC(C)(C)OC(=O)[C@@H]1CCCN1C(=O)OCc1ccccc1
Temperature: 25 °C
Reaction time: 0.08 h
Yield: 2.3 %

Procedure:
An ice-cooled (0° C.) stirred solution of (S)-proline tert-butyl ester (2) (24.5 g, 143 mmol) and anhydrous diisopropylethylamine (DIPEA) (32.4 mL, 186 mmol) in dry THF (400 mL) was treated with benzylchloroformate (24.6 mL, 172 mmol). After 5 min, the cooling bath and removed and the reaction mixture was stirred at room temperature for 6 h. The mixture was poured into ether (500 mL) and 1 N HCl (400 mL). The organic fraction was washed with H2O (200 mL) and brine (200 mL), and dried over MgSO4. The solvent was removed in vacuo and the resultant oil (43.0 g; 99% was used without further purification. A portion (1 g) was purified by flash chromatography (SiO2; 10% EtOAc in hexane, Rƒ0.25) yielding a clear colorless oil (990 mg): 1H NMR (200 MHz, CDCl3) δ 7.22-7.42 (m, 5H, Ar—H), 5.02-5.22 (m, 2H, OCH2), 4.18-4.20 (m, 1H, α-CH), 3.40-3.65 (m, 2H, δ-CH2), 2.10-2.24 (m, 1H), 1.80-2.10 (m, 3H), 1.35 & 1.43 (s, 9H, C(CH3)3).
Reaction SMILES: [Br:1][C:2]1[C:3]([C:9]([F:12])([F:11])[F:10])=[CH:4][C:5](Cl)=[N:6][CH:7]=1.[I-:13].[Na+].C(Cl)(=O)C>C(#N)C>[Br:1][C:2]1[C:3]([C:9]([F:12])([F:11])[F:10])=[CH:4][C:5]([I:13])=[N:6][CH:7]=1
Reactant: [I-]
Reactant: FC(F)(F)c1cc(Cl)ncc1Br
Agent: [Na+]
Solvent: CC#N
Solvent: CC(=O)Cl
Product: FC(F)(F)c1cc(I)ncc1Br
Temperature: 40 °C
Reaction time: 1.5 h
Yield: 39.5 %

Procedure:
Prepared using General Procedure 17: To a stirred a solution of 5-bromo-2-chloro-4-(trifluoromethyl)pyridine (150 mg, 0.576 mmol) in acetonitrile (2 mL) was added sodium iodide (518 mg, 3.45 mmol). The reaction mixture was heated to 40° C. and acetyl chloride (26.0 mg, 0.345 mmol) was added. The reaction mixture was stirred at 40° C. for 90 min. Once cooled, the reaction was quenched with NaHCO3 (5 mL) and extracted with EA (3×5 mL). The combined organics were washed with brine (10 mL), dried over MgSO4 and concentrated to give 80.0 mg (40%) of 5-bromo-2-iodo-4-(trifluoromethyl)pyridine as a white crystalline solid which was used in the subsequent step without purification. LCMS-ESI (m/z) calculated for C6H2BrF3IN, 351.9; found 352.5 [M+H]+, tR=3.91 min. (Method 1).
Reaction SMILES: CS([C:5]1[N:10]=[C:9]([N:11]2[C:15]3[CH:16]=[CH:17][CH:18]=[CH:19][C:14]=3[N:13]=[CH:12]2)[CH:8]=[CH:7][N:6]=1)(=O)=O.[Cl:20][C:21]1[CH:22]=[C:23]([CH:26]=[C:27]([Cl:29])[CH:28]=1)[CH2:24][NH2:25]>>[Cl:20][C:21]1[CH:22]=[C:23]([CH:26]=[C:27]([Cl:29])[CH:28]=1)[CH2:24][NH:25][C:5]1[N:10]=[C:9]([N:11]2[C:15]3[CH:16]=[CH:17][CH:18]=[CH:19][C:14]=3[N:13]=[CH:12]2)[CH:8]=[CH:7][N:6]=1
Reactant: CS(=O)(=O)c1nccc(-n2cnc3ccccc32)n1
Reactant: NCc1cc(Cl)cc(Cl)c1
Product: Clc1cc(Cl)cc(CNc2nccc(-n3cnc4ccccc43)n2)c1

Procedure:
2-Methanesulfonyl-4-[benzimidazol-1-yl]pyrimidine was reacted with 3,5-dichlorobenzylamine according to the procedure described in EXAMPLE 1, Step C to afford the title compound. Mass Spectrum (EI): m/e 370.3 (M+1). 1H NMR (500 MHz, CDCl3): δ 8.58 (s, 1H); 8.45 (d, J=5.5 Hz, 1H); 7.98 (br s, 1H); 7.86 (m, 1H); 7.38 (m, 2H); 7.31 (s, 2H); 6.89 (d, J=5.5 Hz, 1H); 5.88 (br s, 1H); 4.72 (d, J=6.4 Hz, 2H).
Reaction SMILES: [H-].[Al+3].[Li+].[H-].[H-].[H-].C[O:8][C:9]([CH:11]1[CH2:27][N:14]2[CH2:15][CH2:16][N:17]([CH2:20][C:21]3[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=3)[C:18](=O)[CH:13]2[CH2:12]1)=O>C1COCC1>[OH:8][CH2:9][CH:11]1[CH2:27][N:14]2[CH2:15][CH2:16][N:17]([CH2:20][C:21]3[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=3)[CH2:18][CH:13]2[CH2:12]1
Reactant: COC(=O)C1CC2C(=O)N(Cc3ccccc3)CCN2C1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: C1CCOC1
Product: OCC1CC2CN(Cc3ccccc3)CCN2C1
Reaction time: 4 h
Yield: 96.6 %

Procedure:
A three-neck flask fitted with a reflux condenser and dropping funnel was charged with 100 mL of dry THF and 2.4 g (63 mmol) of lithium aluminum hydride (LAH), and a solution of 6.0 g (21 mmol) of (7SR,8aSR)-7-methoxycarbonyl-2-phenylmethyl-1,2,3,4,6,7,8,8a-octahydro-pyrrolo[1,2-a]pyrazin-1-one (Preparation 9) in 60 mL of dry THF was placed in the dropping funnel. The LAH suspension was heated to reflux and the ester solution was added over a 30-60 min period. Reflux continued for another 4 h, the reaction was cooled in an ice bath and quenched by careful addition of 2.4 mL of water, 2.4 mL of 15% sodium hydroxide, and 7.2 mL of water. Stirring continued until a white precipitate formed, the mixture was filtered through Celite, and the filtrate was evaporated to give 5.0 g (97%) of the title compound of sufficient purity for use in subsequent reactions. 13C NMR (CDCl3): δ 31.1, 37.2, 51.3, 52.6, 57.4, 62.8, 62.9, 67.4, 127.0, 128.2, 129.2, 138.2. HRMS calcd for C15H23N2O (MH+) 247.1810, found: 247.1800.