Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl-].[CH3:2][S+](C)(C)=O.[H-].[Na+].[H][H].[OH:11][C:12]1[CH:19]=[C:18]([CH3:20])[CH:17]=[CH:16][C:13]=1[CH:14]=[O:15]>O1CCCC1.O>[OH:15][CH:14]1[C:13]2[CH:16]=[CH:17][C:18]([CH3:20])=[CH:19][C:12]=2[O:11][CH2:2]1
Reactant: C[S+](C)(C)=O
Reactant: [H][H]
Reactant: Cc1ccc(C=O)c(O)c1
Agent: [Cl-]
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: O
Product: Cc1ccc2c(c1)OCC2O

Procedure:
To a solution of trimethylsulfoxonium chloride (12.9 g) in tetrahydrofuran (200 ml) was added sodium hydride (2.4 g of 100%). This solution was heated at reflux until hydrogen evolution had ceased. 13.6 g of 2-hydroxy-4-methylbenzaldehyde dissolved in tetrahydrofuran (100 ml) was then added. The reaction mixture was refluxed until the reaction was complete (3 hours). It was then poured into water (600 ml), extracted with ether, the ether dried over sodium sulphate and evaporated to give 3-hydroxy-6-methyl-2,3-dihydrobenzofuran.
Reaction SMILES: [C:1]([C:3]1[C@@H:8]([C:9]2[CH:14]=[CH:13][C:12]([C:15]#[N:16])=[CH:11][C:10]=2[S:17]([CH3:20])(=[O:19])=[O:18])[N:7]([CH2:21][C:22](O)=[O:23])[C:6](=[O:25])[N:5]([C:26]2[CH:31]=[CH:30][CH:29]=[C:28]([C:32]([F:35])([F:34])[F:33])[CH:27]=2)[C:4]=1[CH3:36])#[N:2].CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.[NH2:61][CH2:62][CH2:63][OH:64].C(N(CC)C(C)C)(C)C>CN(C=O)C>[C:1]([C:3]1[C@@H:8]([C:9]2[CH:14]=[CH:13][C:12]([C:15]#[N:16])=[CH:11][C:10]=2[S:17]([CH3:20])(=[O:18])=[O:19])[N:7]([CH2:21][C:22]([NH:61][CH2:62][CH2:63][OH:64])=[O:23])[C:6](=[O:25])[N:5]([C:26]2[CH:31]=[CH:30][CH:29]=[C:28]([C:32]([F:34])([F:33])[F:35])[CH:27]=2)[C:4]=1[CH3:36])#[N:2]
Reactant: NCCO
Reactant: CC1=C(C#N)[C@@H](c2ccc(C#N)cc2S(C)(=O)=O)N(CC(=O)O)C(=O)N1c1cccc(C(F)(F)F)c1
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
Product: CC1=C(C#N)[C@@H](c2ccc(C#N)cc2S(C)(=O)=O)N(CC(=O)NCCO)C(=O)N1c1cccc(C(F)(F)F)c1
Reaction time: 0.33 h
Yield: 81.9 %

Procedure:
The reaction was carried out under argon. 2-[(6S)-5-Cyano-6-[4-cyano-2-(methylsulfonyl)phenyl]-4-methyl-2-oxo-3-[3-(trifluoromethyl)phenyl]-3,6-dihydropyrimidin-1(2H)-yl]acetic acid (45 mg, 87 μmol; Example 21) was initially charged in DMF (1.5 ml), HATU (165 mg, 434 μmol, 5 eq.) was added at 0° C. and the mixture was stirred for 20 min. 2-Aminoethanol (26.5 mg, 434 μmol, 5 eq.) and N,N-diisopropylethylamine (56 mg, 434 μmol, 5 eq.) were then added, and the mixture was stirred at RT for 16 h until complete conversion had been achieved (HPLC control). The reaction mixture was then concentrated under reduced pressure, and the crude product was purified by preparative HPLC (column: Gromsil C-18 10 μm; mobile phase: acetonitrile/water+0.1% TFA 10:90→90:10). This gave the title compound as a colorless solid (40 mg, 82% of theory).
Reaction SMILES: Cl[C:2]1[N:3]=[CH:4][C:5](I)=[C:6]2[C:11]=1[N:10]=[C:9]([CH3:12])[CH:8]=[CH:7]2.[CH3:14][O:15][C:16]1[CH:17]=[N:18][CH:19]=[C:20](B2OC(C)(C)C(C)(C)O2)[CH:21]=1.[NH2:31][C:32]1[S:33][CH:34]=[C:35]([CH3:37])[N:36]=1>>[CH3:14][O:15][C:16]1[CH:21]=[C:20]([C:5]2[CH:4]=[N:3][C:2]([NH:31][C:32]3[S:33][CH:34]=[C:35]([CH3:37])[N:36]=3)=[C:11]3[C:6]=2[CH:7]=[CH:8][C:9]([CH3:12])=[N:10]3)[CH:19]=[N:18][CH:17]=1
Reactant: Cc1csc(N)n1
Reactant: Cc1ccc2c(I)cnc(Cl)c2n1
Reactant: COc1cncc(B2OC(C)(C)C(C)(C)O2)c1
Product: COc1cncc(-c2cnc(Nc3nc(C)cs3)c3nc(C)ccc23)c1

Procedure:
The title compound, MS: m/e=364.1 (M+H+), was prepared in accordance with the general method of example 15 step 1 and step 3 from 8-chloro-5-iodo-2-methyl-[1,7]naphthyridine (Example I), 3-methoxy-5-pyridineboronic acid pinacol ester and 2-amino-4-methylthiazole.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][N:5]=[C:4]([C:8]2[CH:13]=[C:12]([CH3:14])[CH:11]=[CH:10][N:9]=2)[CH:3]=1.ClC1C=CC=C(C(OO)=[O:23])C=1>C(Cl)(Cl)Cl>[CH3:1][C:2]1[CH:3]=[C:4]([C:8]2[CH:13]=[C:12]([CH3:14])[CH:11]=[CH:10][N:9]=2)[N+:5]([O-:23])=[CH:6][CH:7]=1
Reactant: O=C(OO)c1cccc(Cl)c1
Reactant: Cc1ccnc(-c2cc(C)ccn2)c1
Solvent: ClC(Cl)Cl
Product: Cc1ccnc(-c2cc(C)cc[n+]2[O-])c1
Temperature: 25 °C
Reaction time: 24 h
Yield: 71.1 %

Procedure:
4,4′-Dimethyl-2,2′-bipyridyl (4.8 g, 26 mmol) and 3-chloroperbenzoic acid (77%, 8.7 g, 39 mmol) were dissolved in chloroform (25 ml), and the mixture was stirred at room temperature for 24 hrs. The solvent was evaporated, and the residue was subjected to a silica gel column chromatography. The fractions eluted with ethyl acetate-methanol (4:1, v/v) were collected, concentrated and crystallized from dimethyl ether to give the titled compound (3.7 g, 71%).
Reaction SMILES: [Br-].[O:2]1[CH2:7][CH2:6][CH2:5][O:4][CH:3]1[CH2:8][CH2:9][P+](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.O1CCCC1.CC(C)([O-])C.[K+].[F:40][C:41]1[CH:42]=[C:43]([CH:48]2[CH2:53][CH2:52][CH:51]([CH:54]3[CH2:59][CH2:58][CH2:57][CH2:56][C:55]3=O)[CH2:50][CH2:49]2)[CH:44]=[CH:45][C:46]=1[F:47]>CCOCC>[O:4]1[CH2:5][CH2:6][CH2:7][O:2][CH:3]1[CH2:8][CH:9]=[C:57]1[CH2:56][CH2:55][CH:54]([CH:51]2[CH2:50][CH2:49][CH:48]([C:43]3[CH:44]=[CH:45][C:46]([F:47])=[C:41]([F:40])[CH:42]=3)[CH2:53][CH2:52]2)[CH2:59][CH2:58]1
Reactant: c1ccc([P+](CCC2OCCCO2)(c2ccccc2)c2ccccc2)cc1
Reactant: O=C1CCCCC1C1CCC(c2ccc(F)c(F)c2)CC1
Agent: CC(C)(C)[O-]
Agent: [Br-]
Agent: [K+]
Solvent: CCOCC
Solvent: C1CCOC1
Product: Fc1ccc(C2CCC(C3CCC(=CCC4OCCCO4)CC3)CC2)cc1F
Reaction time: 1 h

Procedure:
Into a three-necked flask equipped with a dropping funnel, a three-way cock and a thermometer was placed 2-(1,3-dioxan-2-yl)ethyltriphenylphosphonium bromide (12.3 g, 27 mmols), followed by adding tetrahydrofuran (100 ml), suspending, and stirring under ice cooling till the liquid temperature reached 10° C. The reaction mixture was added potassium t-butoxide (3.0 g, 27 mmols), followed by elevating the temperature up to room temperature under ice cooling for one hour, stirring for one hour, and dropwise adding a tetrahydrofuran (50 ml) solution of (4-(3,4-difluorophenyl)cyclohexylcyclohexanone (7.3 g, 25 mmols) over 30 minutes from the dropping funnel. Further, the resulting reaction mixture was stirred for 5 hours after completion of the dropwise addition, followed by adding ether (100 ml), allowing to stand for one hour, filtering off deposited insoluble substance, concentrating the filtrate under reduced pressure and isolating and purifying the resulting pale brown oil by means of silica gel column chromatography, to obtain 1-(2-(1,3-dioxan-2-yl)ethylidene)-4-(4-(3,4-difluorophenyl)cyclohexyl)cyclohexane.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:12]([C:13]3[CH:18]=[CH:17][C:16]([Cl:19])=[CH:15][C:14]=3[Cl:20])[N:11]=[C:10]([C:21](O)=O)[C:9]=2[CH3:24])=[CH:4][CH:3]=1.[CH2:25]([NH:28][C:29]([CH3:34])([CH3:33])[C:30]([NH2:32])=[O:31])[CH:26]=[CH2:27]>>[CH2:25]([N:28]1[C:29]([CH3:34])([CH3:33])[C:30](=[O:31])[N:32]=[C:21]1[C:10]1[C:9]([CH3:24])=[C:8]([C:5]2[CH:6]=[CH:7][C:2]([Cl:1])=[CH:3][CH:4]=2)[N:12]([C:13]2[CH:18]=[CH:17][C:16]([Cl:19])=[CH:15][C:14]=2[Cl:20])[N:11]=1)[CH:26]=[CH2:27]
Reactant: Cc1c(C(=O)O)nn(-c2ccc(Cl)cc2Cl)c1-c1ccc(Cl)cc1
Reactant: C=CCNC(C)(C)C(N)=O
Product: C=CCN1C(c2nn(-c3ccc(Cl)cc3Cl)c(-c3ccc(Cl)cc3)c2C)=NC(=O)C1(C)C

Procedure:
Compound 10 was synthesized from 4a (253 mg, 0.66 mmol) and 5e (148 mg, 1.05 mmol) as a white solid (171 mg, 53%) in a manner similar to that described in Example 36. 1H NMR (600 MHz, CDCl3) δ 7.41 (d, 1H), 7.27-7.23 (m, 3H), 7.13 (d, 1H), 7.04 (d, 2H), 5.93-5.88 (m, 1H), 5.13-5.07 (m, 2H), 4.54 (d, 2H), 2.37 (s, 3H), 1.40 (s, 6H); ESMS m/z: 487.1 (M+1).
Reaction SMILES: Cl.[NH2:2][NH:3][C:4]([NH2:6])=[O:5].C(N(CC)CC)C.[CH:14]1([C:17](Cl)=O)[CH2:16][CH2:15]1.[OH-].[Na+].Cl>C(Cl)Cl.O>[CH:14]1([C:17]2[NH:6][C:4](=[O:5])[NH:3][N:2]=2)[CH2:16][CH2:15]1
Reactant: O=C(Cl)C1CC1
Reactant: NNC(N)=O
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: O=c1[nH]nc(C2CC2)[nH]1
Temperature: -10 °C
Reaction time: 0.5 h
Yield: 32.5 %

Procedure:
To a suspension of semicarbazide hydrochloride (5.00 g, 44.8 mmol) in DCM (100 mL) was added triethylamine (10.00 g, 99 mmol) and the mixture was stirred at −10° C. for 30 min. Cyclopropane carbonylchloride (5.00 g, 47.8 mmol) was added at the same temp and the mixture was stirred to RT over night. The solvent from the reaction mixture was completely removed and the residue stirred in MeCN (200 mL) for 1 h. The solids were collected by filtration, washed and dried. The solid was transferred to a RB flask and treated with sodium hydroxide (7.00 g, 175 mmol) and water (20 mL). The resulting reaction mixture was heated at 100° C. for 2 hours. The reaction mixture was cooled and acidified with conc. HCl. The solids were collected by filtration, washed and dried to provide 3-cyclopropyl-1H-1,2,4-triazol-5(4H)-one (1.82 g, 30.4% yield) as white solid. 1H NMR (400 MHz, DMSO-d6): δ11.03 (br s, 2H), 1.67 (m, 1H), 0.82 (m, 2H), 0.73 (m, 2H); MS (ESI) m/z: 126.1 (M+H+).
Reaction SMILES: BrC1C=CC(S(N2CCC2)(=O)=O)=CC=1.[Br:15][C:16]1[CH:21]=[CH:20][C:19]([S:22](Cl)(=[O:24])=[O:23])=[CH:18][CH:17]=1.[F:26][C:27]1[CH:33]=[C:32]([CH3:34])[CH:31]=[CH:30][C:28]=1[NH2:29]>ClCCl.C([O-])([O-])=O.[K+].[K+]>[Br:15][C:16]1[CH:21]=[CH:20][C:19]([S:22]([NH:29][C:28]2[CH:30]=[CH:31][C:32]([CH3:34])=[CH:33][C:27]=2[F:26])(=[O:24])=[O:23])=[CH:18][CH:17]=1
Reactant: O=S(=O)(Cl)c1ccc(Br)cc1
Reactant: Cc1ccc(N)c(F)c1
Agent: O=C([O-])[O-]
Agent: O=S(=O)(c1ccc(Br)cc1)N1CCC1
Agent: [K+]
Solvent: ClCCl
Product: Cc1ccc(NS(=O)(=O)c2ccc(Br)cc2)c(F)c1

Procedure:
The title compound is analogously synthesized as described for 1-(4-bromo-benzenesulfonyl)-azetidine (compound C3) from 767 mg of 4-bromo-benzenesulfonyl chloride, 451 mg of commercially available 2-fluoro-4-methyl-aniline in 12.0 ml of dichloromethane and 6.0 ml of K2CO3 solution to yield 727 mg of the title compound as colorless, amorphous solid of m.p. 111° C. ESI-MS: 361.2/363.3 (MNH4+, 100%:87%). TLC: Rf=0.57 (neat dichloromethane).
Reaction SMILES: [O:1]1[C:9]2[CH2:8][CH2:7][N:6]([C:10](=[O:22])[CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=3)[CH2:5][C:4]=2[CH:3]=[CH:2]1.[CH2:23]([NH:25][CH2:26][CH3:27])[CH3:24].[CH2:28]=O>C(O)(=O)C>[CH2:23]([N:25]([CH2:28][C:2]1[O:1][C:9]2[CH2:8][CH2:7][N:6]([C:10](=[O:22])[CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][C:16]3[CH:17]=[CH:18][CH:19]=[CH:20][CH:21]=3)[CH2:5][C:4]=2[CH:3]=1)[CH2:26][CH3:27])[CH3:24]
Reactant: CCNCC
Reactant: O=C(CCCCCc1ccccc1)N1CCc2occc2C1
Reactant: C=O
Solvent: CC(=O)O
Product: CCN(CC)Cc1cc2c(o1)CCN(C(=O)CCCCCc1ccccc1)C2
Temperature: 100 °C
Reaction time: 1.5 h

Procedure:
To a solution of 0.347 g (1.167 mmol) of 1-(6,7-dihydro-4H-furo[3,2-c]pyridin-5-yl)-6-phenylhexan-1-one in 20 ml of acetic acid, 0.14 ml (1.4 mmol) of diethylamine and 0.11 g (1.4 mmol) of 37% aqueous formaldehyde were added, followed by stirring at 100° C. for 1.5 hours. After the solvent was distilled off under reduced pressure, the residual solution was alkalified with aqueous sodium hydroxide and extracted with dichloromethane 3 times. The combined organic layer was dried over anhydrous magnesium sulfate; the solvent was distilled off under reduced pressure. The resulting crude product was purified by silica gel column chromatography (ethyl acetate to ethyl acetate/methanol=4/1) to yield the desired product.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([Br:8])[N:3]=1.CCN(CC)CC.[CH3:16][C:17]([CH3:22])=[CH:18][C:19](Cl)=[O:20]>C(Cl)Cl>[Br:8][C:4]1[N:3]=[C:2]([NH:1][C:19](=[O:20])[CH:18]=[C:17]([CH3:22])[CH3:16])[CH:7]=[CH:6][CH:5]=1
Reactant: Nc1cccc(Br)n1
Reactant: CC(C)=CC(=O)Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CC(C)=CC(=O)Nc1cccc(Br)n1
Temperature: 25 °C
Reaction time: 12 h

Procedure:
To a solution of 2-amino-6-bromopyridine (3.015 g, 0.017 mol) and Et3N (2.40 mL, 0.017 mol) in CH2Cl2 (20.0 mL), was added 3,3-dimethylacryloylchloride (1.96 mL, 0.017 mol) under N2 at 0° C. The mixture was slowly warmed to RT and stirred for 12 h. The reaction was quenched by the addition of H2O (20.0 mL), the organic layer was separated, dried over Na2SO4 and evaporated to dryness to yield crude compound which was used without purification.
Reaction SMILES: [Cl:1][C:2]1[CH:18]=[CH:17][C:5]([CH:6]([N:9]([CH3:16])[C:10](=O)[C:11]([F:14])([F:13])[F:12])[C:7]#N)=[CH:4][CH:3]=1.ClC(=C)[C:21]#[N:22].[CH3:24]S(O)(=O)=O.C(OCC)(=O)C>C1(C)C=CC=CC=1.O>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C:6]2[N:9]([CH3:16])[C:10]([C:11]([F:12])([F:13])[F:14])=[CH:24][C:7]=2[C:21]#[N:22])=[CH:17][CH:18]=1
Reactant: C=C(Cl)C#N
Reactant: CS(=O)(=O)O
Reactant: CN(C(=O)C(F)(F)F)C(C#N)c1ccc(Cl)cc1
Solvent: O
Solvent: CCOC(C)=O
Solvent: Cc1ccccc1
Product: Cn1c(C(F)(F)F)cc(C#N)c1-c1ccc(Cl)cc1
Temperature: 110 °C
Yield: 34 %

Procedure:
A solution of N-(p-chloro-a-cyanobenzyl)-2,2,2-trifluoro-N-methylacetamide (13.8 g, 0.05 mol) in toluene is treated with 2-chloroacrylonitrile (4.4 g, 0.05 mol) and methanesulfonic acid (4.8 g, 0.05 mol), heated at 110° C. for 4 hours, treated with a second portion of 2-chloroacrylonitrile (4.4 g, 0.05 mol) and methanesulfonic acid (4.8 g, 0.05 mol), heated at 110° C. for 12 hours, cooled and treated with ethyl acetate and water. The phases are separated and the organic phase is washed with water and concentrated to give a residue. The residue is chromatographed using silica gel packed with 15% ethyl acetate in heptane and eluted with 20% ethyl acetate in heptane to give the title product as pale yellow crystals, 4.8 g (34% yield), mp 129°-130° C.
Reaction SMILES: [CH:1]1([CH2:4][O:5][C:6]2[CH:11]=[CH:10][N:9]([C:12]3[S:13][C:14]([C:18]([OH:20])=O)=[C:15]([CH3:17])[N:16]=3)[C:8](=[O:21])[CH:7]=2)[CH2:3][CH2:2]1.[CH2:22]([NH2:29])[C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1>>[CH2:22]([NH:29][C:18]([C:14]1[S:13][C:12]([N:9]2[CH:10]=[CH:11][C:6]([O:5][CH2:4][CH:1]3[CH2:2][CH2:3]3)=[CH:7][C:8]2=[O:21])=[N:16][C:15]=1[CH3:17])=[O:20])[C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1
Reactant: NCc1ccccc1
Reactant: Cc1nc(-n2ccc(OCC3CC3)cc2=O)sc1C(=O)O
Product: Cc1nc(-n2ccc(OCC3CC3)cc2=O)sc1C(=O)NCc1ccccc1
Yield: 58 %

Procedure:
Following the procedure as described in Example 1, making variations only as required to use 2-(4-(cyclopropylmethoxy)-2-oxopyridin-1(2H)-yl)-4-methylthiazole-5-carboxylic acid in place of 4-methyl-2-(2-oxo-4-phenylpyridin-1(2H)-yl)thiazole-5-carboxylic acid to react with benzylamine, the title compound was obtained as a white solid in 58% yield: mp 218-220° C. (hexane/ethyl acetate); 1H NMR (300 MHz, DMSO-d6) δ 8.77 (t, J=5.9 Hz, 1H), 8.58 (d, J=8.1 Hz, 1H), 7.35-7.18 (m, 5H), 6.34 (dd, J=8.1, 2.7 Hz, 1H), 6.05 (d, J=2.7 Hz, 1H), 4.38 (d, J=5.9 Hz, 2H), 3.88 (d, J=7.2 Hz, 2H), 2.53 (s, 3H), 1.26-1.10 (m, 1H), 0.52-0.50 (m, 2H), 0.32-0.27 (m, 2H); 13C NMR (75 MHz, DMSO-d6) δ 167.8, 161.9, 161.6, 153.8, 150.3, 139.9, 131.9, 128.7, 127.7, 127.2, 123.6, 104.4, 96.8, 73.9, 43.1, 17.5, 9.9, 3.6; MS (ES+) m/z 396.2 (M+1).
Reaction SMILES: [Cl:1][C:2]1[C:3]2[N:4]([C:8]([CH:27]3[CH2:30][C:29](=[CH2:31])[CH2:28]3)=[N:9][C:10]=2[C:11]2[CH:20]=[C:19]3[C:14]([CH:15]=[CH:16][C:17]([C:21]4[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=4)=[N:18]3)=[CH:13][CH:12]=2)[CH:5]=[CH:6][N:7]=1.B1C2CCCC1CCC2.[OH-:41].[Na+].OO>C1COCC1.C(Cl)Cl>[Cl:1][C:2]1[C:3]2[N:4]([C:8]([CH:27]3[CH2:30][CH:29]([CH2:31][OH:41])[CH2:28]3)=[N:9][C:10]=2[C:11]2[CH:20]=[C:19]3[C:14]([CH:15]=[CH:16][C:17]([C:21]4[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=4)=[N:18]3)=[CH:13][CH:12]=2)[CH:5]=[CH:6][N:7]=1
Reactant: C=C1CC(c2nc(-c3ccc4ccc(-c5ccccc5)nc4c3)c3c(Cl)nccn23)C1
Reactant: [OH-]
Agent: B1C2CCCC1CCC2
Agent: OO
Agent: [Na+]
Solvent: C1CCOC1
Solvent: ClCCl
Product: OCC1CC(c2nc(-c3ccc4ccc(-c5ccccc5)nc4c3)c3c(Cl)nccn23)C1
Temperature: 25 °C
Reaction time: 0.17 h

Procedure:
To a solution of 7-[8-chloro-3-(3-methylenecyclobutyl)-imidazo[1,5-a]pyrazin-1-yl]-2-phenylquinoline (338 mg, 0.8 mmol) in dry THF (5 mL) was added 9-BBN (2.4 mL, 1.2 mmol, 0.5M in THF) dropwise at 0° C. under nitrogen atmosphere. The temperature was slowly warmed to rt overnight. The mixture was cooled to 0° C., and 3 mL 1N aq. NaOH and 0.6 mL 30% aq. H2O2 were added, the resulting mixture was stirred at 0° C. for 10 min, then rt for 30 min. The mixture was diluted with methylene chloride (30 mL), washed with brine (2×20 mL), and dried over anhydrous sodium sulfate. The filtrate was concentrated under reduced pressure, and the crude material was purified by silica gel column chromatography (eluting with hexanes:EtOAc=50:50→100% ethyl acetate), to obtain the title compound as a yellow solid, a mixture of cis and trans isomers in the ratio of 5:1; MS (ES+): m/z 441/443 (3/1) [MH+]; 1H NMR (CDCl3, 400 MHz) δ 2.44-2.64 (m, 6H), 3.65-3.76 (m, 3H), 7.31, 7.33 (2×d, J=5.0 Hz, 1H, 1:5 ratio), 7.39-7.57 (m, 4H), 7.86-7.98 (m, 3H), 8.18 (m, 2H), 8.26 (d, J=8.6 Hz, 1H), 8.51, 8.53 (2×s, 1H, 5:1 ratio).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[S:11][C:10]3[CH:12]=[CH:13][C:14]([CH3:16])=[CH:15][C:9]=3[CH2:8][CH:7]([N:17]3[CH2:22][CH2:21][NH:20][CH2:19][CH2:18]3)[C:6]=2[CH:23]=1.Cl[CH2:25][CH2:26][N:27]1[CH2:31][CH2:30][O:29][C:28]1=[O:32]>>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[S:11][C:10]3[CH:12]=[CH:13][C:14]([CH3:16])=[CH:15][C:9]=3[CH2:8][CH:7]([N:17]3[CH2:22][CH2:21][N:20]([CH2:25][CH2:26][N:27]4[CH2:31][CH2:30][O:29][C:28]4=[O:32])[CH2:19][CH2:18]3)[C:6]=2[CH:23]=1
Reactant: Cc1ccc2c(c1)CC(N1CCNCC1)c1cc(Cl)ccc1S2
Reactant: O=C1OCCN1CCCl
Product: Cc1ccc2c(c1)CC(N1CCN(CCN3CCOC3=O)CC1)c1cc(Cl)ccc1S2

Procedure:
In a similar manner to that described in Example 1, from 1-(8-chloro-10,11-dihydro-2-methyl-dibenzo[b,f]thiepin-10-yl)-piperazine and N-(beta-chloroethyl)oxazolidinone, there is obtained 3-{2-[4-(8-chloro-10,11-dihydro-2-methyl-dibenzo[b,f]thiepin-10-yl)-1-piperazinyl]-ethyl}-2-oxazolidinone, which after recrystallization from ethyl acetate/petroleum ether, has a melting point of 184°-186°. The maleate salt melts after recrystallization from methanol/ether at 174°-175°.
Reaction SMILES: [OH:1][CH:2]1[C:11]2[C:6](=[CH:7][CH:8]=[C:9]([C:13]([OH:15])=O)[C:10]=2[CH3:12])[S:5](=[O:17])(=[O:16])[CH2:4][CH2:3]1.[CH2:18]([N:20]1[C:24]([OH:25])=[CH:23][CH:22]=[N:21]1)[CH3:19].C1(N=C=NC2CCCCC2)CCCCC1.C(=O)([O-])[O-].[K+].[K+]>C(O)(CC)(C)C>[OH:1][CH:2]1[C:11]2[C:6](=[CH:7][CH:8]=[C:9]([C:13]([C:23]3[CH:22]=[N:21][N:20]([CH2:18][CH3:19])[C:24]=3[OH:25])=[O:15])[C:10]=2[CH3:12])[S:5](=[O:17])(=[O:16])[CH2:4][CH2:3]1
Reactant: CCn1nccc1O
Reactant: Cc1c(C(=O)O)ccc2c1C(O)CCS2(=O)=O
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCC(C)(C)O
Product: CCn1ncc(C(=O)c2ccc3c(c2C)C(O)CCS3(=O)=O)c1O
Temperature: 25 °C
Reaction time: 3 h
Yield: 73.2 %

Procedure:
2.0 Grams (7.8 mmol) of 4-hydroxy-6-carboxy-5-methylthiochroman-1,1-dioxide was dissolved in 10 ml of t-amyl alcohol, and 1.0 g (8.6 mmol, 1.1 eq.) of 1-ethyl-5-hydroxypyrazole and 1.8 g (8.6 mmol, 1.1 eq.) of N,N'-dicyclohexylcarbodiimide were added. The mixture was stirred at room temperature for 3 hours. Then, 0.8 g (5.9 mmol) of potassium carbonate was added. The mixture was heated at 80° C. for 6 hours. After the completion of the reaction, the solvent was distilled off. The remaining oil was dissolved in ethyl acetate, and end product was extracted with a 5 wt % sodium hydrogencarbonate aqueous solution. The resultant aqueous solution was adjusted to a pH of 1 in an ice bath by adding 2N hydrochloric acid, and extracted with ethyl acetate. An organic layer was washed with a saturated sodium chloride aqueous solution and dried over anhydrous sodium sulfate, and the solvent was distilled off to give 2.0 g (yield 73%) of 4-hydroxy-5-methyl-6-(1-ethyl-5-hydroxypyrazol-4-yl)carbonylthiochroman-1,1-dioxide.
Reaction SMILES: [Cl:1]CCC1C=C(Cl)C=[CH:6][C:5]=1[S:11][C:12]1[CH:17]=[CH:16][C:15]([Cl:18])=[CH:14][C:13]=1CCCl.O.C(Cl)(Cl)Cl.[CH:27]([NH2:30])([CH3:29])[CH3:28]>>[ClH:1].[Cl:18][C:15]1[CH:14]=[CH:13][C:12]([S:11][CH2:5][CH2:6][NH:30][CH:27]([CH3:29])[CH3:28])=[CH:17][CH:16]=1
Reactant: CC(C)N
Reactant: ClCCc1cc(Cl)ccc1Sc1ccc(Cl)cc1CCCl
Solvent: ClC(Cl)Cl
Solvent: O
Product: CC(C)NCCSc1ccc(Cl)cc1
Product: Cl

Procedure:
A solution of 24.0 g (0.116 mole) chloroethyl-p-chlorophenyl sulfide in 100 ml of isopropylamine was agitated overnight in a stainless steel bomb at 80° C. The reaction mixture was then stripped to dryness and the residue partitioned between water and chloroform. The chloroform layer was extracted with 1N sulfuric acid. Three layers were obtained: a water phase (lower), a chloroform phase (upper) and an intermediate phase. The aqueous and intermediate phases were combined, made alkaline and extracted with chloroform. Evaporation yielded an oil, the free base of the title compound. A portion of the oil was reacted with ethereal hydrogen chloride and the resulting hydrochloride salt was recrystallized from methanol-diethyl ether to give 2.23 g (22.6%) of white crystalline product, m.p. 126°-128° C.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]2[NH:12][C:11](=[O:13])[N:10]([CH:14]3[CH2:19][CH2:18][NH:17][CH2:16][CH2:15]3)[CH2:9][CH2:8][C:7]=2[CH:20]=1.Cl[C:22]1[N:27]=[CH:26][N:25]=[C:24]([O:28][C:29]2[CH:30]=[C:31]([CH3:41])[C:32]3[N:36]=[C:35]([CH2:37][O:38][CH3:39])[NH:34][C:33]=3[CH:40]=2)[CH:23]=1.CCN(C(C)C)C(C)C>CN(C=O)C>[CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]2[NH:12][C:11](=[O:13])[N:10]([CH:14]3[CH2:19][CH2:18][N:17]([C:22]4[CH:23]=[C:24]([O:28][C:29]5[CH:30]=[C:31]([CH3:41])[C:32]6[N:36]=[C:35]([CH2:37][O:38][CH3:39])[NH:34][C:33]=6[CH:40]=5)[N:25]=[CH:26][N:27]=4)[CH2:16][CH2:15]3)[CH2:9][CH2:8][C:7]=2[CH:20]=1
Reactant: COCc1nc2c(C)cc(Oc3cc(Cl)ncn3)cc2[nH]1
Reactant: COc1ccc2c(c1)CCN(C1CCNCC1)C(=O)N2
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: COCc1nc2c(C)cc(Oc3cc(N4CCC(N5CCc6cc(OC)ccc6NC5=O)CC4)ncn3)cc2[nH]1

Procedure:
52 mg (0.19 mmol) 7-methoxy-3-piperidin-4-yl-1,3,4,5-tetrahydro-1,3-benzodiazepin-2-one, 50 mg (0.16 mmol) 6-(6-chloropyrimidin-4-yloxy)-2-(methoxymethyl)-4-methyl-1H-benzo[d]imidazole and 0.07 mL (0.40 mmol) DIPEA in 2.0 mL DMF were stirred at RT over the weekend. The reaction mixture was purified by preparative HPLC-MS. The fractions containing product were partially evaporated down i.vac. and neutralised with 4M sodium hydroxide solution. The precipitate formed was suction filtered, washed and dried.
Reaction SMILES: C([O:8][NH:9][C:10](=[O:36])[CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][N:16]1[CH2:24][C:23]2[C:18](=[CH:19][CH:20]=[CH:21][C:22]=2[C:25]2[CH:30]=[CH:29][C:28]([O:31][CH3:32])=[CH:27][C:26]=2[O:33][CH3:34])[C:17]1=[O:35])C1C=CC=CC=1.[H][H]>CO.CCOC(C)=O.[Pd]>[CH3:34][O:33][C:26]1[CH:27]=[C:28]([O:31][CH3:32])[CH:29]=[CH:30][C:25]=1[C:22]1[CH:21]=[CH:20][CH:19]=[C:18]2[C:23]=1[CH2:24][N:16]([CH2:15][CH2:14][CH2:13][CH2:12][CH2:11][C:10]([NH:9][OH:8])=[O:36])[C:17]2=[O:35]
Reactant: COc1ccc(-c2cccc3c2CN(CCCCCC(=O)NOCc2ccccc2)C3=O)c(OC)c1
Reactant: [H][H]
Agent: [Pd]
Solvent: CCOC(C)=O
Solvent: CO
Product: COc1ccc(-c2cccc3c2CN(CCCCCC(=O)NO)C3=O)c(OC)c1
Reaction time: 5 h

Procedure:
N-(benzyloxy)-6-(4-(2,4-dimethoxyphenyl)-1-oxoisoindolin-2-yl)hexanamide (22 mg, 0.045 mmol) in the Step 3 of Example 39 was dissolved in a mixture solvent of MeOH and EtOAc (mixture ratio=2:1 (v/v), 10 ml). 10% of Pd/C (2.2 mg) was added thereto and the reaction proceeded at room temperature for 5 hrs in state of the connected with hydrogen balloon. The resulting mixture thus obtained was filtered with Celite, and the filtrates were distilled under a reduced pressure to remove the solvent and obtained the title compound quantitatively.