Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([Cl:8])[C:3]=1[CH2:9][S:10]([C:13]1[CH:14]=[C:15]2[C:19](=[CH:20][CH:21]=1)[NH:18][C:17](=[O:22])/[C:16]/2=[CH:23]\[C:24]1[NH:28][C:27]([CH3:29])=[C:26]([C:30]([OH:32])=O)[C:25]=1[CH3:33])(=[O:12])=[O:11].C1C=CC2N(O)N=NC=2C=1.CCN=C=NCCCN(C)C.Cl.[NH2:56][C:57]([CH2:62][OH:63])([CH2:60][OH:61])[CH2:58][OH:59]>CN(C=O)C>[OH:59][CH2:58][C:57]([NH:56][C:30]([C:26]1[C:25]([CH3:33])=[C:24](/[CH:23]=[C:16]2\[C:17](=[O:22])[NH:18][C:19]3[C:15]\2=[CH:14][C:13]([S:10]([CH2:9][C:3]2[C:2]([Cl:1])=[CH:7][CH:6]=[CH:5][C:4]=2[Cl:8])(=[O:11])=[O:12])=[CH:21][CH:20]=3)[NH:28][C:27]=1[CH3:29])=[O:32])([CH2:62][OH:63])[CH2:60][OH:61]
Reactant: Cc1[nH]c(/C=C2\C(=O)Nc3ccc(S(=O)(=O)Cc4c(Cl)cccc4Cl)cc32)c(C)c1C(=O)O
Reactant: NC(CO)(CO)CO
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Product: Cc1[nH]c(/C=C2\C(=O)Nc3ccc(S(=O)(=O)Cc4c(Cl)cccc4Cl)cc32)c(C)c1C(=O)NC(CO)(CO)CO
Temperature: 25 °C
Reaction time: 216 h

Procedure:
To a mixture of 5-[5-(2,6-dichloro-phenylmethanesulfonyl)-2-oxo-1,2-dihydro-indol-(3Z)-ylidenemethyl]-2,4-dimethyl-1H-pyrrole-3-carboxylic acid (100 mg, 0.19 mmol), HOBt (31 mg, 1.2 eq.), EDAC.HCl (44 mg, 1.2 eq.) and 2-amino-2-hydroxymethyl-propane-1,3-diol (58 mg, 1.1 eq.) in DMF (2 mL) was added TEA (0.066 mL, 2.5 eq.). After stirring at rt for 9 days, the reaction was concentrated, diluted with DCM and then added solid sodium bicarbonate. After stirring at rt for 15 mins, the resulted suspension was loaded onto a silica gel column to give the titled compound as an orange solid.
Reaction SMILES: CS([O:5][CH2:6][C:7]1[C:8]([C:12]2[S:13][C:14]([Cl:17])=[CH:15][CH:16]=2)=[N:9][S:10][CH:11]=1)(=O)=O.O[C:19]1[CH:24]=[CH:23][C:22]([CH2:25][CH2:26][C:27]([O:29]CC)=[O:28])=[C:21]([F:32])[C:20]=1[F:33]>>[Cl:17][C:14]1[S:13][C:12]([C:8]2[C:7]([CH2:6][O:5][C:19]3[CH:24]=[CH:23][C:22]([CH2:25][CH2:26][C:27]([OH:29])=[O:28])=[C:21]([F:32])[C:20]=3[F:33])=[CH:11][S:10][N:9]=2)=[CH:16][CH:15]=1
Reactant: CS(=O)(=O)OCc1csnc1-c1ccc(Cl)s1
Reactant: CCOC(=O)CCc1ccc(O)c(F)c1F
Product: O=C(O)CCc1ccc(OCc2csnc2-c2ccc(Cl)s2)c(F)c1F

Procedure:
The title compound was prepared according to the procedure described in Example 91 following Step 5 and 6 by coupling (3-(5-chlorothiophen-2-yl)isothiazol-4-yl)methyl methanesulfonate and ethyl 3-(4-hydroxy-2,3-difluorophenyl)propanoate followed by hydrolysis to afford the desired product as an off-white solid. 1H NMR (400 MHz, CDCl3) δ 8.75 (s, 1H), 7.27 (m, 1H), 6.95 (m, 1H), 6.90 (m, 1H), 6.73 (m, 1H), 5.24 (s, 2H), 2.98 (t, J=4.5 Hz, 2H), 2.74 (t, J=7.5 Hz, 2H).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:12]=[CH:11][CH:10]=[C:9]2[C:4]=1[CH2:5][CH2:6][C:7](=O)[CH:8]2[CH2:13][C:14]([O:16]CC)=O.[NH2:20][CH2:21][CH2:22][N:23]1[CH2:28][CH2:27][O:26][CH2:25][CH2:24]1.O>C1(C)C=CC=CC=1>[CH3:1][O:2][C:3]1[C:4]2[CH2:5][CH2:6][C@H:7]3[C@H:8]([CH2:13][C:14](=[O:16])[N:20]3[CH2:21][CH2:22][N:23]3[CH2:28][CH2:27][O:26][CH2:25][CH2:24]3)[C:9]=2[CH:10]=[CH:11][CH:12]=1
Reactant: NCCN1CCOCC1
Reactant: CCOC(=O)CC1C(=O)CCc2c(OC)cccc21
Solvent: Cc1ccccc1
Solvent: O
Product: COc1cccc2c1CC[C@H]1[C@@H]2CC(=O)N1CCN1CCOCC1
Yield: 85.7 %

Procedure:
A solution of 6.30 g (0.024 mol) of ethyl rac-1,2,3,4-tetrahydro-5-methoxy-2-oxo-1-napthylacetate in 100 ml of toluene was treated with 3.1 ml (0.024 mol) of 4-(2-aminoethyl)morpholine, whereupon the mixture was boiled on a water separator for 20 hours. After concentration the residue was hydrogenated with 1 g of Raney-nickel in 100 ml of ethanol at 120° and 180 bar. The product was chromatographed over silica gel with methylene chloride/methanol (9:1). There were obtained 6.80 g (86%) of oily rac-cis-1,3,3a, 4,5,9b-hexahydro-6-methoxy-3-(2-morpholinoethyl)-2H-benzo[e]indol-2-one.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([S:8][C:9]2[CH:24]=[CH:23][C:12]([C:13]([NH:15][C:16]3[CH:21]=[CH:20][C:19]([Br:22])=[CH:18][CH:17]=3)=[O:14])=[CH:11][C:10]=2[NH:25][C:26]2[C:27]3[CH:35]=[CH:34][C:33]([CH:36]([CH3:38])[CH3:37])=[N:32][C:28]=3[N:29]=[CH:30][N:31]=2)=[CH:4][CH:3]=1.[NH:39](C(OC(C)(C)C)=O)[C@H:40]([C:43](O)=[O:44])[CH2:41][CH3:42].C(OP(ON1C(=O)C2C=CC=CC=2N=N1)(OCC)=O)C.C(N(CC)CC)C.C(=O)([O-])[O-].[Na+].[Na+]>O1CCCC1>[NH2:39][CH:40]([CH2:41][CH3:42])[C:43]([NH:1][C:2]1[CH:7]=[CH:6][C:5]([S:8][C:9]2[CH:24]=[CH:23][C:12]([C:13]([NH:15][C:16]3[CH:17]=[CH:18][C:19]([Br:22])=[CH:20][CH:21]=3)=[O:14])=[CH:11][C:10]=2[NH:25][C:26]2[C:27]3[CH:35]=[CH:34][C:33]([CH:36]([CH3:38])[CH3:37])=[N:32][C:28]=3[N:29]=[CH:30][N:31]=2)=[CH:4][CH:3]=1)=[O:44]
Reactant: CC[C@H](NC(=O)OC(C)(C)C)C(=O)O
Reactant: CC(C)c1ccc2c(Nc3cc(C(=O)Nc4ccc(Br)cc4)ccc3Sc3ccc(N)cc3)ncnc2n1
Agent: CCOP(=O)(OCC)On1nnc2ccccc2c1=O
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: CCC(N)C(=O)Nc1ccc(Sc2ccc(C(=O)Nc3ccc(Br)cc3)cc2Nc2ncnc3nc(C(C)C)ccc23)cc1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
To a solution of the product from Example 51E (59 mg, 0.1 mmol) and Boc-Abu-OH (22 mg, 0.11 mmol) in tetrahydrofuran (5 ml) was added 3-(diethoxyphosphoryloxy)-1,2,3-benzo-triazin-4(3H)-one (36 mg, 0.11 mmol) and triethylamine (0.07 ml, 0.5 mmol). The mixture was stirred at room temperature for 16 hours then poured into saturated sodium carbonate solution and extracted with ethyl acetate. The organic layer was dried with magnesium sulfate, filtered and evaporated. To the residue was added dichloromethane (2 ml) and trifluoroacetic acid (2 ml) then stirred at room temperature for 1 hour. The solvent was evaporated and the residue was purified by HPLC with NH4OH to provide the title compound. (62 mg, 85%). 1H NMR (300 MHz, DMSO-D6) δ ppm: 0.90 (t, J=7.54 Hz, 3 H) 1.33 (d, J=6.99 Hz, 6 H) 1.48 (m, 1 H) 1.66 (m, 1 H) 1.90 (s, 3 H) 3.22 (m, 2 H) 7.02 (m, 2 H) 7.40 (d, J=8.46 Hz, 2 H) 7.52 (d, J=8.46 Hz, 2 H) 7.61 (d, J=8.46 Hz, 1 H) 7.72 (m, 5 H) 7.94 (s, 1 H) 8.52 (s, 1 H) 8.79 (s, 1 H) 10.33 (s, 1 H); MS (ESI+) m/z 670, 672 (M+H)+.
Reaction SMILES: [Cl-].[Mg+2].[Cl-].[C:4]([O:10][C:11]([CH3:14])([CH3:13])[CH3:12])(=[O:9])[CH2:5][C:6]([CH3:8])=[O:7].[CH2:15]([C:17]1[CH:22]=[CH:21][C:20]([CH2:23][C:24](Cl)=[O:25])=[CH:19][CH:18]=1)[CH3:16].C(O)(=O)CC(CC(O)=O)(C(O)=O)O>ClCCl.N1C=CC=CC=1>[C:6]([CH:5]([C:24](=[O:25])[CH2:23][C:20]1[CH:21]=[CH:22][C:17]([CH2:15][CH3:16])=[CH:18][CH:19]=1)[C:4]([O:10][C:11]([CH3:14])([CH3:13])[CH3:12])=[O:9])(=[O:7])[CH3:8]
Reactant: CCc1ccc(CC(=O)Cl)cc1
Reactant: CC(=O)CC(=O)OC(C)(C)C
Agent: O=C(O)CC(O)(CC(=O)O)C(=O)O
Agent: [Cl-]
Agent: [Mg+2]
Solvent: c1ccncc1
Solvent: ClCCl
Product: CCc1ccc(CC(=O)C(C(C)=O)C(=O)OC(C)(C)C)cc1
Temperature: 0 °C
Reaction time: 2.5 h

Procedure:
A suspension of magnesium chloride (1.74 g) in dichloromethane (30 ml) was cooled to 0° C., and thereto were added t-butyl acetoacetate (3.03 ml) and pyridine (2.96 ml), and successively was added a solution of the above 4-ethylphenylacetyl chloride in dichloromethane (30 ml). The mixture was stirred at the same temperature for 2.5 hours, and an aqueous citric acid solution was added thereto. The mixture was extracted with chloroform. The extract was washed with brine, and dried over sodium sulfate. The solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (hexane:ethyl acetate=15:1) to give t-butyl 2-acetyl-4-(4-ethylphenyl)-3-oxobutyrate (4.75 g) as pale yellow oil. APCI-Mass m/Z 322 (M+NH4).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4](B(O)O)[CH:5]=[C:6]([F:8])[CH:7]=1.Br[C:13]1[S:17][C:16]([C:18]([O:20]CC)=[O:19])=[N:15][C:14]=1[C:23]1[CH:28]=[CH:27][C:26]([F:29])=[C:25]([C:30]#[N:31])[CH:24]=1.C(=O)(O)[O-].[Na+]>COCCOC.O.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>[Cl:1][C:2]1[CH:3]=[C:4]([C:13]2[S:17][C:16]([C:18]([OH:20])=[O:19])=[N:15][C:14]=2[C:23]2[CH:28]=[CH:27][C:26]([F:29])=[C:25]([C:30]#[N:31])[CH:24]=2)[CH:5]=[C:6]([F:8])[CH:7]=1
Reactant: OB(O)c1cc(F)cc(Cl)c1
Reactant: CCOC(=O)c1nc(-c2ccc(F)c(C#N)c2)c(Br)s1
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: [Na+]
Solvent: O
Solvent: COCCOC
Product: N#Cc1cc(-c2nc(C(=O)O)sc2-c2cc(F)cc(Cl)c2)ccc1F

Procedure:
At room temperature, 256 mg (1.48 mmol) of (3-chloro-5-fluorophenyl)boronic acid are added to 350 mg (0.985 mmol) of the compound from Example 29A and 56.9 mg (0.049 mmol) of tetrakis(triphenylphosphine)palladium in 26 ml of DME. 252 mg (3.01 mmol) of sodium bicarbonate in 11 ml of water are subsequently added, and the mixture is stirred under reflux for 1 h. The reaction solution is subsequently concentrated under reduced pressure and the residue is taken up in ethyl acetate and washed with a saturated aqueous sodium chloride solution. The organic phase is dried over magnesium sulfate, filtered and concentrated. The residue is purified by preparative HPLC (RP18 column; mobile phase: acetonitrile/water gradient). 50.0 mg (13% of theory) and 41 mg (9% of theory, purity 84%) of the title compound are obtained.
Reaction SMILES: [Cl:1][C:2]1[N:7]=[CH:6][C:5]([C:8]2[CH:20]=[CH:19][C:11]3[N:12]=[C:13]([NH:15][C:16](=[O:18])[CH3:17])[S:14][C:10]=3[CH:9]=2)=[CH:4][C:3]=1[O:21][CH2:22][O:23]CCOC.Cl.[CH3:29]C(OC(C)=O)=O>>[C:22]([O:21][C:3]1[C:2]([Cl:1])=[N:7][CH:6]=[C:5]([C:8]2[CH:20]=[CH:19][C:11]3[N:12]=[C:13]([NH:15][C:16](=[O:18])[CH3:17])[S:14][C:10]=3[CH:9]=2)[CH:4]=1)(=[O:23])[CH3:29]
Reactant: COCCOCOc1cc(-c2ccc3nc(NC(C)=O)sc3c2)cnc1Cl
Reactant: CC(=O)OC(C)=O
Agent: Cl
Product: CC(=O)Nc1nc2ccc(-c3cnc(Cl)c(OC(C)=O)c3)cc2s1
Temperature: 120 °C
Reaction time: 2 h
Yield: 52 %

Procedure:
A 10 mL flask was charged with N-(6-(6-chloro-5-((2-methoxyethoxy)methoxy)pyridin-3-yl)benzo[d]thiazol-2-yl)acetamide (0.0683 g, 0.167 mmol), 5 mL TFE, a stirbar and 2.0 M HCl (0.251 ml, 0.502 mmol). The flask was fitted with a reflux condenser, heated in a 120° C. oil bath for 45 minutes and cooled. The solvent was removed in vacuo, and the residue was suspended in 3 mL EtOH, and heated with a 120° C. oil bath for 5 minutes and cooled. HPLC-MS showed that a significant amount of de-acetylation had occurred. The solvent was removed in vacuo, the residue was dissolved in 3 mL dry pyridine, and stirred under an Ar atmosphere with 100 mg 5 {acute over (Å)} activated powdered molecular sieves for 1 h. The slurry was filtered, and the molecular sieves were washed with 1 mL dy pyridine. The filtrate was treated with Ac2O (0.0474 ml, 0.502 mmol) and the flask was heated using a 70° C. oil bath for 3 h. An additional aliquot of Ac2O (0.0474 ml, 0.502 mmol) was added, and heating was continued for 2 h. The solution was cooled, and the solvent was removed in vacuo. The residue was treated with 3 mL dry TFE and concentrated in vacuo, and evacuated to 0.4 mm Hg over night. The solids were suspended in 2 mL 10% aqueous EtOH, and filtered. The solids were collected using a glass frit under position pressure nitrogen, and washed with EtOH (2×1 mL). The precipitate was initially dried under a stream of nitrogen, and then at 60° C. and <1 mm Hg for 1 h to afford 5-(2-acetamidobenzo[d]thiazol-6-yl)-2-chloropyridin-3-yl acetate (0.0314 g, 51.8% yield). 1H NMR (400 MHz, CF3CD2OD) δ ppm 2.15 (s, 3H) 2.25 (s, 3H) 7.50 (dd, J=8.51, 1.56 Hz, 1H) 7.67 (d, J=8.51 Hz, 1H) 7.71 (d, J=2.05 Hz, 1H) 7.84 (d, J=1.17 Hz, 1H) 8.31 (d, J=2.05 Hz, 1H). 13C NMR (101 MHz, CF3CD2OD) δ ppm 20.74 (s, 1 C) 23.29 (s, 1 C) 121.66 (s, 1 C) 122.72 (s, 1 C) 127.52 (s, 1 C) 133.32 (s, 1 C) 133.39 (s, 1 C) 134.61 (s, 1 C) 139.71 (s, 1 C) 144.50 (s, 1 C) 145.96 (s, 1 C) 146.19 (s, 1 C) 149.75 (s, 1 C) 162.07 (s, 1 C) 172.51 (s, 1 C) 173.47 (s, 1 C). HPLC-MS: retention time=1.95 min (97.0%@215 nm; 98.5% @254 nm; m/z=361.9, calculated for C16H12ClN3O3S+H+=362.0).
Reaction SMILES: [F:1][C:2]([F:7])([F:6])[C:3]([OH:5])=[O:4].[NH2:8][CH2:9][CH2:10][NH:11][C:12]([C:14]1[N:22]=[C:21]2[C:17]([N:18]=[CH:19][N:20]2[C@@H:23]2[CH2:27][C@H:26]([N:28]3[CH:32]=[C:31]([CH2:33][OH:34])[CH:30]=[N:29]3)[C@@H:25]([OH:35])[C@H:24]2[OH:36])=[C:16]([NH:37][CH2:38][CH:39]([C:46]2[CH:51]=[CH:50][CH:49]=[CH:48][CH:47]=2)[C:40]2[CH:45]=[CH:44][CH:43]=[CH:42][CH:41]=2)[N:15]=1)=[O:13].FC(F)(F)C(O)=O.O[C@@H]1[C@H](O)[C@@H](N2C=C(C)C=N2)C[C@H]1N1C=NC2C1=NC(NC1CCC(N[C:104]([NH:106][CH:107]3[CH2:112][CH2:111][N:110]([C:113]4[CH:118]=[CH:117][CH:116]=[CH:115][N:114]=4)[CH2:109]C3)=[O:105])CC1)=NC=2NCC(C1C=CC=CC=1)C1C=CC=CC=1.N1C=CC=CC=1N1CC[C@H](NC(N2C=CN=C2)=O)C1>>[F:1][C:2]([F:7])([F:6])[C:3]([OH:5])=[O:4].[N:114]1[CH:115]=[CH:116][CH:117]=[CH:118][C:113]=1[N:110]1[CH2:111][CH2:112][C@H:107]([NH:106][C:104](=[O:105])[NH:8][CH2:9][CH2:10][NH:11][C:12]([C:14]2[N:22]=[C:21]3[C:17]([N:18]=[CH:19][N:20]3[C@@H:23]3[CH2:27][C@H:26]([N:28]4[CH:32]=[C:31]([CH2:33][OH:34])[CH:30]=[N:29]4)[C@@H:25]([OH:35])[C@H:24]3[OH:36])=[C:16]([NH:37][CH2:38][CH:39]([C:46]3[CH:47]=[CH:48][CH:49]=[CH:50][CH:51]=3)[C:40]3[CH:41]=[CH:42][CH:43]=[CH:44][CH:45]=3)[N:15]=2)=[O:13])[CH2:109]1
Reactant: NCCNC(=O)c1nc(NCC(c2ccccc2)c2ccccc2)c2ncn([C@@H]3C[C@H](n4cc(CO)cn4)[C@@H](O)[C@H]3O)c2n1
Reactant: Cc1cnn([C@H]2C[C@@H](n3cnc4c(NCC(c5ccccc5)c5ccccc5)nc(NC5CCC(NC(=O)NC6CCN(c7ccccn7)CC6)CC5)nc43)[C@H](O)[C@@H]2O)c1
Agent: O=C(N[C@H]1CCN(c2ccccn2)C1)n1ccnc1
Solvent: O=C(O)C(F)(F)F
Product: O=C(NCCNC(=O)c1nc(NCC(c2ccccc2)c2ccccc2)c2ncn([C@@H]3C[C@H](n4cc(CO)cn4)[C@@H](O)[C@H]3O)c2n1)N[C@H]1CCN(c2ccccn2)C1

Procedure:
This compound is prepared from 9-[(1R,2S,3R,4S)-2,3-dihydroxy-4-(4-hydroxymethyl-pyrazol-1-yl)-cyclopentyl]-6-(2,2-diphenyl-ethylamino)-9H-purine-2-carboxylic acid (2-amino-ethyl)-amide trifluoroacetate (Example 80, first step a) using a procedure analogous to that of 1-{4-[9-[(1R,2S,3R,4S)-2,3-dihydroxy-4-(4-methyl-pyrazol-1-yl)-cyclopentyl]-6-(2,2-diphenyl-ethylamino)-9H-purin-2-ylamino]-cyclohexyl}-3-(3,4,5,6-tetrahydro-2H-[1,2′]bipyridinyl-4-yl)-urea trifluoroacetate (Example 42) replacing N-[1-(2-pyridinyl)-4-piperidinyl]-1H-imidazole-1-carboxamide with imidazole-1-carboxylic acid ((S)-1-pyridin-2-yl-pyrrolidin-3-yl)-amide. MS (ES+) m/e 394 (MH+/2).
Reaction SMILES: [CH3:1][S:2]([N:5]1[CH2:10][CH2:9][N:8](C(OC(C)(C)C)=O)[CH2:7][CH2:6]1)(=[O:4])=[O:3].FC(F)(F)C(O)=O>ClCCl>[CH3:1][S:2]([N:5]1[CH2:10][CH2:9][NH:8][CH2:7][CH2:6]1)(=[O:4])=[O:3]
Reactant: CC(C)(C)OC(=O)N1CCN(S(C)(=O)=O)CC1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CS(=O)(=O)N1CCNCC1
Temperature: 25 °C
Reaction time: 4 h

Procedure:
To a solution of Example 1013 (8.2 g, 28.5 mmol) in dichloromethane (40 mL) was added trifluoroacetic acid (30 mL) at about 0° C. The mixture was stirred at room temperature for about 4 h and was then concentrated under vacuum. The residue was basified with sodium carbonate and was extracted with dichloromethane. The combined organic extracts were dried over Na2SO4, filtered and concentrated under vacuum to provide the desired product. 1H NMR (300 MHz, CDCL3): δ 2.80 (s, 3H), 3.00 (t, J=7.0 Hz, 4H), 3.21 (t, J=7.0 Hz, 4H).
Reaction SMILES: [Cl:1][C:2]1[CH:6]=[CH:5][S:4][C:3]=1B(O)O.ClC1C=CSC=1.Br[C:17]1[CH:18]=[N:19][CH:20]=[CH:21][CH:22]=1>>[Cl:1][C:2]1[CH:6]=[CH:5][S:4][C:3]=1[C:18]1[CH:17]=[CH:22][CH:21]=[CH:20][N:19]=1
Reactant: Brc1cccnc1
Reactant: OB(O)c1sccc1Cl
Agent: Clc1ccsc1
Product: Clc1ccsc1-c1ccccn1
Yield: 14.2 %

Procedure:
3-chlorothiophene-2-boronic acid (1.5 g, 9.24 mmol), prepared as described in EXAMPLE 48, Part A from 3-chlorothiophene was reacted with 3-bromopyridine (0.81 mL, 8.4 mmol) as described in EXAMPLE 48, Part B to give the title compound (0.232 g, 1.19 mmol).
Reaction SMILES: [C-:1]#[N:2].[K+].C1(C)C=CC(S(O[CH2:14][CH:15]2[CH2:24][C:23]3[C:18](=[CH:19][CH:20]=[CH:21][CH:22]=3)[O:17][CH2:16]2)(=O)=O)=CC=1>CS(C)=O>[C:1]([CH2:14][CH:15]1[CH2:24][C:23]2[C:18](=[CH:19][CH:20]=[CH:21][CH:22]=2)[O:17][CH2:16]1)#[N:2]
Reactant: [C-]#N
Reactant: Cc1ccc(S(=O)(=O)OCC2COc3ccccc3C2)cc1
Agent: [K+]
Solvent: CS(C)=O
Product: N#CCC1COc2ccccc2C1
Temperature: 0 °C
Reaction time: 3 h
Yield: 88.2 %

Procedure:
12.53 g (192.5 mmol) of potassium cyanide are added at room temperature to a solution of 55.72 g (175 mmol) of 3-(p-toluenesulphonyloxymethyl)chroman (for manufacture see Example 1) in 300 ml of dimethyl sulphoxide and the whole is heated to 60° while stirring. After 3 hours, ice-water is added to the reaction mixture, the whole is extracted with diethyl ether and washed thoroughly with water. The combined organic phases are dried over sodium sulphate and concentrated by evaporation in vacuo. 26.75 g (88.3%) of 3-cyanomethylchroman are obtained in the form of a pale yellow oil which crystallises from diethyl ether/pentane. The crystals melt at 63°.
Reaction SMILES: [O:1]1[CH2:6][CH2:5][CH:4]([NH2:7])[CH2:3][CH2:2]1.[CH:8]([N:21]1[CH:26]=[CH:25][C:24]([C:27]2[CH:32]=[CH:31][N:30]=[C:29](S(C)(=O)=O)[N:28]=2)=[CH:23][C:22]1=[O:37])([C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)[C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1>CC(N(C)C)=O.O>[CH:8]([N:21]1[CH:26]=[CH:25][C:24]([C:27]2[CH:32]=[CH:31][N:30]=[C:29]([NH:7][CH:4]3[CH2:5][CH2:6][O:1][CH2:2][CH2:3]3)[N:28]=2)=[CH:23][C:22]1=[O:37])([C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1)[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1
Reactant: CS(=O)(=O)c1nccc(-c2ccn(C(c3ccccc3)c3ccccc3)c(=O)c2)n1
Reactant: NC1CCOCC1
Solvent: CC(=O)N(C)C
Solvent: O
Product: O=c1cc(-c2ccnc(NC3CCOCC3)n2)ccn1C(c1ccccc1)c1ccccc1
Temperature: 120 °C
Yield: 55.2 %

Procedure:
Tetrahydro-2H-pyran-4-amine (0.20 g, 2.0 mmol) was added to 1-benzhydryl-4-(2-(methylsulfonyl)pyrimidin-4-yl)pyridin-2(1H)-one (0.12 g, 0.29 mmol) in DMA (3 mL) in a microwave vial. The mixture was heated at 120° C. for 1 hour in a microwave. The reaction mixture was diluted with water and extracted with EtOAc. The EtOAc was washed with water, twice with brine, dried over MgSO4, filtered, and evaporated to yield a crude product (0.09 g) as a film. This was chromatographed on a 10 g Biotage SNAP column with EtOAc. Fractions 9-20 contained a film (0.0764 g). This was triturated with water, dried, then triturated with hexane and dried to afford the desired 1-benzhydryl-4-(2-((tetrahydro-2H-pyran-4-yl)amino)pyrimidin-4-yl)pyridin-2(1H)-one (0.072 g, 0.16 mmol, 57% yield) as a film. 1H NMR (400 MHz, CDCl3) δ 8.38 (d, 1H), 7.52 (s, 1H), 7.40-7.15 (m, 9H), 6.91 (d, 1H), 6.76-6.72 (m, 1H), 5.25-5.21 (m, 1H), 4.15-4.06 (m, 1H), 4.02-3.96 (m, 2H), 3.59-3.51 (m, 2H), 2.09-2.03 (m, 2H), 1.62-1.52 (m, 2H); m/z (APCI-pos) M+1=439.2.
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[CH:7][C:8]([O:14][CH3:15])=[C:9]([O:12][CH3:13])[CH:10]=2)[N:5]=[CH:4][C:3]=1[C:16]#[N:17].Cl.N1C=CC=CC=1.[NH2:25][C:26]1[C:31]([OH:32])=[CH:30][CH:29]=[C:28]([CH3:33])[CH:27]=1>C(OCCO)C>[OH:32][C:31]1[CH:30]=[CH:29][C:28]([CH3:33])=[CH:27][C:26]=1[NH:25][C:2]1[C:11]2[C:6](=[CH:7][C:8]([O:14][CH3:15])=[C:9]([O:12][CH3:13])[CH:10]=2)[N:5]=[CH:4][C:3]=1[C:16]#[N:17]
Reactant: COc1cc2ncc(C#N)c(Cl)c2cc1OC
Reactant: Cc1ccc(O)c(N)c1
Agent: Cl
Solvent: CCOCCO
Solvent: c1ccncc1
Product: COc1cc2ncc(C#N)c(Nc3cc(C)ccc3O)c2cc1OC
Yield: 93.9 %

Procedure:
Using an analogous procedure to that described in Example 286, 248.7 mg (1 mmol) of 4-chloro-6,7-dimethoxy-3-quinolinecarbonitrile, in 15 mL of 2-ethoxyethanol and in the presence of 115.6 mg (1 mmol) of pyridine hydrochloride was reacted with 147.8 mg (1.2 mmol) of 2-amino-p-cresol to give 315.0 mg (94.0%) of the product as a yellow solid, m.p. 198-200° C., mass (electrospray, m/e): M+H 335.8.
Reaction SMILES: [ClH:1].[OH:2][C:3]1[CH:12]=[CH:11][C:10]([CH:13]([OH:31])[CH2:14][N:15]2[CH2:20][CH:19]=[C:18]([N:21]3[C:25]4[CH:26]=[CH:27][CH:28]=[CH:29][C:24]=4[NH:23][C:22]3=[O:30])[CH2:17][CH2:16]2)=[CH:9][C:4]=1[C:5]([O:7]C)=O.Cl.OC1C=CC(C(O)C[N:46]2CCC(N3C4C=CC=CC=4NC3=O)CC2)=CC=1C(OC)=O>>[ClH:1].[OH:2][C:3]1[CH:12]=[CH:11][C:10]([CH:13]([OH:31])[CH2:14][N:15]2[CH2:20][CH:19]=[C:18]([N:21]3[C:25]4[CH:26]=[CH:27][CH:28]=[CH:29][C:24]=4[NH:23][C:22]3=[O:30])[CH2:17][CH2:16]2)=[CH:9][C:4]=1[C:5]([NH2:46])=[O:7]
Reactant: COC(=O)c1cc(C(O)CN2CCC(n3c(=O)[nH]c4ccccc43)CC2)ccc1O
Reactant: COC(=O)c1cc(C(O)CN2CC=C(n3c(=O)[nH]c4ccccc43)CC2)ccc1O
Agent: Cl
Product: NC(=O)c1cc(C(O)CN2CC=C(n3c(=O)[nH]c4ccccc43)CC2)ccc1O

Procedure:
Following essentially the same procedure but substituting methyl 2-hydroxy-5-[1-hydroxy-2-[4-(2-oxo-1-benzimidazolinyl)-1,2,3,6-tetrahydro-1-pyridyl]ethyl]benzoate hydrochloride for the methyl 2-hydroxy-5-[1-hydroxy-2-[4-(2-oxo-1-benzimidazolinyl)piperidino]ethyl]benzoate hydrochloride above results in the formation of 2-hydroxy-5-[1-hydroxy-2-[4-(2-oxo-1-benzimidazolinyl)-1,2,3,6-tetrahydro-1-pyridyl]ethyl]benzamide hydrochloride.
Reaction SMILES: [BH4-].[Na+].Cl[C:4]1([C:14]([O:16][C:17]([CH3:20])([CH3:19])[CH3:18])=[O:15])[CH2:6][CH:5]1[C:7]([O:9][C:10]([CH3:13])([CH3:12])[CH3:11])=[O:8]>CN(C)C(=O)C.O.O.O.O.O.O.[Co](Cl)Cl>[CH:5]1([C:7]([O:9][C:10]([CH3:13])([CH3:12])[CH3:11])=[O:8])[CH2:6][CH:4]1[C:14]([O:16][C:17]([CH3:18])([CH3:19])[CH3:20])=[O:15]
Reactant: CC(C)(C)OC(=O)C1CC1(Cl)C(=O)OC(C)(C)C
Agent: Cl[Co]Cl
Agent: [BH4-]
Agent: [Na+]
Solvent: O
Solvent: CC(=O)N(C)C
Product: CC(C)(C)OC(=O)C1CC1C(=O)OC(C)(C)C
Yield: 96 %

Procedure:
Sodium borohydride (103 mg, 1.81 mmol) was added to and dissolved in N,N-dimethylacetamide (1.5 mL) at room temperature, followed by addition of an N,N-dimethylacetamide solution (1.0 mL) of di-tert-butyl 1-chlorocyclopropane-1,2-dicarboxylate (cis/trans=26/74) (hereinafter the compound will be referred to as “compound (4b)”) (500 mg, 1.81 mmol) at 10° C. Cobalt chloride hexahydrate (2.4 mg, 0.010 mmol) was added to the resultant solution at the same temperature. After completion of addition, the resultant mixture was stirred at 40° C. for six hours. After completion of reaction, the whole reaction mixture was diluted with an HPLC mobile phase to 50 mL, to thereby yield a solution containing 418.8 mg (yield: 96%) of the title compound. Yield was determined by means of high performance liquid chromatography (HPLC) (the same shall apply hereinafter).
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[NH:8][C:7](=[O:12])[N:6]([CH3:13])[CH:5]2[C:14]1[CH:19]=[CH:18][C:17]([Cl:20])=[CH:16][CH:15]=1.[CH3:21][C:22]1[C:26](B(O)O)=[C:25]([CH3:30])[O:24][N:23]=1.C([O-])([O-])=O.[Na+].[Na+]>O1CCOCC1.Cl[Pd]Cl>[Cl:20][C:17]1[CH:18]=[CH:19][C:14]([CH:5]2[C:4]3[C:9](=[CH:10][CH:11]=[C:2]([C:26]4[C:22]([CH3:21])=[N:23][O:24][C:25]=4[CH3:30])[CH:3]=3)[NH:8][C:7](=[O:12])[N:6]2[CH3:13])=[CH:15][CH:16]=1
Reactant: CN1C(=O)Nc2ccc(Br)cc2C1c1ccc(Cl)cc1
Reactant: Cc1noc(C)c1B(O)O
Agent: Cl[Pd]Cl
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: C1COCCO1
Product: Cc1noc(C)c1-c1ccc2c(c1)C(c1ccc(Cl)cc1)N(C)C(=O)N2
Temperature: 120 °C

Procedure:
To a solution of 6-Bromo-4-(4-chloro-phenyl)-3-methyl-3,4-dihydro-1H-quinazolin-2-one (0.2 g, 0.57 mmol) dissolved in dioxane (50 mL) is added 3,5-dimethylisoxazole-4-boronic acid (0.1 g, 0.74 mmol), PdCl2 (0.048 g, 0.057 mmol) and Na2CO3 aq. The mixture is stirred at 120° C. to reflux for 5 hours. Then cooled to RT, concentrated and purified by column chromatography on silica gel to give the desired compound.
Reaction SMILES: [NH2:1][C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[CH:5]=[CH:4][C:3]=1[OH:12].CN(C)C1C=CC=CC=1.[O:22]1CC[CH2:24][CH2:23]1.ClCC(Cl)=O>C(OCC)(=O)C>[NH:1]1[C:23](=[O:22])[CH2:24][O:12][C:3]2[CH:4]=[CH:5][C:6]3[C:11]([C:2]1=2)=[CH:10][CH:9]=[CH:8][CH:7]=3
Reactant: Nc1c(O)ccc2ccccc12
Reactant: C1CCOC1
Agent: O=C(Cl)CCl
Solvent: CN(C)c1ccccc1
Solvent: CCOC(C)=O
Product: O=C1COc2ccc3ccccc3c2N1
Reaction time: 1 h

Procedure:
To a mixture of 1-amino-2-naphthol (16.9 g), N,N-dimethylaniline (19.3 g) and tetrahydrofuran (200 ml) is added dropwise chloroacetyl chloride under ice cooling, and the mixture is stirred at the same temperature for one hour. To the reaction mixture is added ethyl acetate, and the ethyl acetate layer is washed, dried and distilled to remove the solvent. The resulting oil is dissolved in acetone (500 ml) and thereto is added potassium carbonate (75 g), and the mixture is refluxed for 2 hours, and acetone is distilled off. To the residue is added water, and the precipitate is separated by filtration, washed, dried and recrystallized from tetrahyrofuran to give 1H-naphtho[2,1-b][1,4]oxazin-2(3H)-one (13.1 g). M.p. 219°-220.5° C.