Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br[CH2:2][C:3]1[C:11]2[C:10](=[O:12])[NH:9][C:8]([C:13]([O:15][CH2:16][CH3:17])=[O:14])=[N:7][C:6]=2[S:5][CH:4]=1.[C-:18]#[N:19].[Na+].Cl>CN(C=O)C>[C:18]([CH2:2][C:3]1[C:11]2[C:10](=[O:12])[NH:9][C:8]([C:13]([O:15][CH2:16][CH3:17])=[O:14])=[N:7][C:6]=2[S:5][CH:4]=1)#[N:19]
Reactant: [C-]#N
Reactant: CCOC(=O)c1nc2scc(CBr)c2c(=O)[nH]1
Agent: Cl
Agent: [Na+]
Solvent: CN(C)C=O
Product: CCOC(=O)c1nc2scc(CC#N)c2c(=O)[nH]1
Reaction time: 12 h
Yield: 18.1 %

Procedure:
To a mixture of ethyl 5-(bromomethyl)-4-oxo-3,4-dihydrothieno[2,3-d]pyrimidine-2-carboxylate (2000 mg, 6.31 mmol) in DMF (10 mL) was added sodium cyanide (649 mg, 13.2 mmol) at room temperature, and the mixture was stirred for 12 hr. The reaction mixture was acidified with 1N hydrochloric acid, and extracted with ethyl acetate. The organic layer was washed with water and saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was crystallized from ethyl acetate to give the title compound as a pale-brown powder (300 mg, 18%).
Reaction SMILES: [CH3:1][C:2]1[N:7]=[C:6]([CH2:8][S:9][CH2:10][CH2:11][NH2:12])[CH:5]=[CH:4][CH:3]=1.[Cl:13][C:14]1[CH:15]=[C:16]([S:21]([NH:24][C:25](=[N:28][CH3:29])SC)(=[O:23])=[O:22])[CH:17]=[CH:18][C:19]=1[Cl:20]>C(#N)C>[Cl:13][C:14]1[CH:15]=[C:16]([S:21]([NH:24][C:25]([NH:28][CH3:29])=[N:12][CH2:11][CH2:10][S:9][CH2:8][C:6]2[CH:5]=[CH:4][CH:3]=[C:2]([CH3:1])[N:7]=2)(=[O:22])=[O:23])[CH:17]=[CH:18][C:19]=1[Cl:20]
Reactant: Cc1cccc(CSCCN)n1
Reactant: CN=C(NS(=O)(=O)c1ccc(Cl)c(Cl)c1)SC
Solvent: CC#N
Product: CNC(=NCCSCc1cccc(C)n1)NS(=O)(=O)c1ccc(Cl)c(Cl)c1

Procedure:
A solution of 6-methyl-2-((2-aminoethyl)thiomethyl) pyridine (3.7 g) and N-(3,4-dichlorobenzenesulphonyl)-N', S-dimethylisothiourea (6.2 g) in acetonitrile (250 ml) was heated under reflux for 48 hours. Concentration, followed by chromatographic purification on a column of alumina afforded N-(3,4-dichlorobenzenesulphonyl)-N'-methyl-N"-[2-((6-methyl-2-pyridyl)methylthio)ethyl]guanidine.
Reaction SMILES: Cl.Cl.[NH:3]1[CH2:8][CH2:7][NH:6][CH2:5][CH:4]1[C:9]([OH:11])=[O:10].[OH-].[Na+].[C:14](OC([O-])=O)([O:16][C:17]([CH3:20])([CH3:19])[CH3:18])=[O:15].Cl>O1CCOCC1.O>[C:17]([O:16][C:14]([N:6]1[CH2:7][CH2:8][NH:3][CH:4]([C:9]([OH:11])=[O:10])[CH2:5]1)=[O:15])([CH3:20])([CH3:19])[CH3:18]
Reactant: O=C(O)C1CNCCN1
Reactant: CC(C)(C)OC(=O)OC(=O)[O-]
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: C1COCCO1
Solvent: O
Product: CC(C)(C)OC(=O)N1CCNC(C(=O)O)C1
Temperature: 5 °C
Reaction time: 8 h

Procedure:
A mixture of piperazine-2-carboxylic acid dihydrochloride in dioxan (1000 ml) and water (500 ml), at 10–15° C., was treated with aqueous sodium hydroxide solution (50%) over 15 minutes to adjust the pH to 9.1. This mixture was then treated portionwise (0.1 equivalent portions) with tert-butyl dicarbonate (114.6 g) over a period of 1 hour whilst maintaining the temperature at 5° C. and the pH around 8.8. After stirring at room temperature overnight the reaction mixture was cooled to 10° C., then the pH of the mixture was adjusted to 2 by the addition of hydrochloric acid (37%) and then the mixture was concentrated at 40° C. under reduced pressure. The resulting solid was treated with methanol (1500 ml) and this mixture was heated at reflux temperature and then filtered to remove the insoluble inorganics. The filtrate was evaporated to give the title compound (126 g) as an off white solid. MS: 231 [MH]+.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[N:4][C:5](=[O:8])[NH:6][CH:7]=1.Br[CH2:10][C:11]([C:13]1[CH:17]=[CH:16][O:15][CH:14]=1)=[O:12]>C(N(CC)CC)C.C(O)C>[Cl:1][C:2]1[CH:3]=[N:4][C:5](=[O:8])[N:6]([CH2:10][C:11]([C:13]2[CH:17]=[CH:16][O:15][CH:14]=2)=[O:12])[CH:7]=1
Reactant: O=C(CBr)c1ccoc1
Reactant: O=c1ncc(Cl)c[nH]1
Solvent: CCO
Solvent: CCN(CC)CC
Product: O=C(Cn1cc(Cl)cnc1=O)c1ccoc1
Temperature: 25 °C
Yield: 31.2 %

Procedure:
A mixture of 5-chloropyrimidin-2-one (587 mg) and crude 3-bromoacetylfuran (2.00 g, ca. 4.5 mmol, based on purity ca. 40% by 1H n.m.r; contaminated with 3-dibromoacetylfuran and diethyl ether) in triethylamine (0.95 ml) and ethanol (25 ml) was stirred at room temperature. After 45 min with solvent was removed and the residue triturated with ethyl acetate. The resulting solid was collected and retriturated with water. This gave a buff solid which was crystallised from ethyl acetate to give the title pyrimidinone (335 mg), m.p. 195°-197° C. (dec), λmax (EtOH) 333 nm (ε 2,530).
Reaction SMILES: [CH:1]1([C:4]([NH:6][C:7]2[CH:12]=[C:11]([O:13][C:14]3[CH:19]=[CH:18][C:17]([NH:20][C:21]([NH:23][C:24]4[CH:25]=[C:26]([CH:34]([N:36]5[CH2:41][CH2:40][N:39](C(OC(C)(C)C)=O)[CH2:38][CH2:37]5)[CH3:35])[CH:27]=[C:28]([C:30]([F:33])([F:32])[F:31])[CH:29]=4)=[O:22])=[CH:16][C:15]=3[F:49])[CH:10]=[CH:9][N:8]=2)=[O:5])[CH2:3][CH2:2]1.FC(F)(F)C(O)=O>C(Cl)Cl>[F:49][C:15]1[CH:16]=[C:17]([NH:20][C:21](=[O:22])[NH:23][C:24]2[CH:29]=[C:28]([C:30]([F:31])([F:32])[F:33])[CH:27]=[C:26]([CH:34]([N:36]3[CH2:37][CH2:38][NH:39][CH2:40][CH2:41]3)[CH3:35])[CH:25]=2)[CH:18]=[CH:19][C:14]=1[O:13][C:11]1[CH:10]=[CH:9][N:8]=[C:7]([NH:6][C:4]([CH:1]2[CH2:3][CH2:2]2)=[O:5])[CH:12]=1
Reactant: CC(c1cc(NC(=O)Nc2ccc(Oc3ccnc(NC(=O)C4CC4)c3)c(F)c2)cc(C(F)(F)F)c1)N1CCN(C(=O)OC(C)(C)C)CC1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CC(c1cc(NC(=O)Nc2ccc(Oc3ccnc(NC(=O)C4CC4)c3)c(F)c2)cc(C(F)(F)F)c1)N1CCNCC1
Temperature: 25 °C
Reaction time: 2 h
Yield: 89.4 %

Procedure:
Dissolve the compound obtained in Step 1 (230 mg, 0.33 mmol) in DCM (15 mL), add trifluoroacetic acid (400 mg), stir at room temperature for 2 hrs. Remove the volatiles, partition the residue in EtOAc and saturated NaHCO3 solution, and separate the organic layer, dry over anhydrous Na2SO4. Concentrate under reduced pressure to give the crude product. Purification by chromatography (silica gel, EtOAc:PE=3:1) affords the title compound (173 mg, 88.3%). MS: (M+1): 588.
Reaction SMILES: [C:1]1([C:7]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)([CH3:11])[C:8](Cl)=[O:9])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[F:18][C:19]([F:25])([F:24])[CH2:20][CH2:21][CH2:22][NH2:23]>>[C:1]1([C:7]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)([CH3:11])[C:8]([NH:23][CH2:22][CH2:21][CH2:20][C:19]([F:25])([F:24])[F:18])=[O:9])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: CC(C(=O)Cl)(c1ccccc1)c1ccccc1
Reactant: NCCCC(F)(F)F
Product: CC(C(=O)NCCCC(F)(F)F)(c1ccccc1)c1ccccc1

Procedure:
The title compound, white solid, m.p. 82° C. and MS: m/e=336.2 (M+H+) was prepared in accordance with the general method of example 1 from 2,2-diphenylpropionyl chloride and 4,4,4-trifluorobutyl-amine.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:23]=[CH:22][CH:21]=[CH:20][C:4]=1[O:5][C:6]1[CH:11]=[CH:10][C:9]([NH:12][CH2:13][C:14]2[CH:15]=[N:16][CH:17]=[CH:18][CH:19]=2)=[CH:8][CH:7]=1.[F:24][C:25]([F:32])([F:31])[CH2:26][S:27](Cl)(=[O:29])=[O:28].C(=O)([O-])[O-].[K+].[K+]>ClCCCl.N1C=CC=CC=1>[CH3:1][O:2][C:3]1[CH:23]=[CH:22][CH:21]=[CH:20][C:4]=1[O:5][C:6]1[CH:7]=[CH:8][C:9]([N:12]([CH2:13][C:14]2[CH:15]=[N:16][CH:17]=[CH:18][CH:19]=2)[S:27]([CH2:26][C:25]([F:32])([F:31])[F:24])(=[O:29])=[O:28])=[CH:10][CH:11]=1
Reactant: COc1ccccc1Oc1ccc(NCc2cccnc2)cc1
Reactant: O=S(=O)(Cl)CC(F)(F)F
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: c1ccncc1
Solvent: ClCCCl
Product: COc1ccccc1Oc1ccc(N(Cc2cccnc2)S(=O)(=O)CC(F)(F)F)cc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A solution of N-(4-(2-methoxyphenoxy)phenyl)pyridin-3-ylmethylamine (1.0 equiv.) in 2:1 DCE/Pyridine (0.15 M) was cooled to 0° C. and treated with 2,2,2-trifluoroethanesulfonyl chloride (1.8 equiv.). The mixture was allowed to warm to ambient temperature and stir overnight. The reaction was treated with anhydrous potassium carbonate, stirred for 40 min, and filtered. The filtrate was purified via preparative HPLC eluting with 98:2 to 96:4 DCM/MeOH to give the title compound. Anal Calcd for C21H19F3N2O4S: C, 55.75; H, 4.23; N, 6.19. Found: C, 55.65; H, 4.27; N, 6.19. MS found 4.53.0 [M+H]+
Reaction SMILES: [Mg].II.Br[C:5]([CH3:7])=[CH2:6].[CH3:8][C:9]1[CH2:10][CH2:11][CH:12]2[C:18]=1[CH2:17][CH2:16][C:15](=[O:19])[CH2:14][C:13]2=[CH2:20]>O1CCCC1>[OH:19][C:15]1([C:5]([CH3:7])=[CH2:6])[CH2:16][CH2:17][C:18]2[CH:12]([CH2:11][CH2:10][C:9]=2[CH3:8])[C:13](=[CH2:20])[CH2:14]1
Reactant: C=C(C)Br
Reactant: C=C1CC(=O)CCC2=C(C)CCC12
Agent: II
Agent: [Mg]
Solvent: C1CCOC1
Product: C=C1CC(O)(C(=C)C)CCC2=C(C)CCC12
Reaction time: 0.5 h
Yield: 76 %

Procedure:
To a Grignard solution, prepared from 1 g of magnesium chips activated with 1 g of iodine, 5 ml of 2-bromopropene and about 100 ml of tetrahydrofuran, were added over 10 minutes 1.76 g of 1-methyl-4-methylen-6-oxo-2,3,3a,4,5,6,7,8-octahydroazulene. The mixture was stirred vigorously for 30 minutes, cooled to 0° and treated with excess ice-cold ammonium chloride solution. The mixture was then extracted with ether, the organic extract washed with carbonate solution and water, dried over magnesium sulphate and concentrated under reduced pressure. The crude product (2.6 g), which was obtained in the form of a yellow oil, was distilled under high vacuum and yielded 1.6 g (yield 76%) of pure 6-hydroxy-6-isopropenyl-1methyl-4-methylen-2,3,3a,4,5,6,7,8-octahydroazulene; b.p.0.1 ca 100° IR(film): νmax = 3550, 3090, 1640, 1450/40, 1378, 1330, 1220, 1165, 1105, 1065, 1038, 900/895, 780 cm-1. The compound has a woody, slightly camphorous, somewhat spicy odour.
Reaction SMILES: [Cl:1][C:2]1[CH:19]=[CH:18][CH:17]=[CH:16][C:3]=1[C:4]([C:6](=[CH:12][N:13](C)C)[C:7]([O:9][CH2:10][CH3:11])=[O:8])=O.Cl.[C:21]([NH:25]N)([CH3:24])([CH3:23])[CH3:22].C(O)C>O>[C:21]([N:25]1[C:4]([C:3]2[CH:16]=[CH:17][CH:18]=[CH:19][C:2]=2[Cl:1])=[C:6]([C:7]([O:9][CH2:10][CH3:11])=[O:8])[CH:12]=[N:13]1)([CH3:24])([CH3:23])[CH3:22]
Reactant: CCOC(=O)C(=CN(C)C)C(=O)c1ccccc1Cl
Reactant: CC(C)(C)NN
Agent: Cl
Solvent: O
Solvent: CCO
Product: CCOC(=O)c1cnn(C(C)(C)C)c1-c1ccccc1Cl
Temperature: 25 °C
Yield: 15.6 %

Procedure:
A mixture of 2.82 g of ethyl 2-(2-chlorobenzoyl)-3-(N,N-dimethylamino)acrylate (a compound described in JP-A 7-101940), 1.25 g of tert-butylhydrazine hydrochloride and 10 ml of ethanol was heated to reflux for 8 hours. After the reaction mixture was allowed to cool to room temperature, water was poured and the mixture was extracted with ethyl acetate. The organic layer was washed with water, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The resulting residue was subjected to silica gel column chromatography to obtain 0.48 g of ethyl 1-tert-butyl-5-(2-chlorophenyl)-1H-pyrazole-4-carboxylate of the formula:
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:12]=1[O:13][CH3:14])[N:9]=[CH:8][CH:7]=[C:6]2[O:15][C:16]1[C:17]([CH3:27])=[C:18]2[C:23](=[CH:24][CH:25]=1)[CH:22]=[C:21]([NH2:26])[CH:20]=[CH:19]2.[C:28](Cl)(=[O:35])[C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1.C([O-])([O-])=O.[K+].[K+]>C(Cl)Cl>[CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:12]=1[O:13][CH3:14])[N:9]=[CH:8][CH:7]=[C:6]2[O:15][C:16]1[C:17]([CH3:27])=[C:18]2[C:23](=[CH:24][CH:25]=1)[CH:22]=[C:21]([NH:26][C:28](=[O:35])[C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1)[CH:20]=[CH:19]2
Reactant: COc1cc2nccc(Oc3ccc4cc(N)ccc4c3C)c2cc1OC
Reactant: O=C(Cl)c1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: ClCCl
Product: COc1cc2nccc(Oc3ccc4cc(NC(=O)c5ccccc5)ccc4c3C)c2cc1OC

Procedure:
6-(6,7-Dimethoxy-quinolin-4-yloxy)-5-methyl-naphthalen-2-ylamine (Step b, 0.100 g, 0.2 mmol), benzoyl chloride (0.04 mL, 0.3 mmol) and K2CO3 (0.116 g, 0.6 mmol) in CH2Cl2 were stirred overnight under inert atmosphere. The reaction was quenched with water and diluted with CH2Cl2. The aqueous layer was extracted 3 times with CH2Cl2. The organics were collected, dried over Na2SO4, filtered, and concentrated in vacuo. The crude was purified by silica-gel column chromatography in EtOAc/Hexanes to give the titled compound as a rust colored film. MS (ESI, pos. ion) m/z: 465 (M+1). Mass Calc'd for C29H24N2O4: 464.17.
Reaction SMILES: Br[C:2]([C:5]([CH3:7])=[O:6])([CH3:4])[CH3:3].[NH:8]1[CH:12]=[CH:11][CH:10]=[N:9]1>>[CH3:3][C:2]([N:8]1[CH:12]=[CH:11][CH:10]=[N:9]1)([C:5](=[O:6])[CH3:7])[CH3:4]
Reactant: CC(=O)C(C)(C)Br
Reactant: c1cn[nH]c1
Product: CC(=O)C(C)(C)n1cccn1
Yield: 70 %

Procedure:
1 mol of methyl bromoisopropyl ketone is added dropwise at 100° C. to a melt of 4 mols of pyrazole. The reaction mixture is stirred for a further hour. Following customary working up, 2-methyl-2-(pyrazol-1-yl)-butan-3one is obtained in a yield of 70%.
Reaction SMILES: [Na].[F:2][C:3]1[CH:8]=[CH:7][C:6]([OH:9])=[CH:5][CH:4]=1.CS(O[CH2:15][C@H:16]1[CH2:20][O:19][C:18]([CH3:22])([CH3:21])[O:17]1)(=O)=O>COCCO>[F:2][C:3]1[CH:8]=[CH:7][C:6]([O:9][CH2:15][C@H:16]2[CH2:20][O:19][C:18]([CH3:22])([CH3:21])[O:17]2)=[CH:5][CH:4]=1
Reactant: CC1(C)OC[C@H](COS(C)(=O)=O)O1
Reactant: Oc1ccc(F)cc1
Agent: [Na]
Solvent: COCCO
Product: CC1(C)OC[C@H](COc2ccc(F)cc2)O1
Temperature: 0 °C
Reaction time: 0.25 h
Yield: 97.3 %

Procedure:
To a stirred solution of 2.7 parts of sodium in 50 parts of 2-methoxyethanol were added 13.2 parts of 4-fluorophenol. The whole was stirred for 15 minutes. A solution of 24.8 parts of (-)-(R)-2,2-dimethyl-1,3-dioxolane-4-methanol methanesulfonate (ester) in 70 parts of 2-methoxyethanol was added dropwise quickly. Stirring was continued for 1.5 hours at reflux temperature. After cooling, the mixture was poured into ice water. The product was extracted with methylbenzene. The extract was dried, filtered and evaporated, yielding 26 parts (97.3%) of (S)-4-[(4-fluorophenoxy)methyl]-2,2-dimethyl-1,3-dioxolane as a residue (145).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([C:12]([CH3:15])([CH3:14])[CH3:13])[C:5]([O:10][CH3:11])=[C:6]([CH2:8]Br)[CH:7]=1.[N+:16]([C:19]1[CH:24]=[CH:23][C:22]([OH:25])=[CH:21][CH:20]=1)([O-:18])=[O:17].C([O-])([O-])=O.[K+].[K+]>CN(C=O)C>[Br:1][C:2]1[CH:7]=[C:6]([CH2:8][O:25][C:22]2[CH:23]=[CH:24][C:19]([N+:16]([O-:18])=[O:17])=[CH:20][CH:21]=2)[C:5]([O:10][CH3:11])=[C:4]([C:12]([CH3:15])([CH3:14])[CH3:13])[CH:3]=1
Reactant: COc1c(CBr)cc(Br)cc1C(C)(C)C
Reactant: O=[N+]([O-])c1ccc(O)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: COc1c(COc2ccc([N+](=O)[O-])cc2)cc(Br)cc1C(C)(C)C
Temperature: 50 °C
Reaction time: 2 h
Yield: 81.7 %

Procedure:
step 2—A mixture of 114 (0.20 g, 0.59 mmol), 4-nitrophenol (0.082 g, 0.59 mmol) and K2CO3 (0.12 g, 0.89 mmol) in DMF was stirred at 50° C. for 2 h. The mixture was cooled to RT and partitioned between water and Et2O. The ether layer was concentrated, and the crude residue was purified by SiO2 chromatography eluting with EtOAc/hexane to afford 0.19 g (83%) of 5-bromo-1-tert-butyl-2-methoxy-3-(4-nitro-phenoxymethyl)benzene (116) as a white solid.
Reaction SMILES: COC(C1C(O)=C(O)N=C(CC2([C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=3)CCCC2)N=1)=O.[CH3:25][NH:26][C:27]([C:29]1[N:30]=[C:31]([CH2:37][C:38]2([C:43]3[CH:48]=[CH:47][CH:46]=[CH:45][CH:44]=3)[CH2:42][CH2:41][CH2:40][CH2:39]2)[NH:32][C:33](=[O:36])[C:34]=1[OH:35])=[O:28]>>[CH2:25]([NH:26][C:27]([C:29]1[C:34]([OH:35])=[C:33]([OH:36])[N:32]=[C:31]([CH2:37][C:38]2([C:43]3[CH:48]=[CH:47][CH:46]=[CH:45][CH:44]=3)[CH2:39][CH2:40][CH2:41][CH2:42]2)[N:30]=1)=[O:28])[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1
Reactant: COC(=O)c1nc(CC2(c3ccccc3)CCCC2)nc(O)c1O
Reactant: CNC(=O)c1nc(CC2(c3ccccc3)CCCC2)[nH]c(=O)c1O
Product: O=C(NCc1ccccc1)c1nc(CC2(c3ccccc3)CCCC2)nc(O)c1O

Procedure:
5,6-Dihydroxy-2-(1-phenyl-cyclopentylmethyl)-pyrimidine-4-carboxylic acid benzylamide was synthesized as an off-white solid (20 mg, 30%) from 55 mg of 5,6-dihydroxy-2-(1-phenyl-cyclopentylmethyl)-pyrimidine-4-carboxylic acid methyl ester following the procedure described for 5-hydroxy-6-oxo-2-(1-phenyl-cyclopentylmethyl)-1,6-dihydro-pyrimidine-4-carboxylic acid methylamide (Example 9). LCMS: m/z=403.8 (MH+).
Reaction SMILES: [CH3:1][C:2]12[CH:11]([CH:12]=[O:13])[CH2:10][CH2:9][CH:8]=[C:7]1[CH2:6][C:5]1([S:17][CH2:16][CH2:15][S:14]1)[CH2:4][CH2:3]2.[C:18]1([Mg]Br)[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1>C1COCC1>[CH3:1][C:2]12[CH:11]([CH:12]([C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=3)[OH:13])[CH2:10][CH2:9][CH:8]=[C:7]1[CH2:6][C:5]1([S:14][CH2:15][CH2:16][S:17]1)[CH2:4][CH2:3]2
Reactant: Br[Mg]c1ccccc1
Reactant: CC12CCC3(CC1=CCCC2C=O)SCCS3
Solvent: C1CCOC1
Product: CC12CCC3(CC1=CCCC2C(O)c1ccccc1)SCCS3
Temperature: -78 °C
Yield: 92.8 %

Procedure:
Aldehyde 241 (200 mg, 0.746 mmol) was dissolved in 10 mL THF and cooled to −78° C. Phenylmagnesium bromide (1M in THF, 1.12 mL, 1.12 mmol) was added to the solution dropwise and the mixture was allowed to warm to room temperature over 2 hours. The reaction mixture was then cooled to 0° C. and quenched with 10 mL of water. The layers were separated and the aqueous layer was extracted with (3×10 mL) ether. The pooled organic extracts was washed with brine, dried (MgSO4), filtered, and concentrated under vacuum. Purification by flash chromatography over silica gel (10% ethyl acetate-hexanes) afforded alcohol 247 (240 mg, 93%) as a white solid.
Reaction SMILES: S(Cl)([Cl:3])=O.[C:5]([OH:15])(=O)[C:6]1[NH:13][C:11](=[O:12])[NH:10][C:8](=[O:9])[CH:7]=1>O>[O:12]=[C:11]1[NH:13][C:6]([C:5]([Cl:3])=[O:15])=[CH:7][C:8](=[O:9])[NH:10]1
Reactant: O=C(O)c1cc(=O)[nH]c(=O)[nH]1
Reactant: O=S(Cl)Cl
Solvent: O
Product: O=C(Cl)c1cc(=O)[nH]c(=O)[nH]1
Temperature: 55 °C
Reaction time: 0.75 h

Procedure:
In a dry 2-necked, round bottomed flask, equipped with a magnetic stirrer and fixed with a separatory funnel, containing 13.13 ml (180 mmol) of thionyl chloride, and a water condenser, is placed 15.61 g (100 mmol) of orotic acid. Addition of the thionyl chloride is completed with heating to about 55° C. over the course of about 45 minutes. When addition of the thionyl chloride is complete the mixture is heated and stirred for an additional 45 minutes. The water condenser is then replaced with a distillation side arm condenser and the crude mixture is distilled. The crude distillate in the receiving flask is then fractionally distilled to obtain the acyl chloride, 2,6-dioxo-1,2,3,6-tetrahydropyrimidine-4-carbonyl chloride (orotoyl chloride). This acyl chloride, 6.11 g (35 mmol), is put into a dry separatory funnel and combined with 50 mL of dry DCM for use in the next step of the reaction.
Reaction SMILES: [F:1][C:2]([F:47])([F:46])[CH2:3][CH2:4][NH:5][C:6]([C:8]1[C:35]([N:36]2[CH2:41][CH2:40][CH:39]([C:42]([F:45])([F:44])[F:43])[CH2:38][CH2:37]2)=[CH:34][C:11]2[N:12]([CH3:33])[C:13]([NH:15][C:16]3[C:21]([Cl:22])=[CH:20][CH:19]=[C:18]([CH2:23][NH:24]C(OC(C)(C)C)=O)[C:17]=3[Cl:32])=[N:14][C:10]=2[CH:9]=1)=[O:7].Cl>C1COCC1>[F:46][C:2]([F:1])([F:47])[CH2:3][CH2:4][NH:5][C:6]([C:8]1[C:35]([N:36]2[CH2:41][CH2:40][CH:39]([C:42]([F:45])([F:44])[F:43])[CH2:38][CH2:37]2)=[CH:34][C:11]2[N:12]([CH3:33])[C:13]([NH:15][C:16]3[C:21]([Cl:22])=[CH:20][CH:19]=[C:18]([CH2:23][NH2:24])[C:17]=3[Cl:32])=[N:14][C:10]=2[CH:9]=1)=[O:7]
Reactant: Cn1c(Nc2c(Cl)ccc(CNC(=O)OC(C)(C)C)c2Cl)nc2cc(C(=O)NCCC(F)(F)F)c(N3CCC(C(F)(F)F)CC3)cc21
Agent: Cl
Solvent: C1CCOC1
Product: Cn1c(Nc2c(Cl)ccc(CN)c2Cl)nc2cc(C(=O)NCCC(F)(F)F)c(N3CCC(C(F)(F)F)CC3)cc21
Reaction time: 2 h

Procedure:
A mixture of N-(3,3,3-trifluoropropyl)-2-{2,6-dichloro-3-[(tert.-butoxycarbonylamino)-methyl]-phenylamino}-6-[4-trifluoromethyl-piperidinyl]-1-methyl-1H-benzimidazole-5-carboxylic acid amide (2.73 g, 3.8 mmol), 15 mL 6M aq HCl and 15 mL THF is stirred for 2 h, concentrated and the sub title compound is purified by chromatography (silica gel, DCM→DCM/10% EtOH+few drops of NH4OH). Yield: 2.3 g. Rf=0.27 (DCM/EtOH/NH4OH 90:10:1). MS m/z: 712 [M+H]+.
Reaction SMILES: [C:1]([N:8]([CH3:42])[CH:9]1[CH2:14][CH2:13][CH:12]([N:15]([CH2:30][C:31]2[CH:32]=[C:33](B(O)O)[CH:34]=[CH:35][C:36]=2[O:37][CH3:38])[C:16]([C:18]2[S:22][C:21]3[C:23]([F:28])=[CH:24][CH:25]=[C:26]([F:27])[C:20]=3[C:19]=2[Cl:29])=[O:17])[CH2:11][CH2:10]1)([O:3][C:4]([CH3:7])([CH3:6])[CH3:5])=[O:2].Cl.Br[C:45]1[CH:50]=[CH:49][N:48]=[CH:47][CH:46]=1>>[Cl:29][C:19]1[C:20]2[C:26]([F:27])=[CH:25][CH:24]=[C:23]([F:28])[C:21]=2[S:22][C:18]=1[C:16]([N:15]([CH2:30][C:31]1[CH:32]=[C:33]([C:45]2[CH:50]=[CH:49][N:48]=[CH:47][CH:46]=2)[CH:34]=[CH:35][C:36]=1[O:37][CH3:38])[CH:12]1[CH2:11][CH2:10][CH:9]([N:8]([CH3:42])[C:1](=[O:2])[O:3][C:4]([CH3:5])([CH3:7])[CH3:6])[CH2:14][CH2:13]1)=[O:17]
Reactant: COc1ccc(B(O)O)cc1CN(C(=O)c1sc2c(F)ccc(F)c2c1Cl)C1CCC(N(C)C(=O)OC(C)(C)C)CC1
Reactant: Brc1ccncc1
Agent: Cl
Product: COc1ccc(-c2ccncc2)cc1CN(C(=O)c1sc2c(F)ccc(F)c2c1Cl)C1CCC(N(C)C(=O)OC(C)(C)C)CC1

Procedure:
Boronic acid 9 (5.70 g, 9.14 mmol) is coupled to 4-bromopyridine hydrochloride (2.13 g, 11.0 mmol) using Method A to give the title compound.
Reaction SMILES: Cl[C:2]1[CH:3]=[C:4]2[C:9](=[C:10]([CH3:12])[CH:11]=1)[S:8][C:7](=[O:13])[C:6]([C:14]([NH:16][CH2:17][C:18]([OH:20])=[O:19])=[O:15])=[C:5]2[OH:21]>[OH-].[Na+].O.[Pd]>[OH:21][C:5]1[C:4]2[C:9](=[C:10]([CH3:12])[CH:11]=[CH:2][CH:3]=2)[S:8][C:7](=[O:13])[C:6]=1[C:14]([NH:16][CH2:17][C:18]([OH:20])=[O:19])=[O:15]
Reactant: Cc1cc(Cl)cc2c(O)c(C(=O)NCC(=O)O)c(=O)sc12
Agent: [Pd]
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: Cc1cccc2c(O)c(C(=O)NCC(=O)O)c(=O)sc12
Temperature: 25 °C
Reaction time: 18 h
Yield: 88.2 %

Procedure:
[(6-Chloro-4-hydroxy-8-methyl-2-oxo-2H-thiochromene-3-carbonyl)-amino]-acetic acid (95 mg, 0.29 mmol) was dissolved in 1N sodium hydroxide (1.16 mL) and water (1.84 mL). 10% Palladium on carbon (9.5 mg) was added and the solution was vacuum purged and treated with hydrogen gas (1 atm). The reaction stirred overnight (18 h) at ambient temperature and the crude mixture was filtered through Celite® and the filter cake was washed with 1N sodium hydroxide. The aqueous phase was acidified to pH 3 with 1N hydrochloric acid and the product was collected by filtration to give [(4-hydroxy-8-methyl-2-oxo-2H-thiochromene-3-carbonyl)-amino]-acetic acid (75 mg, 88%).
Reaction SMILES: C([O:8][C:9]1[C:10]2[N:11]([CH:40]=[CH:41][N:42]=2)[C:12]([C:15]2[N:16]=[C:17]([N:34]3[CH2:39][CH2:38][O:37][CH2:36][CH2:35]3)[C:18]3[S:23][C:22]([CH2:24][N:25]4[CH2:30][CH2:29][CH:28]([N:31]([CH3:33])[CH3:32])[CH2:27][CH2:26]4)=[CH:21][C:19]=3[N:20]=2)=[CH:13][CH:14]=1)C1C=CC=CC=1>C(O)(C(F)(F)F)=O>[CH3:32][N:31]([CH3:33])[CH:28]1[CH2:29][CH2:30][N:25]([CH2:24][C:22]2[S:23][C:18]3[C:17]([N:34]4[CH2:39][CH2:38][O:37][CH2:36][CH2:35]4)=[N:16][C:15]([C:12]4[N:11]5[CH:40]=[CH:41][N:42]=[C:10]5[C:9]([OH:8])=[CH:14][CH:13]=4)=[N:20][C:19]=3[CH:21]=2)[CH2:26][CH2:27]1
Reactant: CN(C)C1CCN(Cc2cc3nc(-c4ccc(OCc5ccccc5)c5nccn45)nc(N4CCOCC4)c3s2)CC1
Solvent: O=C(O)C(F)(F)F
Product: CN(C)C1CCN(Cc2cc3nc(-c4ccc(O)c5nccn45)nc(N4CCOCC4)c3s2)CC1
Temperature: 140 °C
Yield: 10 %

Procedure:
A mixture of {1-[2-(8-benzyloxyimidazo[1,2-a]pyridin-5-yl)-4-morpholin-4-yl-thieno[3,2-d]pyrimidin-6-ylmethyl]piperidin-4-yl}dimethylamine (381 mg, 0.65 mmol) in TFA was heated at 140° C., for 10 min, in a microwave reactor. The reaction mixture was loaded onto an Isolute® SCX-2 cartridge (10 g). The cartridge was washed with MeOH then the desired product was eluted with 2 M NH3 in MeOH. The appropriate fractions were combined and evaporated. The resulting residue was purified by reverse phase HPLC (Phenomenex Gemini 5u C18, 20 mM triethylamine in water on a gradient of acetonitrile 95:5 to 2:98) to give 689 as a yellow solid (32 mg, 10%). LCMS (Method F) RT 3.98 min; [M+H]+ 494. 1H NMR (400 MHz, CH3OH-d4): δ 9.43 (d, J=1.6 Hz, 1 H); 8.04 (d, J=8.2 Hz, 1 H); 7.65 (d, J=1.6 Hz, 1 H); 7.34 (s, 1 H); 6.71 (d, J=8.2 Hz, 1 H); 4.03 (t, J=4.7 Hz, 4 H); 3.87 (m, 7 H); 3.07 (d, J=11.5 Hz, 2 H); 2.37 (s, 6 H); 2.34 (m, 1 H); 2.16 (t, J=11.5 Hz, 2 H); 1.91 (d, J=12.3 Hz, 2 H); 1.66-1.54 (m, 2 H)