Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[CH2:3][CH2:2]1.[CH2:10]1[O:13][C@H:11]1[CH3:12]>C(O)C>[OH:13][CH:11]([CH3:12])[CH2:10][N:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[CH2:3][CH2:2]1
Reactant: c1ccc2c(c1)CCN2
Reactant: C[C@H]1CO1
Solvent: CCO
Product: CC(O)CN1CCc2ccccc21
Temperature: 25 °C
Yield: 62.9 %

Procedure:
A mixture of 2,3-dihydro-1H-indole (5.74 g, 48.2 mmol), and (S)-propylene oxide (2.8 g, 48.2 mmol) in ethanol (200 mL) is heated at reflux for 18 hours. The resulting mixture is cooled to room temperature, and evaporated to give a crude oil. The material is purified by flash chromatography (25% ethyl acetate/hexanes) to give 5.37 g (63%) of 2,3-dihydro-1-(2-hydroxypropyl)indole.
Reaction SMILES: [CH:1]1[CH2:5][CH2:4][CH2:3][CH:2]=1.[Cl:6][SiH2:7][Cl:8]>>[CH:1]1([Si:7]([CH:1]2[CH2:5][CH2:4][CH2:3][CH2:2]2)([Cl:8])[Cl:6])[CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: Cl[SiH2]Cl
Reactant: C1=CCCC1
Product: Cl[Si](Cl)(C1CCCC1)C1CCCC1

Procedure:
Cyclopentene in an amount of 136 g (2.00 moles) was made to react with dichlorosilane under various conditions set forth in Table 1, and then the solvent was distilled away. Thus, in analogy with Example 1, dicyclopentyldichlorosilane having a boiling point of 104° C./5 mmHg was obtained in various yields. The yield attained under each reaction condition is shown in Table 1.
Reaction SMILES: Br[C:2]1[CH:27]=[CH:26][C:5]([CH2:6][O:7][CH2:8][C@@H:9]2[CH2:11][C@@H:10]2[CH:12]2[CH2:17][CH2:16][N:15]([C:18]3[N:23]=[CH:22][C:21]([CH2:24][CH3:25])=[CH:20][N:19]=3)[CH2:14][CH2:13]2)=[CH:4][CH:3]=1.[CH:28]1([S:31]([O-:33])=[O:32])[CH2:30][CH2:29]1.[Na+].CNCCNC>CS(C)=O>[CH:28]1([S:31]([C:2]2[CH:27]=[CH:26][C:5]([CH2:6][O:7][CH2:8][C@@H:9]3[CH2:11][C@@H:10]3[CH:12]3[CH2:17][CH2:16][N:15]([C:18]4[N:23]=[CH:22][C:21]([CH2:24][CH3:25])=[CH:20][N:19]=4)[CH2:14][CH2:13]3)=[CH:4][CH:3]=2)(=[O:33])=[O:32])[CH2:30][CH2:29]1
Reactant: O=S([O-])C1CC1
Reactant: CCc1cnc(N2CCC([C@H]3C[C@H]3COCc3ccc(Br)cc3)CC2)nc1
Agent: CNCCNC
Agent: [Na+]
Solvent: CS(C)=O
Product: CCc1cnc(N2CCC([C@H]3C[C@H]3COCc3ccc(S(=O)(=O)C4CC4)cc3)CC2)nc1
Temperature: 120 °C

Procedure:
The product of example 54 (step A) (100 mg, 0.2 mmol), sodium cyclopropanesulfinate (36 mg, 0.28 mmol), copper (I) trifluoromethanesulfonate benzene complex (6 mg, 0.012 mmol), and N,N′-dimethylethylenediamine (2 mg, 0.02 mmol) were dissolved in DMSO (1 mL), and the solution was heated at 120° C. The solution was partitioned between water and Et2O. The aqueous layer was extracted with Et2O. The combined organic layers were washed with brine, dried (Na2SO4), filtered, and concentrated in vacuo. The residue was purified via silica gel column chromatography (2/1 EtOAc/hexanes) to provide the title compound. MS (ESI) m/z 456 [M+H]+. GPR119 Human EC50: 1.2 nM
Reaction SMILES: [C:1](=O)([O-])[O-].[Cs+].[Cs+].[CH3:7][O:8][C:9]1[CH:18]=[C:17]2[C:12]([N:13]=[CH:14][C:15]([S:19][CH2:20][CH2:21][N:22]3[CH2:27][CH2:26][CH:25]([NH:28][S:29]([C:32]4[CH:37]=[CH:36][CH:35]=[CH:34][C:33]=4[N+:38]([O-:40])=[O:39])(=[O:31])=[O:30])[CH2:24][CH2:23]3)=[N:16]2)=[CH:11][CH:10]=1.CI.C1CCCCC1>CN(C)C=O.C(OCC)(=O)C>[CH3:7][O:8][C:9]1[CH:18]=[C:17]2[C:12]([N:13]=[CH:14][C:15]([S:19][CH2:20][CH2:21][N:22]3[CH2:23][CH2:24][CH:25]([N:28]([CH3:1])[S:29]([C:32]4[CH:37]=[CH:36][CH:35]=[CH:34][C:33]=4[N+:38]([O-:40])=[O:39])(=[O:30])=[O:31])[CH2:26][CH2:27]3)=[N:16]2)=[CH:11][CH:10]=1
Reactant: COc1ccc2ncc(SCCN3CCC(NS(=O)(=O)c4ccccc4[N+](=O)[O-])CC3)nc2c1
Reactant: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CCOC(C)=O
Solvent: CI
Solvent: CN(C)C=O
Product: COc1ccc2ncc(SCCN3CCC(N(C)S(=O)(=O)c4ccccc4[N+](=O)[O-])CC3)nc2c1
Temperature: 25 °C
Reaction time: 15 h
Yield: 34.1 %

Procedure:
Cesium carbonate (293 mg, 0.90 mmol, 1.5 eq) is added at room temperature to a stirred solution of N-{1-[2-(7-methoxy-quinoxalin-2-ylsulfanyl)-ethyl]-piperidin-4-yl}-2-nitro-benzenesulfonamide (307 mg, 0.60 mmol, 1.0 eq) in N,N-dimethylformamide (4 mL), followed by methyl iodide (56 μL, 0.90 mmol, 1.5 eq). After 15 hours stirring at room temperature, solvent is evaporated and the residue is extracted with ethyl acetate (3×10 mL) and water (10 mL). The combined organic layers are dried over sodium sulfate, filtered and concentrated to give a residue that is purified by column chromatography (silica gel, eluent: cyclohexane: ethyl acetate, 4:1 to 1:0, v/v) to afford N-{1-[2-(7-methoxy-quinoxalin-2-ylsulfanyl)-ethyl]-piperidin-4-yl}-N-methyl-2-nitro-benzenesulfonamide as a yellow solid (106 mg, 34% yield).
Reaction SMILES: C[O:2][C:3]([C@H:5]1[CH2:10][CH2:9][C@H:8]([O:11][C:12]2[CH:17]=[CH:16][CH:15]=[C:14]([O:18][CH3:19])[CH:13]=2)[CH2:7][CH2:6]1)=O.O.[NH2:21][NH2:22]>>[CH3:19][O:18][C:14]1[CH:13]=[C:12]([CH:17]=[CH:16][CH:15]=1)[O:11][C@H:8]1[CH2:9][CH2:10][C@H:5]([C:3]([NH:21][NH2:22])=[O:2])[CH2:6][CH2:7]1
Reactant: NN
Reactant: COc1cccc(O[C@H]2CC[C@H](C(=O)OC)CC2)c1
Solvent: O
Product: COc1cccc(O[C@H]2CC[C@H](C(=O)NN)CC2)c1
Temperature: 120 °C

Procedure:
A mixture of trans-4-(3-methoxy-phenoxy)-cyclohexanecarboxylic acid methyl ester (0.20 g, 0.75 mmol) and hydrazine hydrate (0.035 ml, 0.73 mmol) was heated at 120° C. for 22 h. After cooling to room temperature the reaction mixture was partitioned between ethyl acetate (50 ml) and 1 M aqueous sodium hydroxide solution (50 ml). The organic layer was separated, dried over anhydrous sodium sulfate and concentrated in vacuo to give the crude title compound (0.18 g, 92%) as white solid, which was used in the next step without further purification.
Reaction SMILES: Br[CH2:2][C:3]1[CH:4]=[N:5][CH:6]=[C:7]([C:9]2[CH:10]=[N:11][CH:12]=[CH:13][CH:14]=2)[CH:8]=1.[CH3:15][C:16]1[N:21]=[C:20]([SH:22])[N:19]=[C:18]([OH:23])[CH:17]=1>>[CH3:15][C:16]1[N:21]=[C:20]([S:22][CH2:2][C:3]2[CH:4]=[N:5][CH:6]=[C:7]([C:9]3[CH:10]=[N:11][CH:12]=[CH:13][CH:14]=3)[CH:8]=2)[N:19]=[C:18]([OH:23])[CH:17]=1
Reactant: BrCc1cncc(-c2cccnc2)c1
Reactant: Cc1cc(O)nc(S)n1
Product: Cc1cc(O)nc(SCc2cncc(-c3cccnc3)c2)n1
Yield: 15 %

Procedure:
The title compound was prepared by following the procedure described for Example 55. 5-(pyridin-3-yl)pyridine-3-carbaldehyde provided [5-(pyridin-3-yl)pyridin-3-yl]methanol, which was reacted with phosphorus tribromide to give 3-(bromomethyl)-5-(pyridin-3-yl)pyridine. The reaction of 3-(bromomethyl)-5-(pyridin-3-yl)pyridine with 6-methyl-2-sulfanylpyrimidin-4-ol gave 6-methyl-2-({[5-(pyridin-3-yl)pyridin-3-yl]methyl}sulfanyl)pyrimidin-4-ol as a white solid (0.18 g, 15% yield); 1H NMR (400 MHz, DMSO-d6): δ 2.21 (s, 3H), 4.45 (s, 2H), 6.04 (bs, 1H), 7.54 (m, 1H), 8.24 (d, J=4.7 Hz, 1H), 8.30 (s, 1H), 8.63 (d, J=4.7 Hz, 1H), 8.64 (s, 1H), 8.83 (s, 1H), 8.93 (s, 1H); M+310.1.
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4]([CH:8]=[CH:9][C:10]=1[C:11]([N:13]1[CH2:17][CH2:16][CH2:15][CH2:14]1)=[O:12])[C:5]([OH:7])=O.CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.[B-](F)(F)(F)F.C(N(C(C)C)CC)(C)C.[Cl:49][C:50]1[CH:60]=[CH:59][C:53]2[NH:54][C:55]([CH2:57][NH2:58])=[N:56][C:52]=2[CH:51]=1.ClCl>O1CCCC1.ClCCl.C(O)C>[Cl:49][C:50]1[CH:60]=[CH:59][C:53]2[NH:54][C:55]([CH2:57][NH:58][C:5](=[O:7])[C:4]3[CH:8]=[CH:9][C:10]([C:11]([N:13]4[CH2:17][CH2:16][CH2:15][CH2:14]4)=[O:12])=[C:2]([CH3:1])[CH:3]=3)=[N:56][C:52]=2[CH:51]=1
Reactant: Cc1cc(C(=O)O)ccc1C(=O)N1CCCC1
Reactant: NCc1nc2cc(Cl)ccc2[nH]1
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: ClCl
Agent: F[B-](F)(F)F
Solvent: CCO
Solvent: CCN(C(C)C)C(C)C
Solvent: C1CCOC1
Product: Cc1cc(C(=O)NCc2nc3cc(Cl)ccc3[nH]2)ccc1C(=O)N1CCCC1
Yield: 99 %

Procedure:
Prepared analogously to Example 1g from 3-methyl-4-(pyrrolidin-1-ylcarbonyl)benzoic acid, TBTU, diisopropylethylamine and C-(5-chloro-1H-benzimidazol-2-yl)methylamine in tetrahydrofuran. Yield: 99% (over 2 steps); Rf value: 0.77 (silica gel; dichloromethane/ethanol=4:1); C21H21ClN4O2 (396.88); mass spectrum: (M+H)+=397/399 (chlorine isotope).
Reaction SMILES: Cl.[NH2:2][C@H:3]1[CH2:8][CH2:7][C@H:6]([NH:9][C:10]([C:12]2[C:16]3[N:17]=[CH:18][N:19]=[C:20]([C:21]4[CH:26]=[CH:25][C:24]([O:27][CH3:28])=[CH:23][C:22]=4[O:29][CH2:30][CH:31]4[CH2:33][CH2:32]4)[C:15]=3[NH:14][C:13]=2[CH3:34])=[O:11])[CH2:5][CH2:4]1.[C:35](Cl)(=[O:37])[CH3:36]>>[C:35]([NH:2][C@H:3]1[CH2:8][CH2:7][C@H:6]([NH:9][C:10]([C:12]2[C:16]3[N:17]=[CH:18][N:19]=[C:20]([C:21]4[CH:26]=[CH:25][C:24]([O:27][CH3:28])=[CH:23][C:22]=4[O:29][CH2:30][CH:31]4[CH2:32][CH2:33]4)[C:15]=3[NH:14][C:13]=2[CH3:34])=[O:11])[CH2:5][CH2:4]1)(=[O:37])[CH3:36]
Reactant: COc1ccc(-c2ncnc3c(C(=O)N[C@H]4CC[C@H](N)CC4)c(C)[nH]c23)c(OCC2CC2)c1
Reactant: CC(=O)Cl
Agent: Cl
Product: COc1ccc(-c2ncnc3c(C(=O)N[C@H]4CC[C@H](NC(C)=O)CC4)c(C)[nH]c23)c(OCC2CC2)c1

Procedure:
Starting from N-(trans-4-aminocyclohexyl)-4-[2-(cyclopropylmethoxy)-4-methoxyphenyl]-6-methyl-5H-pyrrolo[3,2-d]pyrimidine-7-carboxamide hydrochloride (example D.f19) and commercially acetyl chloride the title compound is obtained as colorless solid.
Reaction SMILES: [C:1]([C:3]1[C:8]([CH3:9])=[CH:7][CH:6]=[CH:5][C:4]=1[S:10]([NH2:13])(=[O:12])=[O:11])#[N:2].[CH2:14]([O:16][C:17](OCC)(OCC)[O:18][CH2:19][CH3:20])[CH3:15]>C(O)C>[C:1]([C:3]1[C:8]([CH3:9])=[CH:7][CH:6]=[CH:5][C:4]=1[S:10]([N:13]=[C:17]([O:18][CH2:19][CH3:20])[O:16][CH2:14][CH3:15])(=[O:12])=[O:11])#[N:2]
Reactant: CCOC(OCC)(OCC)OCC
Reactant: Cc1cccc(S(N)(=O)=O)c1C#N
Solvent: CCO
Product: CCOC(=NS(=O)(=O)c1cccc(C)c1C#N)OCC
Temperature: 25 °C
Yield: 90 %

Procedure:
3.60 g (18.4 mmol) 2-cyano-3-methyl-benzenesulfonamide and 5.29 g tetraethoxymethane (27.5 mmol) were heated to 160° C. slowly with stirring under removal of ethanol from the mixture. The mixture was cooled to room temperature. The residue was digerated with petrol ether, filtered and dried to afford 4.91 g (90% of theory) 2-Cyano-N-diethoxymethylene-3-methyl-benzene-sulfon-amide.
Reaction SMILES: Cl.[CH3:2][O:3][CH2:4][CH2:5][NH:6][C:7]([C:9]1[CH:17]=[CH:16][C:15]2[C:11](=[CH:12][N:13]([CH2:18][CH:19]3[CH2:24][CH2:23][NH:22][CH2:21][CH2:20]3)[N:14]=2)[C:10]=1[CH3:25])=[O:8].C(N(CC)CC)C.[F:33][C:34]([S:37][C:38]1[CH:46]=[CH:45][C:41]([C:42](Cl)=[O:43])=[CH:40][CH:39]=1)([F:36])[F:35]>C(Cl)Cl>[CH3:2][O:3][CH2:4][CH2:5][NH:6][C:7]([C:9]1[CH:17]=[CH:16][C:15]2[C:11](=[CH:12][N:13]([CH2:18][CH:19]3[CH2:20][CH2:21][N:22]([C:42](=[O:43])[C:41]4[CH:45]=[CH:46][C:38]([S:37][C:34]([F:36])([F:33])[F:35])=[CH:39][CH:40]=4)[CH2:23][CH2:24]3)[N:14]=2)[C:10]=1[CH3:25])=[O:8]
Reactant: COCCNC(=O)c1ccc2nn(CC3CCNCC3)cc2c1C
Reactant: O=C(Cl)c1ccc(SC(F)(F)F)cc1
Agent: Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: COCCNC(=O)c1ccc2nn(CC3CCN(C(=O)c4ccc(SC(F)(F)F)cc4)CC3)cc2c1C
Temperature: 0 °C
Reaction time: 2 h

Procedure:
60 mg of the amine prepared in Example 1a were first dissolved in 2 ml DCM at 0° C. 0.034 ml of triethylamine and 43.2 mg of 4-[(trifluoromethyl)sulphanyl]benzoyl chloride were then added and the mixture stirred for 2 hrs at 0° C. The reaction mixture was then diluted with DCM and washed with 1-molar hydrochloric acid, saturated sodium hydrogen carbonate solution (pH 9) and saturated sodium chloride solution. The organic phase was dried over sodium sulphate, filtered and concentrated. The residue was purified chromatographically on the Biotage SP4. Gradient: DCM/Methanol 0-10%. The product fraction was taken up in ethyl acetate and extracted twice with saturated sodium hydrogen carbonate solution. The organic phase was concentrated and the residue again purified by HPLC. Yield: 26.5 mg of the title compound.
Reaction SMILES: [Cl:1][C:2]1[N:3]=[C:4]([N:13]2[CH2:18][CH2:17][O:16][CH2:15][CH2:14]2)[C:5]2[S:10][C:9]([CH:11]=O)=[CH:8][C:6]=2[N:7]=1.[CH3:19][NH2:20]>CO>[Cl:1][C:2]1[N:3]=[C:4]([N:13]2[CH2:18][CH2:17][O:16][CH2:15][CH2:14]2)[C:5]2[S:10][C:9](/[CH:11]=[N:20]/[CH3:19])=[CH:8][C:6]=2[N:7]=1
Reactant: O=Cc1cc2nc(Cl)nc(N3CCOCC3)c2s1
Reactant: CN
Solvent: CO
Product: C/N=C/c1cc2nc(Cl)nc(N3CCOCC3)c2s1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To 2-chloro-4-morpholin-4-yl-thieno[3,2-d]pyrimidine-6-carbaldehyde 10 (1.0 g) in methanol under nitrogen was added methylamine solution (11.79 g methylamine in 50 ml methanol) (1.39 ml). The reaction mixture was stirred at room temperature overnight. The solvents were then removed in vacuo to yield [1-(2-Chloro-4-morpholin-4-yl-thieno[3,2-d]pyrimidin-6-yl)-meth-(E)-ylidene]-methyl-amine.
Reaction SMILES: [ClH:1].[NH:2]([CH2:6][CH2:7][CH2:8][CH2:9][C@H:10](O)[CH2:11][C:12]([NH2:14])=[O:13])[C:3]([NH2:5])=[NH:4].C1(N=C=NC2CCCCC2)CCCCC1>CN(C)C=O.[Cu](Cl)Cl>[ClH:1].[NH:2]([CH2:6][CH2:7][CH2:8][CH2:9][CH:10]=[CH:11][C:12]([NH2:14])=[O:13])[C:3]([NH2:5])=[NH:4]
Reactant: N=C(N)NCCCC[C@H](O)CC(N)=O
Agent: Cl[Cu]Cl
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: Cl
Solvent: CN(C)C=O
Product: N=C(N)NCCCCC=CC(N)=O
Temperature: 25 °C
Reaction time: 48 h
Yield: 89.5 %

Procedure:
To a solution of 955 mg (4mmoles) of (S)-7-guanidino-3-hydroxyheptanamide hydrochloride in 20 ml of anhydrous N,N-dimethylformamide were added 2.48 g (12 mmoles) of dicyclohexylcarbodiimide and 40 mg of copper(II) chloride. The mixture was stirred for 2 days at room temperature. The reaction mixture was filtered to remove the precipitate and the filtrate was concentrated under reduced pressure. The residue was dissolved in 10 ml of water and washed twice with 10 ml of ethyl acetate. The aqueous layer was evaporated to dryness, dissolved in 5 ml of water, passed through a column (20 mm inner diameter) packed with 50 ml of CM-Sephadex® C-25 (Na-type) and the column was eluted with 200 ml of 0.5M aqueous sodium chloride solution (10 ml fraction size). Fractions No. 17 to No. 30 were combined, evaporated to dryness and extracted 3 times with methanol. The methanol solution was passed through a column (20 mm inner diameter) packed with 150 ml of Sephadex® LH-20 and developed with methanol (5 ml fraction size). Fractions No. 9 to No. 16 were combined and evaporated to dryness. The residue, weighing 950 mg, was crystallized from ethanol-acetone to obtain 790 mg (89.5% yield) of 7-guanidino-2-heptenamide hydrochloride having a melting point of 162°-168° C. Proton NMR (measured in deuteromethanol), δ: 1.4-1.8 (CH2 ×2); 2.27 (CH2); 3.20 (CH2); 5.98 (CH); 6.80 (CH).
Reaction SMILES: Cl[CH2:2][C:3]1[C:8]([CH2:9]Cl)=[CH:7][N:6]=[C:5]([C:11]([F:14])([F:13])[F:12])[CH:4]=1.[C:15]1([C:21]([NH2:34])([C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=2)[C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1>>[F:12][C:11]([F:14])([F:13])[C:5]1[N:6]=[CH:7][C:8]2[CH2:9][N:34]([C:21]([C:15]3[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=3)([C:28]3[CH:29]=[CH:30][CH:31]=[CH:32][CH:33]=3)[C:22]3[CH:23]=[CH:24][CH:25]=[CH:26][CH:27]=3)[CH2:2][C:3]=2[CH:4]=1
Reactant: NC(c1ccccc1)(c1ccccc1)c1ccccc1
Reactant: FC(F)(F)c1cc(CCl)c(CCl)cn1
Product: FC(F)(F)c1cc2c(cn1)CN(C(c1ccccc1)(c1ccccc1)c1ccccc1)C2

Procedure:
Prepared in analogy to Example A2(b) from 4,5-Bis-chloromethyl-2-trifluoromethyl-pyridine and triphenylmethylamine. White solid.
Reaction SMILES: Br.CO[C:4]([C:6]1[C:7]([Br:22])=[N:8][C:9]2[CH:10]=[C:11]3[O:21][CH2:20][CH2:19][O:18][C:12]3=[CH:13][C:14]=2[C:15]=1[CH2:16]Br)=[O:5].C(N(CC)CC)C.[CH3:30][N:31]1[CH2:36][CH2:35][NH:34][CH2:33][CH2:32]1.[H-].C([Al+]CC(C)C)C(C)C.O.O.O.O.C(C(C(C([O-])=O)O)O)([O-])=O.[Na+].[K+]>ClCCl.O>[Br:22][C:7]1[C:6]([CH2:4][OH:5])=[C:15]([CH2:16][N:34]2[CH2:35][CH2:36][N:31]([CH3:30])[CH2:32][CH2:33]2)[C:14]2[CH:13]=[C:12]3[O:18][CH2:19][CH2:20][O:21][C:11]3=[CH:10][C:9]=2[N:8]=1
Reactant: CN1CCNCC1
Reactant: COC(=O)c1c(Br)nc2cc3c(cc2c1CBr)OCCO3
Agent: Br
Agent: CC(C)C[Al+]CC(C)C
Agent: O=C([O-])C(O)C(O)C(=O)[O-]
Solvent: ClCCl
Solvent: O
Solvent: CCN(CC)CC
Product: CN1CCN(Cc2c(CO)c(Br)nc3cc4c(cc23)OCCO4)CC1
Reaction time: 0.5 h
Yield: 85.8 %

Procedure:
To a mixture of 7-bromo-9-bromomethyl-2,3-dihydro[1,4]dioxino[2,3-g]quinoline-8-carboxylic acid methyl ester hydrobromic acid salt (Intermediate 10, 10 g, 19.6 mmol) in dichloromethane (DCM, 100 mL) is added triethylamine (5.4 mL. 39.2 mmol) followed by N-methylpiperazine (2.79 mL, 25.5 mmol). After stirring 30 min, water (50 mL) is added and the mixture is stirred 10 min. The layers are separated and the aqueous phase is extracted with DCM (50 mL). The organic phases are combined and washed with water (2×50 mL). The organic solution is then concentrated to an oil. The oil is diluted with DCM (50 mL) and stirred while diisobutylaluminum hydride (1.0 M in dichloromethane, 53 mL. 53 mmol) is added slowly while keeping the reaction temperature below 30° C. using an ice bath. The reaction is stirred for 10 min and then slowly poured into an aqueous solution (75 mL) saturated with potassium sodium tartrate tetrahydrate (Rochelle's salt). The temperature is kept <30° C. with an ice bath during the addition. The mixture gels and is stirred overnight at room temperature. The layers are separated and the aqueous phase is extracted with DCM (2×75 mL). The organics are combined and washed with water (2×50 mL). The organic phase is then concentrated under vacuum (crystallization occurs during concentration) to about 20 mL and the rest of the product crystallized out by adding tert-butyl methyl ether. The slurry is filtered and dried on high vacuum at room temperature overnight to provide 6.87 g (86%) of [7-bromo-9-(4-methyl-piperazin-1-ylmethyl)-2,3-dihydro-[1,4]dioxino[2,3-g] quinolin-8-yl]-methanol as a tan solid.
Reaction SMILES: [CH3:1][N:2]([CH3:11])[C:3](=[O:10])[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1.[Cl:12][C:13]1[C:14](=[O:40])[N:15]([CH2:30]C2C=CC(C(O)=O)=CC=2)[C:16]([CH3:29])=[CH:17][C:18]=1[O:19][CH2:20][C:21]1[CH:26]=[CH:25][C:24]([F:27])=[CH:23][C:22]=1[F:28].ON1C2C=CC=CC=2N=N1.CN1CCOCC1.CNC.Cl.CN(C)CCCN=C=NCC>CN(C)C=O.O>[Cl:12][C:13]1[C:14](=[O:40])[N:15]([CH2:30][C:7]2[CH:6]=[CH:5][C:4]([C:3]([N:2]([CH3:11])[CH3:1])=[O:10])=[CH:9][CH:8]=2)[C:16]([CH3:29])=[CH:17][C:18]=1[O:19][CH2:20][C:21]1[CH:26]=[CH:25][C:24]([F:27])=[CH:23][C:22]=1[F:28]
Reactant: CN(C)C(=O)c1ccccc1
Reactant: Cc1cc(OCc2ccc(F)cc2F)c(Cl)c(=O)n1Cc1ccc(C(=O)O)cc1
Agent: CCN=C=NCCCN(C)C
Agent: CNC
Agent: Cl
Solvent: CN(C)C=O
Solvent: CN1CCOCC1
Solvent: O
Product: Cc1cc(OCc2ccc(F)cc2F)c(Cl)c(=O)n1Cc1ccc(C(=O)N(C)C)cc1
Temperature: 25 °C
Reaction time: 3 h
Yield: 78 %

Procedure:
Preparation of 4-{[3-chloro-4-[(2,4-difluorobenzyl)oxy]-6-methyl-2-oxopyridin-1(2H)-yl]methyl}}-N,N-dimethylbenzamide. 4-{[3-chloro-4-[(2,4-difluorobenzyl)oxy]-6-methyl-2-oxopyridin-1(2H)-yl]methyl}benzoic acid (2.00 g, 4.76 mmol) was suspended in N,N-dimethylformamide (20 mL). 1-Hydroxybenzotriazole (0.773 g, 5.72 mmol) was added followed by 4-methylmorpholine (1.57 mL, 14.28 mmol), dimethylamine (7.14 mL, 2.0 M in tetrahydrofuran, 14.28 mmol) and then 1-[3-(dimethylamino)propyl]-3-ethylcarbodiimide hydrochloride (1.28 g, 6.66 mmol). The resulting mixture was stirred at room temperature for 3 hours at which time the reaction was diluted with H2O (75 mL). The reaction mixture was then extracted with ethyl acetate. The combined organic extracts were washed with saturated NaHCO3, brine, dried over Na2SO4, filtered and concentrated. The resulting solid was washed with ethyl acetate to provide the title compound as a white solid (1.67 g, 78%). 1H NMR (400 MHz, CDCl3) δ 7.53 (app q, J=7.8 Hz, H), 7.33 (d, J=8.3 Hz, 2H), 7.16 (d, J=8.3 Hz, 2H), 6.95-6.90 (m, 1H), 6.84 (app dt, J=2.5, 9.4 Hz, 1H), 6.02 (s, 1H), 5.35 (s, 2H), 5.19 (s, 2H), 2.97-2.93 (br m, 6H), 2.26 (s, 3H). ES-HRMS m/z 447.1246 (M+H calcd for C23H22ClF2N2O3 requires 447.1282).
Reaction SMILES: [CH3:1][C:2]1[C:11]([CH3:12])=[CH:10][C:5]2[NH:6][C:7](=[O:9])[NH:8][C:4]=2[CH:3]=1.C([O-])([O-])=O.[K+].[K+].C[N+](C)(C)[CH2:21][C:22]1[C:23]2[C:30]([CH3:31])=[CH:29][CH:28]=[CH:27][C:24]=2[S:25][CH:26]=1.[I-].[H-].[Na+]>CC(N(C)C)=O.C(OCC)(=O)C.CO>[CH3:1][C:2]1[C:11]([CH3:12])=[CH:10][C:5]2[N:6]([CH2:21][C:22]3[C:23]4[C:30]([CH3:31])=[CH:29][CH:28]=[CH:27][C:24]=4[S:25][CH:26]=3)[C:7](=[O:9])[NH:8][C:4]=2[CH:3]=1
Reactant: Cc1cccc2scc(C[N+](C)(C)C)c12
Reactant: Cc1cc2[nH]c(=O)[nH]c2cc1C
Agent: O=C([O-])[O-]
Agent: [H-]
Agent: [I-]
Solvent: CC(=O)N(C)C
Solvent: CCOC(C)=O
Solvent: CO
Product: Cc1cc2[nH]c(=O)n(Cc3csc4cccc(C)c34)c2cc1C
Temperature: 130 °C

Procedure:
To a slurry of 5,6-Dimethyl-2-benzimidazolinone (0.2 g, 1.2 mmol) in DMA (2 mL) (poor solubility) were added K2CO3 (0.10 g, 0.74 mmol) and trimethyl-(4-methyl-benzo[b]thiophen-3-ylmethyl)-ammonium; iodide (0.21 g, 0.62 mmol). The heterogeneous reaction mixture was heated to 130° C. for 10 min. Since there was still un-reacted starting material left, NaH (15 mg, 0.38 mmol) was added to the reaction mixture and heated to 150° C. for 10 min. The reaction was complete. The reaction mixture was then diluted with ethyl acetate (some MeOH was added to solubilize the reaction mixture into the organic phase) and washed with water (×5). The organic phase was dried over Na2SO4 and concentrated. The resulting solid had poor solubility. To the solid, CH2Cl2 was added and the resulting solid was filtered. The filtered solid was identified as the desired product (with a minimal amount of excess 5,6-Dimethyl-2-benzimidazolinone). Therefore, this filtered solid was used for the next reaction. LCMS (ESMS): m/z 323.13 (M+H+).
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[C:6](O)[N:5]2[N:9]=[C:10]([CH:12]([CH3:14])[CH3:13])[N:11]=[C:4]2[N:3]=1.P(Cl)(Cl)([Cl:17])=O.C([O-])([O-])=O.[Na+].[Na+]>O>[Cl:17][C:6]1[N:5]2[N:9]=[C:10]([CH:12]([CH3:14])[CH3:13])[N:11]=[C:4]2[N:3]=[C:2]([CH3:1])[CH:7]=1
Reactant: O=P(Cl)(Cl)Cl
Reactant: Cc1cc(O)n2nc(C(C)C)nc2n1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Product: Cc1cc(Cl)n2nc(C(C)C)nc2n1

Procedure:
A suspension of Intermediate 17 (0.225 g, 1.171 mmol) in phosphorous oxychloride (ALDRICH, 0.327 ml, 3.51 mmol) was heated under reflux for 1 h. The reaction mixture was added dropwise into iced water, neutralized with solid Na2CO3 and product was extracted with DCM. The combined organic layers were washed with brine and dried over anhydrous Na2SO4. A brown oil was obtained upon solvent removal in vacuo which was purified by flash chromatography (Si, eluting with Hexane:EtOAc mixtures from 100:0 to 40:60%) to yield the title compound as a white solid.
Reaction SMILES: [CH3:1][C:2]1[N:7]=[CH:6][N:5]=[C:4]([C:8]([O-:10])=[O:9])[CH:3]=1.[K+].S(=O)(=O)(O)O.[CH3:17]O>>[CH3:17][O:9][C:8]([C:4]1[CH:3]=[C:2]([CH3:1])[N:7]=[CH:6][N:5]=1)=[O:10]
Reactant: CO
Reactant: Cc1cc(C(=O)[O-])ncn1
Agent: O=S(=O)(O)O
Agent: [K+]
Product: COC(=O)c1cc(C)ncn1

Procedure:
1.77 g (16.37 mmol) of 4,6-dimethylpyrimidine was dissolved in 20 ml of water and stirred. 5.69 g (36.01 mmol) of potassium permanganate solution in 60 ml of water was added thereto and heated at temperature of 70° C. to 75° C. After the color of potassium permanganate disappeared, the mixture was filtered with celite and extracted with dichloromethane to collect the remaining starting material. The aqueous layer was removed under reduced pressure to obtain potassium 6-methylpyrimidine-4-carboxylate (Intermediate compound 57). 3.45 g of the intermediate compound 57 was mixed with 250 ml of methanol and 1.7 ml of conc. sulfuric acid, and the mixture was refluxed under heating for 6 hours. The solvent in the mixture was then removed under reduced pressure. The residue was diluted with ethyl acetate and water, and neutralized by sodium bicarbonate solution, and then extracted with ethyl acetate. The organic layer was dried over anhydrous magnesium sulfate, filtered and concentrated under reduced pressure. The concentrated product was purified by the column chromatography (ethylacetate:hexane=1:1) to obtain 6-methylpyrimidine-4-carboxylic acid methyl ester (Intermediate compound 58, 930 mg, Yield of the first and second steps: 37%). The intermediate compound 58 was then subjected to the fifth step in the reaction of Example 1 to obtain 6-methylpyrimine-4-carboxylic acid (Intermediate compound 59, Yield of the third step: 62%). Next, the intermediate compound 59 and (−)-thiodeacetyl colchicine were subjected to the sixth step in the reaction of Example 1 to obtain the title compound 21 (Yield of the fourth step: 37%).