Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl.[CH3:2][N:3]([CH2:5][C:6]([NH2:8])=[S:7])[CH3:4].[Cl:9][CH2:10][C:11](=O)[CH2:12]Cl.C(=O)(O)[O-].[Na+]>ClCCCl>[ClH:9].[Cl:9][CH2:10][C:11]1[N:8]=[C:6]([CH2:5][N:3]([CH3:4])[CH3:2])[S:7][CH:12]=1
Reactant: O=C(CCl)CCl
Reactant: CN(C)CC(N)=S
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCCl
Product: CN(C)Cc1nc(CCl)cs1
Temperature: 25 °C
Reaction time: 26 h

Procedure:
To a 1000 ml. flask were added 77 g. of dimethylaminothioacetamide, hydrochloride, 70 g. of 1,3-dichloropropanone, 92.4 g. of sodium bicarbonate and 350 ml. of 1,2-dichloroethane. The mixture was stirred at ambient temperature for 26 hours and filtered, and the filter cake was washed with 118 ml. of 1,2-dichloroethane. The filtrates were combined and cooled in an acetone-ice bath. To the filtrate was added, dropwise, 39.5 ml. of thionyl chloride at a temperature between 13° and 18°. The mixture was stirred at 20° for 30 minutes, then heated to 50°. An additional 100 ml. of 1,2-dichloroethane was added, and the mixture was stirred for 30 minutes at 60°. It was then cooled to ambient temperature, and 82 ml. of deionized water was added. The layers were separated, and the organic layer was extracted with 28 ml. and 14 ml. portions of deionized water. The aqueous layers were combined, and it was confirmed by tlc that the desired product had been collected in the aqueous layers.
Reaction SMILES: [Br-:1].[Br-].[Br-].C([N+](CCCC)(CCCC)CCCC)CCC.C([N+](CCCC)(CCCC)CCCC)CCC.C([N+](CCCC)(CCCC)CCCC)CCC.[CH2:55]([O:57][C:58]1[CH:59]=[CH:60][C:61]([CH2:65][CH3:66])=[C:62]([OH:64])[CH:63]=1)[CH3:56]>C(Cl)(Cl)Cl>[Br:1][C:59]1[C:58]([O:57][CH2:55][CH3:56])=[CH:63][C:62]([OH:64])=[C:61]([CH2:65][CH3:66])[CH:60]=1
Reactant: CCOc1ccc(CC)c(O)c1
Reactant: [Br-]
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Solvent: ClC(Cl)Cl
Product: CCOc1cc(O)c(CC)cc1Br
Reaction time: 0.5 h
Yield: 57 %

Procedure:
A solution of tetrabutyl ammonium tribromide (9.9 g, 20.5 mmol) in CHCl3 (60 mL) was added to a stirred solution of 5-ethoxy-2-ethyl-phenol (3.1 g, 18.6 mmol) dissolved in CHCl3 (90 mL). The reaction mixture was stirred for 30 mins and then quenched with 5% solution of sodium thiosulfate (30 mL). The biphasic mixture was stirred for 30 mins and then the layers were separated. The organic layer was washed with 1 N HCl, brine, dried over Na2SO4 and concentrated to a red oil. Purification by flash column chromatography (0% to 15% EtOAc in hexanes) gave the product as an oil (2.6 g, 58%). 1H NMR (400 MHz, CDCl3): δ 1.20 (t, J=7.6 Hz, 3H), 1.44 (t, J=7.1 Hz, 3H), 2.53 (q, J=7.6 Hz, 2H), 4.03 (q, J=7.1 Hz, 2H), 4.85 (s, 1H), 6.41 (s, 1H), 7.25 (s, 1H).
Reaction SMILES: [Cl:1][CH2:2][C:3]1[CH:11]=[CH:10][C:6]([C:7]([OH:9])=O)=[CH:5][CH:4]=1.Cl.[NH2:13][CH2:14][CH2:15][CH2:16][C:17]([O:19][CH2:20][CH3:21])=[O:18]>>[Cl:1][CH2:2][C:3]1[CH:4]=[CH:5][C:6]([C:7]([NH:13][CH2:14][CH2:15][CH2:16][C:17]([O:19][CH2:20][CH3:21])=[O:18])=[O:9])=[CH:10][CH:11]=1
Reactant: O=C(O)c1ccc(CCl)cc1
Reactant: CCOC(=O)CCCN
Agent: Cl
Product: CCOC(=O)CCCNC(=O)c1ccc(CCl)cc1

Procedure:
Ethyl 4-(4-(chloromethyl)benzamido)butanoate 13g was prepared by coupling 4-(chloromethyl)benzoic acid 24 with ethyl 4-aminobutyrate 26 according to the procedure described for the compound 13e in Example 21 (Scheme 8). The compound 13g was isolated as colorless oil in 89% yield (2.52 g). 1H NMR (400 MHz, CDCl3): δ 1.24 (3H, t, J=6.8 Hz); 1.96 (2H, quint, J=7.2 Hz); 2.44 (2H, t, J=7.2 Hz); 3.52 (2H, t, J=7.2 Hz); 4.10 (2H, q, J=6.8 Hz); 4.60 (2H, s); 6.62 (1H, broad s); 7.44 (1H, s); 7.46 (1H, s); 7.76 (1H, s); 7.78 (1H, s). MS (ESI): m/z=284.00 (M+H+).
Reaction SMILES: [CH2:1]([C:3]1[C:8]([CH2:9][CH:10]=O)=[CH:7][CH:6]=[CH:5][C:4]=1[C:12]1[S:16][C:15]([C:17]2[CH:18]=[CH:19][C:20]([O:25][CH:26]([CH3:28])[CH3:27])=[C:21]([CH:24]=2)[C:22]#[N:23])=[N:14][CH:13]=1)[CH3:2].[NH:29]1[CH2:36][CH2:35][CH2:34][C@H:30]1[C:31]([OH:33])=[O:32].C(O)(=O)C.C([BH3-])#N.[Na+]>>[C:22]([C:21]1[CH:24]=[C:17]([C:15]2[S:16][C:12]([C:4]3[C:3]([CH2:1][CH3:2])=[C:8]([CH2:9][CH2:10][N:29]4[CH2:36][CH2:35][CH2:34][C@H:30]4[C:31]([OH:33])=[O:32])[CH:7]=[CH:6][CH:5]=3)=[CH:13][N:14]=2)[CH:18]=[CH:19][C:20]=1[O:25][CH:26]([CH3:28])[CH3:27])#[N:23]
Reactant: CCc1c(CC=O)cccc1-c1cnc(-c2ccc(OC(C)C)c(C#N)c2)s1
Reactant: O=C(O)[C@@H]1CCCN1
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CC(=O)O
Product: CCc1c(CCN2CCC[C@H]2C(=O)O)cccc1-c1cnc(-c2ccc(OC(C)C)c(C#N)c2)s1
Temperature: 25 °C
Reaction time: 2 h
Yield: 14.6 %

Procedure:
A solution of 5-{5-[2-ethyl-3-(2-oxoethyl)phenyl]-1,3-thiazol-2-yl}-2-[(1-methylethyl) oxy]benzonitrile (D76) (60 mg, 0.154 mmol), L-proline (35.4 mg, 0.307 mmol) and acetic acid (0.1 ml, 1.747 mmol) was stirred at room temperature for 15 min, then sodium cyanoborohydride (29.0 mg, 0.461 mmol) was added. The mixture was stirred at room temperature for 2 h. After concentration, the residue was partitioned between ethyl acetate and aqueous HCl (2M). The organic phase was washed with saturated brine, concentrated and purified by Mass Directed AutoPrep to afford 1-{2-[3-(2-{3-cyano-4-[(1-methylethyl)oxy]phenyl}-1,3-thiazol-5-yl)-2-ethylphenyl]ethyl}-L-proline (E88) (11 mg) as a TFA salt.
Reaction SMILES: Br[CH2:2][CH2:3][CH2:4][C:5](=[O:7])[CH3:6].[CH:8]1[C:21]2[C:20](=[C:22]3[CH2:27][CH2:26][NH:25][CH2:24][CH2:23]3)[C:19]3[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=3)[O:13][C:12]=2[CH:11]=[CH:10][CH:9]=1.C(=O)([O-])[O-].[Na+].[Na+]>C(Cl)(Cl)Cl>[CH:18]1[C:19]2[C:20](=[C:22]3[CH2:27][CH2:26][N:25]([CH2:2][CH2:3][CH2:4][C:5](=[O:7])[CH3:6])[CH2:24][CH2:23]3)[C:21]3[C:12](=[CH:11][CH:10]=[CH:9][CH:8]=3)[O:13][C:14]=2[CH:15]=[CH:16][CH:17]=1
Reactant: c1ccc2c(c1)Oc1ccccc1C2=C1CCNCC1
Reactant: CC(=O)CCCBr
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: ClC(Cl)Cl
Product: CC(=O)CCCN1CCC(=C2c3ccccc3Oc3ccccc32)CC1

Procedure:
7.2 g of 5-bromo-2-pentanone in 50 cc of chloroform are added dropwise to a suspension of 10.0 g of 4-(9-xanthenylidene)piperidine [M.P. 147°-149°, produced from N-methyl-4-(9-xanthenylidene)piperidine] and 9.25 g of sodium carbonate in 200 cc of chloroform. The reaction mixture is boiled at reflux for 17 hours, is filtered, concentrated by evaporation, the evaporation residue is placed on a column of 100 g of silica gel and elution is effected with chloroform containing 1% of methanol. The evaporation residue of the eluate is dissolved in acetone and made weakly acid to Congo red with hydrogen chloride in ether. The 5-[4-(9-xanthenylidene)piperidino]-2-pentanone hydrochloride which precipitates immediately is recrystallized from alcohol. M.P. 248°-251° (decomp.).
Reaction SMILES: [C:1]([N:8]1[CH2:16][CH2:15][CH:11]([C:12]([OH:14])=[O:13])[CH2:10][CH2:9]1)([O:3][C:4]([CH3:7])([CH3:6])[CH3:5])=[O:2].[CH3:17][Si](C=[N+]=[N-])(C)C>ClCCl.CO>[C:4]([O:3][C:1]([N:8]1[CH2:16][CH2:15][CH:11]([C:12]([O:14][CH3:17])=[O:13])[CH2:10][CH2:9]1)=[O:2])([CH3:7])([CH3:6])[CH3:5]
Reactant: CC(C)(C)OC(=O)N1CCC(C(=O)O)CC1
Reactant: C[Si](C)(C)C=[N+]=[N-]
Solvent: ClCCl
Solvent: CO
Product: COC(=O)C1CCN(C(=O)OC(C)(C)C)CC1
Yield: 96.6 %

Procedure:
To a solution of BOC-isonipecotic acid (45.0 g, 0.20 mol) dissolved in a 3:1 solution of dichloromethane/methanol (1200 mL) at 0° C. was added a solution of trimethylsilyldiazomethane (147 mL, 0.29 mol, 2.0M in hexane) over 30 min via an addition funnel. The reaction mixture was then concentrated to afford the title compound (47 g) as a light yellow oil. This was used directly in the next step without further purification.
Reaction SMILES: [Li+].[Cl-].[Br:3][C:4]1[CH:27]=[CH:26][C:7]([CH2:8][C:9]([CH2:18][C:19]2[CH:24]=[CH:23][C:22]([Br:25])=[CH:21][CH:20]=2)([C:15](=[O:17])[CH3:16])C(OCC)=O)=[CH:6][CH:5]=1.O>CN(C=O)C>[Br:3][C:4]1[CH:5]=[CH:6][C:7]([CH2:8][CH:9]([CH2:18][C:19]2[CH:20]=[CH:21][C:22]([Br:25])=[CH:23][CH:24]=2)[C:15](=[O:17])[CH3:16])=[CH:26][CH:27]=1
Reactant: CCOC(=O)C(Cc1ccc(Br)cc1)(Cc1ccc(Br)cc1)C(C)=O
Agent: [Cl-]
Agent: [Li+]
Solvent: O
Solvent: CN(C)C=O
Product: CC(=O)C(Cc1ccc(Br)cc1)Cc1ccc(Br)cc1
Temperature: 120 °C
Yield: 52 %

Procedure:
A mixed liquid containing LiCl (0.175 g, 4 mmol), ethyl 2,2-bis(4-bromobenzyl)-3-oxobutanoate (0.94 g, 2 mmol) and H2O (0.036 mL) in DMF (4 mL) was stirred under heating at 120° C. for 48 hours. The mixed liquid was then cooled to room temperature, water (10 mL) was added, and the resulting mixture was extracted with ethyl acetate. The resulting organic layer was washed with a saturated saline solution and then dried using MgSO4. The organic layer was concentrated under reduced pressure, and then purified using silica gel column chromatography, yielding the title compound (41) in a yield of 52%.
Reaction SMILES: [CH2:1]([C@H:4]1[CH2:9][CH2:8][C@H:7]([CH2:10]O)[CH2:6][CH2:5]1)[CH2:2][CH3:3].P(Br)(Br)[Br:13]>N1C=CC=CC=1.C1C=CC=CC=1>[CH2:1]([C@H:4]1[CH2:9][CH2:8][C@H:7]([CH2:10][Br:13])[CH2:6][CH2:5]1)[CH2:2][CH3:3]
Reactant: CCC[C@H]1CC[C@H](CO)CC1
Reactant: BrP(Br)Br
Solvent: c1ccncc1
Solvent: c1ccccc1
Product: CCC[C@H]1CC[C@H](CBr)CC1
Temperature: 0 °C

Procedure:
Compound (31) obtained according to section (A) (15.6 g, 0.1 mole) was added at 0° C. to 150 ml of pyridine-benzene mixture (1:1), and while being stirred, the solution was added to 9.0 g (0.033 mole) of PBr3. The reaction mixture was stirred for 2 hours at 0° C. and then 2 hours at room temperature, poured over ice/2 N HCl and extracted with diethyl ether. The ether extract was washed once each with 2 N HCl, 2 N NaOH, and NaCl solution, dried with Na2SO4, and concentrated. The bromide of formula (32) was purified chromatographically with silica gel.
Reaction SMILES: Br[CH:2]1[CH2:7][CH2:6][CH2:5][CH2:4][CH2:3]1.[N+:8]([C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=1[OH:17])([O-:10])=[O:9]>>[CH:2]1([O:17][C:12]2[CH:13]=[CH:14][CH:15]=[CH:16][C:11]=2[N+:8]([O-:10])=[O:9])[CH2:7][CH2:6][CH2:5][CH2:4][CH2:3]1
Reactant: O=[N+]([O-])c1ccccc1O
Reactant: BrC1CCCCC1
Product: O=[N+]([O-])c1ccccc1OC1CCCCC1

Procedure:
In a similar manner as in Example 1, bromocyclohexane was reacted with o-nitrophenol to yield 2-cyclohexoxynitrobenzene; which was reduced to the corresponding aniline; then reacted with N-methylolpyrrolidone to form the corresponding N-methylenepyrrolidonyl derivative; which was acylated with chloroacetyl chloride to form the desired product.
Reaction SMILES: [OH:1][C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[N:5]([N:12]=CC2C=CC=CC=2)[C:4](=[O:20])[C:3]=1[C:21](OCC)=O.[NH2:26][C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][C:28]=1[S:33]([NH2:36])(=[O:35])=[O:34].Cl>C1(C)C=CC=CC=1>[NH2:12][N:5]1[C:6]2[C:11](=[CH:10][CH:9]=[CH:8][CH:7]=2)[C:2]([OH:1])=[C:3]([C:21]2[NH:26][C:27]3[CH:32]=[CH:31][CH:30]=[CH:29][C:28]=3[S:33](=[O:34])(=[O:35])[N:36]=2)[C:4]1=[O:20]
Reactant: CCOC(=O)c1c(O)c2ccccc2n(N=Cc2ccccc2)c1=O
Reactant: Nc1ccccc1S(N)(=O)=O
Agent: Cl
Solvent: Cc1ccccc1
Product: Nn1c(=O)c(C2=NS(=O)(=O)c3ccccc3N2)c(O)c2ccccc21
Temperature: 25 °C
Yield: 70.2 %

Procedure:
The product of Example 226C (4.51 g, 14.00 mmol) was reacted with 2-amino benzenesulfonamide (2.41 g, 14.00 mmol) in toluene (65 mL) at reflux for 6 hours. After cooling to 25° C., the solid (5.52 g) was collected by filtration and reacted further with aqueous 10% potassium hydroxide (100 mL) for 8 hours at 130° C. After cooling to 25° C., the reaction was poured into ice and acidified to pH 2 with 1 M hydrochloric acid. The resulting solid was isolated by filtration and dried to give the title compound (3.50 g, 71%). The sodium salt of the title compound was prepared according to the procedure of Example 1D. 1H NMR (300 MHz, DMSO-d6) δ 5.31 (s, 2 H) 7.05 (t, J=8.09 Hz, 1 H) 7.27 (m, 2 H) 7.53 (m, 2 H) 7.67 (m, 2 H) 8.07 (dd, J=8.09, 1.47 Hz, 1 H) 16.38 (s, 1 H).
Reaction SMILES: [NH2:1][C:2]1[C:9]([N+:10]([O-:12])=[O:11])=[C:8]([CH3:13])[C:7]([N+:14]([O-:16])=[O:15])=[CH:6][C:3]=1[C:4]#[N:5].CO[CH:19](OC)[N:20]([CH3:22])[CH3:21]>C1(C)C=CC=CC=1>[C:4]([C:3]1[C:2]([N:1]=[CH:19][N:20]([CH3:22])[CH3:21])=[C:9]([N+:10]([O-:12])=[O:11])[C:8]([CH3:13])=[C:7]([N+:14]([O-:16])=[O:15])[CH:6]=1)#[N:5]
Reactant: Cc1c([N+](=O)[O-])cc(C#N)c(N)c1[N+](=O)[O-]
Reactant: COC(OC)N(C)C
Solvent: Cc1ccccc1
Product: Cc1c([N+](=O)[O-])cc(C#N)c(N=CN(C)C)c1[N+](=O)[O-]
Temperature: 25 °C
Yield: 99 %

Procedure:
To a suspension of 2-amino-4-methyl-3,5-dinitrobenzonitrile (5) (3.129 g, 14.1 mmol) in anhydrous toluene is added N,N-dimethylformamide dimethyl acetal (4 mL). The resultant mixture is heated to about 100° C. for about 2.5 hours. The mixture is cooled to ambient temperature and the solvent is removed using a rotary evaporator. The residue is dried to provide crude N′-(6-Cyano-3-methyl-2,4-dinitro-phenyl)-N,N-dimethyl-methanimidamide (8) (3.85 g, 99% Yield) as a red solid.
Reaction SMILES: [NH2:1][C:2]1[C:11]2[C:6](=[C:7](Br)[C:8]([F:12])=[CH:9][CH:10]=2)[N:5]=[N:4][C:3]=1[C:14]([NH:16][CH:17]1[CH2:20][CH2:19][CH2:18]1)=[O:15].[CH3:21][O:22][C:23]1[N:28]=[C:27]([O:29][CH3:30])[C:26](B(O)O)=[CH:25][N:24]=1>>[NH2:1][C:2]1[C:11]2[C:6](=[C:7]([C:26]3[C:27]([O:29][CH3:30])=[N:28][C:23]([O:22][CH3:21])=[N:24][CH:25]=3)[C:8]([F:12])=[CH:9][CH:10]=2)[N:5]=[N:4][C:3]=1[C:14]([NH:16][CH:17]1[CH2:20][CH2:19][CH2:18]1)=[O:15]
Reactant: COc1ncc(B(O)O)c(OC)n1
Reactant: Nc1c(C(=O)NC2CCC2)nnc2c(Br)c(F)ccc12
Product: COc1ncc(-c2c(F)ccc3c(N)c(C(=O)NC4CCC4)nnc23)c(OC)n1
Yield: 42.8 %

Procedure:
Using Method A, 4-amino-8-bromo-7-fluoro-N-cyclobutyl-cinnoline-3-carboxamide (175 mg) and 2,4-dimethoxypyrimidin-5-yl boronic acid (207 mg) were reacted to afford the title compound (88 mg) as white solid. 1H NMR (500 MHz, DMSO-d6) δ 9.24 (d, 1H), 8.57 (m, 1H), 8.38 (s, 1H), 7.77 (m, 1H), 4.49 (m, 1H), 4.00 (s, 3H), 3.84 (s, 3H), 2.26-2.10(m, 4H), 1.72-1.62 (m, 2H). MS APCI, m/z=399 (M+H).
Reaction SMILES: C([Li])CCC.Br[C:7]1[C:12]([CH2:13][O:14][CH:15]2[CH2:20][CH2:19][CH2:18][CH2:17][O:16]2)=[C:11]([CH2:21][CH2:22][CH3:23])[C:10]([O:24][CH2:25][O:26][CH3:27])=[CH:9][CH:8]=1.[F:28][C:29]([F:37])([F:36])[C:30]([C:32]([F:35])([F:34])[F:33])=[O:31].O>O1CCCC1>[F:28][C:29]([F:37])([F:36])[C:30]([C:7]1[CH:8]=[CH:9][C:10]([O:24][CH2:25][O:26][CH3:27])=[C:11]([CH2:21][CH2:22][CH3:23])[C:12]=1[CH2:13][O:14][CH:15]1[CH2:20][CH2:19][CH2:18][CH2:17][O:16]1)([OH:31])[C:32]([F:35])([F:34])[F:33]
Reactant: O=C(C(F)(F)F)C(F)(F)F
Reactant: CCCc1c(OCOC)ccc(Br)c1COC1CCCCO1
Agent: [Li]CCCC
Solvent: O
Solvent: C1CCOC1
Product: CCCc1c(OCOC)ccc(C(O)(C(F)(F)F)C(F)(F)F)c1COC1CCCCO1
Reaction time: 0.25 h
Yield: 90 %

Procedure:
Under an argon atmosphere, n-butyl lithium (1.58 mol/L hexane solution 1.55 mL, 2.45 mmol) was dropped at −78° C. into a solution of 2-(6-bromo-3-(methoxymethoxy)-2-propylbenzyloxy)tetrahydro-2H-pyrane (725 mg, 1.75 mmol) in tetrahydrofuran (8 mL). The mixture was stirred at the same temperature for 15 minutes and then stirred at the elevated temperature of −45° C. for 1.5 hours. A tetrahydrofuran (4 mL) solution of hexafluoroacetone was dropped at −78° C., and the mixture was stirred at 0° C. for 5 hours and then stirred at room temperature for 12 hours. The reaction solution was added with water and extracted with ethyl acetate. Subsequently, the organic layer was washed with saturated saline, dried using anhydrous sodium sulfate, and concentrated in vacuum. The residue was purified by silica-gel column chromatography (hexane/ethyl acetate), and the title compound (728 mg, 90%) was obtained as colorless oil.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[S:9][C:8](=[O:10])[N:7]([CH2:11][C:12]([N:14]([CH3:19])[CH2:15][C:16](O)=O)=[O:13])[C:6]=2[CH:20]=1.[Cl:21][C:22]1[CH:23]=[C:24]([NH2:30])[C:25]([NH2:29])=[CH:26][C:27]=1[Cl:28].C1C=CC2N(O)N=NC=2C=1.CCN=C=NCCCN(C)C.Cl>CCOC(C)=O.CN(C=O)C>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[S:9][C:8](=[O:10])[N:7]([CH2:11][C:12]([N:14]([CH2:15][C:16]3[NH:29][C:25]4[CH:26]=[C:27]([Cl:28])[C:22]([Cl:21])=[CH:23][C:24]=4[N:30]=3)[CH3:19])=[O:13])[C:6]=2[CH:20]=1
Reactant: Nc1cc(Cl)c(Cl)cc1N
Reactant: CN(CC(=O)O)C(=O)Cn1c(=O)sc2ccc(Cl)cc21
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: CN(Cc1nc2cc(Cl)c(Cl)cc2[nH]1)C(=O)Cn1c(=O)sc2ccc(Cl)cc21
Temperature: 25 °C
Reaction time: 8 h
Yield: 41.4 %

Procedure:
To a mixture of N-[(5-chloro-2-oxo-1,3-benzothiazol-3(2H)-yl)acetyl]-N-methylglycine (90 mg), 4,5-dichlorobenzene-1,2-diamine (53 mg), and DMF (3 mL) were added TEA (95 μL), HOBt (43 mg), and WSC.HCl (60 mg), followed by stirring at room temperature overnight. The reaction mixture was diluted with EtOAc. The organic layer was washed with water, a saturated aqueous NaHCO3 solution, and brine in this order, dried over Na2SO4, and then concentrated under reduced pressure. To the residue was added acetic acid (3 mL), followed by heating and stirring at 110° C. for 5 hours. The reaction mixture was cooled to room temperature and then concentrated under reduced pressure. The residue was diluted with EtOAc. The organic layer was washed with a saturated aqueous NaHCO3 solution and brine in this order, dried over Na2SO4, and then concentrated under reduced pressure. The resulting solid was collected by filtration and then washed with MeOH to obtain 2-(5-chloro-2-oxo-1,3-benzothiazol-3(2H)-yl)-N-[(5,6-dichloro-1H-benzimidazol-2-yl)methyl]-N-methylacetamide (54 mg).
Reaction SMILES: [Br:1][C:2]1[CH:13]=[CH:12][C:5]([C:6](N(OC)C)=[O:7])=[C:4]([Cl:14])[CH:3]=1.[CH:15]1([Mg]Br)[CH2:17][CH2:16]1.[Cl-].[NH4+]>O1CCCC1>[Br:1][C:2]1[CH:13]=[CH:12][C:5]([C:6]([CH:15]2[CH2:17][CH2:16]2)=[O:7])=[C:4]([Cl:14])[CH:3]=1
Reactant: Br[Mg]C1CC1
Reactant: CON(C)C(=O)c1ccc(Br)cc1Cl
Agent: [Cl-]
Agent: [NH4+]
Solvent: C1CCOC1
Product: O=C(c1ccc(Br)cc1Cl)C1CC1
Reaction time: 4 h
Yield: 68 %

Procedure:
To a solution of 4-bromo-2-chloro-N-methoxy-N-methylbenzamide (synthesized by the method of Bioorganic & Medicinal Chemistry Letters 2003, 13, 3983, 5.90 g, 21.0 mmol) in tetrahydrofuran (180 mL) was added dropwise a solution of 0.7 mol/L cyclopropylmagnesium bromide in tetrahydrofuran (65.0 mL, 45.5 mmol) at 0° C. The mixture was stirred at the same temperature for 4 hours, and then to the reaction solution was added saturated aqueous ammonium chloride solution, and the mixture was extracted with ethyl acetate three times. The organic layer was combined, washed with water and saturated brine, dried over anhydrous sodium sulfate, and then concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography (hexane:ethyl acetate=100:0→93:7) to give (4-bromo-2-chlorophenyl)(cyclopropyl)methanone (3.75 g, 68%) as a pale yellow oil.
Reaction SMILES: [CH3:1][C:2]1[C:7]2[O:8][CH2:9][C:10]3([CH2:12][CH2:11]3)[C:6]=2[C:5]([O:13][C:14]2[N:19]=[CH:18][C:17]([NH:20][C:21]([C@H:23]([NH:26]C(=O)OC(C)(C)C)[CH2:24][CH3:25])=[O:22])=[CH:16][N:15]=2)=[CH:4][CH:3]=1.C(O)(C(F)(F)F)=O>C(Cl)Cl>[NH2:26][C@H:23]([CH2:24][CH3:25])[C:21]([NH:20][C:17]1[CH:16]=[N:15][C:14]([O:13][C:5]2[C:6]3[C:10]4([CH2:9][O:8][C:7]=3[C:2]([CH3:1])=[CH:3][CH:4]=2)[CH2:12][CH2:11]4)=[N:19][CH:18]=1)=[O:22]
Reactant: CC[C@@H](NC(=O)OC(C)(C)C)C(=O)Nc1cnc(Oc2ccc(C)c3c2C2(CC2)CO3)nc1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CC[C@@H](N)C(=O)Nc1cnc(Oc2ccc(C)c3c2C2(CC2)CO3)nc1
Reaction time: 3 h
Yield: 76.3 %

Procedure:
To a solution of tert-butyl N-[(1R)-1-[[2-(7-methylspiro[2H-benzofuran-3,1′-cyclopropane]-4-yl)oxypyrimidin-5-yl]carbamoyl]propyl]carbamate (Intermediate 163, 42 mg) in dry DCM (3 ml) at 0° C. TFA (1 ml) was slowly added and the reaction mixture was stirred for 3 hours at the same temperature. The solvent and the excess of TFA were removed under reduced pressure and the residue was diluted with DCM (10 ml) and an aqueous saturated solution NaHCO3 was added while the pH was allowed to reach ˜8. Two phases were separated and the organic layer was dried (Na2SO4), filtered and evaporated affording the title compound (25 mg) as light yellow gum.
Reaction SMILES: [F:1][C:2]([F:18])([F:17])[CH:3]([C:5]1[CH:10]=[CH:9][C:8]([C:11]2[CH:16]=[CH:15][N:14]=[CH:13][CH:12]=2)=[CH:7][CH:6]=1)[OH:4].[NH2:19][C:20]1[N:25]=[C:24](Cl)[CH:23]=[C:22]([Cl:27])[N:21]=1.C(=O)([O-])[O-].[Cs+].[Cs+].C(OCC)(=O)C>O1CCOCC1>[Cl:27][C:22]1[CH:23]=[C:24]([O:4][CH:3]([C:5]2[CH:6]=[CH:7][C:8]([C:11]3[CH:12]=[CH:13][N:14]=[CH:15][CH:16]=3)=[CH:9][CH:10]=2)[C:2]([F:1])([F:17])[F:18])[N:25]=[C:20]([NH2:19])[N:21]=1
Reactant: Nc1nc(Cl)cc(Cl)n1
Reactant: OC(c1ccc(-c2ccncc2)cc1)C(F)(F)F
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: C1COCCO1
Solvent: CCOC(C)=O
Product: Nc1nc(Cl)cc(OC(c2ccc(-c3ccncc3)cc2)C(F)(F)F)n1
Temperature: 110 °C
Yield: 82.9 %

Procedure:
The mixture of 2,2,2-trifluoro-1-(4-pyridin-4-yl-phenyl)ethanol (100 mg, 0.40 mmol), 2-amino-4,6-dichloropyrimidine (60 mg, 0.38 mmol), and cesium carbonate (468 mg, 1.44 mmol) was dissolved in 2 ml of 1,4-dioxane in a 50 ml sealed tube. The mixture was heated at 110° C. overnight, then was cooled to room temperature; 10 ml of ethyl acetate was added and then filtered through Celite. The filtrate was concentrated to give 120 mg of 4-chloro-6-[2,2,2-trifluoro-1-(4-pyridin-4-yl-phenyl)-ethoxy]-pyrimidin-2-ylamine, yield: 80%.
Reaction SMILES: [OH:1][NH:2][C:3]([C:5]1[CH:6]=[C:7]2[C:11](=[CH:12][CH:13]=1)[NH:10][CH:9]=[CH:8]2)=[NH:4].[Cl:14][C:15]1[CH:16]=[C:17]([CH:21]=[CH:22][C:23]=1[O:24][CH:25]([CH3:27])[CH3:26])[C:18](O)=O.C1CN([P+](ON2N=NC3C=CC=CC2=3)(N2CCCC2)N2CCCC2)CC1.F[P-](F)(F)(F)(F)F>CN(C=O)C>[Cl:14][C:15]1[CH:16]=[C:17]([C:18]2[O:1][N:2]=[C:3]([C:5]3[CH:6]=[C:7]4[C:11](=[CH:12][CH:13]=3)[NH:10][CH:9]=[CH:8]4)[N:4]=2)[CH:21]=[CH:22][C:23]=1[O:24][CH:25]([CH3:26])[CH3:27]
Reactant: CC(C)Oc1ccc(C(=O)O)cc1Cl
Reactant: N=C(NO)c1ccc2[nH]ccc2c1
Agent: F[P-](F)(F)(F)(F)F
Agent: c1ccc2c(c1)nnn2O[P+](N1CCCC1)(N1CCCC1)N1CCCC1
Solvent: CN(C)C=O
Product: CC(C)Oc1ccc(-c2nc(-c3ccc4[nH]ccc4c3)no2)cc1Cl
Reaction time: 8 h
Yield: 11.9 %

Procedure:
D1 (500 mg), D4 (611 mg) and PyBOP (1.66 g) were dissolved in DMF and stirred overnight. The reaction mixture was then evaporated and partitioned between EtOAc and H2O. The organic layer was washed with H2O (×2) then brine, dried over MgSO4, filtered and evaporated to give the crude product. This was purified on a silica cartridge, eluting with a 0 to 50% mixture of Et2O in hexane to give the title compound (120 mg) as a white solid. δH (CDCl3, 400 MHz): 1.43 (6H, d), 4.69 (1H, septet), 6.92 (1H, s), 7.04 (1H, d), 7.25 (1H, s), 7.48 (1H, d), 8.00 (1H, d), 8.07 (1H, d), 8.25 (1H, s), 8.39 (1H, br. s), 8.50 (1H, s). MS (ES): C19H16ClN3O2 requires 353; found 354 (MH+).
Reaction SMILES: Cl.[CH2:2]([NH2:4])[CH3:3].[S:5]1[CH:9]=[CH:8][CH:7]=[C:6]1[CH:10]=O.C(N(CC)CC)C.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>CO>[S:5]1[CH:9]=[CH:8][CH:7]=[C:6]1[CH2:10][NH:4][CH2:2][CH3:3]
Reactant: O=Cc1cccs1
Reactant: CCN
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: Cl
Agent: [Na+]
Solvent: CCN(CC)CC
Solvent: CO
Product: CCNCc1cccs1
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 77.4 %

Procedure:
To a 0° C. chilled round bottom flask was added ethyl amine hydrochloride (4.58 g, 56.17 mmol) and thiophene-2-carbaldehyde (5.0 mL, 53.50 mmol) in methanol (20.0 mL), followed by triethylamine (7.83 mL, 56.17 mmol) and the reaction was stirred for 30 minutes. Sodiumtriacetoxyborohydride (15.87 g, 74.90 mmol) was added in one portion under vigorous stirring. The ice bath was removed and the flask was attached to a bubbler to allow gas evolution and expansion. The reaction was stirred overnight at room temp. Most of the volatiles were evaporated in vacuo. The reaction mixture was quenched by adding 1 N NaOH, and the product was extracted with dichloromethane. The organic extract was washed with brine and dried over MgSO4. The volatiles were evaporated to give the crude free base N-(thiophen-2-ylmethyl)ethanamine (5.85 g, 41.42 mmol, 77%), which resulted of a purity grade >97% by 1H-NMR analysis, therefore it was used in the next step without any further purification. 1H NMR (400 MHz, CDCl3) δ 1.13 (t, J=7.1 Hz, 3H), 2.71 (q, J=7.2 Hz, 2H), 4.00 (d, J=0.7 Hz, 2H), 6.90-6.97 (m, 2H), 7.21 (dd, J=5.0, 1.3 Hz, 1H).