Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH:1]1[C:13]2[C:12](=[O:14])[C:11]3[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=3)[C:5]=2[CH:4]=[CH:3][CH:2]=1.O1CCCC1.[CH:20]([NH:23][CH2:24][C:25]#[CH:26])([CH3:22])[CH3:21].C([Li])CCC>O>[CH:20]([NH:23][CH2:24][C:25]#[C:26][C:12]1([OH:14])[C:13]2[CH:1]=[CH:2][CH:3]=[CH:4][C:5]=2[C:6]2[C:11]1=[CH:10][CH:9]=[CH:8][CH:7]=2)([CH3:22])[CH3:21]
Reactant: O=C1c2ccccc2-c2ccccc21
Reactant: C#CCNC(C)C
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: O
Product: CC(C)NCC#CC1(O)c2ccccc2-c2ccccc21
Temperature: 25 °C

Procedure:
A solution of 9.0 g. of fluoren-9-one dissolved in 500 ml. of tetrahydrofuran was added dropwise over one hour to a stirred cold (-80° C.) solution of 500 ml. of tetrahydrofuran containing 9.7 g. of 3-isopropylaminopropyne and 75 ml. of a 1.6 molar tetrahydrofuran solution of n-butyl lithium. After the addition was complete, the reaction mixture was warmed to room temperature and then heated to reflux for sixteen hours. The reaction mixture was next cooled to room temperature and diluted by the dropwise addition of 200 ml. of water. The aqueous mixture was extracted several times with diethyl ether, and the ethereal extracts were combined, and the reaction product was converted to the hydrochloride salt by the addition of 300 ml. of 6N hydrochloric acid to the ethereal solution. The aqueous acid layer containing the reaction product was separated, washed once with fresh diethyl ether, and then made alkaline by the addition of 10 percent sodium hydroxide, which effected liberation of the hydrochloride salt back to the free amine. The free amine was extracted into fresh diethyl ether. The ethereal extracts were combined, washed with water and dried. Removal of the solvent by evaporation under reduced pressure then afforded 2.3 g of 9-(3-isopropylaminopropynyl)-9-hydroxyfluorene. M.P. 214°-215° C.
Reaction SMILES: [CH3:1][C:2]1[N:7]=[C:6]([NH:8][C:9]2[CH:14]=[CH:13][CH:12]=[C:11]([CH3:15])[N:10]=2)[CH:5]=[CH:4][CH:3]=1.[OH-].[K+].I[CH2:19][CH2:20][CH3:21]>CN(C)C=O>[CH3:1][C:2]1[N:7]=[C:6]([N:8]([C:9]2[CH:14]=[CH:13][CH:12]=[C:11]([CH3:15])[N:10]=2)[CH2:19][CH2:20][CH3:21])[CH:5]=[CH:4][CH:3]=1
Reactant: Cc1cccc(Nc2cccc(C)n2)n1
Reactant: CCCI
Agent: [K+]
Agent: [OH-]
Solvent: CN(C)C=O
Product: CCCN(c1cccc(C)n1)c1cccc(C)n1
Reaction time: 1 h
Yield: 911.6 %

Procedure:
To a flask were added 1.0 g 6-methyl-N-(6-methylpyridin-2-yl)pyridin-2-amine, 0.84 g of pulverized potassium hydroxide and 15 ml of N,N-dimethylformamide. After stirring for 1 hour under nitrogen, the mixture was cooled to 5 C and 0.85 g of 1-iodopropane were added. The mixture was allowed to warm to 22 C and stirred for 16 hours. After quenching with 15 ml water, the product was extracted twice with diethyl ether and washed with water. Following removal of solvent, the product was purified by silica gel chromatography using 10% ethyl acetate in hexane to give 11.0 g of a colorless oil.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][C:9]#[N:10])=[CH:4][CH:3]=1.[H-].[Na+].[CH3:13][O:14][C:15]1[CH:16]=[C:17]2[C:22](=[CH:23][C:24]=1[O:25][CH3:26])[N:21]=[CH:20][CH:19]=[C:18]2Cl.O>C1(C)C=CC=CC=1>[CH3:13][O:14][C:15]1[CH:16]=[C:17]2[C:22](=[CH:23][C:24]=1[O:25][CH3:26])[N:21]=[CH:20][CH:19]=[C:18]2[CH:8]([C:5]1[CH:6]=[CH:7][C:2]([Br:1])=[CH:3][CH:4]=1)[C:9]#[N:10]
Reactant: COc1cc2nccc(Cl)c2cc1OC
Reactant: N#CCc1ccc(Br)cc1
Agent: [H-]
Agent: [Na+]
Solvent: Cc1ccccc1
Solvent: O
Product: COc1cc2nccc(C(C#N)c3ccc(Br)cc3)c2cc1OC
Temperature: 50 °C
Reaction time: 1 h
Yield: 22.5 %

Procedure:
Commercially available 4-bromophenylacetonitrile (4.3 g) was dissolved in toluene (10 ml) and the temperature was lowered to 0° C., after which sodium hydride (1.0 g) was added, the temperature was raised to 50° C., and the admixture was then stirred for 1 hour. Next, 6,7-dimethoxy-4-chloroquinoline (2.2 g) was added, and the admixture was stirred for 15 hours, after which water was poured and the mixture was extracted with ethyl acetate. After drying with anhydrous sodium sulfate and removing the solvent by distillation, the resulting residue was purified by column chromatography on silica gel eluting with hexane/ethyl acetate (2/1) to obtain 850 mg of the title compound (yield: 22%).
Reaction SMILES: I.CS[C:4](=[NH:18])[NH:5][C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][C:7]=1[N:12]1[CH2:17][CH2:16][O:15][CH2:14][CH2:13]1.[CH3:19][NH:20][CH2:21][CH2:22][CH2:23]N>C(O)C>[CH3:19][N:20]1[CH2:21][CH2:22][CH2:23][NH:18][C:4]1=[N:5][C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][C:7]=1[N:12]1[CH2:17][CH2:16][O:15][CH2:14][CH2:13]1
Reactant: CSC(=N)Nc1ccccc1N1CCOCC1
Reactant: CNCCCN
Agent: I
Solvent: CCO
Product: CN1CCCNC1=Nc1ccccc1N1CCOCC1

Procedure:
A mixture of 2-methyl-1-(2-morpholinophenyl)-2-thiopseudourea hydroiodide (3.8 g prepared as described in Example 166), 3-methylaminopropylamine (2.6 g) and absolute ethanol (40 ml) was heated under reflux for 6 hours to give a solid which was recrystallised from ether to give 4-[2-(1-methylperhydropyrimidin-2-ylideneamino)phenyl]morpholine (m.p. 138°-139° C.).
Reaction SMILES: ClC[C:3]1[C:11]2[C:6](=[CH:7][N:8]=[C:9]([C:12]([O:14][CH3:15])=[O:13])[CH:10]=2)[N:5](CC2C=CC(F)=CC=2F)[CH:4]=1.[CH3:25][C:26]1([CH3:33])[O:30][C@H:29]([CH2:31][OH:32])[CH2:28][O:27]1.CCN(C(C)C)C(C)C>CN(C=O)C>[CH3:25][C:26]1([CH3:33])[O:30][C@H:29]([CH2:31][O:32][CH2:15][O:14][C:12]([C:9]2[CH:10]=[C:11]3[CH:3]=[CH:4][NH:5][C:6]3=[CH:7][N:8]=2)=[O:13])[CH2:28][O:27]1
Reactant: COC(=O)c1cc2c(CCl)cn(Cc3ccc(F)cc3F)c2cn1
Reactant: CC1(C)OC[C@@H](CO)O1
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: CC1(C)OC[C@@H](COCOC(=O)c2cc3cc[nH]c3cn2)O1
Temperature: 40 °C
Reaction time: 24 h

Procedure:
To a solution of methyl 3-(chloromethyl)-1-(2,4-difluorobenzyl)-1H-pyrrolo[2,3-c]pyridine-5-carboxylate (3 mL, 0.197M in CH2Cl2, 0.591 mmol)) [prepared as described in step 2 of example 40] in anhydrous DMF (5 mL) was added (R)-(−)-2,2-Dimethyl-1,3-dioxolane-4-methanol (0.37 ml, 2.955 mmol, 5.0 eq.) followed by i-Pr2NEt (0.4079, 3.14 mmol, 0.55 mL, 4 eq.). The mixture, under nitrogen, was placed in an oil bath and the bath was warmed to 40° C. After stirring for 24 hours (40° C.) the reaction was judged to by complete by HPLC-MS analysis and the volatiles were removed in vacuo (ca. 2 torr) to give a golden yellow oil. The crude material was purified by chromatography on a column of silica gel (40 mm OD, 100 g, 230-400 mesh, packed with CH2Cl2, eluted with CH2Cl2-EtOAc 50:50 v/v, 1.0 L, 25 mL fractions) using the flash technique. Fractions 30-54 were combined to afford 0.224 g (85%) of Methyl 1-(2,4-difluorobenzyl)-3-({([(4R)-2,2-dimethyl -1,3-dioxolan-4-yl]methoxy}methyl)-1H-pyrrolo[2,3-c]pyridine-5-carboxylate as a colorless oil.
Reaction SMILES: [NH2:1][C:2]1[O:6][N:5]=[C:4]([CH:7]([CH3:9])[CH3:8])[C:3]=1[C:10]([NH2:12])=[O:11].CN(C1C=CC=CN=1)C.[C:22](Cl)(=[O:27])[CH2:23][CH:24]([CH3:26])[CH3:25]>C1(C)C=CC=CC=1.N1C=CC=CC=1>[CH3:25][CH:24]([CH3:26])[CH2:23][C:22]([NH:1][C:2]1[O:6][N:5]=[C:4]([CH:7]([CH3:8])[CH3:9])[C:3]=1[C:10]([NH2:12])=[O:11])=[O:27]
Reactant: CC(C)c1noc(N)c1C(N)=O
Reactant: CC(C)CC(=O)Cl
Agent: CN(C)c1ccccn1
Solvent: Cc1ccccc1
Solvent: c1ccncc1
Product: CC(C)CC(=O)Nc1onc(C(C)C)c1C(N)=O
Reaction time: 16 h

Procedure:
1.7 g of 5-amino-3-isopropylisoxazole-4-carboxamide in a mixture of 40 ml of toluene and 40 ml of pyridine are initially taken together with a pinch of dimethylaminopyridine, and a solution of 2.5 g of isovaleroyl chloride in 20 ml of toluene is added. Stirring is carried out for 16 hours at room temperature, after which the solution is evaporated to dryness and the residue is stirred with ethyl acetate. The organic phase is then extracted with aqueous hydrochloric acid and sodium bicarbonate solution, dried and evaporated down. Purification is effected by chromatography over silica gel (cyclohexane/ethyl acetate).
Reaction SMILES: [OH:1][N:2]1[CH:7]([C:8]([Cl:11])([Cl:10])[Cl:9])[C:6]([Cl:13])([Cl:12])[C:5](=[O:14])[O:4][C:3]1([CH3:21])[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1.[C:22]1([N:28]=[C:29]=[O:30])[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1>C(N(CC)CC)C.ClCCl>[C:22]1([NH:28][C:29]([O:1][N:2]2[CH:7]([C:8]([Cl:9])([Cl:10])[Cl:11])[C:6]([Cl:13])([Cl:12])[C:5](=[O:14])[O:4][C:3]2([CH3:21])[C:15]2[CH:16]=[CH:17][CH:18]=[CH:19][CH:20]=2)=[O:30])[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1
Reactant: O=C=Nc1ccccc1
Reactant: CC1(c2ccccc2)OC(=O)C(Cl)(Cl)C(C(Cl)(Cl)Cl)N1O
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CC1(c2ccccc2)OC(=O)C(Cl)(Cl)C(C(Cl)(Cl)Cl)N1OC(=O)Nc1ccccc1
Yield: 39 %

Procedure:
A solution of 8 g (0.02 mol) N-hydroxy-2-methyl-2-phenyl-4-trichloromethyl-5,5-dichloro-6-oxotetrahydro-1,3-oxazine, 2.4 g (0.02 mol) phenylisocyanate and several drops triethylamine in 90 ml dichloromethane was stirred at about 10° C. for about 2 days. The reaction mixture was filtered and the filtrate was evaporated under reduced pressure to give a yellow oil. The oil crystallized from ethanol/hexane to give 4 g of product, m.p. 154°-157° C. The product is tabulated in Table I as Compound No. 8.
Reaction SMILES: [ClH:1].O1CCOCC1.C(OC([N:15]1[CH2:20][CH2:19][O:18][C@@H:17]([C:21]([N:23]([CH2:27][C:28]2[CH:33]=[CH:32][C:31]([O:34][CH2:35][C:36]3[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=3)=[C:30]([O:42][CH2:43][CH2:44][CH2:45][O:46][CH3:47])[CH:29]=2)[CH:24]2[CH2:26][CH2:25]2)=[O:22])[CH2:16]1)=O)(C)(C)C>C(Cl)(Cl)Cl>[ClH:1].[CH2:35]([O:34][C:31]1[CH:32]=[CH:33][C:28]([CH2:27][N:23]([CH:24]2[CH2:25][CH2:26]2)[C:21]([C@@H:17]2[O:18][CH2:19][CH2:20][NH:15][CH2:16]2)=[O:22])=[CH:29][C:30]=1[O:42][CH2:43][CH2:44][CH2:45][O:46][CH3:47])[C:36]1[CH:37]=[CH:38][CH:39]=[CH:40][CH:41]=1
Reactant: COCCCOc1cc(CN(C(=O)[C@H]2CN(C(=O)OC(C)(C)C)CCO2)C2CC2)ccc1OCc1ccccc1
Agent: Cl
Solvent: ClC(Cl)Cl
Solvent: C1COCCO1
Product: COCCCOc1cc(CN(C(=O)[C@H]2CNCCO2)C2CC2)ccc1OCc1ccccc1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
4N HCl/dioxane (1 ml) was added under ice cooling to (2R)-2-{[[4-benzyloxy-3-(3-methoxypropoxy)benzyl](cyclopropyl)amino]carbonyl}morpholine-4-carboxylic acid tert-butyl ester (a compound of Reference Example 9, 217 mg) dissolved in chloroform (1 ml), and the mixture is stirred at room temperature for 2 hours. The mixture was concentrated in vacuo. the residue was added water (1 ml) and diethyl ether (2 ml), and then the mixture was slightly stirred. The layer of diethyl ether was removed by decantation and the resulted residue is lyophilized to give (2R)—N-[4-(benzyloxy)-3-(3-methoxypropoxy)benzyl]-N-cyclopropylmorpholin-2-carboxamide hydrochloride (166 mg) as a colorless powder. APCI-MS m/z: 455[M+H]+.
Reaction SMILES: C(OC([NH:8][CH2:9][C:10](O)=[O:11])=O)(C)(C)C.CCN(C(C)C)C(C)C.CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.[B-](F)(F)(F)F.[CH:44]1([CH2:50][C@H:51]([C:53]([OH:55])=[O:54])[NH2:52])[CH2:49][CH2:48][CH2:47][CH2:46][CH2:45]1>C(Cl)Cl>[NH2:8][CH2:9][C:10]([NH:52][C@@H:51]([C:53]([OH:55])=[O:54])[CH2:50][CH:44]1[CH2:49][CH2:48][CH2:47][CH2:46][CH2:45]1)=[O:11]
Reactant: CC(C)(C)OC(=O)NCC(=O)O
Reactant: N[C@H](CC1CCCCC1)C(=O)O
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[B-](F)(F)F
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: NCC(=O)N[C@H](CC1CCCCC1)C(=O)O
Temperature: 25 °C
Reaction time: 0.25 h

Procedure:
N-(tert-butoxycarbonyl)glycine (2.0 g, 11.4 mmol) and DIPEA (4.0 g, 31 mmol) were dissolved in methylene chloride (25 ml). TBTU (4.1 g, 12.8 mmol) was added and the mixture was stirred for 15 min at room temperature. 3-cyclohexyl-D-alanine (2.1 g, 12.2 mmol) was added and the reaction mixture was stirred over night at room temperature. The reaction mixture was transferred to a separation funnel and was then extracted with a water/acetic acid solution (100 ml 5% acetic acid). The organic layer was separated and evaporated under reduced pressure. The residue was dissolved in formic acid (20 ml) and the mixture was stirred over night at 40° C. The formic acid was removed under reduced pressure. The residue was washed with water (50 ml) and then stirred in aceton (25 ml) for 1 h at room temperature. The solid material was filtered off and washed with aceton (20 ml). The title compound was obtained.
Reaction SMILES: Br[C:2]1[C:10]2[N:9]3[CH2:11][CH2:12][NH:13][C:14](=[O:15])[C:8]3=[C:7]([CH3:16])[C:6]=2[CH:5]=[C:4]([C:17]#[N:18])[CH:3]=1.[F:19][C:20]1[CH:25]=[CH:24][C:23](B(O)O)=[CH:22][C:21]=1[CH3:29]>>[F:19][C:20]1[CH:25]=[CH:24][C:23]([C:2]2[C:10]3[N:9]4[CH2:11][CH2:12][NH:13][C:14](=[O:15])[C:8]4=[C:7]([CH3:16])[C:6]=3[CH:5]=[C:4]([C:17]#[N:18])[CH:3]=2)=[CH:22][C:21]=1[CH3:29]
Reactant: Cc1cc(B(O)O)ccc1F
Reactant: Cc1c2n(c3c(Br)cc(C#N)cc13)CCNC2=O
Product: Cc1cc(-c2cc(C#N)cc3c(C)c4n(c23)CCNC4=O)ccc1F

Procedure:
The title compound, light yellow solid (73 mg, 88%), MS (ISP) m/z=334.6 [(M+H)+], mp 232° C., was prepared in accordance with the general method of example 1 from 6-bromo-10-methyl-1-oxo-1,2,3,4-tetrahydro-pyrazino[1,2-a]indole-8-carbonitrile (intermediate 16) (76 mg, 0.25 mmol) and commercially available 4-fluoro-3-methyl-phenylboronic acid (50.0 mg, 0.325 mmol).
Reaction SMILES: N(C(OCC)=O)=NC(OCC)=O.[C:13]([O:17][C:18]([NH:20][CH2:21][C:22]([NH:24][C@H:25]1[CH2:29][N:28]([C:30]([O:32][C:33]([CH3:36])([CH3:35])[CH3:34])=[O:31])[C@H:27]([CH2:37][OH:38])[CH2:26]1)=[O:23])=[O:19])([CH3:16])([CH3:15])[CH3:14].[C:39]1([C:45]2[CH:50]=[CH:49][C:48](O)=[CH:47][CH:46]=2)[CH:44]=[CH:43][CH:42]=[CH:41][CH:40]=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>O1CCCC1>[C:13]([O:17][C:18]([NH:20][CH2:21][C:22]([NH:24][C@H:25]1[CH2:29][N:28]([C:30]([O:32][C:33]([CH3:36])([CH3:35])[CH3:34])=[O:31])[C@H:27]([CH2:37][O:38][C:48]2[CH:49]=[CH:50][C:45]([C:39]3[CH:44]=[CH:43][CH:42]=[CH:41][CH:40]=3)=[CH:46][CH:47]=2)[CH2:26]1)=[O:23])=[O:19])([CH3:15])([CH3:14])[CH3:16]
Reactant: Oc1ccc(-c2ccccc2)cc1
Reactant: CC(C)(C)OC(=O)NCC(=O)N[C@@H]1C[C@@H](CO)N(C(=O)OC(C)(C)C)C1
Agent: CCOC(=O)N=NC(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)NCC(=O)N[C@@H]1C[C@@H](COc2ccc(-c3ccccc3)cc2)N(C(=O)OC(C)(C)C)C1
Reaction time: 17 h

Procedure:
Diethyl azodicarboxylate (158 mL) was added to a mixture of (2S,4R)-4-(N-tert-butoxycarbonylglycylamino)-2-hydroxymethyl-N-tert-butoxycarbonylpyrrolidine (A, 310 mg), 4-phenylphenol (148 mg), and triphenyl phosphine (229 mg) in tetrahydrofuran (10 mL) under argon at room temperature. After stirring at room Ad temperature for 17 hr, the mixture was concentrated in vacuo to give a residue, which was purified by silica gel column chromatography (chloroform:methanol=200:1, v/v) to afford title compound (431 mg): 1H NMR (400 MHz, CDCl3) δ 1.44 (s, 18H), 2.01 (m, 1H), 2.38 (m, 1H), 3.21 (m, 1H), 3.72 (m, 1H), 3.77 (d, J=4.4 Hz, 2H), 3.99-4.25 (m, 3H), 4.68 (m, 1H), 5.49 (m, 1H), 6.85 (m, 1H), 6.97 (d, J=7.3 Hz, 2H), 7.29 (d, J=7.3 Hz, 1H), 7.40 (t, J=7.3 Hz, 2H), 7.48-7.63 (m, 4H).
Reaction SMILES: [C:1]([C:5]1[CH:10]=[C:9]([CH3:11])[CH:8]=[C:7]([C:12]([CH3:15])([CH3:14])[CH3:13])[C:6]=1[OH:16])([CH3:4])([CH3:3])[CH3:2].[Br:17]N1C(=O)CCC1=O>C(Cl)(Cl)(Cl)Cl>[C:12]([C:7]1[CH:8]=[C:9]([CH2:11][Br:17])[CH:10]=[C:5]([C:1]([CH3:4])([CH3:3])[CH3:2])[C:6]=1[OH:16])([CH3:15])([CH3:14])[CH3:13]
Reactant: Cc1cc(C(C)(C)C)c(O)c(C(C)(C)C)c1
Reactant: O=C1CCC(=O)N1Br
Solvent: ClC(Cl)(Cl)Cl
Product: CC(C)(C)c1cc(CBr)cc(C(C)(C)C)c1O
Reaction time: 1.5 h

Procedure:
A mixture of 1 g of 2,6-di-t-butyl-4-methyl phenol, 0.9 g of N-bromosuccinimide and 40 ml of carbon tetrachloride was boiled for 1.5 hours. Succinimide was removed by filtration, and the resulting organic solution was evaporated to give a viscous liquid with the following 1H NMR spectrum (CDCl3, ppm from TMS): 7.05 ppm (s, ArH, 2), 5,15 ppm (s, OH, 1), 4.35 ppm (s, CH2Br, 2) and 1.3 ppm (s, CH3, 18).
Reaction SMILES: [CH3:1][O:2][CH2:3][CH2:4][N:5]1[C:9]2[CH:10]=[CH:11][C:12]([C:14](O)=[O:15])=[CH:13][C:8]=2[N:7]=[C:6]1[NH:17][C:18]1[S:19][C:20]2[CH:26]=[C:25]([O:27][C:28]([F:31])([F:30])[F:29])[CH:24]=[CH:23][C:21]=2[N:22]=1.[CH2:32]([O:34][CH2:35][CH2:36][NH2:37])[CH3:33].CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C>CN(C=O)C>[CH2:32]([O:34][CH2:35][CH2:36][NH:37][C:14]([C:12]1[CH:11]=[CH:10][C:9]2[N:5]([CH2:4][CH2:3][O:2][CH3:1])[C:6]([NH:17][C:18]3[S:19][C:20]4[CH:26]=[C:25]([O:27][C:28]([F:29])([F:31])[F:30])[CH:24]=[CH:23][C:21]=4[N:22]=3)=[N:7][C:8]=2[CH:13]=1)=[O:15])[CH3:33]
Reactant: COCCn1c(Nc2nc3ccc(OC(F)(F)F)cc3s2)nc2cc(C(=O)O)ccc21
Reactant: CCOCCN
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: CCOCCNC(=O)c1ccc2c(c1)nc(Nc1nc3ccc(OC(F)(F)F)cc3s1)n2CCOC
Yield: 42.3 %

Procedure:
1-(2-Methoxy-ethyl)-2-(6-trifluoromethoxy-benzothiazol-2-ylamino)-1H-benzoimidazole-5-carboxylic acid (2-ethoxy-ethyl)-amide (49.0 mg) was prepared by following General Procedure F starting from 1-(2-methoxy-ethyl)-2-(6-trifluoromethoxy-benzothiazol-2-ylamino)-1H-benzoimidazole-5-carboxylic acid (100.0 mg), 2-ethoxy-ethylamine (30.0 mg), HBTU (130.0 mg) and DIEA (0.1 mL) in DMF (1.0 mL). LCMS: m/z 525; and 1H NMR (DMSO-d6, 400 MHz): δ 8.44 (1H, br. s), 8.06 (1H, br. s), 7.91 (1H, br. s), 7.71 (1H, br. m), 7.49-7.47 (1H, m), 7.35-7.34 (1H, m), 4.34 (2H, br. s), 3.72-3.69 (2H, br. t), 3.52-3.40 (6H, m), 3.22 (3H, s), 1.13-1.09 (3H, t), 2 —NH proton signals were not observed.
Reaction SMILES: [C:1]([N:4]1[CH2:9][CH2:8][N:7]([C:10]2[CH:11]=[CH:12][C:13]([NH:16][C:17](=[O:34])[CH2:18][C:19]3[CH:24]=[CH:23][C:22](B4OC(C)(C)C(C)(C)O4)=[CH:21][CH:20]=3)=[N:14][CH:15]=2)[CH2:6][CH2:5]1)(=[O:3])[CH3:2].Cl[C:36]1[CH:41]=[C:40]([CH3:42])[N:39]=[CH:38][N:37]=1.[O-]P([O-])([O-])=O.[K+].[K+].[K+]>>[C:1]([N:4]1[CH2:9][CH2:8][N:7]([C:10]2[CH:11]=[CH:12][C:13]([NH:16][C:17](=[O:34])[CH2:18][C:19]3[CH:20]=[CH:21][C:22]([C:36]4[CH:41]=[C:40]([CH3:42])[N:39]=[CH:38][N:37]=4)=[CH:23][CH:24]=3)=[N:14][CH:15]=2)[CH2:6][CH2:5]1)(=[O:3])[CH3:2]
Reactant: Cc1cc(Cl)ncn1
Reactant: CC(=O)N1CCN(c2ccc(NC(=O)Cc3ccc(B4OC(C)(C)C(C)(C)O4)cc3)nc2)CC1
Agent: O=P([O-])([O-])[O-]
Agent: [K+]
Product: CC(=O)N1CCN(c2ccc(NC(=O)Cc3ccc(-c4cc(C)ncn4)cc3)nc2)CC1
Temperature: 110 °C

Procedure:
A mixture of N-(5-(4-acetylpiperazin-1-yl)pyridin-2-yl)-2-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)acetamide 196-1 (20 mg, 0.04 mmol), 4-chloro-6-methylpyrimidine 198-1 (8 mg, 0.06 mmol) Pd(PPh3)4 (2 mg, 0.002 mmol) and K3PO4 (25 mg, 0.12 mmol) in dioaxane (0.6 mL) was flushed with nitrogen and heated to 110° C. for 2 hours. The salt was removed by filtration and the filtrate was taken to dryness by rotary evaporation. The residue was purified by reverse phase HPLC to give N-(5-(4-acetylpiperazin-1-yl)pyridin-2-yl)-2-(4-(6-methylpyrimidin-4-yl)phenyl)acetamide 198. MS m/z 431.20 (M+1). 1H NMR 400 MHz (DMSO-d6) δ10.59 (s, 1H), 8.16 (d, 2H), 8.04 (d, 1H), 7.98 (s, 1H), 7.92 (m, 1H), 7.51 (d, 2H), 7.45-7.40 (m, 2H), 3.77 (s, 2H), 3.58 (b, 2H), 3.15 (b, 2H), 3.08 (b, 2H), 2.55 (s, 3H), 2.53 (s, 2H), 2.04 (s, 3H).
Reaction SMILES: COC1C=C(OC)C=CC=1C[N:6]1[C:11](=[O:12])[C:10]2[CH:13]=[C:14]([CH2:16][CH3:17])[S:15][C:9]=2[NH:8][C:7]1=[O:18].Br[CH2:26][C:27]1[CH:32]=[CH:31][C:30]([C:33]2[C:34]([C:39]#[N:40])=[CH:35][CH:36]=[CH:37][CH:38]=2)=[C:29]([F:41])[CH:28]=1.C(=O)([O-])[O-].[K+].[K+]>C(#N)C>[CH2:16]([C:14]1[S:15][C:9]2[N:8]([CH2:26][C:27]3[CH:32]=[CH:31][C:30]([C:33]4[C:34]([C:39]#[N:40])=[CH:35][CH:36]=[CH:37][CH:38]=4)=[C:29]([F:41])[CH:28]=3)[C:7](=[O:18])[NH:6][C:11](=[O:12])[C:10]=2[CH:13]=1)[CH3:17]
Reactant: N#Cc1ccccc1-c1ccc(CBr)cc1F
Reactant: CCc1cc2c(=O)n(Cc3ccc(OC)cc3OC)c(=O)[nH]c2s1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: CCc1cc2c(=O)[nH]c(=O)n(Cc3ccc(-c4ccccc4C#N)c(F)c3)c2s1
Temperature: 50 °C
Reaction time: 1.5 h
Yield: 68.3 %

Procedure:
A mixture of 3-(2,4-dimethoxybenzyl)-6-ethylthieno[2,3-d]pyrimidine-2,4(1H,3H)-dione (2 g), 4′-(bromomethyl)-2′-fluorobiphenyl-2-carbonitrile (2 g), potassium carbonate (1.6 g) and acetonitrile (40 mL) was stirred at 50° C. for 1.5 hr. Insoluble material was filtered off, and the solvent was evaporated under reduced pressure. The obtained residue was dissolved in trifluoroacetic acid (15 mL), and the mixture was stirred at 50° C. for 2 hr. The reaction mixture was concentrated under reduced pressure. To the obtained residue was added ethyl acetate, and insoluble material was filtered off. The filtrate was concentrated and recrystallized from diethyl ether to give the title compound as a colorless solid (1.6 g, 90%).
Reaction SMILES: [N:1]([O-:3])=O.[Na+].[CH3:5][O:6][C:7]1[CH:8]=[C:9]2[C:14](=[CH:15][CH:16]=1)[CH:13]=[C:12]([OH:17])[CH:11]=[CH:10]2>O.C(O)(=O)C>[CH3:5][O:6][C:7]1[CH:8]=[C:9]2[C:14](=[CH:15][CH:16]=1)[C:13]([N:1]=[O:3])=[C:12]([OH:17])[CH:11]=[CH:10]2
Reactant: COc1ccc2cc(O)ccc2c1
Reactant: O=N[O-]
Agent: [Na+]
Solvent: O
Solvent: CC(=O)O
Product: COc1ccc2c(N=O)c(O)ccc2c1

Procedure:
A solution of sodium nitrite (3.19 g) in water (23.6 ml) is slowly added to a stirring solution of 6-methoxy-2-naphthol [8.0 g, prepared as described in Organic Synthesis 49, 90 (1969)] in acetic acid (46 ml) and water (4.6 ml) at 0° C. The resulting slurry is allowed to stand at room temperature for several hours and diluted with water. The solid is collected, washed, dried and crystallized from methanol to give 6-methoxy-1nitroso-2-naphthol, mp 147°-148° C.
Reaction SMILES: Cl[C:2]1[C:7]([F:8])=[C:6]([O:9][CH2:10][C:11]#[C:12][CH2:13][CH3:14])[N:5]=[CH:4][N:3]=1.[CH3:15][CH:16]1[CH2:20][CH2:19][CH:18]([CH3:21])[NH:17]1>>[CH3:15][CH:16]1[CH2:20][CH2:19][CH:18]([CH3:21])[N:17]1[C:2]1[C:7]([F:8])=[C:6]([O:9][CH2:10][C:11]#[C:12][CH2:13][CH3:14])[N:5]=[CH:4][N:3]=1
Reactant: CC1CCC(C)N1
Reactant: CCC#CCOc1ncnc(Cl)c1F
Product: CCC#CCOc1ncnc(N2C(C)CCC2C)c1F
Reaction time: 13 h
Yield: 46.4 %

Procedure:
0.2 g of 4-chloro-5-fluoro-6-(2-pentynyloxy)pyrimidine and 0.2 g of 2,5-dimethylpyrrolidine were mixed and left for 13 hours at room temperature. The reaction mixture was subjected to silica gel column chromatography to obtain 0.12 g of 4-(2,5-dimethyl-1-pyrrolidinyl)-5-fluoro-6-(2-pentynyloxy)pyrimidine (hereinafter, referred to as Compound (13)).
Reaction SMILES: [C:1]([C:3]1[CH:21]=[CH:20][C:6]2[N:7]([CH2:15][CH2:16][CH2:17][CH2:18][F:19])[C:8]([CH2:10][O:11]C(=O)C)=[N:9][C:5]=2[CH:4]=1)#[N:2]>CO.CCO.Cl.[Pd]>[NH2:2][CH2:1][C:3]1[CH:21]=[CH:20][C:6]2[N:7]([CH2:15][CH2:16][CH2:17][CH2:18][F:19])[C:8]([CH2:10][OH:11])=[N:9][C:5]=2[CH:4]=1
Reactant: CC(=O)OCc1nc2cc(C#N)ccc2n1CCCCF
Agent: [Pd]
Agent: Cl
Solvent: CCO
Solvent: CO
Product: NCc1ccc2c(c1)nc(CO)n2CCCCF
Yield: 28.3 %

Procedure:
To a solution of acetic acid 5-cyano-1-(4-fluoro-butyl)-1H-benzoimidazol-2-ylmethyl ester (1.3 g, 4.5 mmol) in MeOH (50 ml), EtOH (10 ml), concentrated HCl (10 ml) and 10% Pd/C (100 mg) was hydrogenated for 2 h. The solution was filtered and concentrated. The residue was dissolved in EtOAc and washed with aq NaHCO3. The product remains in the aqueous layer. The water was removed and the residue washed with hot EtOAc. The EtOAc extracts are concentrated to give 0.32 g (18%) of [5-aminomethyl-1-(4-fluoro-butyl)-1H-benzoimidazol-2-yl]-methanol as a white solid.