Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C:2]1[N:3]=[C:4]2[CH:9]=[CH:8][C:7]([O:10][C:11]3[CH:12]=[C:13]([NH:17][C:18]([C:20]4[N:24]([CH3:25])[N:23]=[C:22]([CH3:26])[CH:21]=4)=[O:19])[CH:14]=[CH:15][CH:16]=3)=[CH:6][N:5]2[CH:27]=1.C(N(CC)CC)C.[CH:35]1([C:38](Cl)=[O:39])[CH2:37][CH2:36]1>O1CCCC1.O>[CH:35]1([C:38]([NH:1][C:2]2[N:3]=[C:4]3[CH:9]=[CH:8][C:7]([O:10][C:11]4[CH:12]=[C:13]([NH:17][C:18]([C:20]5[N:24]([CH3:25])[N:23]=[C:22]([CH3:26])[CH:21]=5)=[O:19])[CH:14]=[CH:15][CH:16]=4)=[CH:6][N:5]3[CH:27]=2)=[O:39])[CH2:37][CH2:36]1
Reactant: O=C(Cl)C1CC1
Reactant: Cc1cc(C(=O)Nc2cccc(Oc3ccc4nc(N)cn4c3)c2)n(C)n1
Solvent: O
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: Cc1cc(C(=O)Nc2cccc(Oc3ccc4nc(NC(=O)C5CC5)cn4c3)c2)n(C)n1
Yield: 59.6 %

Procedure:
To a solution of N-{3-[(2-aminoimidazo[1,2-a]pyridin-6-yl)oxy]phenyl}-1,3-dimethyl-1H-pyrazole-5-carboxamide (270 mg, 0.745 mmol) and triethylamine (310 μL, 2.24 mmol) in tetrahydrofuran (5 mL) was added with stirring under ice-cooling cyclopropanecarbonyl chloride (88.0 μL, 0.969 mmol), and the mixture was stirred at room temperature for 15 hr. The reaction mixture was diluted with water and extracted with ethyl acetate. The organic layer was washed with water and saturated brine, dried over anhydrous magnesium sulfate and filtrated. The filtrate was concentrated under reduced pressure, and the residue was purified by column chromatography (silica gel, hexane/ethyl acetate=50/50→0/100) and recrystallized from ethyl acetate-hexane to give the title compound (191 mg, 60%) as a white solid.
Reaction SMILES: [CH3:1][N:2]([CH3:13])[C:3]1[CH:12]=[CH:11][C:6]([CH:7]=[CH:8][CH:9]=O)=[CH:5][CH:4]=1.[CH3:14][N:15]([CH3:33])[C:16]1[CH:21]=[CH:20][C:19]([CH:22]([C:24]2[CH:29]=[CH:28][C:27]([N:30]([CH3:32])[CH3:31])=[CH:26][CH:25]=2)[CH3:23])=[CH:18][CH:17]=1.[CH2:34](O)[CH3:35]>C(O)(=O)C>[CH3:1][N:2]([CH3:13])[C:3]1[CH:12]=[CH:11][C:6]([C:7]([C:35]2[CH:34]=[CH:21][C:16]([N:15]([CH3:33])[CH3:14])=[CH:17][CH:18]=2)=[CH:8][CH:9]([CH:23]=[C:22]([C:19]2[CH:18]=[CH:17][C:16]([N:15]([CH3:14])[CH3:33])=[CH:21][CH:20]=2)[C:24]2[CH:25]=[CH:26][C:27]([N:30]([CH3:31])[CH3:32])=[CH:28][CH:29]=2)[CH:19]=[CH:22][C:24]2[CH:29]=[CH:28][C:27]([N:30]([CH3:32])[CH3:31])=[CH:26][CH:25]=2)=[CH:5][CH:4]=1
Reactant: CC(c1ccc(N(C)C)cc1)c1ccc(N(C)C)cc1
Reactant: CN(C)c1ccc(C=CC=O)cc1
Reactant: CCO
Solvent: CC(=O)O
Product: CN(C)c1ccc(C=CC(C=C(c2ccc(N(C)C)cc2)c2ccc(N(C)C)cc2)C=C(c2ccc(N(C)C)cc2)c2ccc(N(C)C)cc2)cc1
Temperature: 5 °C

Procedure:
A mixture of 5.7 g of 4-dimethylaminocinnamaldehyde, 16.2 g of 1,1-bis(4-dimethylaminophenyl)ethane, 300.0 ml of ethyl alcohol and 6.0 ml of glacial acetic acid was refluxed approximately eighteen hours. After cooling slightly an additional 3.0 g of 1,1-bis(4-dimethylaminophenyl)ethane was added and reflux maintained for an additional four hours. The resulting reaction mixture was cooled to approximately 5° C. and the solid which formed was collected by filtration. The solid was recrystallized from isopropyl alcohol, filtered and dried to obtain 16.3 g of bis{[2,2-bis(4-dimethylaminophenyl)]ethenyl}[2-(4-dimethylaminophenyl)ethenyl]methane (Formula II: R,R1,R3,R4,R9 and R10 =CH3 ; R2, R5 and R11 =H) a yellow solid which melted at 78°-82° C. Significant infrared maxims appeared at 1610 cm-1 (v.s.) and 830 cm-1 (v.s.). An acetone solution of the product spotted onto clay, phenolic resin and organic acid coated papers slowly developed a blue-colored image. Exposure of the spotted papers to bromine vapor increased the speed of color development.
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]([N:10]2[CH2:15][CH2:14][O:13][CH2:12][CH2:11]2)[CH:7]=[CH:8][CH:9]=1)([O-])=O.[H][H]>[Pd].C(O)C.CN(C)C=O>[N:10]1([C:6]2[CH:5]=[C:4]([NH2:1])[CH:9]=[CH:8][CH:7]=2)[CH2:11][CH2:12][O:13][CH2:14][CH2:15]1
Reactant: [H][H]
Reactant: O=[N+]([O-])c1cccc(N2CCOCC2)c1
Agent: [Pd]
Solvent: CN(C)C=O
Solvent: CCO
Product: Nc1cccc(N2CCOCC2)c1
Yield: 75.3 %

Procedure:
A flask containing 5% palladium on carbon (1.95 g) was evacuated and refilled with hydrogen. 4-(3-Nitrophenyl)morpholine (intermediate 2) (19.5 g, 93.75 mmol) was introduced into the flask as a solution in ethanol and dimethylformamide (1000 ml, 4:1 v/v). The reaction was stirred at room temperature until further uptake of hydrogen ceased (after approximately 7 L). The reaction was then filtered through celite and solvent removed in vacuo to yield the desired product (12.6 g, 70.6 mmol) as a beige solid.
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:18]=[C:17]2[C:12]([C:13]([NH:20][CH2:21][CH:22]3[CH2:27][CH2:26][O:25][CH2:24][CH2:23]3)=[C:14]([NH2:19])[CH:15]=[N:16]2)=[CH:11][CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(N(CC)CC)C.[Cl:35][CH2:36][C:37](Cl)=O>ClCCl>[CH2:1]([O:8][C:9]1[CH:10]=[CH:11][C:12]2[C:13]3[N:20]([CH2:21][CH:22]4[CH2:27][CH2:26][O:25][CH2:24][CH2:23]4)[C:37]([CH2:36][Cl:35])=[N:19][C:14]=3[CH:15]=[N:16][C:17]=2[CH:18]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: O=C(Cl)CCl
Reactant: Nc1cnc2cc(OCc3ccccc3)ccc2c1NCC1CCOCC1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: ClCc1nc2cnc3cc(OCc4ccccc4)ccc3c2n1CC1CCOCC1
Temperature: 25 °C
Reaction time: 17 h
Yield: 190.4 %

Procedure:
To a stirred solution of 7-(benzyloxy)-N4-(tetrahydro-2H-pyran-4-ylmethyl)quinoline-3,4-diamine (51.2 g, 0.141 mol) and triethylamine (39.94 g, 0.395 mol) in dichloromethane (410 mL) at 0° C. was added a solution of chloroacetyl chloride (8.67 g, 76.80 mmol) in dichloromethane (40 mL) drop wise by addition funnel. The reaction was stirred at ambient temperature for 17 hours then heated to reflux for 6 hours. The crude mixture was cooled to ambient temperature and partitioned between water and dichloromethane (200 mL). The layers were separated and the aqueous layer extracted with dichloromethane (2×300 mL). The organic layers were combined, washed with brine (2×300 mL), dried over magnesium sulfate, filtered and concentrated under reduced pressure to provide 7-(benzyloxy)-2-(chloromethyl)-1-(tetrahydro-2H-pyran-4-ylmethyl)-1H-imidazo[4,5-c]quinoline (61.7 g) as a brown solid.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[C@H:13]([CH2:14][NH2:15])[CH2:12][C@H:11]2[C@@H:9]1[CH2:10]2)=[O:7])([CH3:4])([CH3:3])[CH3:2].[N:16]1[C:25]2[C:20](=[CH:21][CH:22]=[CH:23][C:24]=2[C:26](O)=[O:27])[CH:19]=[CH:18][CH:17]=1>>[C:1]([O:5][C:6]([N:8]1[C@H:13]([CH2:14][NH:15][C:26]([C:24]2[CH:23]=[CH:22][CH:21]=[C:20]3[C:25]=2[N:16]=[CH:17][CH:18]=[CH:19]3)=[O:27])[CH2:12][C@H:11]2[C@@H:9]1[CH2:10]2)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)OC(=O)N1[C@H](CN)C[C@@H]2C[C@@H]21
Reactant: O=C(O)c1cccc2cccnc12
Product: CC(C)(C)OC(=O)N1[C@H](CNC(=O)c2cccc3cccnc23)C[C@@H]2C[C@@H]21

Procedure:
prepared by reaction of (1S,3S,5S)-3-aminomethyl-2-aza-bicyclo[3.1.0]hexane-2-carboxylic acid tert-butyl ester with quinoline-8-carboxylic acid. LC-MS (acidic): tR=0.95 min; [M+H]+=368.1.
Reaction SMILES: [C:1]([C:5]1[CH:9]=[C:8]([NH:10][C:11]([NH:13][C@@H:14]2[C:23]3[C:18](=[CH:19][CH:20]=[CH:21][CH:22]=3)[C@H:17]([O:24][C:25]3[CH:26]=[CH:27][C:28]4[N:29]([C:31]([N:34]5[CH2:39][CH2:38][CH2:37][CH2:36][C@@H:35]5[CH3:40])=[N:32][N:33]=4)[CH:30]=3)[CH2:16][CH2:15]2)=[O:12])[N:7]([C:41]2[CH:42]=[C:43]([CH:52]=[CH:53][CH:54]=2)[O:44][C@@H:45]([CH3:51])[CH2:46][NH:47][C:48](N)=[O:49])[N:6]=1)([CH3:4])([CH3:3])[CH3:2].[CH3:55]S(O)(=O)=[O:57].CNC>C1COCC1>[CH:48]([OH:49])=[O:57].[C:1]([C:5]1[CH:9]=[C:8]([NH:10][C:11]([NH:13][C@@H:14]2[C:23]3[C:18](=[CH:19][CH:20]=[CH:21][CH:22]=3)[C@H:17]([O:24][C:25]3[CH:26]=[CH:27][C:28]4[N:29]([C:31]([N:34]5[CH2:39][CH2:38][CH2:37][CH2:36][C@@H:35]5[CH3:40])=[N:32][N:33]=4)[CH:30]=3)[CH2:16][CH2:15]2)=[O:12])[N:7]([C:41]2[CH:54]=[CH:53][CH:52]=[C:43]([O:44][C@@H:45]([CH3:51])[CH2:46][N:47]([CH3:48])[CH3:55])[CH:42]=2)[N:6]=1)([CH3:2])([CH3:3])[CH3:4]
Reactant: C[C@@H](CNC(N)=O)Oc1cccc(-n2nc(C(C)(C)C)cc2NC(=O)N[C@H]2CC[C@@H](Oc3ccc4nnc(N5CCCC[C@@H]5C)n4c3)c3ccccc32)c1
Reactant: CS(=O)(=O)O
Agent: CNC
Solvent: C1CCOC1
Product: C[C@@H](CN(C)C)Oc1cccc(-n2nc(C(C)(C)C)cc2NC(=O)N[C@H]2CC[C@@H](Oc3ccc4nnc(N5CCCC[C@@H]5C)n4c3)c3ccccc32)c1
Product: O=CO
Temperature: 60 °C
Reaction time: 42 h
Yield: 9.9 %

Procedure:
A solution of Intermediate 152e (51 mg, 0.066 mmol) in THF (0.4 mL) was treated with a 2M solution of dimethylamine in THF (0.66 mL, 1.32 mmol) and the mixture was stirred at 60° C. for 42 h. The cooled solution was concentrated in vacuo, and the residue was partitioned between DCM and water. The phases were separated and the aqueous layer was extracted with DCM (×2). The combined organic phase was washed with brine, dried (Na2SO4) and concentrated in vacuo to a brown glass. The glass was purified by HPLC (Phenomenex Gemini C18 column, 5-95% MeCN in H2O, 0.1% HCO2H) over 25 mins. Concentration of the fractions in vacuo gave a pale yellow glass. The glass was triturated with diethyl ether to give title compound as a fawn coloured solid (2.5 mg, 5%). LCMS (Method 5): Rt 3.68 min, m/z 720.5 [MH+]. 1H NMR (400 MHz, d6-DMSO): 0.91 (3H, d, J=6.5 Hz), 1.24 (3H, d, J=6.5 Hz), 1.27 (9H, s), 1.46-1.56 (2H, m), 1.61-1.72 (2H, m), 1.74-1.98 (4H, m), 1.99-2.16 (2H, m), 2.18 (6H, s), 2.32-2.38 (1H, m), 2.86-2.95 (1H, m), 3.12-3.19 (1H, m), 4.56-4.65 (1H, m), 4.78-4.86 (1H, m), 5.52 (1H, t, J=4.1 Hz), 6.32 (1H, s), 6.94-6.99 (1H, m), 7.03-7.11 (3H, m), 7.19 (1H, dd, J=9.6, 2.4 Hz), 7.24-7.41 (5H, m), 7.64 (1H, d, J=10.0 Hz), 7.68-7.70 (1H, m), 8.15 (1H, s), 8.21 (1H, s).
Reaction SMILES: [C:1]1([S:7][C:8]2[CH2:9][CH2:10][NH:11][CH2:12][CH:13]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[Cl:14][CH2:15][CH2:16][CH2:17][C:18]([C:20]1[CH:25]=[CH:24][C:23]([F:26])=[CH:22][CH:21]=1)=O.C(=O)([O-])[O-:28].[K+].[K+]>C1(C)C=CC=CC=1>[ClH:14].[F:26][C:23]1[CH:24]=[CH:25][C:20]([CH2:18][C:17](=[O:28])[CH2:16][CH2:15][N:11]2[CH2:10][CH:9]=[C:8]([S:7][C:1]3[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=3)[CH2:13][CH2:12]2)=[CH:21][CH:22]=1
Reactant: O=C(CCCCl)c1ccc(F)cc1
Reactant: O=C([O-])[O-]
Reactant: C1=C(Sc2ccccc2)CCNC1
Agent: [K+]
Solvent: Cc1ccccc1
Product: Cl
Product: O=C(CCN1CC=C(Sc2ccccc2)CC1)Cc1ccc(F)cc1
Yield: 36.5 %

Procedure:
A mixture of 16.7 g of 4-(phenylthio)-1,2,3,6-tetrahydropyridine, 17.6 g of 4-chloro-p-fluorobutyrophenone and 20 g of potassium carbonate in 200 ml of toluene is refluxed for 48 hours. The inorganic salts are separated by filtration. The filtrate is evaporated, and the residue is treated with dilute hydrochloric acid. The resulting precipitate is collected to afford 12.5 g (36.4%) of tan powder, m.p. 165°-170° C. dec. Three recrystallizations from acetonitrile gives tan plates, m.p. 172°-174° C. dec.
Reaction SMILES: [N+](C1C=CC=CC=1)([O-])=O.[C:10]([CH2:13][C:14]1C2[C:18](=[CH:19]C=CC=2)[CH:17]=[CH:16][CH:15]=1)(=O)[CH3:11]>>[CH3:11][CH2:10][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH3:19]
Reactant: CC(=O)Cc1cccc2ccccc12
Solvent: O=[N+]([O-])c1ccccc1
Product: CCCCCCCCC

Procedure:
A crude isomer mixture weighing 33.71 grams and containing 59.4 weight percent 2,6-AMN, 12.8 weight percent nitrobenzene and 27.8 weight percent of other materials which were believed to be mainly other isomers of acetylmethylnaphthalene was used for the present evaluation.
Reaction SMILES: [C:1]([N:8]1[CH2:11][CH:10]([C:12]([OH:14])=O)[CH2:9]1)([O:3][C:4]([CH3:7])([CH3:6])[CH3:5])=[O:2].Cl.[CH3:16][NH:17][O:18][CH3:19].C1C=CC2N(O)N=NC=2C=1.Cl.C(N=C=N)C.C(N(CC)C(C)C)(C)C>C(Cl)Cl.CCOCC>[C:4]([O:3][C:1]([N:8]1[CH2:9][CH:10]([C:12]([N:17]([O:18][CH3:19])[CH3:16])=[O:14])[CH2:11]1)=[O:2])([CH3:5])([CH3:6])[CH3:7]
Reactant: CC(C)(C)OC(=O)N1CC(C(=O)O)C1
Reactant: CNOC
Agent: CCN=C=N
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Solvent: CCOCC
Product: CON(C)C(=O)C1CN(C(=O)OC(C)(C)C)C1
Temperature: 25 °C
Reaction time: 6 h

Procedure:
To a solution of 980 mg (4.87 mmol) of boc-azetidine-3-carboxylic acid, 951 mg (9.75 mmol) of N,O-dimethylhydroxylamine hydrochloride, 329 mg (2.435 mmol) of HOBT and 1.87 g (9.75 mmol) of 1-[3-dimethylamino)propyl]-3-ethylcarbodiimide hydrochloride in 30 mL of CH2Cl2 was added 2.54 mL 44.61 mmol) of N,N-diisopropylethylamine at 0° C. and it was stirred for 6 h at rt. Then the reaction mixture was poured into 100 mL of ether and washed with 20 mL of aq NaHCO3. The organic layer was dried over Na2SO4 and concentrated to afford the title compound. 1NMR(CDCl3) δ 1.46 (s, 9H), 3.23 (s, 3H), 3.62 (m, 1H), 3.68 (s, 3H), 4.07 (m, 2H), 4.09 (m, 2H).
Reaction SMILES: Br[C:2]1[S:6][C:5]([CH:7]=[O:8])=[CH:4][CH:3]=1.[CH2:9]([C:11]1[CH:16]=[CH:15][C:14]([C:17]2[CH:22]=[CH:21][C:20](B(O)O)=[C:19]([F:26])[CH:18]=2)=[CH:13][CH:12]=1)[CH3:10].C(=O)([O-])[O-].[Na+].[Na+].C1COCC1>C1(C)C=CC=CC=1.C(O)C.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[CH2:9]([C:11]1[CH:12]=[CH:13][C:14]([C:17]2[CH:22]=[CH:21][C:20]([C:2]3[S:6][C:5]([CH:7]=[O:8])=[CH:4][CH:3]=3)=[C:19]([F:26])[CH:18]=2)=[CH:15][CH:16]=1)[CH3:10]
Reactant: CCc1ccc(-c2ccc(B(O)O)c(F)c2)cc1
Reactant: O=Cc1ccc(Br)s1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: Cc1ccccc1
Solvent: CCO
Product: CCc1ccc(-c2ccc(-c3ccc(C=O)s3)c(F)c2)cc1
Temperature: 80 °C

Procedure:
A mixture of 58.5 g (0.31 mol) of 5-bromothiophene-2-carbaldehyde, 75.5 g (0.31 mol) of 4′-ethyl-3-fluoro-4-biphenylboronic acid, 17.0 g (14.7 mmol) of tetrakis(triphenylphosphine)palladium(0) and 375 ml of 2 N sodium carbonate solution in 935 ml of toluene/ethanol (1:1.5) is heated at 80° C. for 1 h. After cooling, the precipitated product is firstly dissolved by addition of THF. The organic phase is separated off, and the aqueous phase is extracted with MTBE. The combined organic phases are washed with sat. sodium chloride solution, and the solution is dried using sodium sulfate. The residue remaining after removal of the solvents is digested in toluene, and the product is filtered off, giving 5-(4′-ethyl-3-fluorobiphenyl-4-yl)thiophene-2-carbaldehyde as a yellow solid.
Reaction SMILES: [NH:1]([C:13]([O:15][CH2:16][C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1)=[O:14])[C@H:2]([C@H:7]([CH2:9][C:10]([OH:12])=O)[OH:8])[CH2:3][CH:4]([CH3:6])[CH3:5].[NH2:23][CH2:24][CH2:25][C:26]([NH:28][C@H:29]([C:36](N)=[O:37])[CH2:30][C:31]1[N:35]=[CH:34][NH:33][CH:32]=1)=[O:27].C1C=CC2N([OH:48])N=[N:45]C=2C=1.C1CCC(N=C=NC2CCCCC2)CC1>CN(C=O)C.O>[NH:1]([C:13]([O:15][CH2:16][C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1)=[O:14])[C@H:2]([C@H:7]([CH2:9][C:10]([NH:23][CH2:24][CH2:25][C:26]([NH:28][C@H:29]([C:36]([OH:37])=[O:48])[CH2:30][C:31]1[N:35]=[CH:34][NH:33][CH:32]=1)=[O:27])=[O:12])[OH:8])[CH2:3][CH:4]([CH3:5])[CH3:6].[NH3:45]
Reactant: On1nnc2ccccc21
Reactant: CC(C)C[C@H](NC(=O)OCc1ccccc1)[C@@H](O)CC(=O)O
Reactant: NCCC(=O)N[C@@H](Cc1c[nH]cn1)C(N)=O
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Solvent: CN(C)C=O
Solvent: O
Product: CC(C)C[C@H](NC(=O)OCc1ccccc1)[C@@H](O)CC(=O)NCCC(=O)N[C@@H](Cc1c[nH]cn1)C(=O)O
Product: N
Temperature: 25 °C
Reaction time: 8 h

Procedure:
370 mg of Z-Sta-OH, 225 mg of H-β-Ala-His-NH2, 153 mg of HOBt×H2O and 247 mg of DCCI are suspended in 4.5 ml of DMF and stirred at room temperature. After approximately 10 minutes a clear solution has formed and afrer approximately 20 minutes DCH begins to crystallize out. The mixture is left to stand overnight, then stirred for 30 minutes at 0°, DCH is filtered off und the filtrate is concentrated to an oil. This is heated for 1 hour at 60° in 14 ml of methanol/glacial acetic acid/H2O (94:3:3), the solution is concentrated to 3 ml and the crude product is precipitated by 30 ml of diisopropyl ether and dried. To remove the acetic acid, the residue is dissolved in n-butanol, washed in succession with 5% strength NaHCO3 solution and with water, and the butanol phase is again concentrated to dryness. After purification by chromatography over 30 g of silica gel (Merck No. 60, 230-400 mesh) using as eluant chloroform/methanol (75:25), Z-Sta-β-Ala-His-NH3 is obtained; Rf (G)=0.28.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([NH:9][CH2:10][C:11]([N:13]2[CH2:18][CH2:17][CH2:16][C@H:15]([NH:19][C:20]3[C:21]4[CH:28]=[CH:27][N:26](S(C5C=CC(C)=CC=5)(=O)=O)[C:22]=4[N:23]=[CH:24][N:25]=3)[CH2:14]2)=[O:12])[CH:5]=[C:6]([F:8])[CH:7]=1.O.C([O-])([O-])=O.[K+].[K+]>CO.CCOC(C)=O>[Cl:1][C:2]1[CH:3]=[C:4]([NH:9][CH2:10][C:11]([N:13]2[CH2:18][CH2:17][CH2:16][C@H:15]([NH:19][C:20]3[C:21]4[CH:28]=[CH:27][NH:26][C:22]=4[N:23]=[CH:24][N:25]=3)[CH2:14]2)=[O:12])[CH:5]=[C:6]([F:8])[CH:7]=1
Reactant: Cc1ccc(S(=O)(=O)n2ccc3c(N[C@H]4CCCN(C(=O)CNc5cc(F)cc(Cl)c5)C4)ncnc32)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CCOC(C)=O
Solvent: CO
Product: O=C(CNc1cc(F)cc(Cl)c1)N1CCC[C@H](Nc2ncnc3[nH]ccc23)C1
Temperature: 60 °C
Yield: 114.6 %

Procedure:
To a solution of 2-(3-chloro-5-fluorophenylamino)-1-((S)-3-(7-tosyl-7H-pyrrolo[2,3-d]pyrimidin-4-ylamino)piperidin-1-yl)ethanone (220 mg, 0.39 mmol) in MeOH:H2O (8:2 mL) was added K2CO3 (164 mg, 1.18 mmol) and the reaction mixture was heated to 60° C. for 1 h. The reaction mixture was concentrated in vacuo and the residue obtained was diluted with EtOAc. The EtOAc suspension was filtered through celite, the filtrate was then dried over Na2SO4, and concentrated in vacuo to give a residue that was subjected to purification by column chromatography (silica gel, gradient MeOH in CH2Cl2) to afford the titled compound (180 mg, 83%). 1H NMR (400 MHz, CD3OD): δ 8.20 and 8.09 (2s, 1H), 7.06 (d, J=3.6 Hz, 1H), 6.61 and 6.58 (2d, J=3.6 Hz, 1H), 6.47 and 6.45 (2s, 1H), 6.35-6.27 (m, 2H), 4.97-4.79 (m, 2H), 4.25-3.95 (m, 3H), 3.11-3.05 (m, 1H), 2.95-2.86 (m, 1H), 2.14-1.85 (m, 2H), 1.80-1.55 (m, 2H). LC-MS: m/z [M+1]=403.
Reaction SMILES: [CH:1]1([N:6]2[CH2:12][C:11]([F:14])([F:13])[C:10](=[O:15])[N:9]([CH3:16])[C:8]3[CH:17]=[N:18][C:19]([NH:21][C:22]4[CH:30]=[CH:29][C:25]([C:26](O)=[O:27])=[CH:24][C:23]=4[CH2:31][CH3:32])=[N:20][C:7]2=3)[CH2:5][CH2:4][CH2:3][CH2:2]1.ON1C2C=CC=CC=2N=N1.F[P-](F)(F)(F)(F)F.CN(C(N(C)C)=[N+]1C2C=CC=CC=2[N+]([O-])=N1)C.C(N(C(C)C)CC)(C)C.[NH2:76][CH:77]1[CH2:82][CH2:81][O:80][CH2:79][CH2:78]1>CN(C)C=O>[CH:1]1([N:6]2[CH2:12][C:11]([F:13])([F:14])[C:10](=[O:15])[N:9]([CH3:16])[C:8]3[CH:17]=[N:18][C:19]([NH:21][C:22]4[CH:30]=[CH:29][C:25]([C:26]([NH:76][CH:77]5[CH2:82][CH2:81][O:80][CH2:79][CH2:78]5)=[O:27])=[CH:24][C:23]=4[CH2:31][CH3:32])=[N:20][C:7]2=3)[CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: NC1CCOCC1
Reactant: CCc1cc(C(=O)O)ccc1Nc1ncc2c(n1)N(C1CCCC1)CC(F)(F)C(=O)N2C
Agent: CN(C)C(N(C)C)=[N+]1N=[N+]([O-])c2ccccc21
Agent: F[P-](F)(F)(F)(F)F
Agent: On1nnc2ccccc21
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: CCc1cc(C(=O)NC2CCOCC2)ccc1Nc1ncc2c(n1)N(C1CCCC1)CC(F)(F)C(=O)N2C
Reaction time: 0.17 h
Yield: 73.4 %

Procedure:
To a mixture of 0.040 g (0.0899 mmole) of 4-(9-cyclopentyl-7,7-difluoro-5-methyl-6-oxo-6,7,8,9-tetrahydro-5H-pyrimido[4,5-b][1,4]diazepin-2-ylamino)-3-ethyl-benzoic acid (I-194) and 6 mL of dimethylformamide was added 0.0182 g (0.135 mmole) of 1-hydroxybenzotriazole, 0.0520 g (0.135 mmole) of 1-[bis(dimethylamino)methylene]-1H-benzotriazolium-3-oxide hexafluorophosphate and 0.047 g (0.359 mmole) of diisopropylethylamine. The mixture was stirred for 10 minutes, then 0.0136 g (0.135 mmole) of 4-aminotetrahydropyran was added. The reaction mixture was stirred for 2 hours and then concentrated under reduced pressure. The residue was dissolved in 80 mL of ethyl acetate and washed three times with 10 mL of 1M sodium hydroxide, twice with 15 mL of brine, dried, filtered and concentrated under reduced pressure. Purification by silica gel chromatography, eluting with dichloromethane-methanol (gradient, 95:5-90:10) gave 0.0349 g of 4-(9-cyclopentyl-7,7-difluoro-5-methyl-6-oxo-6,7,8,9-tetrahydro-5H-pyrimido[4,5-b][1,4]diazepin-2-ylamino)-3-ethyl-N-(tetrahydro-pyran-4-yl)-benzamide (I-197).
Reaction SMILES: [C:1]([C:3]1[CH:36]=[CH:35][C:6]2[NH:7][C:8]([C:10]([C:23]3[C:31]([O:32][CH3:33])=[CH:30][C:29]([CH3:34])=[C:28]4[C:24]=3[CH:25]=[CH:26][NH:27]4)([O:15][CH:16]([F:22])[C:17]([O:19]CC)=[O:18])[C:11]([F:14])([F:13])[F:12])=[N:9][C:5]=2[CH:4]=1)#[N:2].[Li+].[OH-]>C1COCC1.O.CO>[C:1]([C:3]1[CH:36]=[CH:35][C:6]2[NH:7][C:8]([C:10]([C:23]3[C:31]([O:32][CH3:33])=[CH:30][C:29]([CH3:34])=[C:28]4[C:24]=3[CH:25]=[CH:26][NH:27]4)([O:15][CH:16]([F:22])[C:17]([OH:19])=[O:18])[C:11]([F:12])([F:13])[F:14])=[N:9][C:5]=2[CH:4]=1)#[N:2]
Reactant: CCOC(=O)C(F)OC(c1nc2cc(C#N)ccc2[nH]1)(c1c(OC)cc(C)c2[nH]ccc12)C(F)(F)F
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CO
Solvent: O
Product: COc1cc(C)c2[nH]ccc2c1C(OC(F)C(=O)O)(c1nc2cc(C#N)ccc2[nH]1)C(F)(F)F
Temperature: 25 °C
Reaction time: 16 h

Procedure:
To a solution of (±)-ethyl 2-(1-(5-cyano-1H-benzo[d]imidazol-2-yl)-2,2,2-trifluoro-1-(5-methoxy-7-methyl-1H-indol-4-yl)ethoxy)-2-fluoroacetate (Example 35-F) (60 mg, 0.119 mmol) in THF (1.0 mL), water (1.0 mL) and MeOH (0.20 mL) was added LiOH (25 mg, 0.595 mmol) and this mixture was stirred for 16 hr at room temperature. The reaction was partitioned between EtOAc and cold 1N HCl solution and the layers separated and the organic layer was washed with brine, dried over sodium sulfate, filtered, and concentrated. This material was purified with FCC eluting with dichloromethane/MeOH (0-10%) to afford the title compound. 1H NMR (400 MHz, DMSO-d6) δ ppm 11.03 (br.s., 1H) 10.96 (br.s, 1H), 8.17-8.34 (br.s., 1H) 7.78-7.97 (br.s., 1H) 7.53-7.59 (m, 1H) 7.19-7.29 (m, 1H) 7.00-7.02 (br.s, 1H) 6.74-6.79 (br.s., 1H), 6.65 (s., 1H), 4.87-5.37 (m, 1H) 3.01 (s, 3H) 2.46 (s, 3H). HRMS calcd. for C22H16F4N4O4 (M+H)+ 477.1141. found 477.1154.
Reaction SMILES: C(O[CH:4]([C:16](=O)[CH3:17])[CH2:5][S:6][CH2:7][CH2:8][NH:9][C:10]([NH:13][C:14]#[N:15])=[N:11][CH3:12])=O.C([O-])([O-])OC.[CH:24]([NH2:26])=O.C([O-])=O.[NH4+:30]>>[CH3:17][C:16]1[NH:26][CH:24]=[N:30][C:4]=1[CH2:5][S:6][CH2:7][CH2:8]/[N:9]=[C:10](/[NH:13][C:14]#[N:15])\[NH:11][CH3:12]
Reactant: CN=C(NC#N)NCCSCC(OC=O)C(C)=O
Reactant: NC=O
Reactant: [NH4+]
Agent: COC([O-])[O-]
Agent: O=C[O-]
Product: CN/C(=N\CCSCc1nc[nH]c1C)NC#N
Temperature: 100 °C
Reaction time: 2 h
Yield: 56 %

Procedure:
136 mg of N-{2-(2-formyloxy-3-oxobutylthio)ethyl}-N'-cyano-N"-methylguanidine and 530 mg of methyl orthoformate were dissolved in 2.5 m; of formamide, and 320 mg of ammonium formate was added. The mixture was stirred at 100° C. for 2 hours. Formamide was evaporated from the reaction mixture under reduced pressure. The residue was chromatographed on a column of silica gel (eluent: chloroform/methanol=4/1), and then recrystallized from isopropanol to give 71 mg (yield 56%) of the desired product (Cimetidine) as white crystals.
Reaction SMILES: Cl[CH2:2][C:3]1[C:12]2[C:7](=[C:8]([CH3:14])[C:9]([OH:13])=[CH:10][CH:11]=2)[O:6][C:5](=[O:15])[CH:4]=1.[CH3:16][O-:17].[Na+].Cl>CO.C(O)(C)C>[OH:13][C:9]1[C:8]([CH3:14])=[C:7]2[C:12]([C:3]([CH2:2][O:17][CH3:16])=[CH:4][C:5](=[O:15])[O:6]2)=[CH:11][CH:10]=1
Reactant: C[O-]
Reactant: Cc1c(O)ccc2c(CCl)cc(=O)oc12
Agent: Cl
Agent: [Na+]
Solvent: CO
Solvent: CC(C)O
Product: COCc1cc(=O)oc2c(C)c(O)ccc12
Temperature: 25 °C

Procedure:
A mixture of 4-chloromethyl-7-hydroxy-8-methylcoumarin (2.00 g, 8.90 mmol) and sodium methoxide (12.0 g, 222 mmol) in methanol (400 mL) was refluxed overnight. The solution was allowed to cool to room temperature, acidified to pH 0-1 with 5-6N HCl in isopropanol and evaporated. The residue was azeotroped with toluene several times to give crude product 7-hydroxy-4-methoxymethyl-8-methylcoumarin, a yellow oil. 1H NMR (CD3OD): δ 7.38 (d, J=8.5 Hz, 1H), 6.82 (d, J=8.8 Hz, 1H), 6.29 (s, 1H), 4.66 (s, 2H), 3.51 (s, 3H), 2.26 (s, 3H).