Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: CC1C=CC(S(O[CH2:12][C@@H:13]2[O:18][C:17]3[CH:19]=[C:20]([S:24]([CH3:27])(=[O:26])=[O:25])[CH:21]=[C:22]([F:23])[C:16]=3[O:15][CH2:14]2)(=O)=O)=CC=1.[CH2:28]([NH2:30])[CH3:29].Cl>C(#N)C>[F:23][C:22]1[C:16]2[O:15][CH2:14][C@H:13]([CH2:12][NH:30][CH2:28][CH3:29])[O:18][C:17]=2[CH:19]=[C:20]([S:24]([CH3:27])(=[O:25])=[O:26])[CH:21]=1
Reactant: CCN
Reactant: Cc1ccc(S(=O)(=O)OC[C@H]2COc3c(F)cc(S(C)(=O)=O)cc3O2)cc1
Agent: Cl
Solvent: CC#N
Product: CCNC[C@H]1COc2c(F)cc(S(C)(=O)=O)cc2O1

Procedure:
Preparation according to Example 5 using [(2R)-5-fluoro-7-(methylsulfonyl)-2,3-dihydro-1,4-benzodioxin-2-yl]methyl 4-methylbenzenesulfonate (0.56 g, 1.33 mmol), ethanamine (1 ml, 70% in water) and ACN (3 ml). Yield: 0.32 g, 83%. The amine was converted to the hydrochloric acid salt and crystallized from MeOH/Et2O. M.p. 274° C. MS m/z (rel. intensity, 70 eV) 289 (M+, 3), 70 (3), 59 (4), 58 (bp), 56 (3). [α]=−58° (MeOH).
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[CH:10]=[CH:9][C:8]([C:11]2[CH:16]=[CH:15][C:14]([OH:17])=[CH:13][CH:12]=2)=[CH:7][CH:6]=1)=[O:4].[H-].[Na+].Cl[CH2:21][O:22][CH2:23][CH2:24][O:25][CH3:26].Cl>CN(C=O)C.C1COCC1>[CH3:21][O:22][CH2:23][CH2:24][O:25][CH2:26][O:17][C:14]1[CH:15]=[CH:16][C:11]([C:8]2[CH:9]=[CH:10][C:5]([C:3]([O:2][CH3:1])=[O:4])=[CH:6][CH:7]=2)=[CH:12][CH:13]=1
Reactant: COCCOCCl
Reactant: COC(=O)c1ccc(-c2ccc(O)cc2)cc1
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CN(C)C=O
Product: COCCOCOc1ccc(-c2ccc(C(=O)OC)cc2)cc1
Temperature: 25 °C
Reaction time: 15 h
Yield: 87 %

Procedure:
10 g (43.8 mmol) of 4′-hydroxybiphenyl-4-carboxylic acid methyl ester, 100 ml of THF and 150 ml of DMF are introduced in order and under a nitrogen stream into a 500 ml three-necked flask. 1.93 g (48.2 mmol) of NaH at 60% in oil are added in small portions and the mixture is stirred at room temperature for 15 hours. 5.75 ml of 1-chloromethoxy-2-methoxyethane are added dropwise, and the mixture is stirred at room temperature for 30 minutes. The reaction medium is poured over a 1N HCl solution and extracted with ethyl acetate. The organic phase is washed with water and dried over magnesium sulphate. After filtration and evaporation 12 g of 4′-(2-methoxyethoxymethoxy)biphenyi-4-carboxylic acid methyl ester are obtained in the form of a beige powder after filtration and evaporation (yield=87%).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[CH:13]=[CH:12][C:11]([OH:14])=[CH:10][CH:9]=1.C(=O)([O-])[O-].[K+].[K+].CN(C)C=O.[NH2:26][C:27]1[C:32]([N+:33]([O-:35])=[O:34])=[CH:31][C:30]([CH:36]2[CH2:40][CH2:39][CH2:38][N:37]2[C:41]([O:43][C:44]([CH3:47])([CH3:46])[CH3:45])=[O:42])=[C:29](F)[CH:28]=1>C(OCC)(=O)C>[NH2:26][C:27]1[C:32]([N+:33]([O-:35])=[O:34])=[CH:31][C:30]([CH:36]2[CH2:40][CH2:39][CH2:38][N:37]2[C:41]([O:43][C:44]([CH3:47])([CH3:46])[CH3:45])=[O:42])=[C:29]([O:14][C:11]2[CH:10]=[CH:9][C:8]([C:3]3[CH:4]=[CH:5][CH:6]=[CH:7][C:2]=3[F:1])=[CH:13][CH:12]=2)[CH:28]=1
Reactant: Oc1ccc(-c2ccccc2F)cc1
Reactant: CC(C)(C)OC(=O)N1CCCC1c1cc([N+](=O)[O-])c(N)cc1F
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)N1CCCC1c1cc([N+](=O)[O-])c(N)cc1Oc1ccc(-c2ccccc2F)cc1
Temperature: 80 °C
Reaction time: 8 h

Procedure:
200 mg of 2′-fluorobiphenyl-4-ol and 184 mg of potassium carbonate were added to an N,N-dimethylformamide (3 ml) solution of 288 mg of t-butyl 2-(4-amino-2-fluoro-5-nitrophenyl)pyrrolidine-1-carboxylate, and the reaction liquid was stirred overnight at 80° C. The reaction liquid was diluted with ethyl acetate, washed with water and saturated saline in order, and dried with anhydrous magnesium sulfate. The solvent was evaporated away, and the resulting residue was purified through silica gel column chromatography (developing solvent: hexane/ethyl acetate=5/1) to obtain the entitled compound as a yellow solid.
Reaction SMILES: [Br:1][C:2]1[CH:11]=[C:10]2[C:5]([CH2:6][CH2:7][CH:8]([NH:12][CH2:13][CH2:14][CH3:15])[CH2:9]2)=[CH:4][CH:3]=1.[CH3:16][S:17]([N:20]1[CH2:25][CH2:24][CH:23]([CH:26]=O)[CH2:22][CH2:21]1)(=[O:19])=[O:18].C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>ClC(Cl)C>[Br:1][C:2]1[CH:11]=[C:10]2[C:5]([CH2:6][CH2:7][CH:8]([N:12]([CH2:26][CH:23]3[CH2:24][CH2:25][N:20]([S:17]([CH3:16])(=[O:19])=[O:18])[CH2:21][CH2:22]3)[CH2:13][CH2:14][CH3:15])[CH2:9]2)=[CH:4][CH:3]=1
Reactant: CS(=O)(=O)N1CCC(C=O)CC1
Reactant: CCCNC1CCc2ccc(Br)cc2C1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: CC(Cl)Cl
Product: CCCN(CC1CCN(S(C)(=O)=O)CC1)C1CCc2ccc(Br)cc2C1
Temperature: 25 °C
Reaction time: 24 h
Yield: 96.6 %

Procedure:
To a solution of (7-bromo-1,2,3,4-tetrahydro-naphthalen-2-yl)-propyl-amine (536 mg, 2 mmol) and 1-methanesulfonyl-piperidine-4-carboxaldehyde (458 mg, 2.47mmol) in dichloroethane (10 mL) was added sodium triacetoxyborohydride (551 mg, 2.6 mmol) in a single portion. The reaction was stirred at room temperature for 24 h. The reaction was concentrated in vacuo and partitioned between EtOAc (75 mL) and 5% aq. KOH (75 mL). The organic layer was dried (MgSO4), filtered, and concentrated to afford (7-bromo-1,2,3,4-tetrahydro-naphthalen-2-yl)-(1-methanesulfonyl-piperidin-4-ylmethyl)-propyl-amine (857 mg) 111[M+H]+=444.
Reaction SMILES: Cl.[CH2:2]([CH:4]1[CH2:9][NH:8][CH2:7][CH2:6][NH:5]1)[CH3:3].[Cl:10][C:11]1[CH:12]=[C:13]2[C:17](=[CH:18][CH:19]=1)[N:16]([S:20]([C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1)(=[O:22])=[O:21])[C:15]([S:29](Cl)(=[O:31])=[O:30])=[CH:14]2.C(N(CC)CC)C>C(Cl)Cl.O>[Cl:10][C:11]1[CH:12]=[C:13]2[C:17](=[CH:18][CH:19]=1)[N:16]([S:20]([C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1)(=[O:21])=[O:22])[C:15]([S:29]([N:8]1[CH2:7][CH2:6][NH:5][CH:4]([CH2:2][CH3:3])[CH2:9]1)(=[O:31])=[O:30])=[CH:14]2
Reactant: O=S(=O)(Cl)c1cc2cc(Cl)ccc2n1S(=O)(=O)c1ccccc1
Reactant: CCC1CNCCN1
Agent: Cl
Solvent: ClCCl
Solvent: O
Solvent: CCN(CC)CC
Product: CCC1CN(S(=O)(=O)c2cc3cc(Cl)ccc3n2S(=O)(=O)c2ccccc2)CCN1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
To a methylene chloride solution (700 ml) of 2-ethylpiperazine hydrochloride (5.00 g) were added 5-chloro -1-phenylsulfonylindol-2-sulfonyl chloride (7.14 g) and triethylamine (11.16 ml) and the resulting mixture was stirred at room temperature for 3 hours. Distilled water and methylene chloride were added and the water layer was extracted three times. The organic layers were combined, dried over anhydrous sodium sulfate and distilled under reduced pressure to remove the solvent. The residue was purified by chromatography on a silica gel column (methanol:methylene chloride=1:100), whereby the title compound (5.86 g) was obtained as a pale yellow oil.
Reaction SMILES: C(OC([N:8]1[CH2:13][CH2:12][C@@H:11]([NH:14][C:15]([NH:17][C:18]2[CH:23]=[CH:22][CH:21]=[C:20]([C:24]3[N:28]([CH3:29])[N:27]=[N:26][N:25]=3)[CH:19]=2)=[O:16])[C@H:10]([CH2:30][N:31]2[CH2:36][CH2:35][CH2:34][C@@H:33]([CH2:37][C:38]3[CH:43]=[CH:42][C:41]([F:44])=[CH:40][CH:39]=3)[CH2:32]2)[CH2:9]1)=O)(C)(C)C.FC(F)(F)C(O)=O>ClCCl>[F:44][C:41]1[CH:42]=[CH:43][C:38]([CH2:37][C@@H:33]2[CH2:34][CH2:35][CH2:36][N:31]([CH2:30][C@H:10]3[C@H:11]([NH:14][C:15]([NH:17][C:18]4[CH:23]=[CH:22][CH:21]=[C:20]([C:24]5[N:28]([CH3:29])[N:27]=[N:26][N:25]=5)[CH:19]=4)=[O:16])[CH2:12][CH2:13][NH:8][CH2:9]3)[CH2:32]2)=[CH:39][CH:40]=1
Reactant: Cn1nnnc1-c1cccc(NC(=O)N[C@@H]2CCN(C(=O)OC(C)(C)C)C[C@H]2CN2CCC[C@@H](Cc3ccc(F)cc3)C2)c1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: Cn1nnnc1-c1cccc(NC(=O)N[C@@H]2CCNC[C@H]2CN2CCC[C@@H](Cc3ccc(F)cc3)C2)c1
Reaction time: 3 h
Yield: 55 %

Procedure:
In a dry flask (3R,4R)-3-[(S)-3-(4-fluoro-benzyl)-piperidin-1-ylmethyl]-4-{3-[3-(1-methyl-1H-tetrazol-5-yl)-phenyl]-ureido}-piperidine-1-carboxylic acid t-butyl ester (48 mg, 0.079 mmol) was dissolved in dichloromethane (1.5 mL), and trifluoroacetic acid (0.5 mL) was added. The reaction mixture was stirred for 3 hours. The reaction mixture was concentrated in vacuo then purified by preparative reverse-phase HPLC (10-80% acetonitrile in water with 0.05% trifluoroacetic acid) to give a white amorphous solid (22 mg, 38%). 1H NMR (500 MHz, CD3OD, 30° C.), δ: 8.01 (t, 1H, J=1), 7.59 (dq, 1H, J=8, J′=1), 7.52 (t, 1H, J=8), 7.43 (dt, 1H, J=8, J′=1), 7.17 (m, 2H), 6.96 (t, 2H, J=9), 4.18 (s, 3H), 3.73 (m, 2H), 3.51 (m, 3H), 3.38 (d, 1H, J=13), 3.13 (m, 2H), 2.99 (m, 2H), 2.64 (dd, 2H, J=14, J′=6), 2.50 (bs, 2H), 2.21 (m, 1H), 2.11 (bs, 1H), 1.92 (m, 2H), 1.76 (m, 2H), 1.19 (m, 1H). HRMS (ESI), C27H36FN8O M+/z: calc. 507.2996, found=507.2976.
Reaction SMILES: Br[C:2]1[S:6][C:5]([NH:7][C:8]([NH:10][C:11]2[CH:16]=[CH:15][C:14]([CH3:17])=[CH:13][C:12]=2[C:18]([CH:20]2[CH2:24][CH2:23][CH2:22][CH2:21]2)=[O:19])=[O:9])=[N:4][CH:3]=1.[SH:25][C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][N:27]=1>>[CH:20]1([C:18]([C:12]2[CH:13]=[C:14]([CH3:17])[CH:15]=[CH:16][C:11]=2[NH:10][C:8]([NH:7][C:5]2[S:6][C:2]([S:25][C:26]3[CH:31]=[CH:30][CH:29]=[CH:28][N:27]=3)=[CH:3][N:4]=2)=[O:9])=[O:19])[CH2:24][CH2:23][CH2:22][CH2:21]1
Reactant: Cc1ccc(NC(=O)Nc2ncc(Br)s2)c(C(=O)C2CCCC2)c1
Reactant: Sc1ccccn1
Product: Cc1ccc(NC(=O)Nc2ncc(Sc3ccccn3)s2)c(C(=O)C2CCCC2)c1
Yield: 31.9 %

Procedure:
1-(2-Cyclopentanecarbonyl-4-methyl-phenyl)-3-[5-(pyridin-2-ylsulfanyl)-thiazol-2-yl]-urea (140 mg, 32%) was prepared from 1-(5-bromo-thiazol-2-yl)-3-(2-cyclo pentanecarbonyl-4-methyl-phenyl)-urea (408 mg, 1 mmol) and 2-mercaptopyridine (222 mg, 2 mmol) following the general procedure Q.
Reaction SMILES: [CH3:1][C:2](=[CH2:11])[CH:3]([C:5]1[CH:6]=[N:7][CH:8]=[CH:9][CH:10]=1)[OH:4].[CH2:12]([Zn]CC)C.ICI.[Cl-].[NH4+]>ClCCl.O>[CH3:11][C:2]1([CH:3]([C:5]2[CH:6]=[N:7][CH:8]=[CH:9][CH:10]=2)[OH:4])[CH2:12][CH2:1]1
Reactant: C=C(C)C(O)c1cccnc1
Reactant: CC[Zn]CC
Agent: [Cl-]
Agent: [NH4+]
Solvent: O
Solvent: ClCCl
Solvent: ICI
Product: CC1(C(O)c2cccnc2)CC1
Temperature: 0 °C
Reaction time: 2.5 h
Yield: 78.3 %

Procedure:
In dichloromethane (40.0 mL) was dissolved 2-methyl-1-(pyridin-3-yl)prop-2-en-1-ol (1.04 g, 6.95 mmol) obtained in Step 1. Diethylzinc (1.09 mol/L solution in n-hexane, 31.9 mL, 34.7 mmol) and diiodomethane (2.80 mL, 34.7 mmol) were added dropwise at −10° C. and the mixture was stirred at 0° C. for 2.5 hours. A saturated aqueous ammonium chloride solution and water were added to the reaction mixture. Extraction with ethyl acetate, washing with saturated brine and drying over anhydrous sodium sulfate were performed. After filtration, the solvent in the filtrate was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (hexane/ethyl acetate=3/7) to give (1-methylcyclopropyl)(pyridin-3-yl)methanol (888 mg, 78% yield).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[C@H:9]1[C:14]([C:15]([O:17][CH3:18])=[O:16])=[C:13]([CH2:19]Br)[NH:12][C:11]([C:21]2[S:22][CH:23]=[CH:24][N:25]=2)=[N:10]1.[CH:26]12[NH:37][CH:33]([CH2:34][O:35][CH2:36]1)[CH2:32][C:31]1[O:30][N:29]=[CH:28][C:27]2=1>>[CH3:18][O:17][C:15]([C:14]1[C@H:9]([C:3]2[CH:4]=[CH:5][C:6]([F:8])=[CH:7][C:2]=2[Cl:1])[N:10]=[C:11]([C:21]2[S:22][CH:23]=[CH:24][N:25]=2)[NH:12][C:13]=1[CH2:19][N:37]1[CH:33]2[CH2:34][O:35][CH2:36][CH:26]1[C:27]1[CH:28]=[N:29][O:30][C:31]=1[CH2:32]2)=[O:16]
Reactant: c1noc2c1C1COCC(C2)N1
Reactant: COC(=O)C1=C(CBr)NC(c2nccs2)=N[C@H]1c1ccc(F)cc1Cl
Product: COC(=O)C1=C(CN2C3COCC2c2cnoc2C3)NC(c2nccs2)=N[C@H]1c1ccc(F)cc1Cl

Procedure:
The title compound was prepared in analogy to Example 1a in Scheme 3 by using methyl (4R)-4-(2-chloro-4-fluoro-phenyl)-6-(bromomethyl)-2-thiazol-2-yl-1,4-dihydropyrimidine-5-carboxylate C (200 mg) and 5,10-Dioxa-4,12-diaza-tricyclo[6.3.1.0*2,6*]dodeca-2(6),3-diene 105a (100 mg). 20 mg of the title compound was isolated as yellow powder.
Reaction SMILES: [CH2:1]([C:5]1[N:6]=[C:7]([CH3:37])[N:8]([CH2:31][C:32]([O:34]CC)=[O:33])[C:9](=[O:30])[C:10]=1[CH2:11][C:12]1[CH:17]=[CH:16][C:15]([C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=2[C:24]2[NH:28][C:27](=[O:29])[O:26][N:25]=2)=[CH:14][CH:13]=1)[CH2:2][CH2:3][CH3:4].[OH-].[Na+].O1CCCC1.Cl>C(OCC)(=O)C.C(O)C>[CH2:1]([C:5]1[N:6]=[C:7]([CH3:37])[N:8]([CH2:31][C:32]([OH:34])=[O:33])[C:9](=[O:30])[C:10]=1[CH2:11][C:12]1[CH:13]=[CH:14][C:15]([C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=2[C:24]2[NH:28][C:27](=[O:29])[O:26][N:25]=2)=[CH:16][CH:17]=1)[CH2:2][CH2:3][CH3:4]
Reactant: CCCCc1nc(C)n(CC(=O)OCC)c(=O)c1Cc1ccc(-c2ccccc2-c2noc(=O)[nH]2)cc1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Solvent: CCO
Product: CCCCc1nc(C)n(CC(=O)O)c(=O)c1Cc1ccc(-c2ccccc2-c2noc(=O)[nH]2)cc1
Temperature: 25 °C
Reaction time: 3 h
Yield: 93.2 %

Procedure:
A mixture of ethyl [4-butyl-2-methyl-6-oxo-5-{[2′-(5-oxo-4,5-dihydro-1,2,4-oxadiazol-3-yl)biphenyl-4-yl]methyl}pyrimidin-1(6H)-yl]acetate (0.25 g), 1 M aqueous sodium hydroxide solution (1.2 mL), tetrahydrofuran (3 mL) and ethanol (3 mL) was stirred at room temperature for 3 hr. 1 M hydrochloric acid (1.2 mL) was added to the reaction solution, and the mixture was stirred for 10 min. The reaction mixture was diluted with ethyl acetate, washed with saturated brine, and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure to give the title compound as colorless crystals (0.22 g, 92%).
Reaction SMILES: [O:1]=[S:2]1(=[O:28])[C:7]2[CH:8]=[CH:9][CH:10]=[CH:11][C:6]=2[NH:5][C:4]([C:12]2[C:17](=[O:18])[N:16]([N:19]=[CH:20][CH:21](C)[CH3:22])[C:15]3[CH:24]=[CH:25][S:26][C:14]=3[C:13]=2[OH:27])=[N:3]1.CO.[BH4-].[Li+].Cl>O1CCCC1.O>[O:28]=[S:2]1(=[O:1])[C:7]2[CH:8]=[CH:9][CH:10]=[CH:11][C:6]=2[NH:5][C:4]([C:12]2[C:17](=[O:18])[N:16]([NH:19][CH2:20][CH2:21][CH3:22])[C:15]3[CH:24]=[CH:25][S:26][C:14]=3[C:13]=2[OH:27])=[N:3]1
Reactant: CC(C)C=Nn1c(=O)c(C2=NS(=O)(=O)c3ccccc3N2)c(O)c2sccc21
Agent: Cl
Agent: [BH4-]
Agent: [Li+]
Solvent: C1CCOC1
Solvent: O
Solvent: CO
Product: CCCNn1c(=O)c(C2=NS(=O)(=O)c3ccccc3N2)c(O)c2sccc21
Temperature: 25 °C
Reaction time: 1 h

Procedure:
The product of Example 269A (0.073 g, 0.18 mmol) in tetrahydrofuran (4 mL) and methanol (0.020 mL, 0.5 mmol) at 0° C. was treated dropwise with a 2.0M solution of lithium borohydride in tetrahydrofuran (0.150 mL, 0.3 mmol). The reaction was stirred at 25° C. for 1 hour, acidified with 1M hydrochloric acid to a pH of approximately 2-4, diluted with water (15 mL), and the resulting precipitate was collected by filtration and dried. The crude product was chromatographed on silica gel with 2% methanol in chloroform to give the title compound. The sodium salt of the title compound was prepared according to the procedure of Example 1D. 1H NMR (300 MHz, DMSO-d6) δ ppm 0.95 (t, J=7.35 Hz, 3 H) 1.54 (m, 2 H) 2.99 (t, J=6.99 Hz, 2 H) 6.66 (s, 1 H) 7.44 (d, J=5.15 Hz, 1 H) 7.55 (t, J=7.54 Hz, 1 H) 7.64 (d, J=8.09 Hz, 1 H) 7.78 (t, J=7.17 Hz, 1 H) 7.93 (d, J=7.72 Hz, 1 H) 8.35 (d, J=5.15 Hz, 1 H) 14.20 (s, 1 H) 14.81 (s, 1 H). MS (ESI−) m/z 403 (M−H)−.
Reaction SMILES: [F:1][C:2]([F:7])([F:6])[C:3]([OH:5])=[O:4].FC(F)(F)C(O)=O.[Cl:15][C:16]1[CH:17]=[N:18][C:19]2[NH:20][C:21]3[CH:22]=[CH:23][CH:24]=[C:25]([CH:38]=3)[CH2:26][CH2:27][C:28]3[CH:36]=[C:32]([NH:33][C:34]=1[N:35]=2)[CH:31]=[C:30]([NH2:37])[CH:29]=3.[N:39]1[CH:44]=[CH:43][CH:42]=[CH:41][C:40]=1[C:45](Cl)=[O:46]>>[F:1][C:2]([F:7])([F:6])[C:3]([OH:5])=[O:4].[Cl:15][C:16]1[CH:17]=[N:18][C:19]2[NH:20][C:21]3[CH:22]=[CH:23][CH:24]=[C:25]([CH:38]=3)[CH2:26][CH2:27][C:28]3[CH:36]=[C:32]([NH:33][C:34]=1[N:35]=2)[CH:31]=[C:30]([NH:37][C:45]([C:40]1[CH:41]=[CH:42][CH:43]=[CH:44][N:39]=1)=[O:46])[CH:29]=3
Reactant: O=C(Cl)c1ccccn1
Reactant: Nc1cc2cc(c1)Nc1nc(ncc1Cl)Nc1cccc(c1)CC2
Solvent: O=C(O)C(F)(F)F
Product: O=C(Nc1cc2cc(c1)Nc1nc(ncc1Cl)Nc1cccc(c1)CC2)c1ccccn1
Yield: 35 %

Procedure:
The desired compound was prepared according to the procedure of Example B26, using 6-chloro-2,4,8,22-tetraazatetracyclo[14.3.1.1(3,7).1(9,13)]docosa-1(20),3(22),4,6,9(21),10,12,16,18-nonaen-11-amine bis(trifluoroacetate) and pyridine-2-carbonyl chloride as the starting materials in 35% yield. LCMS for C24H20ClN6O (M+H)+: m/z=443.2. 1H NMR (400 MHz, DMSO-d6): δ 10.54 (s, 1H), 9.51 (s, 2H), 8.72 (m, 1H), 8.16 (s, 1H), 8.13 (m, 1H), 8.05 (m, 1H), 7.92 (m, 1H), 7.75 (m, 1H), 7.66 (m, 1H), 7.49 (m, 1H), 7.45 (m, 1H), 7.11 (dd, 1H), 6.89 (m, 1H), 6.84 (m, 1H), 2.89 (m, 4H).
Reaction SMILES: Cl[CH2:2][C:3]1[N:4]=[N:5][C:6]2[C:7](=[C:9]([NH2:14])[N:10]=[C:11]([NH2:13])[N:12]=2)[N:8]=1.[CH3:15][N:16]1[CH2:21][CH2:20][NH:19][CH2:18][CH2:17]1>>[CH3:15][N:16]1[CH2:21][CH2:20][N:19]([CH2:2][C:3]2[N:4]=[N:5][C:6]3[C:7](=[C:9]([NH2:14])[N:10]=[C:11]([NH2:13])[N:12]=3)[N:8]=2)[CH2:18][CH2:17]1
Reactant: CN1CCNCC1
Reactant: Nc1nc(N)c2nc(CCl)nnc2n1
Product: CN1CCN(Cc2nnc3nc(N)nc(N)c3n2)CC1
Temperature: 80 °C

Procedure:
A mixture of 3-Chloromethyl-pyrimido[5,4-e][1,2,4]triazine-5,7-diamine 3 (200 mg; 0.95 mmol) and N-methylpiperazine (2.00 mL) were heated to 80° C. in a sealed tube for 7 h. The mixture was then allowed to cool to room temperature and concentrated in vacuo. The crude product was purified by reverse phase HPLC (Rainin C18, 0% CH3CN to 30% CH3CN gradient, CH3CN/H2O, 0.1% TFA) and the bright yellow fractions containing the product were lyophilized after removal of CH3CN in vacuo to give 178 mg of yellow colored 3-(4-Methyl-piperazin-1-ylmethyl)-pyrimido[5,4-e][1,2,4]triazine-5,7-diamine as the trifluoroacetate salt.
Reaction SMILES: [CH2:1]([N:8]1[CH:12]=[C:11]([CH:13]=O)[C:10]([O:15][CH2:16][C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)=[N:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:23]([O:26][CH2:27][CH2:28]P(OCC)(OCC)=O)(=[O:25])[CH3:24].CN(C)C=O.[H-]>O>[CH2:1]([N:8]1[CH:12]=[C:11](/[CH:13]=[CH:24]/[C:23]([O:26][CH2:27][CH3:28])=[O:25])[C:10]([O:15][CH2:16][C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)=[N:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=Cc1cn(Cc2ccccc2)nc1OCc1ccccc1
Reactant: CCOP(=O)(CCOC(C)=O)OCC
Agent: [H-]
Solvent: CN(C)C=O
Solvent: O
Product: CCOC(=O)/C=C/c1cn(Cc2ccccc2)nc1OCc1ccccc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 91 %

Procedure:
To a mixture of 1-benzyl-3-benzyloxy-1H-pyrazole-4-carbaldehyde (12.90 g), diethylphosphonoethyl acetate (9.60 ml) and N,N-dimethylformamide (200 ml) was added hydride (60% in oil, 1.94 g) at 0° C., and the mixture was stirred at room temperature for 2 hrs. The reaction mixture was poured into water and the mixture was extracted with ethyl acetate. The ethyl acetate layer was dilute hydrochloric acid, washed successively with saturated brine, dried (MgSO4) and concentrated. The obtained crystals were collected by filtration to give ethyl (E)-3-(1-benzyl-3-benzyloxy-1H-pyrazol-4-yl)propenoate (14.50 g, yield 91%). The crystals were recrystallized from ethyl acetate-hexane. melting point: 88–89° C.
Reaction SMILES: [C:1]([O:5][C:6](=[O:15])[NH:7][CH2:8][CH:9](Cl)[CH2:10][CH2:11][CH2:12]Cl)([CH3:4])([CH3:3])[CH3:2].O.O.O.O.O.O.O.O.O.[S-2:25].[Na+].[Na+]>CO>[C:1]([O:5][C:6](=[O:15])[NH:7][CH2:8][CH:9]1[CH2:10][CH2:11][CH2:12][S:25]1)([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)OC(=O)NCC(Cl)CCCCl
Reactant: [S-2]
Agent: [Na+]
Solvent: O
Solvent: CO
Product: CC(C)(C)OC(=O)NCC1CCCS1
Reaction time: 5 h
Yield: 100.1 %

Procedure:
A solution of N-tbutoxycarbonyl-2.5-dichloroamylamine 221 (1.75 g, 6.8 mmol) in MeOH (70 mL) was stirred at rt and sodium sulphide nonahydrate (3 g, 12.5 mmol) was added. The mixture was heated at reflux for 1 hour, when TLC indicated that starting material was still present. Further sodium sulphide nonahydrate (1.5 g, 6 mmol) was added and reflux was continued for 5 hours. The MeOH was evaporated and the residue partitioned between water (50 mL) and DCM (100 mL). The layers were separated and the DCM washed with water (20 mL), 0.25 M HCl (20 mL) and brine (20 mL) and dried over MgSO4. Evaporation of the solvents gave 222 as a pale yellow solid (1.48 g, quant.) which was used without further purification.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[CH:8]([CH3:10])[CH3:9].C([Li])CCC.[CH2:16]=[O:17]>C1COCC1>[CH:8]([C:3]1[CH:4]=[CH:5][CH:6]=[CH:7][C:2]=1[CH2:16][OH:17])([CH3:10])[CH3:9]
Reactant: CC(C)c1ccccc1Br
Reactant: C=O
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: CC(C)c1ccccc1CO
Temperature: 78 °C
Reaction time: 0.5 h
Yield: 58.8 %

Procedure:
To a solution of 1-bromo-2-isopropylbenzene (2.50 g, 12.56 mmol) in anhydrous THF (40 mL), 2,2′-dipyridyl (ca 2 mg) was added under nitrogen atmosphere (Zhi et al., 2003, which is incorporated herein by reference). The mixture was cooled down minus 78° C., and a solution of n-butyllithium (5.52 mL, 2.5 M in hexanes, 13.82 mmol) was added dropwise via syringe within the period of ten minutes. Upon addition, the mixture was stirred for 30 minutes, then warmed up to minus 30° C., and a flow of formaldehyde (generated from 1.77 g of paraformaldehyde by heating at 160° C.) was passed through the solution until the deep red color disappeared completely. The mixture was quenched with saturated ammonium chloride (5 mL), then poured into brine (15 mL). Organic layer was separated; aqueous layer was extracted twice with dichloromethane (20 mL each); combined extracts were dried over anhydrous Na2SO4, evaporated, and purified by silica gel chromatography to yield 2-isopropylbenzyl alcohol (1.11 g, 59%) as an oil. 1H NMR (400 MHz, CDCl3): δ 7.30 (m, 3 H, Ph-H), 7.18 (m, 3 H, Ph-H), 4.75 (s, 2 H, CH2OH), 3.27 (sep, J=6.6 Hz, 1 H, CH(CH3)2), 1.53 (s, 1 H, CH2OH), 1.26 (d, J=6.6 Hz, 1 H, CH(CH3)2).
Reaction SMILES: [C:1]([C:4]1[CH:5]=[C:6]([NH:10][C:11]2[CH:16]=[C:15]([CH3:17])[N:14]=[C:13]([NH2:18])[N:12]=2)[CH:7]=[CH:8][CH:9]=1)(=[O:3])[CH3:2].[CH3:19][I:20]>CC(C)=O>[I-:20].[C:1]([C:4]1[CH:5]=[C:6]([NH:10][C:11]2[CH:16]=[C:15]([CH3:17])[N+:14]([CH3:19])=[C:13]([NH2:18])[N:12]=2)[CH:7]=[CH:8][CH:9]=1)(=[O:3])[CH3:2]
Reactant: CI
Reactant: CC(=O)c1cccc(Nc2cc(C)nc(N)n2)c1
Solvent: CC(C)=O
Product: CC(=O)c1cccc(Nc2cc(C)[n+](C)c(N)n2)c1
Product: [I-]

Procedure:
Compound No. 14: 4-(3-acetylphenyl)amino-2-amino-6-methylpyrimidine, Compound No. 15, (0.968 g) was suspended in acetone (5 mL) containing methyl iodide (2 mL) was heated at reflux for 48 hr. Filtration after cooling gave 0.657 g of 4-(3-acetylphenyl)amino-2-amino-1,6-dimethylpyrimidinium iodide as a white powder, mp 238°-40° C.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]([N+:27]([O-])=O)=[C:6]([CH2:8][CH:9]([CH:18]([C:23]([O:25][CH3:26])=[O:24])[C:19]([O:21][CH3:22])=[O:20])[C:10]2[CH:15]=[CH:14][C:13]([O:16][CH3:17])=[CH:12][CH:11]=2)[CH:7]=1.CO.O.[OH-].[NH4+]>C(OCC)(=O)C>[NH2:27][C:5]1[CH:4]=[CH:3][C:2]([Cl:1])=[CH:7][C:6]=1[CH2:8][CH:9]([CH:18]([C:23]([O:25][CH3:26])=[O:24])[C:19]([O:21][CH3:22])=[O:20])[C:10]1[CH:11]=[CH:12][C:13]([O:16][CH3:17])=[CH:14][CH:15]=1
Reactant: COC(=O)C(C(=O)OC)C(Cc1cc(Cl)ccc1[N+](=O)[O-])c1ccc(OC)cc1
Agent: [NH4+]
Agent: [OH-]
Solvent: CO
Solvent: O
Solvent: CCOC(C)=O
Product: COC(=O)C(C(=O)OC)C(Cc1cc(Cl)ccc1N)c1ccc(OC)cc1
Temperature: 25 °C
Yield: 75.8 %

Procedure:
To a refluxing mixture of [2-(5-chloro-2-nitrophenyl)-1-(4-methoxyphenyl)ethyl]propanedioic acid, dimethyl ester (40 g, 95.0 mmole) and hydrated ferrous sulfate (184.5 g, 0.663 mole) in a (1:10 solution of methanol:water (1.2 L) was added concentrated ammonium hydroxide (142.5 ml) over a 30 minute period. The reaction was stirred at reflux for 20 minutes then cooled to room temperature. Ethyl acetate and Celite were added and the mixture was filtered through Celite. The filtrate was partitioned between ethyl acetate and water. The organic phase was dried over magnesium sulfate and concentrated in vacuo. The product was recrystallized from isopropyl alcohol to yield 28.22 g of the title compound, melting point 114°-116° C.
Reaction SMILES: Br[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][C:7]([O:9][CH2:10][CH3:11])=[O:8].C([CH2:19][NH2:20])C1C=CC=CC=1>>[CH3:19][NH:20][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][C:7]([O:9][CH2:10][CH3:11])=[O:8]
Reactant: CCOC(=O)CCCCCBr
Reactant: NCCc1ccccc1
Product: CCOC(=O)CCCCCNC
Yield: 99.8 %

Procedure:
Ethyl 6-bromohexanoate (6.00 g, 26.9 mmol) and benzylmethylamine (6.52 g, 53.8 mmol) were used to give the title compound (4.65 g; yield, 99%) as a colorless oily substance according to the method described in Example 68a.