Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: S(Cl)(C1C=CC(C)=CC=1)(=O)=O.O[CH:13]1[CH2:17][CH:16]([NH:18][C:19](=[O:28])[O:20][CH2:21][C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)[CH:15]([CH2:29][OH:30])[CH2:14]1.N1C=CC=CC=1>C1(C)C=CC=CC=1>[CH:13]12[CH2:14][CH:15]([CH:16]([NH:18][C:19](=[O:28])[O:20][CH2:21][C:22]3[CH:23]=[CH:24][CH:25]=[CH:26][CH:27]=3)[CH2:17]1)[CH2:29][O:30]2
Reactant: O=C(NC1CC(O)CC1CO)OCc1ccccc1
Agent: Cc1ccc(S(=O)(=O)Cl)cc1
Solvent: Cc1ccccc1
Solvent: c1ccncc1
Product: O=C(NC1CC2CC1CO2)OCc1ccccc1
Temperature: 25 °C
Reaction time: 48 h
Yield: 61.7 %

Procedure:
A solution of TsCl (290 mg, 1.52 mmol) in dry toluene (3.0 mL) was added dropwise to a solution of benzyl 4-hydroxy-2-(hydroxymethyl)cyclopentylcarbamate (100 mg, 0.380 mmol) and dry pyridine (3.0 mL) in dry toluene (6.0 mL) at 0° C. The mixture was then warmed to room temperature and stirred for 2 days. The reaction mixture was heated to 120° C. and stirred for another 16 hours. After concentration, the residue was purified by reverse phase Combi-flash (0.3% NH4HCO3/CH3CN) to afford benzyl 2-oxa-bicyclo[2.2.1]heptan-5-ylcarbamate as a solid (58 mg, 62% yield). 1H NMR (500 MHz, CD3OD) δ 7.37-7.31 (m, 5H), 5.09 (s, 2H), 4.33 (s, 1H), 3.73 (d, J=5.5 Hz, 1H), 3.63-3.61 (m, 1H), 3.48 (d, J=7.5 Hz, 1H), 2.53 (s, 1H), 2.07-2.04 (m, 1H), 1.72 (d, J=10.5 Hz, 1H), 1.61 (d, J=11.0 Hz, 1H), 1.42 (d, J=14.0 Hz, 1H).
Reaction SMILES: F[C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[C:9]1[N:14]=[CH:13][N:12]=[C:11]([NH:15][C:16]2[CH:21]=[CH:20][CH:19]=[C:18]([CH2:22][S:23]([CH3:26])(=[O:25])=[O:24])[CH:17]=2)[N:10]=1.[CH3:27][C:28]1[CH:33]=[C:32]([CH2:34][OH:35])[CH:31]=[CH:30][N:29]=1>>[F:8][C:6]1[CH:5]=[CH:4][C:3]([C:9]2[N:14]=[CH:13][N:12]=[C:11]([NH:15][C:16]3[CH:21]=[CH:20][CH:19]=[C:18]([CH2:22][S:23]([CH3:26])(=[O:25])=[O:24])[CH:17]=3)[N:10]=2)=[C:2]([O:35][CH2:34][C:32]2[CH:31]=[CH:30][N:29]=[C:28]([CH3:27])[CH:33]=2)[CH:7]=1
Reactant: Cc1cc(CO)ccn1
Reactant: CS(=O)(=O)Cc1cccc(Nc2ncnc(-c3ccc(F)cc3F)n2)c1
Product: Cc1cc(COc2cc(F)ccc2-c2ncnc(Nc3cccc(CS(C)(=O)=O)c3)n2)ccn1

Procedure:
Starting with 4-(2,4-difluorophenyl)-N-{3-[(methylsulfonyl)methyl]phenyl}-1,3,5-triazin-2-amine (70 mg; 0.184 mmol), intermediate 42.1, and (2-methyl-pyridin-4-yl)-methanol (91 mg; 0.736 mmol), example 87 was prepared analogously to the procedure for the preparation of example 42.
Reaction SMILES: COC(=O)NC(C(N1C(C2NC(C3C=CC4C(=CC=C(C5C=CC(C6NC(C7C8CC(CC8)N7C(=O)C(NC(OC)=O)C(C)C)=NC=6)=CC=5)C=4)C=3)=CN=2)CC2(CC2)C1)=O)C(C)C.[CH3:63][O:64][C:65](=[O:104])[NH:66][CH:67]([C:71]([N:73]1[CH:78]([C:79]2[NH:80][C:81]([C:84]3[CH:93]=[CH:92][C:91]4[C:86](=[CH:87][CH:88]=[C:89](B5OC(C)(C)C(C)(C)O5)[CH:90]=4)[CH:85]=3)=[CH:82][N:83]=2)[CH:77]2[CH2:103][CH:74]1[CH2:75][CH2:76]2)=[O:72])[CH:68]([CH3:70])[CH3:69].[C:105]([O:109][C:110]([N:112]1[CH:118]([C:119]2[NH:120][C:121]([C:124]3[CH:129]=[CH:128][C:127](Br)=[CH:126][CH:125]=3)=[CH:122][N:123]=2)[CH2:117][C:114]2([CH2:116][CH2:115]2)[CH2:113]1)=[O:111])([CH3:108])([CH3:107])[CH3:106].C(=O)([O-])[O-].[K+].[K+]>C(OCC)(=O)C>[C:105]([O:109][C:110]([N:112]1[CH:118]([C:119]2[NH:120][C:121]([C:124]3[CH:129]=[CH:128][C:127]([C:89]4[CH:88]=[CH:87][C:86]5[C:91](=[CH:92][CH:93]=[C:84]([C:81]6[NH:80][C:79]([CH:78]7[CH:77]8[CH2:103][CH:74]([CH2:75][CH2:76]8)[N:73]7[C:71](=[O:72])[CH:67]([NH:66][C:65]([O:64][CH3:63])=[O:104])[CH:68]([CH3:70])[CH3:69])=[N:83][CH:82]=6)[CH:85]=5)[CH:90]=4)=[CH:126][CH:125]=3)=[CH:122][N:123]=2)[CH2:117][C:114]2([CH2:116][CH2:115]2)[CH2:113]1)=[O:111])([CH3:108])([CH3:107])[CH3:106]
Reactant: COC(=O)NC(C(=O)N1C2CCC(C2)C1c1ncc(-c2ccc3cc(B4OC(C)(C)C(C)(C)O4)ccc3c2)[nH]1)C(C)C
Reactant: CC(C)(C)OC(=O)N1CC2(CC2)CC1c1ncc(-c2ccc(Br)cc2)[nH]1
Agent: COC(=O)NC(C(=O)N1CC2(CC2)CC1c1ncc(-c2ccc3cc(-c4ccc(-c5cnc(C6C7CCC(C7)N6C(=O)C(NC(=O)OC)C(C)C)[nH]5)cc4)ccc3c2)[nH]1)C(C)C
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Product: COC(=O)NC(C(=O)N1C2CCC(C2)C1c1ncc(-c2ccc3cc(-c4ccc(-c5cnc(C6CC7(CC7)CN6C(=O)OC(C)(C)C)[nH]5)cc4)ccc3c2)[nH]1)C(C)C
Yield: 59.5 %

Procedure:
This compound was prepared using the procedure used to prepare [1-(6-{5-[6-(4-{2-[2-(2-Methoxycarbonylamino-3-methyl-butyryl)-2-aza-bicyclo [2.2.1]hept-3-yl]-3H-imidazol-4-yl}-phenyl)-naphthalen-2-yl]-1H-imidazol-2-yl}-5-aza-spiro[2.4]heptane-5-carbonyl)-2-methyl-propyl]-carbamic acid methyl ester (example EZ) using [2-Methyl-1-(3-{5-[6-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-naphthalen-2-yl]-1H-imidazol-2-yl}-2-aza-bicyclo[2.2.1]heptane-2-carbonyl)-propyl]-carbamic acid methyl ester (2.25 mmol), 6-[5-(4-Bromo-phenyl)-1H-imidazol-2-yl]-5-aza-spiro[2.4]heptane-5-carboxylic acid tert-butyl ester (2.39 mmol), and potassium carbonate (2M, 4.3 mL, 8.55 mmol). The reaction was performed under an argon atmosphere. The crude reaction was diluted in ethyl acetate, washed with water and purified by normal phase silica chromatography (50-100% Hexanes:EthylAcetate+10% Methanol). 6-{5-[4-(6-{2-[2-(2-Methoxycarbonylamino-3-methyl-butyryl)-2-aza-bicyclo[2.2.1]hept-3-yl]-3H-imidazol-4-yl}-naphthalen-2-yl)-phenyl]-1H-imidazol-2-yl}-5-aza-spiro[2.4]heptane-5-carboxylic acid tert-butyl ester (1.05 g, 60%) was obtained as a tan solid.
Reaction SMILES: O.[C:2](=[S:8])([S-:7])[S:3][CH:4]([CH3:6])[CH3:5].[K+].Cl[CH2:11][C:12]#[N:13]>S(=O)(=O)(O)[O-].C([N+](CCCC)(CCCC)CCCC)CCC.C1(C)C=CC=CC=1>[C:2](=[S:7])([S:8][CH2:11][C:12]#[N:13])[S:3][CH:4]([CH3:6])[CH3:5]
Reactant: CC(C)SC(=S)[S-]
Reactant: N#CCCl
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: O=S(=O)([O-])O
Agent: [K+]
Solvent: Cc1ccccc1
Solvent: O
Product: CC(C)SC(=S)SCC#N
Yield: 59.6 %

Procedure:
To a two phase system containing 100 ml of water, 100 ml of toluene, 19.0 g (100 mmol) of potassium isopropyl trithiocarbonate and 50 mg of tetrabutyl ammonium bisulfate, a phase transfer catalyst, is added 6.3 ml (100 mmol) of chloroacetonitrile. The temperature of the reaction is maintained at between 20° and 30° C. After 4.5 hours the layers are separated and the toluene layer washed with water, brine, dried with Na2SO4, filtered, and concentrated in vacuo. The residue is distilled to give 11.4 g of isopropyl cyanomethyl trithiocarbonate as a yellow oil, boiling point 110°-113° C. at 0.1 mm Hg.
Reaction SMILES: Br[CH2:2][CH2:3][C:4](Br)=[O:5].[CH2:7]([O:9][C:10](=[O:45])[CH2:11][CH2:12][C:13]1[CH:14]=[C:15]2[C:20](=[CH:21][CH:22]=1)[N:19]([C:23](=[O:44])[CH2:24][C:25]1[CH:30]=[CH:29][C:28]([NH:31][C:32]([NH:34][C:35]3[CH:40]=[CH:39][CH:38]=[CH:37][C:36]=3[CH3:41])=[O:33])=[C:27]([O:42][CH3:43])[CH:26]=1)[CH2:18][CH2:17][NH:16]2)[CH3:8].C(N(CC)CC)C.O>O1CCCC1>[C:4]([N:16]1[C:15]2[C:20](=[CH:21][CH:22]=[C:13]([CH2:12][CH2:11][C:10]([O:9][CH2:7][CH3:8])=[O:45])[CH:14]=2)[N:19]([C:23](=[O:44])[CH2:24][C:25]2[CH:30]=[CH:29][C:28]([NH:31][C:32]([NH:34][C:35]3[CH:40]=[CH:39][CH:38]=[CH:37][C:36]=3[CH3:41])=[O:33])=[C:27]([O:42][CH3:43])[CH:26]=2)[CH2:18][CH2:17]1)(=[O:5])[CH:3]=[CH2:2]
Reactant: O=C(Br)CCBr
Reactant: CCOC(=O)CCc1ccc2c(c1)NCCN2C(=O)Cc1ccc(NC(=O)Nc2ccccc2C)c(OC)c1
Solvent: O
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: C=CC(=O)N1CCN(C(=O)Cc2ccc(NC(=O)Nc3ccccc3C)c(OC)c2)c2ccc(CCC(=O)OCC)cc21
Temperature: 0 °C
Reaction time: 1 h

Procedure:
3-Bromo propionyl bromide (262 μl) was added to a stirred suspension of 3-(1-{[3-methoxy-4-(3-o-tolyl-ureido)-phenyl]-acetyl}-1,2,3,4-tetrahydro-quinoxalin-6-yl)-propionic acid ethyl ester (0.229 g, Reference Example 1) and triethylamine (680 μl) in tetrahydrofuran (10 ml) cooled to 0° C. under argon atmosphere. After stirring at 0° C. for 1 hour then at 20° C. overnight the mixture was treated with 3-bromo propionyl bromide (90 μl) and stirring was continued for 2 hours at 21° C. The reaction mixture was treated with water (25 ml) and after stirring for 15 minutes at 20° C. the mixture was extracted three times with ethyl acetate (25 ml). The combined extracts were washed with saturated aqueous sodium bicarbonate (10 ml), then washed four times with water (10 ml), then dried over magnesium sulfate and then evaporated to dryness under reduced pressure (40° C., 40 mbar). The residue (1.7 g) was subjected to flash chromatography on silica (50 g, 0.040-0.063 mm particle size) eluting with a mixture of cyclohexane and ethyl acetate (1:1, v/v) to give the title compound as a yellow foam (550 mg). TLC: RF=30/72, silica, eluting with a mixture of dichloromethane and methanol (9:1, v/v). 1H NMR [400 MHz, (CD3)2SO, at a temperature of 373° K.]: δ1.20 (t, J=7 Hz, 3H); 2.28 (s,, 3H); 2.64 (t, J=7.5 Hz, 2H); 2.91 (t, J=7.5 Hz, 2H); 3.81 (s, 3H); 3.84 (s, 2H); 3.87 (m, 2H); 3.93 (m, 2H); 4.11 (q, J=7 Hz, 2H); 5.68 (dd, J=10.5 and 2 Hz, 1H); 6.21 (dd, J=17 and 2 Hz, 1H); 6.38 (dd, J=17 and 10.5 Hz, 1H); 6.58 (broad d, J=8 Hz, 1H); 6.75 (broad s, 1H); 6.99 (broad t, J=7.5 Hz, 1H); from 7.10 to 7.25 (m, 4H); 7.57 (d, J=8.5 Hz, 1H); 7.69 (broad d, J=8 Hz, 1H); 7.92 (d, J=8.5 Hz, 1H); 8.18 (broad s, 1H); 8.28 (broad s, 1H). MS (EI): 584 (M+).
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[C:9]2[C:5]([CH:6]=[C:7]([C:13](=[O:30])[NH:14][CH:15]([C:20]3[CH:25]=[CH:24][CH:23]=[C:22]([C:26]([F:29])([F:28])[F:27])[CH:21]=3)[C:16]([F:19])([F:18])[F:17])[N:8]2[CH2:11][CH3:12])=[CH:4][C:3]=1[C:31]([O:33]CC)=[O:32].B(Br)(Br)Br.O>ClCCl>[Cl:1][C:2]1[CH:10]=[C:9]2[C:5]([CH:6]=[C:7]([C:13](=[O:30])[NH:14][CH:15]([C:20]3[CH:25]=[CH:24][CH:23]=[C:22]([C:26]([F:29])([F:28])[F:27])[CH:21]=3)[C:16]([F:17])([F:18])[F:19])[N:8]2[CH2:11][CH3:12])=[CH:4][C:3]=1[C:31]([OH:33])=[O:32]
Reactant: CCOC(=O)c1cc2cc(C(=O)NC(c3cccc(C(F)(F)F)c3)C(F)(F)F)n(CC)c2cc1Cl
Agent: BrB(Br)Br
Solvent: O
Solvent: ClCCl
Product: CCn1c(C(=O)NC(c2cccc(C(F)(F)F)c2)C(F)(F)F)cc2cc(C(=O)O)c(Cl)cc21
Temperature: -10 °C
Reaction time: 1 h
Yield: 82.2 %

Procedure:
Ethyl 6-chloro-1-ethyl-2-({2,2,2-trifluoro-1-[3-(trifluoromethyl)phenyl]ethyl}carbamoyl)-1H-indole-5-carboxylate (0.10 g, 0.19 mmol) was dissolved in 5 ml of dichloromethane and a solution of boron tribromide in dichloromethane (0.96 ml, 0.96 mmol) was added dropwise at −10° C. The reaction mixture was stirred at −10° C. for 1 h and then at room temperature for 2 h. Water was added and the precipitated solid was filtered off with suction and dried. 0.077 g (71% of theory) of 6-chloro-1-ethyl-2-({2,2,2-trifluoro-1-[3-(trifluoromethyl)phenyl]ethyl}carbamoyl)-1H-indole-5-carboxylic acid was obtained.
Reaction SMILES: [CH2:1]([O:5][CH2:6][CH2:7][O:8][C:9]1[CH:14]=[CH:13][C:12]([C:15]2[CH:16]=[CH:17][C:18]3[N:24]([CH2:25][CH:26]([CH3:28])[CH3:27])[CH2:23][CH2:22][C:21]([C:29]([NH:31][C:32]4[CH:37]=[CH:36][C:35]([S:38][CH2:39][C:40]5[N:41]([CH2:45][CH2:46][CH3:47])[CH:42]=[CH:43][N:44]=5)=[CH:34][CH:33]=4)=[O:30])=[CH:20][C:19]=3[CH:48]=2)=[CH:11][CH:10]=1)[CH2:2][CH2:3][CH3:4].ClC1C=CC=C(C(OO)=[O:57])C=1.S([O-])([O-])(=O)=S.[Na+].[Na+]>ClCCl>[CH2:1]([O:5][CH2:6][CH2:7][O:8][C:9]1[CH:10]=[CH:11][C:12]([C:15]2[CH:16]=[CH:17][C:18]3[N:24]([CH2:25][CH:26]([CH3:27])[CH3:28])[CH2:23][CH2:22][C:21]([C:29]([NH:31][C:32]4[CH:33]=[CH:34][C:35]([S:38]([CH2:39][C:40]5[N:41]([CH2:45][CH2:46][CH3:47])[CH:42]=[CH:43][N:44]=5)=[O:57])=[CH:36][CH:37]=4)=[O:30])=[CH:20][C:19]=3[CH:48]=2)=[CH:13][CH:14]=1)[CH2:2][CH2:3][CH3:4]
Reactant: CCCCOCCOc1ccc(-c2ccc3c(c2)C=C(C(=O)Nc2ccc(SCc4nccn4CCC)cc2)CCN3CC(C)C)cc1
Reactant: O=C(OO)c1cccc(Cl)c1
Agent: O=S([O-])([O-])=S
Agent: [Na+]
Solvent: ClCCl
Product: CCCCOCCOc1ccc(-c2ccc3c(c2)C=C(C(=O)Nc2ccc(S(=O)Cc4nccn4CCC)cc2)CCN3CC(C)C)cc1
Reaction time: 1 h
Yield: 35.9 %

Procedure:
To a solution of 7-[4-(2-butoxyethoxy)phenyl]-1-isobutyl-N-[4-[[(1-propylimidazol-2-yl)methyl]sulfanyl]phenyl]-2,3-dihydro-1-benzazepine-4-carboxamide (200 mg) in dichloromethane (10 ml) was added dropwise 70% solution of 3-chloroperbenzoic acid (111 mg) in dichloromethane (10 ml) at −78° C. After finishing the dropping, the mixture was stirred for 1 hour at −10° C. to −25° C. To the mixture was added an aqueous solution of sodium thiosulfate, and the mixture was allowed to be at room temperature, stirred for 30 minutes, and extracted with ethyl acetate. The organic layer was washed with an aqueous solution of saturated sodium bicarbonate, and saturated brine, and dried over magnesium sulfate. The solvent was distilled off under reduced pressure. The obtained residue was separated and purified by silica gel column chromatography (ethyl acetate→methanol:ethyl acetate=1:9), to give 7-[4-(2-butoxyethoxy)phenyl]-1-isobutyl-N-[4-[[(1-propylimidazol-2-yl)methyl]sulfinyl]phenyl]-2,3-dihydro-1-benzazepine-4-carboxamide (73.5 mg) (Compound 335) as yellow amorphous, and to give 7-[4-(2-butoxyethoxy)phenyl]-1-isobutyl-N-[4-[[(1-propylimidazol-2-yl)methyl]sulfonyl]phenyl]-2,3-dihydro-1-benzazepine-4-carboxamide (18.8 mg) (Compound 336) as yellow amorphous.
Reaction SMILES: [S:1]1(=[O:12])(=[O:11])[C:6]2[N:7]=[CH:8][CH:9]=[CH:10][C:5]=2[NH:4][CH:3]=[N:2]1.[CH2:13](Br)[CH3:14]>>[CH2:13]([N:4]1[C:5]2[CH:10]=[CH:9][CH:8]=[N:7][C:6]=2[S:1](=[O:12])(=[O:11])[N:2]=[CH:3]1)[CH3:14]
Reactant: O=S1(=O)N=CNc2cccnc21
Reactant: CCBr
Product: CCN1C=NS(=O)(=O)c2ncccc21

Procedure:
The compound is obtained according to the same procedure as that described for Example 63, starting from 0. 1 g of 4H-pyrido[3,2-e][1,2,4]thiadiazine 1,1-dioxide (Example 16) and 0.17 g of ethyl bromide.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[C:12]3[CH:13]=[C:14]4[C@:19]([C:21]([OH:23])=[O:22])([CH2:20][C:11]=3[CH:10]=[N:9]2)[CH2:18][N:17]([S:24]([C:27]2[CH:28]=[N:29][C:30]([N:33]3[CH2:38][CH2:37][O:36][CH2:35][CH2:34]3)=[CH:31][CH:32]=2)(=[O:26])=[O:25])[CH2:16][CH2:15]4)=[CH:4][CH:3]=1.C(=O)([O-])[O-].[Cs+].[Cs+].[CH3:45][C:46]1([CH3:51])[CH2:49][O:48][CH:47]1Br>CN(C)C=O.O>[CH3:45][C:46]1([CH2:51][O:22][C:21]([C@@:19]23[CH2:18][N:17]([S:24]([C:27]4[CH:28]=[N:29][C:30]([N:33]5[CH2:38][CH2:37][O:36][CH2:35][CH2:34]5)=[CH:31][CH:32]=4)(=[O:25])=[O:26])[CH2:16][CH2:15][C:14]2=[CH:13][C:12]2[N:8]([C:5]4[CH:6]=[CH:7][C:2]([F:1])=[CH:3][CH:4]=4)[N:9]=[CH:10][C:11]=2[CH2:20]3)=[O:23])[CH2:49][O:48][CH2:47]1
Reactant: O=C(O)[C@]12Cc3cnn(-c4ccc(F)cc4)c3C=C1CCN(S(=O)(=O)c1ccc(N3CCOCC3)nc1)C2
Reactant: CC1(C)COC1Br
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Solvent: O
Product: CC1(COC(=O)[C@]23Cc4cnn(-c5ccc(F)cc5)c4C=C2CCN(S(=O)(=O)c2ccc(N4CCOCC4)nc2)C3)COC1
Yield: 19.2 %

Procedure:
A solution of (R)-1-(4-fluorophenyl)-6-(6-morpholin-4-yl-pyridine-3-sulfonyl]-1,4,5,6,7,8-hexahydro-1,2,6-triaza-cyclopenta[b]naphthalene-4a-carboxylic acid (0.09 g) in N,N-dimethylformamide (1 mL) was treated with cesium carbonate (0.16 g) and 3-methyl-3-methylbromo-oxetane (0.14 g) at room temperature for 30 minutes. The reaction mixture was diluted with water and the precipitate collected by filtration and dried under vacuum. The solid was purified by preparative reverse-phase HPLC eluting with a mixture of methanol and water containing 0.1% formic acid (3:2 to 4:1 by volume) to give the title compound as a white solid (0.02 g). 1H NMR (400 MHz, CHCl3-d): δ 8.53 (d, 1H), 7.78 (dd, 1H), 7.49-7.41 (m, 3H), 7.16 (t, 2H), 6.62 (d, 1H), 6.45 (s, 1H), 4.49-4.38 (m, 3H), 4.34 (dd, 2H), 4.15 (s, 2H), 3.81 (t, 4H), 3.67 (t, 4H), 3.32 (d, 1H), 2.91 (d, 1H), 2.62 (d, 1H), 2.52 (d, 1H), 2.40 (d, 2H), 1.28 (s, 3H).
Reaction SMILES: [C:1]([C:5]1[CH:10]=[CH:9][C:8]([NH2:11])=[C:7]([NH2:12])[CH:6]=1)([CH3:4])([CH3:3])[CH3:2].[OH2:13]>>[NH2:11][C@@H:8]([C:9]1[NH:11][C:8]2[CH:9]=[CH:10][C:5]([C:1]([CH3:4])([CH3:2])[CH3:3])=[CH:6][C:7]=2[N:12]=1)[CH2:7][CH2:6][OH:13]
Reactant: CC(C)(C)c1ccc(N)c(N)c1
Reactant: O
Product: CC(C)(C)c1ccc2[nH]c([C@H](N)CCO)nc2c1

Procedure:
The title compound was prepared using Method 4 Steps 1 and 2 followed by the method described for Example 140 using 4-tert-butyl-1,2-diaminobenzene and N-α-t-Butyloxylcarbonyl-O-benzyl-D-homoserine. The residue was diluted with water and washed with EtOAc. Dilute aqueous LiOH solution was added to pH=10 and extracted with EtOAc. The organic layer was collected, dried over Na2SO4 and concentrated in vacuo (56 mg, 79%).
Reaction SMILES: [Cl:1][C:2]1[C:3]([N:8]2[C:12]([C:13]([O:15][CH3:16])=[O:14])=[CH:11][C:10]([CH2:17][C:18]3[CH:19]=[N:20][C:21]([C:24]([F:27])([F:26])[F:25])=[CH:22][CH:23]=3)=[N:9]2)=[N:4][CH:5]=[CH:6][CH:7]=1.[O:28]1CCOCC1>[O-2].[Mn+4].[O-2]>[Cl:1][C:2]1[C:3]([N:8]2[C:12]([C:13]([O:15][CH3:16])=[O:14])=[CH:11][C:10]([C:17]([C:18]3[CH:19]=[N:20][C:21]([C:24]([F:27])([F:25])[F:26])=[CH:22][CH:23]=3)=[O:28])=[N:9]2)=[N:4][CH:5]=[CH:6][CH:7]=1
Reactant: C1COCCO1
Reactant: COC(=O)c1cc(Cc2ccc(C(F)(F)F)nc2)nn1-c1ncccc1Cl
Agent: [Mn+4]
Agent: [O-2]
Product: COC(=O)c1cc(C(=O)c2ccc(C(F)(F)F)nc2)nn1-c1ncccc1Cl

Procedure:
1.29 g (3.20 mmol) of methyl 1-(3-chloropyridin-2-yl)-3-{[6-(trifluoromethyl)pyridin-3-yl]methyl}-1H-pyrazole-5-carboxylate were dissolved in 80 ml of dioxane, 16.72 g (192 mmol) of manganese(IV) oxide were added and the mixture was stirred at reflux for 12 h. The mixture was filtered off with suction and the filtrate was freed from the solvent. The desired product was obtained by chromatographic purification.
Reaction SMILES: [NH2:1][C:2]1[C:22]([Cl:23])=[CH:21][C:5]([C:6]([NH:8][CH2:9][CH:10]2[CH2:15][CH2:14][N:13]([CH2:16][CH2:17][CH2:18][CH2:19][NH2:20])[CH2:12][CH2:11]2)=[O:7])=[C:4]([O:24][CH3:25])[CH:3]=1.[CH2:26]([N:29]=[C:30]=[O:31])[CH2:27][CH3:28]>CN(C)C=O>[NH2:1][C:2]1[C:22]([Cl:23])=[CH:21][C:5]([C:6]([NH:8][CH2:9][CH:10]2[CH2:11][CH2:12][N:13]([CH2:16][CH2:17][CH2:18][CH2:19][NH:20][C:30]([NH:29][CH2:26][CH2:27][CH3:28])=[O:31])[CH2:14][CH2:15]2)=[O:7])=[C:4]([O:24][CH3:25])[CH:3]=1
Reactant: CCCN=C=O
Reactant: COc1cc(N)c(Cl)cc1C(=O)NCC1CCN(CCCCN)CC1
Solvent: CN(C)C=O
Product: CCCNC(=O)NCCCCN1CCC(CNC(=O)c2cc(Cl)c(N)cc2OC)CC1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
4-Amino-N-(1-(4-aminobutyl)piperidin-4-ylmethyl)-5-chloro-2-methoxybenzamide (1.0 g) was dissolved in dimethylformamide (10 ml) and n-propyl isocyanate (0.26 ml) was dropwise added under ice-cooling. The mixture was stirred at room temperature for 1 hr, and the reaction mixture was concentrated under reduced pressure. The obtained residue was purified by silica gel chromatography to give 0.2 g of 4 -amino-5-chloro-2-methoxy-N-(1-(4-(3-n-propylureido)butyl)-piperidin-4-ylmethyl)benzamide.
Reaction SMILES: C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[F:20][C:21]1[CH:28]=[CH:27][CH:26]=[CH:25][C:22]=1[CH2:23]Br.[CH:29]([C:31]1[CH:32]=[C:33]([CH:39]=[CH:40][C:41]=1[O:42][CH3:43])[C:34]([O:36][CH2:37][CH3:38])=[O:35])=O.C[O-].[Na+]>C(OCC)(=O)C.CO.CN(C)C=O>[F:20][C:21]1[CH:28]=[CH:27][CH:26]=[CH:25][C:22]=1[CH:23]=[CH:29][C:31]1[CH:32]=[C:33]([CH:39]=[CH:40][C:41]=1[O:42][CH3:43])[C:34]([O:36][CH2:37][CH3:38])=[O:35]
Reactant: Fc1ccccc1CBr
Reactant: CCOC(=O)c1ccc(OC)c(C=O)c1
Agent: C[O-]
Agent: [Na+]
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CCOC(C)=O
Solvent: CO
Solvent: CN(C)C=O
Product: CCOC(=O)c1ccc(OC)c(C=Cc2ccccc2F)c1
Temperature: 80 °C
Reaction time: 10 h
Yield: 76.3 %

Procedure:
N,N-Dimethylformamide (5 mL) was added to 1.0 g of polymer-supported triphenylphosphine (produced by Fluka, CAS registry number 39319-11-4) and 1.1 g of 2-fluorobenzyl bromide, and the mixture was stirred for 10 hours at 80° C. The reaction mixture was filtered, and then washed with N,N-dimethylformamide, dichloromethane, and methanol. The residue was dried under reduced pressure to prepare polymer-supported (2-fluorobenzyl)-triphenylphosphonium bromide. This product (144 mg) was added to a methanol solution (2 mL) of 30 mg of ethyl 3-formyl-4-methoxybenzoate obtained in step C of Example 1-2-1. After 80 μL of 28% sodium methoxide was added, the reactor was sealed, and the mixture was stirred for 4 hours at 70° C. The residue was diluted with ethyl acetate, washed with purified water, and dried over anhydrous sodium sulfate. The anhydrous sodium sulfate was separated by filtration, and then the filtrate was concentrated under reduced pressure. The residue was dried under reduced pressure to obtain 33 mg (80%) of ethyl 3-[2-(2-fluorophenyl)-vinyl]-4-methoxybenzoate.
Reaction SMILES: [NH:1]1[CH:5]=[C:4]([CH2:6][C:7]([N:9]2[CH2:14][CH2:13][N:12](C(OCC3C=CC=CC=3)=O)[CH2:11][C@H:10]2[C:25](=[O:41])[NH:26][C:27]2[CH:32]=[CH:31][C:30]([O:33][C:34]3[CH:39]=[CH:38][C:37]([F:40])=[CH:36][CH:35]=3)=[CH:29][CH:28]=2)=[O:8])[N:3]=[CH:2]1>[Pd].CO>[NH:1]1[CH:5]=[C:4]([CH2:6][C:7]([N:9]2[CH2:14][CH2:13][NH:12][CH2:11][C@H:10]2[C:25]([NH:26][C:27]2[CH:28]=[CH:29][C:30]([O:33][C:34]3[CH:39]=[CH:38][C:37]([F:40])=[CH:36][CH:35]=3)=[CH:31][CH:32]=2)=[O:41])=[O:8])[N:3]=[CH:2]1
Reactant: O=C(Nc1ccc(Oc2ccc(F)cc2)cc1)[C@@H]1CN(C(=O)OCc2ccccc2)CCN1C(=O)Cc1c[nH]cn1
Agent: [Pd]
Solvent: CO
Product: O=C(Nc1ccc(Oc2ccc(F)cc2)cc1)[C@@H]1CNCCN1C(=O)Cc1c[nH]cn1
Temperature: 25 °C
Yield: 84.3 %

Procedure:
Step (a) A flask was charged with (S)-benzyl 4-(2-(1H-imidazol-4-yl)acetyl)-3-(4-(4-fluorophenoxy)phenylcarbamoyl)piperazine-1-carboxylate (0.80 g, 1.4 mmol), prepared as in Example 13, methanol (10 mL) and palladium on carbon (10%, 100 mg) and the mixture was stirred at ambient temperature. The reaction mixture was placed under a hydrogen atmosphere (balloon) for 14 hours and then exposed to air, filtered through celite and concentrated. Product was purified from residue by reverse phase HPLC to give (S)-1-(2-(1H-imidazol-4-yl)acetyl)-N-(4-(4-fluorophenoxy)phenyl)piperazine-2-carboxamide (0.5 g, 83% yield) as an off-white solid. 1H-NMR (400 MHz, CDCl3): 10.02 (s, 1H), 9.20 (s, 1H), 7.63-7.56 (m, 2H), 7.52 (s, 1H), 7.05-6.93 (m, 7H), 5.34 (s, 1H), 4.05-4.00 (m, 1H), 3.94-3.86 (m, 1H), 3.78-3.71 (m, 2H), 3.28-3.20 (m, 1H), 3.00-2.94 (m, 1H), 2.89-2.74 (m, 2H), 2.61-2.53 (m, 1H). MS (EI) for C22H22FN5O3. found 424.2 (MH+).
Reaction SMILES: O[CH2:2][CH2:3][N:4]1[C:9]([CH2:10]O)=[CH:8][C:7]2[CH:12]=[CH:13][S:14][C:6]=2[S:5]1(=[O:16])=[O:15].CN(C)C.C1(C)C=CC(S([Cl:30])(=O)=O)=CC=1.[CH3:32][O:33][CH2:34][CH2:35][NH2:36].C(=O)(O)[O-].[Na+]>C(Cl)Cl>[ClH:30].[CH3:32][O:33][CH2:34][CH2:35][N:36]1[CH2:2][CH2:3][N:4]2[S:5](=[O:16])(=[O:15])[C:6]3[S:14][CH:13]=[CH:12][C:7]=3[CH:8]=[C:9]2[CH2:10]1
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Reactant: COCCN
Reactant: O=S1(=O)c2sccc2C=C(CO)N1CCO
Agent: CN(C)C
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Product: COCCN1CCN2C(=Cc3ccsc3S2(=O)=O)C1
Product: Cl
Reaction time: 3 h
Yield: 62 %

Procedure:
To a solution of the product from Step D (1.37 g, 5.25 mmol and trimethylamine (2.12 g, 21.0 mmol) in methylene chloride (100 mL) at 0° C. was added p-toluenesulfonyl chloride (2.50 g, 13.13 mmol). The mixture was stirred for 3 h, cooled (about 7° C.) overnight, and 2-methoxyethylamine (5 mL) was added, followed by stirring for 2 h at ambient temperature and heating at reflux temperature for 2 h. A saturated solution of sodium bicarbonate (80 mL) was added to the reaction mixture which was extracted with ethyl acetate (2×80 mL). The combined extracts were evaporated to a residue which was purified by column chromatography (silica, ethyl acetate) to give a viscous oil (0.98 g, 62%). Dissolution of the oil in ethyl acetate (50 mL) and treatment with 2N HCl/EtOH (2 mL) provided a crystalline solid which was collected by filtration and dried to give a colorless solid: mp 208°-210° C.
Reaction SMILES: [C:1](Cl)(=[O:3])[CH3:2].[CH2:5]([O:7][C:8](=[O:40])[C:9]1[C:14]([NH2:15])=[CH:13][CH:12]=[C:11]([C:16]2[CH2:20][CH2:19][CH2:18][C:17]=2[C:21]2[CH:26]=[C:25]([C:27]([F:30])([F:29])[F:28])[CH:24]=[CH:23][C:22]=2[O:31][CH2:32][C:33]2[CH:38]=[CH:37][C:36]([F:39])=[CH:35][CH:34]=2)[CH:10]=1)[CH3:6]>>[CH2:5]([O:7][C:8](=[O:40])[C:9]1[C:14]([NH:15][C:1](=[O:3])[CH3:2])=[CH:13][CH:12]=[C:11]([C:16]2[CH2:20][CH2:19][CH2:18][C:17]=2[C:21]2[CH:26]=[C:25]([C:27]([F:30])([F:29])[F:28])[CH:24]=[CH:23][C:22]=2[O:31][CH2:32][C:33]2[CH:34]=[CH:35][C:36]([F:39])=[CH:37][CH:38]=2)[CH:10]=1)[CH3:6]
Reactant: CCOC(=O)c1cc(C2=C(c3cc(C(F)(F)F)ccc3OCc3ccc(F)cc3)CCC2)ccc1N
Reactant: CC(=O)Cl
Product: CCOC(=O)c1cc(C2=C(c3cc(C(F)(F)F)ccc3OCc3ccc(F)cc3)CCC2)ccc1NC(C)=O

Procedure:
Prepared by general procedure E but using acetyl chloride instead of propionyl chloride and 3-{2[5-trifluoromethyl-2-(4-fluorobenzyloxy)phenyl]cyclopent-1-enyl}-6-aminobenzoic acid ethyl ester instead of 5-[2-(2-benzyloxy-5-chlorophenyl)-cyclopent-1-enyl]-2-aminobenzoic acid methyl ester.