Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: CCOCC.N.[CH2:7]([C:9]1[CH:14]=[CH:13][C:12]([O:15]C)=[CH:11][CH:10]=1)[CH3:8].[Li]>C(O)C>[CH2:7]([C:9]1[CH2:14][CH2:13][C:12](=[O:15])[CH2:11][CH:10]=1)[CH3:8]
Reactant: CCc1ccc(OC)cc1
Agent: N
Agent: [Li]
Solvent: CCOCC
Solvent: CCO
Product: CCC1=CCC(=O)CC1
Reaction time: 0.25 h

Procedure:
To a stirred refluxing mixture of 600 ml. of dry ether and 1600 ml of liquid ammonia was added 136 g of p-ethylanisole. After 15 minutes, there was added portionwise, at -35° to -32° C., 26.4 g of lithium ribbon over 0.5-1 hour. After an additional 15 minutes, 193 g of dry ethanol was added dropwise at -35° to -32° C. Stirring was continued until the blue color disappeared, and the ammonia was allowed to evaporate on standing overnight. The residue was poured into 1 l of ice water and extracted twice with ether. The combined ether extracts concentrated to a volume of about 300 ml was stirred with 250 ml of water containing 46 g of oxalic acid overnight at ambient temperature. This mixture was diluted with 1 liter of water and extracted twice with ether. The combined ether extracts was washed with 5% sodium bicarbonate and then with water. After drying, the ether solution was vacuumconcentrated to a residue of 104.4 g of desired product; it was 94% pure by GLC analysis and used without distillation.
Reaction SMILES: N1C=CC=CC=1.Cl.CN(C)CCCN=C=NCC.[C:19]([OH:23])(=O)[CH:20]=[CH2:21].[NH2:24][CH2:25][CH2:26][C:27]([NH:29][C:30]1[CH:31]=[C:32]2[C:37](=[CH:38][CH:39]=1)[N:36]=[CH:35][N:34]=[C:33]2[NH:40][C:41]1[CH:46]=[CH:45][C:44]([O:47][CH2:48][C:49]2[CH:50]=[N:51][CH:52]=[CH:53][CH:54]=2)=[C:43]([Cl:55])[CH:42]=1)=[O:28]>C1COCC1>[Cl:55][C:43]1[CH:42]=[C:41]([NH:40][C:33]2[C:32]3[C:37](=[CH:38][CH:39]=[C:30]([NH:29][C:27]([CH2:26][CH2:25][NH:24][C:19](=[O:23])[CH:20]=[CH2:21])=[O:28])[CH:31]=3)[N:36]=[CH:35][N:34]=2)[CH:46]=[CH:45][C:44]=1[O:47][CH2:48][C:49]1[CH:50]=[N:51][CH:52]=[CH:53][CH:54]=1
Reactant: C=CC(=O)O
Reactant: NCCC(=O)Nc1ccc2ncnc(Nc3ccc(OCc4cccnc4)c(Cl)c3)c2c1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Solvent: c1ccncc1
Solvent: C1CCOC1
Product: C=CC(=O)NCCC(=O)Nc1ccc2ncnc(Nc3ccc(OCc4cccnc4)c(Cl)c3)c2c1
Temperature: 25 °C
Reaction time: 2 h
Yield: 18 %

Procedure:
46 μl of pyridine and 85 mg of 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride were added to 31 μl of acrylic acid dissolved in 3 ml of THF at 0° C., reacted with 100 mg of the compound (132-1) of Example 132 for 30 mins, and stirred for 2 hours while heating to room temperature. The reacted solution was extracted with 6 ml of ethylacetate 3 times after adding 4 ml of water, dried over anhydrous magnesium sulfate, filtered and distilled under a reduced pressure, and the resulting residue was subjected to column chromatography (eluent-chloroform:methanol=15:1) to obtain the title compound (20 mg, 18%).
Reaction SMILES: [CH:1]1([NH:4][CH:5]2[CH2:10][CH2:9][N:8]([C:11]3[C:16]([F:17])=[CH:15][C:14]([C:18]([F:21])([F:20])[F:19])=[CH:13][N:12]=3)[CH2:7][CH2:6]2)[CH2:3][CH2:2]1.[N:22]1([C:27]2[CH:35]=[CH:34][C:30]([C:31](O)=[O:32])=[CH:29][CH:28]=2)[CH:26]=[N:25][N:24]=[N:23]1>>[CH:1]1([N:4]([CH:5]2[CH2:10][CH2:9][N:8]([C:11]3[C:16]([F:17])=[CH:15][C:14]([C:18]([F:20])([F:19])[F:21])=[CH:13][N:12]=3)[CH2:7][CH2:6]2)[C:31](=[O:32])[C:30]2[CH:34]=[CH:35][C:27]([N:22]3[CH:26]=[N:25][N:24]=[N:23]3)=[CH:28][CH:29]=2)[CH2:2][CH2:3]1
Reactant: O=C(O)c1ccc(-n2cnnn2)cc1
Reactant: Fc1cc(C(F)(F)F)cnc1N1CCC(NC2CC2)CC1
Product: O=C(c1ccc(-n2cnnn2)cc1)N(C1CC1)C1CCN(c2ncc(C(F)(F)F)cc2F)CC1

Procedure:
The title compound is prepared from cyclopropyl-(3′-fluoro-5′-trifluoromethyl-3,4,5,6-tetrahydro-2H-[1,2′]bipyridinyl-4-yl)-amine and 4-tetrazol-1-yl-benzoic acid following a procedure analogous to that described in Example 107. LC (method 19): tR=4.46 min; Mass spectrum (ESI+): m/z=476 [M+H]+.
Reaction SMILES: [OH:1][CH2:2][CH2:3][N:4]([CH3:30])[C:5](=[O:29])[C:6]1[CH:11]=[CH:10][C:9]([C:12](=[C:23]2[CH2:28][CH2:27][NH:26][CH2:25][CH2:24]2)[C:13]2[CH:14]=[CH:15][CH:16]=[C:17]3[C:22]=2[N:21]=[CH:20][CH:19]=[CH:18]3)=[CH:8][CH:7]=1.[S:31]1[CH:35]=[C:34]([CH:36]=O)[N:33]=[CH:32]1.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>ClC(Cl)C.C(Cl)Cl>[OH:1][CH2:2][CH2:3][N:4]([CH3:30])[C:5](=[O:29])[C:6]1[CH:7]=[CH:8][C:9]([C:12]([C:13]2[CH:14]=[CH:15][CH:16]=[C:17]3[C:22]=2[N:21]=[CH:20][CH:19]=[CH:18]3)=[C:23]2[CH2:28][CH2:27][N:26]([CH2:36][C:34]3[N:33]=[CH:32][S:31][CH:35]=3)[CH2:25][CH2:24]2)=[CH:10][CH:11]=1
Reactant: O=Cc1cscn1
Reactant: CN(CCO)C(=O)c1ccc(C(=C2CCNCC2)c2cccc3cccnc23)cc1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: CC(Cl)Cl
Solvent: ClCCl
Product: CN(CCO)C(=O)c1ccc(C(=C2CCN(Cc3cscn3)CC2)c2cccc3cccnc23)cc1
Reaction time: 20 h
Yield: 48.6 %

Procedure:
Compound 1C (3.3 g, 8.3 mmol) and 4-thiazolecarboxaldehyde (1.4 g, 12.4 mmol) in dichloroethane (16 mL) were stirred for 30 min. under nitrogen. Sodium triacetoxyborohydride (5.3 g, 24 9 mmol) was added and the reaction was stirred for 20 h. The mixture was diluted with CH2Cl2 (20 mL) and washed with saturated aqueous NaHCO3. The organic phase was dried over Na2SO4 and concentrated. Column chromatography (120 g silica gel, eluting with 4% 7N NH3/MeOH in CH2Cl2) gave 2.01 g 1D as a white solid (49%). 1H NMR (500.333 MHz, CDCl3) δ 8.90 (dd, J=4.1, 1.7 Hz, 1H), 8.76 (d, J=1.9 Hz, 1H), 8.11 (dd, J=8.0, 1.5 Hz, 1H), 7.72 (dd, J=7.3, 2.3 Hz, 1H), 7.51-7.46 (m, 2H), 7.37-7.33 (m, 3H), 7.31-7.29 (m, 2H), 7.18 (s, 1H), 3.85 (s, br, 2H), 3.76 (s, 2H), 3.67 (br s, 2H), 3.26 (br s, 1H), 3.02 (s, 3H), 2.78-2.71 (m, 1H), 2.67-2.52 (m, 4H), 2.46-2.37 (m, 1H), 2.14-2.04 (m, 2H). TOF MS E+ 499.21.
Reaction SMILES: Cl[C:2]1[CH:7]=[C:6]([N:8]2[CH2:13][CH2:12][O:11][CH2:10][CH2:9]2)[N:5]=[C:4]([O:14][CH2:15][CH2:16][N:17]2[CH2:22][CH2:21][O:20][CH2:19][CH2:18]2)[N:3]=1.[NH2:23][NH2:24]>O1CCOCC1>[NH:23]([C:2]1[CH:7]=[C:6]([N:8]2[CH2:13][CH2:12][O:11][CH2:10][CH2:9]2)[N:5]=[C:4]([O:14][CH2:15][CH2:16][N:17]2[CH2:22][CH2:21][O:20][CH2:19][CH2:18]2)[N:3]=1)[NH2:24]
Reactant: Clc1cc(N2CCOCC2)nc(OCCN2CCOCC2)n1
Reactant: NN
Solvent: C1COCCO1
Product: NNc1cc(N2CCOCC2)nc(OCCN2CCOCC2)n1
Yield: 102.8 %

Procedure:
4-[2-(4-Chloro-6-(morpholin-4-yl)-pyrimidin-2-yloxy)-ethyl]-morpholine (2.0 g; 6 mmol) was dissolved in dioxane (100 mL) and hydrazine (2 mL; 60 mmol) was added. The solution was heated to reflux for one hour, at which point the solvent was evaporated. The solid was dissolved in dichloromethane (100 mL) and washed with 10% sodium carbonate (10 mL). The organic layer was dried over magnesium sulfate and evaporated to give 4-[2-(4-Hydrazino-6-(morpholin-4-yl)-pyrimidin-2-yloxy)-ethyl]-morpholine (2.0 g)
Reaction SMILES: Br[C:2]1[CH:20]=[CH:19][C:5]2[N:6]=[C:7]([C@H:9]3[CH2:12][C@H:11]([N:13]4[CH2:17][CH2:16][CH2:15][C@H:14]4[CH3:18])[CH2:10]3)[S:8][C:4]=2[CH:3]=1.[CH3:21][O:22][C:23]1[N:28]=[CH:27][C:26](B(O)O)=[C:25]([O:32][CH3:33])[N:24]=1.N1C=C(B(O)O)C=NC=1>>[CH3:21][O:22][C:23]1[N:24]=[C:25]([O:32][CH3:33])[C:26]([C:2]2[CH:20]=[CH:19][C:5]3[N:6]=[C:7]([C@H:9]4[CH2:12][C@H:11]([N:13]5[CH2:17][CH2:16][CH2:15][C@@H:14]5[CH3:18])[CH2:10]4)[S:8][C:4]=3[CH:3]=2)=[CH:27][N:28]=1
Reactant: C[C@@H]1CCCN1[C@H]1C[C@H](c2nc3ccc(Br)cc3s2)C1
Reactant: COc1ncc(B(O)O)c(OC)n1
Agent: OB(O)c1cncnc1
Product: COc1ncc(-c2ccc3nc([C@H]4C[C@H](N5CCC[C@@H]5C)C4)sc3c2)c(OC)n1

Procedure:
The title compound was prepared according to the procedure described in Example 1F, substituting the product of Example 11A for the product of Example 1E and substituting 2,6-dimethoxy-5-pyrimidineboronic acid for pyrimidine-5-boronic acid. 1H NMR (500 MHz, CDCl3) δ ppm 8.32 (s, 1H) 8.02 (d, J=8.54 Hz, 1H) 7.98 (d, J=1.53 Hz, 1H) 7.57 (dd, J=8.39, 1.68 Hz, 1H) 4.06 (s, 3H) 4.05 (s, 3H) 3.83-3.95 (m, 1H) 3.51-3.72 (m, 1H) 3.10-3.29 (m, 1H) 2.68-2.80 (m, 3H) 2.40-2.65 (m, 3H) 1.49-2.13 (m, 4H) 1.10-1.27 (s, 3H). MS: (M+H)+=411.
Reaction SMILES: [C:1]([O:4][C@H:5]1[CH2:29][CH2:28][C@@:27]2([CH3:30])[C:7](=[C:8]([CH2:32]Br)[CH2:9][C@@H:10]3[C@@H:26]2[CH2:25][CH2:24][C@@:23]2([CH3:31])[C@H:11]3[CH2:12][CH2:13][C@@H:14]2[C@H:15]([CH3:22])[CH2:16][CH2:17][CH2:18][CH:19]([CH3:21])[CH3:20])[CH2:6]1)(=[O:3])[CH3:2].[CH2:34]([O:36][CH2:37][CH2:38][NH:39][CH2:40][CH2:41][O:42][CH2:43][CH3:44])[CH3:35].ClCCl>O>[C:1]([O:4][C@H:5]1[CH2:29][CH2:28][C@@:27]2([CH3:30])[C:7](=[C:8]([CH2:32][N:39]([CH2:40][CH2:41][O:42][CH2:43][CH3:44])[CH2:38][CH2:37][O:36][CH2:34][CH3:35])[CH2:9][C@@H:10]3[C@@H:26]2[CH2:25][CH2:24][C@@:23]2([CH3:31])[C@H:11]3[CH2:12][CH2:13][C@@H:14]2[C@H:15]([CH3:22])[CH2:16][CH2:17][CH2:18][CH:19]([CH3:21])[CH3:20])[CH2:6]1)(=[O:3])[CH3:2]
Reactant: CC(=O)O[C@H]1CC[C@@]2(C)C(=C(CBr)C[C@H]3[C@@H]4CC[C@H]([C@H](C)CCCC(C)C)[C@@]4(C)CC[C@@H]32)C1
Reactant: CCOCCNCCOCC
Solvent: ClCCl
Solvent: O
Product: CCOCCN(CCOCC)CC1=C2C[C@@H](OC(C)=O)CC[C@]2(C)[C@H]2CC[C@]3(C)[C@@H]([C@H](C)CCCC(C)C)CC[C@H]3[C@@H]2C1

Procedure:
A solution of 10 parts of 3β-acetoxy-6-(bromomethyl)cholest-5-ene and 20 parts of bis(ethoxyethyl)amine in 13 parts of dichloromethane is allowed to stand at room temperatures for 24 hours, whereupon 5 volumes of water is introduced and the oil which separates is extracted with diethyl ether. The extract is washed with water, dried over anhydrous sodium sulfate, and stripped of solvent by vacuum distillation to give 3β-acetoxy-6-[di(2-ethoxyethyl)aminomethyl]cholest-5-ene as the residue. The product, an oil, has the formula ##SPC9##
Reaction SMILES: [C:1]([C:5]1[N:6]=[C:7]([N:22]2[CH2:27][CH2:26][O:25][CH2:24][CH2:23]2)[C:8]2[N:13]=[N:12][N:11]([CH2:14][C:15]3[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=3[Cl:21])[C:9]=2[N:10]=1)([CH3:4])([CH3:3])[CH3:2].[C:28](C1N=C(Cl)C2N=NN(CC3C=CC=CC=3Cl)C=2N=1)(C)(C)C.Cl.N1CCC[C@H](O)C1>>[C:1]([C:5]1[N:6]=[C:7]([N:22]2[CH2:27][CH2:26][CH2:28][C@H:24]([OH:25])[CH2:23]2)[C:8]2[N:13]=[N:12][N:11]([CH2:14][C:15]3[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=3[Cl:21])[C:9]=2[N:10]=1)([CH3:2])([CH3:3])[CH3:4]
Reactant: CC(C)(C)c1nc(Cl)c2nnn(Cc3ccccc3Cl)c2n1
Reactant: CC(C)(C)c1nc(N2CCOCC2)c2nnn(Cc3ccccc3Cl)c2n1
Agent: Cl
Agent: O[C@H]1CCCNC1
Product: CC(C)(C)c1nc(N2CCC[C@H](O)C2)c2nnn(Cc3ccccc3Cl)c2n1

Procedure:
In analogy to the procedure described for the synthesis of 5-tert-butyl-3-(2-chloro-benzyl)-7-morpholin-4-yl-3H-[1,2,3]triazolo[4,5-d]pyrimidine (example 1, step c), the title compound was prepared from 5-tert-butyl-7-chloro-3-(2-chlorobenzyl)-3H-[1,2,3]triazolo[4,5-d]pyrimidine and (S)-piperidin-3-ol hydrochloride and isolated as light-yellow gum (13.3 mg, 70%). MS (m/e): 401.4 (MH+).
Reaction SMILES: [NH2:1][CH2:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]2[CH:10]=[CH:11][C:12](=[O:16])[N:13]([CH3:15])[CH:14]=2)=[C:5]([F:17])[CH:4]=1.[N:18]1[CH:23]=[CH:22][N:21]=[CH:20][C:19]=1[C:24]1[CH:32]=[CH:31][C:27]([C:28](O)=[O:29])=[CH:26][CH:25]=1.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.C(N(CC)C(C)C)(C)C>CN(C=O)C>[F:17][C:5]1[CH:4]=[C:3]([CH:8]=[CH:7][C:6]=1[C:9]1[CH:10]=[CH:11][C:12](=[O:16])[N:13]([CH3:15])[CH:14]=1)[CH2:2][NH:1][C:28](=[O:29])[C:27]1[CH:26]=[CH:25][C:24]([C:19]2[CH:20]=[N:21][CH:22]=[CH:23][N:18]=2)=[CH:32][CH:31]=1
Reactant: Cn1cc(-c2ccc(CN)cc2F)ccc1=O
Reactant: O=C(O)c1ccc(-c2cnccn2)cc1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: Cn1cc(-c2ccc(CNC(=O)c3ccc(-c4cnccn4)cc3)cc2F)ccc1=O
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a mixture of the 5-(4-(aminomethyl)-2-fluorophenyl)-1-methylpyridin-2(1H)-one 21-7 (obtained in Step 4), 4-(pyrazin-2-yl)benzoic acid 18-3 (5.0 mg, 0.025 mmol), and HATU (9.5 mg, 0.025 mmol) were added N,N-diisopropylethylamine (DIEA, 17 μL, 0.1 mmol) and DMF (0.5 mL). The solution was stirred overnight at room temperature and was subjected directly to reverse phase preparative HPLC to give N-(3-fluoro-4-(1-methyl-6-oxo-1,6-dihydropyridin-3-yl)benzyl)-4-(pyrazin-2-yl)benzamide 21 (2.5 mg). MS m/z 415.2 (M+1).
Reaction SMILES: [CH3:1][N:2]1[C:6]([CH2:7][O:8][C:9]2[CH:14]=[CH:13][CH:12]=[C:11]([C@H:15]([C:28]3[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=3)[NH:16][C:17]([O:19][C@@H:20]3[CH:25]4[CH2:26][CH2:27][N:22]([CH2:23][CH2:24]4)[CH2:21]3)=[O:18])[CH:10]=2)=[CH:5][C:4]([C:34]([OH:36])=[O:35])=[N:3]1.[O:37]1[CH2:41][CH2:40][O:39][CH:38]1[CH2:42][CH2:43][CH2:44]O.OCCOC1C=CC(C=O)=CC=1C>>[CH3:1][N:2]1[C:6]([CH2:7][O:8][C:9]2[CH:14]=[CH:13][CH:12]=[C:11]([C@H:15]([C:28]3[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=3)[NH:16][C:17]([O:19][C@@H:20]3[CH:25]4[CH2:26][CH2:27][N:22]([CH2:23][CH2:24]4)[CH2:21]3)=[O:18])[CH:10]=2)=[CH:5][C:4]([C:34]([O:36][CH2:44][CH2:43][CH2:42][CH:38]2[O:39][CH2:40][CH2:41][O:37]2)=[O:35])=[N:3]1
Reactant: OCCCC1OCCO1
Reactant: Cn1nc(C(=O)O)cc1COc1cccc([C@@H](NC(=O)O[C@H]2CN3CCC2CC3)c2ccccc2)c1
Agent: Cc1cc(C=O)ccc1OCCO
Product: Cn1nc(C(=O)OCCCC2OCCO2)cc1COc1cccc([C@@H](NC(=O)O[C@H]2CN3CCC2CC3)c2ccccc2)c1

Procedure:
The title compound was prepared as described in Example 1 Step 10 with 1-methyl-5((3-((S)-phenyl((((R)-quinuclidin-3-yloxy)carbonyl)amino)methyl)phenoxy)-methyl)-1H-pyrazole-3-carboxylic acid and 3(1,3-dioxolan-2-yl)propan-1-ol replacing 4-((3-((S)-phenyl((((R)-quinuclidin-3-yloxy)carbonyl)amino)methyl)phenoxy)methyl)-benzoic acid and 4-(2-hydroxyethoxy)-3-methylbenzaldehyde respectively.
Reaction SMILES: [N:1]1([C:7](Cl)=[O:8])[CH2:6][CH2:5][O:4][CH2:3][CH2:2]1.[NH2:10][CH2:11][CH2:12][CH2:13][CH2:14][N:15]1[C:23]2[CH:22]=[C:21]([CH3:24])[N:20]=[C:19]([NH2:25])[C:18]=2[N:17]=[C:16]1[CH2:26][O:27][CH2:28][CH3:29].C(N(CC)CC)C>C(Cl)(Cl)Cl>[NH2:25][C:19]1[C:18]2[N:17]=[C:16]([CH2:26][O:27][CH2:28][CH3:29])[N:15]([CH2:14][CH2:13][CH2:12][CH2:11][NH:10][C:7]([N:1]3[CH2:6][CH2:5][O:4][CH2:3][CH2:2]3)=[O:8])[C:23]=2[CH:22]=[C:21]([CH3:24])[N:20]=1
Reactant: O=C(Cl)N1CCOCC1
Reactant: CCOCc1nc2c(N)nc(C)cc2n1CCCCN
Solvent: ClC(Cl)Cl
Solvent: CCN(CC)CC
Product: CCOCc1nc2c(N)nc(C)cc2n1CCCCNC(=O)N1CCOCC1
Temperature: 25 °C
Reaction time: 4 h
Yield: 68 %

Procedure:
4-Morpholinecarbonyl chloride (202 μL, 1.73 mmol) was added to a solution of 1-(4-aminobutyl)-2-ethoxymethyl-6-methyl-1H-imidazo[4,5-c]pyridin-4-amine (0.435, 1.57 mmol) in a mixture of triethylamine (280 μL, 2.04 mmol) and chloroform (8 mL). The reaction mixture was stirred at ambient temperature for 4 hours then it was diluted with chloroform (20 mL) and washed with saturated sodium bicarbonate (10 mL). The organic layer was dried over magnesium sulfate and then concentrated under reduced pressure. The residue was purified by column chromatography (30 g of silica gel eluting with 1 L of 2% methanol in chloroform containing 0.5% triethylamine. The resulting glassy solid was triturated with acetonitrile to provide 0.417 g of N-{4-[4-amino-2-(ethoxymethyl)-6-methyl-1H-imidazo[4,5-c]pyridin-1-yl]butyl}morpholine-4-carboxamide as an off white powder, m.p. 156.5-159.5° C. Analysis: C19H30N6O3.0.20 HCl: %C, 57.37; %H, 7.65; %Cl, 1.78; %N, 21.13; Found: %C, 57.19; %H, 7.56; %Cl, 1.84; %N, 21.14. 1H NMR (300 MHz, CDCl3) δ6.51 (s, 1 H), 5.46 (bs, 2 H), 4.71 (s, 2 H), 4.45 (bs, 1 H), 4.17 (t, J=7.5 Hz, 2 H), 3.68 (t, J=4.9 Hz, 4 H), 3.57 (quartet, J=7.1 Hz, 2 H), 3.32 (m, 6 H), ), 2.49 (s, 3 H), 1.86 (quintet, J=7.5 Hz, 2 H), 1.58 (quintet, J=7.3 Hz, 2 H), 1.22 (t, J=7.2 Hz, 3 H); MS(CI) m/e 391 (M+H)
Reaction SMILES: Cl[S:2]([C:5]1[C:6]([F:15])=[CH:7][C:8]([F:14])=[C:9]([CH:13]=1)[C:10]([OH:12])=[O:11])(=[O:4])=[O:3].[C:16]([NH2:20])([CH3:19])([CH3:18])[CH3:17].CCN(C(C)C)C(C)C.ClC1C(S(NC)(=O)=O)=CC=C(Cl)C=1C(O)=O>>[CH3:17][C:16]([NH:20][S:2]([C:5]1[C:6]([F:15])=[CH:7][C:8]([F:14])=[C:9]([CH:13]=1)[C:10]([OH:12])=[O:11])(=[O:4])=[O:3])([CH3:19])[CH3:18]
Reactant: O=C(O)c1cc(S(=O)(=O)Cl)c(F)cc1F
Reactant: CC(C)(C)N
Agent: CNS(=O)(=O)c1ccc(Cl)c(C(=O)O)c1Cl
Solvent: CCN(C(C)C)C(C)C
Product: CC(C)(C)NS(=O)(=O)c1cc(C(=O)O)c(F)cc1F

Procedure:
Prepared from a mixture of 5-(chlorosulfonyl)-2,4-difluorobenzoic acid (200 mg, 0.78 mmol, 1 equiv), tert-butyl amine (98 mL, 0.94 mmol, 1.2 equiv) and DIEA (280 μL, 1.56 mmol, 2 equiv) following the general procedure for 2,6-dichloro-3-[(methylamino)sulfonyl]benzoic acid 880-1b. The crude reaction mixture was carried on without further purification.
Reaction SMILES: Cl.[CH3:2][O:3][C:4]1[CH:5]=[C:6]([C:12]2[C:13]([CH3:25])([CH3:24])[C:14](=[O:23])[N:15]([CH:17]3[CH2:22][CH2:21][NH:20][CH2:19][CH2:18]3)[N:16]=2)[CH:7]=[CH:8][C:9]=1[O:10][CH3:11].C(N(CC)CC)C.[C:33]([NH:40][CH2:41][C:42](O)=[O:43])([O:35][C:36]([CH3:39])([CH3:38])[CH3:37])=[O:34].Cl.CN(C)CCCN=C=NCC>C(Cl)Cl>[CH3:2][O:3][C:4]1[CH:5]=[C:6]([C:12]2[C:13]([CH3:25])([CH3:24])[C:14](=[O:23])[N:15]([CH:17]3[CH2:22][CH2:21][N:20]([C:42](=[O:43])[CH2:41][NH:40][C:33](=[O:34])[O:35][C:36]([CH3:37])([CH3:38])[CH3:39])[CH2:19][CH2:18]3)[N:16]=2)[CH:7]=[CH:8][C:9]=1[O:10][CH3:11]
Reactant: CC(C)(C)OC(=O)NCC(=O)O
Reactant: COc1ccc(C2=NN(C3CCNCC3)C(=O)C2(C)C)cc1OC
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: COc1ccc(C2=NN(C3CCN(C(=O)CNC(=O)OC(C)(C)C)CC3)C(=O)C2(C)C)cc1OC
Reaction time: 0.25 h

Procedure:
A mixture of 5 g of 5-(3,4-dimethoxyphenyl)-4,4-dimethyl-2-piperidin-4-yl-2,4-dihydro-3H-pyrazol-3-one hydrochloride (compound B1), 1.9 ml of triethylamine and 2.5 g of N-BOC-glycine in 25 ml of DCM is stirred until complete dissolution (about 15 min). 3.9 g of 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride is added and the resulting mixture is stirred at RT for 3 h. After washing with 1 M sodium carbonate, the organic layer is dried over magnesium sulphate and evaporated. The residue is purified by column chromatography [silica, ethyl acetate]. The title compound is crystallized from diethyl ether.
Reaction SMILES: B#B.[CH3:3][S:4]([O:7][CH2:8][CH2:9][CH2:10][C:11]1([CH3:21])[CH:17]2[O:18][C:14]([CH:19]=[CH2:20])([CH2:15][CH2:16]2)[CH2:13][O:12]1)(=[O:6])=[O:5].[OH-:22].[Na+].OO>O1CCCC1.O>[CH3:3][S:4]([O:7][CH2:8][CH2:9][CH2:10][C:11]1([CH3:21])[CH:17]2[O:18][C:14]([CH2:19][CH2:20][OH:22])([CH2:15][CH2:16]2)[CH2:13][O:12]1)(=[O:5])=[O:6]
Reactant: C=CC12CCC(O1)C(C)(CCCOS(C)(=O)=O)OC2
Reactant: [OH-]
Agent: B#B
Agent: OO
Agent: [Na+]
Solvent: C1CCOC1
Solvent: O
Product: CC1(CCCOS(C)(=O)=O)OCC2(CCO)CCC1O2
Temperature: 25 °C
Yield: 80 %

Procedure:
A mixture of diborane in tetrahydrofuran (1 ml, 1 mM) is added slowly to a mixture of (1RS,4SR,5RS)-4-(3-methanesulfonyloxypropyl)-4-methyl-1-vinyl-3,8-dioxabicyclo[3.2.1]octane (350 mg, 1.2 mM) and tetrahydrofuran (5 ml) at 0° C. under nitrogen and stirred for thirty minutes. The resulting mixture is allowed to warm to room temperature and stirred for an additional two hours. The mixture is cooled to 0° C. and 3 N sodium hydroxide (0.3 ml) is added followed by the addition of 30% hydrogen peroxide (0.3 ml). The resulting mixture is allowed to warm to room temperature and stirred for 2.5 hours. The mixture is then treated with water (10 ml) and extracted with ether (5×20 ml). The combined organic phases are dried (Na2SO4) and the solvent is removed in vacuo. The residue is purified by column chromatography on silica gel (30 g) with ether to give (1RS,4SR,5RS)-4-(3-methanesulfonyloxypropyl)-4-methyl-3,8-dioxabicyclo[3.2.1]octane-1-ethanol (275 mg, 80%) as a colorless oil.
Reaction SMILES: [Br:1][CH2:2][C:3]1[N:4]=[C:5]([C:19]2[CH:24]=[CH:23][C:22]([C:25]([F:28])([F:27])[F:26])=[CH:21][CH:20]=2)[S:6][C:7]=1[CH2:8][CH2:9][C:10]1[CH:15]=[CH:14][C:13]([O:16]C)=[C:12]([CH3:18])[CH:11]=1.C(=O)=O.CC(C)=O.B(Br)(Br)Br>C(Cl)Cl>[Br:1][CH2:2][C:3]1[N:4]=[C:5]([C:19]2[CH:24]=[CH:23][C:22]([C:25]([F:28])([F:27])[F:26])=[CH:21][CH:20]=2)[S:6][C:7]=1[CH2:8][CH2:9][C:10]1[CH:15]=[CH:14][C:13]([OH:16])=[C:12]([CH3:18])[CH:11]=1
Reactant: COc1ccc(CCc2sc(-c3ccc(C(F)(F)F)cc3)nc2CBr)cc1C
Agent: BrB(Br)Br
Agent: O=C=O
Solvent: CC(C)=O
Solvent: ClCCl
Product: Cc1cc(CCc2sc(-c3ccc(C(F)(F)F)cc3)nc2CBr)ccc1O
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a 50 ml round-bottom flask equipped with a magnetic stir-bar, an addition funnel and N2 inlet was added 4-(Bromomethyl)-5-[2-(4-methoxy-3-methylphenyl)ethyl]-2-[4-(trifluoromethyl)phenyl]-1,3-thiazole (468 mg, 1.0 mmoles, 1 eq) and dry CH2Cl2 (15 ml, 0.1M). The mixture was cooled to −78° C. (dry ice/acetone) after which boron tribromide (1M in CH2Cl2, 3 ml, 3.0 mmoles, 3 eq) was added dropwise over the course of 15 minutes. After the addition was complete, the cold bath was removed and the reaction was allowed to warm to room temperature and stirred for 1 hour. After this time, the reaction was cooled to 0° C. and quenched very carefully with water. Once the reaction was quenched, it was transferred to a separatory funnel where the phases were separated. The aqueous fraction was washed three times with CH2Cl2 and the combined organic fractions were dried over Na2SO4, filtered, concentrated in vacuo to yield a quantitative yield of the titled phenol. The product was used without purification.
Reaction SMILES: [Br:1][CH:2]1[CH2:8][CH2:7][CH2:6][CH2:5][NH:4][C:3]1=[O:9].[H-].[Na+].Br[CH2:13][C:14]1[CH:19]=[CH:18][C:17]([O:20][CH3:21])=[CH:16][CH:15]=1>O1CCCC1>[Br:1][CH:2]1[CH2:8][CH2:7][CH2:6][CH2:5][N:4]([CH2:13][C:14]2[CH:19]=[CH:18][C:17]([O:20][CH3:21])=[CH:16][CH:15]=2)[C:3]1=[O:9]
Reactant: O=C1NCCCCC1Br
Reactant: COc1ccc(CBr)cc1
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: COc1ccc(CN2CCCCC(Br)C2=O)cc1
Temperature: 0 °C
Reaction time: 1 h
Yield: 61.7 %

Procedure:
To a solution of 3-bromoazepan-2-one (1.398 g, 7.28 mmol) in tetrahydrofuran (10 ml), was added sodium hydride (0.48 g, 12.00 mmol) at 0° C. The mixture was stirred at 0° C. for 1 hour, and 1-(bromomethyl)-4-methoxybenzene (1.610 g, 8.01 mmol) was added. The mixture was warmed to room temperature over the span of 2 hours. The reaction was quenched with saturated aqueous ammonium chloride and extracted with ethyl acetate. The organic phase was washed with brine, dried and concentrated to afford crude product, which was purified by chromatography on silica gel (ethyl acetate/hexanes=2/8) to afford 3-bromo-1-(4-methoxybenzyl)azepan-2-one (1.403 g, 4.49 mmol, 61.7% yield). MS ESI: [M+H]+ m/z 313.2.
Reaction SMILES: [Br:1]N1C(C)(C)C(=O)N(Br)C1=O.C1([C@H](N)C)C=CC=CC=1.[C@H:21]1([C:27]([OH:29])=[O:28])[CH2:26][CH2:25][CH:24]=[CH:23][CH2:22]1.C(OCC)(=O)C.S([O-])([O-])(=O)=S.[Na+].[Na+]>C(#N)C>[Br:1][C@@H:24]1[C@@H:25]2[CH2:26][C@@H:21]([C:27](=[O:29])[O:28]2)[CH2:22][CH2:23]1
Reactant: CC1(C)C(=O)N(Br)C(=O)N1Br
Reactant: O=C(O)[C@@H]1CC=CCC1
Agent: C[C@@H](N)c1ccccc1
Agent: O=S([O-])([O-])=S
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CC#N
Product: O=C1O[C@H]2C[C@@H]1CC[C@@H]2Br
Temperature: 25 °C
Reaction time: 2 h
Yield: 83.3 %

Procedure:
Under a nitrogen atmosphere, 1,3-dibromo-5,5-dimethylhydantoin (4) (11.6 g, 40.6 mol) was added to a solution of (S)-3-cyclohexene-1-carboxylic acid (R)-α-phenylethylamine salt (2-b) (10.0 g, 40.4 mmol) in acetonitrile (25 ml) that had been cooled on ice. The temperature of the reaction solution was increased to room temperature, and the reaction solution was then stirred for 2 hours. Thereafter, ethyl acetate (50 ml) and a 10% sodium thiosulfate aqueous solution (40 ml) were added to the reaction solution to separate it. The aqueous layer was extracted with ethyl acetate (50 ml), and the organic layers were gathered and were then washed with a 5% citric acid aqueous solution (40 ml). The resulting organic layer was washed with saturated saline (30 ml) and was then concentrated under reduced pressure. Thereafter, isopropyl alcohol (50 ml) was added to the residue, and the solvent was then concentrated under reduced pressure, so that the volume became 30 ml. The obtained slurry liquid was cooled to −10° C., and a precipitate was filtered and was then washed with ice-cooled isopropyl alcohol (10 ml) to obtain the title compound (6.9 g, yield: 84%).