Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([C:3]1[N:8]=[C:7]2[N:9]([CH2:14][C:15]3[CH:20]=[CH:19][C:18]([C:21]4[CH:26]=[CH:25][CH:24]=[CH:23][C:22]=4[C:27]4[NH:31][N:30]=[N:29][N:28]=4)=[CH:17][CH:16]=3)[C:10]([CH2:12][CH3:13])=[N:11][C:6]2=[C:5]([CH3:32])[CH:4]=1)#[N:2].C[Sn]([N:37]=[N+:38]=[N-:39])(C)C.C1(C)C=CC=CC=1>CN(C=O)C>[CH2:12]([C:10]1[N:9]([CH2:14][C:15]2[CH:16]=[CH:17][C:18]([C:21]3[CH:26]=[CH:25][CH:24]=[CH:23][C:22]=3[C:27]3[NH:31][N:30]=[N:29][N:28]=3)=[CH:19][CH:20]=2)[C:7]2=[N:8][C:3]([C:1]3[NH:39][N:38]=[N:37][N:2]=3)=[CH:4][C:5]([CH3:32])=[C:6]2[N:11]=1)[CH3:13]
Reactant: C[Sn](C)(C)N=[N+]=[N-]
Reactant: CCc1nc2c(C)cc(C#N)nc2n1Cc1ccc(-c2ccccc2-c2nnn[nH]2)cc1
Solvent: Cc1ccccc1
Solvent: CN(C)C=O
Product: CCc1nc2c(C)cc(-c3nnn[nH]3)nc2n1Cc1ccc(-c2ccccc2-c2nnn[nH]2)cc1
Temperature: 110 °C
Yield: 79 %

Procedure:
A mixture of 5-Cyano-2-ethyl-7-methyl-3-(2'-(tetrazol-5-yl)biphen-4-yl)methyl-3H-imidazo[4,5-b]pyridine (54 mg), trimethylstannyl azide (79 mg), toluene (5 mL), and DMF (1 mL) was heated to 110° C. for 24 hour. Concentration and purification (SiO2, 70/30/1CH2Cl2 /MeOH/NH4OH) gave 47 mg solid. 1H NMR (300 MHz, CD3OD) δ 7.93 (s, 1H), 7.56-7.38 (m, 4H), 7.14-7.05 (AB quartet, 4H), 5.61 (s, 2H), 2.86 (q, H, J=7.5 Hz), 2.71 (s, 3H), 1.27 (t, 3H, J=7.5 Hz)
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:9]=[C:10]([N:18]3[CH:22]=[CH:21][N:20]=[C:19]3[S:23]([CH3:26])(=[O:25])=[O:24])[O:11][C:12]=2[CH2:13][CH2:14][C:15]([OH:17])=O)=[CH:4][CH:3]=1.ON1C2N=CC=CC=2N=N1.C(N=C=NCCCN(C)C)C.[CH3:48][N:49]1[CH2:54][CH2:53][CH:52]([CH2:55][N:56]2[CH2:61][CH2:60][NH:59][CH2:58][CH2:57]2)[CH2:51][CH2:50]1>O.CN(C)C=O>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[N:9]=[C:10]([N:18]3[CH:22]=[CH:21][N:20]=[C:19]3[S:23]([CH3:26])(=[O:25])=[O:24])[O:11][C:12]=2[CH2:13][CH2:14][C:15]([N:59]2[CH2:58][CH2:57][N:56]([CH2:55][CH:52]3[CH2:53][CH2:54][N:49]([CH3:48])[CH2:50][CH2:51]3)[CH2:61][CH2:60]2)=[O:17])=[CH:6][CH:7]=1
Reactant: CN1CCC(CN2CCNCC2)CC1
Reactant: CS(=O)(=O)c1nccn1-c1nc(-c2ccc(Cl)cc2)c(CCC(=O)O)o1
Agent: CCN=C=NCCCN(C)C
Agent: On1nnc2cccnc21
Solvent: O
Solvent: CN(C)C=O
Product: CN1CCC(CN2CCN(C(=O)CCc3oc(-n4ccnc4S(C)(=O)=O)nc3-c3ccc(Cl)cc3)CC2)CC1
Temperature: 25 °C
Reaction time: 8 h
Yield: 89.5 %

Procedure:
A mixture of 3-{4-(4-chlorophenyl)-2-[2-(methylsulfonyl)-1H-imidazol-1-yl]-5-oxazolyl}propionic acid (50 mg), 1-hydroxy-7-aza-1H-1,2,3-benzotriazole (41 mg), 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide (46 mg), 4-[(1-methyl-4-piperidinyl)methyl]piperazine (60 mg) and N,N-dimethylformamide (0.5 ml) was stirred overnight at room temperature. The reaction mixture was poured into water, and the mixture was extracted with ethyl acetate. The ethyl acetate layer was concentrated, introduced into preparative HPLC and purified. Ethyl acetate was added to the obtained oil and the mixture was washed with saturated aqueous sodium hydrogen carbonate. A 4N hydrochloric acid ethyl acetate solution was added to the ethyl acetate layer and the mixture was concentrated to give 1-(3-{4-(4-chlorophenyl)-2-[2-(methylsulfonyl)-1H-imidazol-1-yl]-5-oxazolyl}propanoyl)-4-[(1-methyl-4-piperidinyl)methyl]piperazine 3 hydrochloric acid (65.0 mg, yield 66%).
Reaction SMILES: [NH2:1][C:2]1[N:7]=[C:6]([Cl:8])[C:5]([Cl:9])=[N:4][C:3]=1Cl.O.O.O.O.O.O.O.O.O.[S-2:20].[Na+].[Na+]>CC(O)C>[NH2:1][C:2]1[C:3]([SH:20])=[N:4][C:5]([Cl:9])=[C:6]([Cl:8])[N:7]=1
Reactant: Nc1nc(Cl)c(Cl)nc1Cl
Reactant: [S-2]
Agent: [Na+]
Solvent: CC(C)O
Solvent: O
Product: Nc1nc(Cl)c(Cl)nc1S
Yield: 58 %

Procedure:
A mixture of 19.9 g. (0.1 mol.) of aminotrichloropyrazine, 25.2 g. (0.105 mol.) of sodium sulfide nonahydrate in 500 ml. of 2-propanol was heated to boiling under reflux for 5 hours. After cooling, the reaction mixture was filtered. The filtrate was neutralized with hydrochloric acid and filtered. The solid was washed with water and dried to give 11.4 g. (58% yield) of product.
Reaction SMILES: [CH:1]1([CH:4]([C:11]2[CH:16]=[CH:15][N:14]=[C:13]([O:17]C)[CH:12]=2)[CH2:5][C:6]([O:8][CH2:9][CH3:10])=[O:7])[CH2:3][CH2:2]1.[Cl-].[NH+]1C=CC=CC=1.C(OCC)(=O)C>CN(C=O)C>[CH:1]1([CH:4]([C:11]2[CH:16]=[CH:15][N:14]=[C:13]([OH:17])[CH:12]=2)[CH2:5][C:6]([O:8][CH2:9][CH3:10])=[O:7])[CH2:3][CH2:2]1
Reactant: CCOC(=O)CC(c1ccnc(OC)c1)C1CC1
Agent: [Cl-]
Agent: c1cc[nH+]cc1
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: CCOC(=O)CC(c1ccnc(O)c1)C1CC1
Temperature: 130 °C
Reaction time: 0.25 h
Yield: 91.7 %

Procedure:
Under a nitrogen atmosphere, to a solution of ethyl 3-cyclopropyl-3-(2-methoxypyridin-4-yl)propanoate (4.17 g) in DMF (10 mL) was added pyridinium chloride (19.3 g), and the mixture was stirred at 130° C. for 15 min. Ethyl acetate was added to the reaction mixture at 0° C., and the resulting white precipitate was filtered off. The solvent in the filtrate was evaporated under reduced pressure, and the residue was purified by silica gel column chromatography (methanol/ethyl acetate) to give the title compound (3.61 g) as a yellow oil.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]2[CH2:14][C:13](=[O:15])[O:12][C:10](=O)[CH2:9]2)=[CH:4][CH:3]=1.[Cl:16][C:17]1[CH:25]=[C:21]([C:22]([NH2:24])=[O:23])[C:20]([NH2:26])=[CH:19][CH:18]=1>>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([CH:8]([CH2:9][C:10]2[N:24]=[C:22]([OH:23])[C:21]3[C:20](=[CH:19][CH:18]=[C:17]([Cl:16])[CH:25]=3)[N:26]=2)[CH2:14][C:13]([OH:12])=[O:15])=[CH:6][CH:7]=1
Reactant: NC(=O)c1cc(Cl)ccc1N
Reactant: O=C1CC(c2ccc(Cl)cc2)CC(=O)O1
Product: O=C(O)CC(Cc1nc(O)c2cc(Cl)ccc2n1)c1ccc(Cl)cc1

Procedure:
By a procedure similar to that of 1.133, starting from 3-(4-chlorophenyl)glutaric anhydride and 5-chloroanthranilamide, 3-(4-chlorophenyl)-4-(6-chloro-4-hydroxy-2-quinazolinyl)butanoic acid was obtained as colourless solid.
Reaction SMILES: [H-].[Na+].[CH3:3][N:4]1[CH2:9][CH2:8][C:7]([C:11]#[CH:12])([OH:10])[CH2:6][CH2:5]1.F[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=1[N+:20]([O-:22])=[O:21].[ClH:23]>CS(C)=O.O>[ClH:23].[CH3:3][N:4]1[CH2:9][CH2:8][C:7]([C:11]#[CH:12])([O:10][C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=2[N+:20]([O-:22])=[O:21])[CH2:6][CH2:5]1
Reactant: O=[N+]([O-])c1ccccc1F
Reactant: C#CC1(O)CCN(C)CC1
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: CS(C)=O
Solvent: O
Product: C#CC1(Oc2ccccc2[N+](=O)[O-])CCN(C)CC1
Temperature: 25 °C
Reaction time: 0.08 h
Yield: 54.8 %

Procedure:
A suspension of 0.58 g of sodium hydride (59% in oil; washed three times with hexanes) in 15 ml of dimethylsulfoxide was heated at 80°-90° for 0.5 hour under nitrogen. The resultant solution was cooled in an ice bath and 2.0 g of 1-methyl-4-ethynyl-4-hydroxypiperidine was added. After five min, the mixture was cooled to 0° and a solution of 2.4 g of 2-fluoronitrobenzene was added dropwise. The mixture was stirred 1 hr at 0°, 3 hrs at room temperature, poured into water, extracted twice with ether, washed with saturated sodium chloride solution and dried over anhydrous potassium carbonate. Filtration followed by evaporation of the solvent provided an oil, which was treated with ethereal hydrogen chloride to yield 2.34 g (54.8%) of product.
Reaction SMILES: [CH2:1]([O:8][C:9](=[O:19])[NH:10][C:11]1[CH:16]=[CH:15][C:14]([F:17])=[CH:13][C:12]=1[F:18])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[O:20]1CCC[CH2:21]1.C([Li])CCC.CN(C)C=O>O>[CH2:1]([O:8][C:9](=[O:19])[NH:10][C:11]1[CH:16]=[CH:15][C:14]([F:17])=[C:13]([CH:21]=[O:20])[C:12]=1[F:18])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: O=C(Nc1ccc(F)cc1F)OCc1ccccc1
Reactant: C1CCOC1
Agent: [Li]CCCC
Solvent: O
Solvent: CN(C)C=O
Product: O=Cc1c(F)ccc(NC(=O)OCc2ccccc2)c1F
Temperature: -78 °C
Reaction time: 8 h
Yield: 71 %

Procedure:
Into a round bottom flask was added (2,4-difluoro-phenyl)-carbamic acid benzyl ester (613, 3.83 g, 14.5 mmol) in tetrahydrofuran (148 mL, 1.82 mol). The solution was chilled to −78° C. and n-butyllithium (1.60 M in hexane, 19.1 mL, 30.0 mmol) was added over 30 minutes followed by the addition of, N,N-dimethylformamide (1.12 mL, 14.5 mol). The reaction mixture was allowed to warm to ambient temperature and was stirred overnight. The reaction mixture was poured into water and extracted with ethyl acetate. The organic layer was washed with brine, dried over sodium sulfate, concentrated and crystallized from ether to give compound 614 (3.0 g, 71%).
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[NH:8][C:9]1[CH:23]=[CH:22][C:12]([C:13]([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=2[CH3:21])=[O:14])=[C:11]([Cl:24])[CH:10]=1.[C:25](=O)([O:36]C1C=CC([N+]([O-])=O)=CC=1)[O:26][CH2:27][O:28][C:29](=[O:35])[CH2:30][CH2:31][CH2:32][CH2:33][CH3:34].ON1C2C=CC=CC=2N=N1.C(N(C(C)C)C(C)C)C>CN(C=O)C>[Cl:24][C:11]1[CH:10]=[C:9]([NH:8][C:3]2[CH:4]=[CH:5][CH:6]=[CH:7][C:2]=2[NH:1][C:25](=[O:36])[O:26][CH2:27][O:28][C:29](=[O:35])[CH2:30][CH2:31][CH2:32][CH2:33][CH3:34])[CH:23]=[CH:22][C:12]=1[C:13](=[O:14])[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=1[CH3:21]
Reactant: CCCCCC(=O)OCOC(=O)Oc1ccc([N+](=O)[O-])cc1
Reactant: Cc1ccccc1C(=O)c1ccc(Nc2ccccc2N)cc1Cl
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: CCCCCC(=O)OCOC(=O)Nc1ccccc1Nc1ccc(C(=O)c2ccccc2C)c(Cl)c1
Temperature: 25 °C
Reaction time: 72 h

Procedure:
A solution of 4-(2-aminophenylamino)-2-chloro-2′-methylbenzophenone (305 mg, 1.0 mmol) and hexanoyloxymethyl 4-nitrophenyl carbonate (Compound 207) (3.3 g, 10 mmol) in DMF (50 ml) was added 1-hydroxybenzotriazole (270 mg, 2.0 mmol) followed by N-ethyl di-iso-propylamine (0.18 ml, 1.05 mmol). The reaction mixture was stirred at room temperature. After 72 hours, the reaction mixture was poured into ice/water and extracted with diethylether. The etheral extracts were washed with a saturated sodium carbonate solution, water, and brine and dried over anhydrous sodium sulphate. Filtration and concentration in vacuo afforded the crude product. This was further purified by chromatography using Et2O/hexane 2:1 as eluent.
Reaction SMILES: [NH2:1][CH2:2][CH2:3][N:4]1[CH2:9][CH2:8][CH:7]([N:10]2[C:18]3[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=3)[CH2:12][CH2:11]2)[CH2:6][CH2:5]1.[Cl:19][C:20]1[CH:25]=[CH:24][C:23]([S:26](Cl)(=[O:28])=[O:27])=[CH:22][CH:21]=1.O>C(Cl)(Cl)Cl>[Cl:19][C:20]1[CH:25]=[CH:24][C:23]([S:26]([NH:1][CH2:2][CH2:3][N:4]2[CH2:9][CH2:8][CH:7]([N:10]3[C:18]4[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=4)[CH2:12][CH2:11]3)[CH2:6][CH2:5]2)(=[O:28])=[O:27])=[CH:22][CH:21]=1
Reactant: NCCN1CCC(N2CCc3ccccc32)CC1
Reactant: O=S(=O)(Cl)c1ccc(Cl)cc1
Solvent: O
Solvent: ClC(Cl)Cl
Product: O=S(=O)(NCCN1CCC(N2CCc3ccccc32)CC1)c1ccc(Cl)cc1
Yield: 69.4 %

Procedure:
1-[1-(2-Aminoethyl)piperidin-4-yl]indoline (113 mg) was dissolved in chloroform (3 ml). Under ice cooling, 4-chlorobenzenesulfonyl chloride (97 mg) was added thereto and the resultant mixture was stirred for 6 hr. After adding water, the reaction solution was extracted with chloroform. The organic layer was washed with brine and dried over magnesium sulfate. After evaporating the solvent, the resulting residue (205 mg) was purified by NH-silica gel column chromatography (methanol/methylene chloride system) to give the title compound (134 mg) as an oil.
Reaction SMILES: [Cl:1][C:2]1[N:7]=[C:6](Cl)[CH:5]=[CH:4][N:3]=1.[NH2:9][C:10]1[CH:19]=[CH:18][CH:17]=[CH:16][C:11]=1[C:12]([O:14][CH3:15])=[O:13].N1C(C)=CC=CC=1C>C(O)CCC>[CH3:18][CH2:19][CH2:10][CH:11]([CH3:16])[CH3:12].[Cl:1][C:2]1[N:7]=[C:6]([NH:9][C:10]2[CH:19]=[CH:18][CH:17]=[CH:16][C:11]=2[C:12]([O:14][CH3:15])=[O:13])[CH:5]=[CH:4][N:3]=1
Reactant: Clc1ccnc(Cl)n1
Reactant: COC(=O)c1ccccc1N
Solvent: Cc1cccc(C)n1
Solvent: CCCCO
Product: CCCC(C)C
Product: COC(=O)c1ccccc1Nc1ccnc(Cl)n1
Temperature: 120 °C

Procedure:
2,4-Dichloropyrimidine (596 mg, 4 mmol), methyl 2-aminobenzoate (517 ml, 4 mmol) and 2,6-lutidine (465 ml, 4 mmol) were dissolved in n-butanol (20 ml) with stirring. The reaction mixture was heated to 120° C. for 24 hours, allowed to cool to ambient temperature and evaporated onto silica (3 ml). The residue was purified by column chromatography eluting with EtOAc (0–20%): isohexane to give the title product as a colourless solid on evaporation (137 mg, 13%). NMR (CDCl3, 300 MHz): 3.97 (s, 3H), 6.63 (d, 1H), 7.09 (t, 1H) 7.61 (m, 1H), 8.05 (d, 1H), 8.19 (d, 1H), 8.74 (d, 1H); m/z: (ES+) 264.3 (MH+).
Reaction SMILES: C(=O)([O-])[O-].[Cs+].[Cs+].[CH3:7][C:8]1[C:16]2[C:11](=[N:12][CH:13]=[N:14][C:15]=2[NH2:17])[NH:10][N:9]=1.[Cl:18][C:19]1[C:20]([C:41]#[N:42])=[C:21]([C:30]2[CH:31]=[CH:32][C:33]([C:36]([N:38]([CH3:40])[CH3:39])=[O:37])=[N:34][CH:35]=2)[C:22]([O:28][CH3:29])=[C:23]([CH:25](Cl)[CH3:26])[CH:24]=1>CN(C)C=O.CCOC(C)=O>[NH2:17][C:15]1[N:14]=[CH:13][N:12]=[C:11]2[N:10]([CH:25]([C:23]3[C:22]([O:28][CH3:29])=[C:21]([C:30]4[CH:31]=[CH:32][C:33]([C:36]([N:38]([CH3:39])[CH3:40])=[O:37])=[N:34][CH:35]=4)[C:20]([C:41]#[N:42])=[C:19]([Cl:18])[CH:24]=3)[CH3:26])[N:9]=[C:8]([CH3:7])[C:16]=12
Reactant: COc1c(C(C)Cl)cc(Cl)c(C#N)c1-c1ccc(C(=O)N(C)C)nc1
Reactant: Cc1n[nH]c2ncnc(N)c12
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: COc1c(C(C)n2nc(C)c3c(N)ncnc32)cc(Cl)c(C#N)c1-c1ccc(C(=O)N(C)C)nc1
Temperature: 80 °C
Reaction time: 3 h
Yield: 84.9 %

Procedure:
Cesium carbonate (3000 mg, 10 mmol) was added to a mixture of 3-methyl-1H-pyrazolo[3,4-d]pyrimidin-4-amine (1100 mg, 7.1 mmol) and 5-[3-chloro-5-(1-chloroethyl)-2-cyano-6-methoxyphenyl]-N,N-dimethylpyridine-2-carboxamide (1.8 g, 4.8 mmol) in N,N-dimethylformamide (50 mL). The reaction was stirred at 80° C. for 3 hrs and was allowed to cool to room temperature. The reaction was diluted with EtOAc, washed with water, brine, dried over Na2SO4, filtered and concentrated to give the crude product. This was purified by FCC on silica gel eluting (hexanes/10% EtOH in EtOAc, 0-100%) gradient to give the title compound as light yellow oil (2.0 g, 80%). LCMS calculated for C24H24ClN8O2 (M+H)+: m/z=491.1; found: 491.2. NMR (400 MHz, CD3OD) δ 8.74 (d, J=1.4 Hz, 1H), 8.15 (d, J=2.2 Hz, 1H), 8.13 (s, 1H), 7.77 (d, J=8.1 Hz, 1H), 7.74 (s, 1H), 6.43 (q, J=7.0 Hz, 1H), 3.32 (s, 3H), 3.16 (s, 3H), 3.07 (s, 3H), 2.64 (s, 3H), 1.89 (d, J=7.1 Hz, 3H).
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]2[C:13](=[CH:14][C:15]=1[F:16])[CH:12]1[CH2:17][CH:10]([CH2:11]1)[N:9]1[C:5]2=[N:6][C:7]([C:18]([NH2:20])=[O:19])=[CH:8]1.Br[C:22]1[CH:23]=[C:24]2[C:33](=[CH:34][C:35]=1[F:36])[CH:32]1[CH2:37][CH:30]([CH2:31]1)[N:29]1[C:25]2=[N:26][C:27]([C:42]([NH2:44])=[O:43])=[C:28]1[C:38]([NH:40][CH3:41])=[O:39].[CH3:45][C:46]([OH:51])([C:49]#[CH:50])[CH2:47][OH:48]>>[OH:51][C:46]([CH3:45])([CH2:47][OH:48])[C:49]#[C:50][C:22]1[CH:23]=[C:24]2[C:33](=[CH:34][C:35]=1[F:36])[CH:32]1[CH2:37][CH:30]([CH2:31]1)[N:29]1[C:25]2=[N:26][C:27]([C:42]([NH2:44])=[O:43])=[C:28]1[C:38]([NH:40][CH3:41])=[O:39].[OH:51][C:46]([CH3:45])([CH2:47][OH:48])[C:49]#[C:50][C:2]1[CH:3]=[C:4]2[C:13](=[CH:14][C:15]=1[F:16])[CH:12]1[CH2:17][CH:10]([CH2:11]1)[N:9]1[C:5]2=[N:6][C:7]([C:18]([NH2:20])=[O:19])=[CH:8]1
Reactant: C#CC(C)(O)CO
Reactant: CNC(=O)c1c(C(N)=O)nc2n1C1CC(C1)c1cc(F)c(Br)cc1-2
Reactant: NC(=O)c1cn2c(n1)-c1cc(Br)c(F)cc1C1CC2C1
Product: CC(O)(C#Cc1cc2c(cc1F)C1CC(C1)n1cc(C(N)=O)nc1-2)CO
Product: CNC(=O)c1c(C(N)=O)nc2n1C1CC(C1)c1cc(F)c(C#CC(C)(O)CO)cc1-2

Procedure:
A mixture of 9-bromo-10-fluoro-2,5-diazatetracyclo[11.1.1.0[2,6].0[7,12]]pentadeca-3,5,7,9,11-pentaene-4-carboxamide and 9-bromo-10-fluoro-3-N-methyl-2,5-diazatetracyclo[11.1.1.0[2,6].0[7,12]]pentadeca-3,5,7,9,11-pentaene-3,4-dicarboxamide (125 mg) was reacted with 2-methylbut-3-yne-1,2-diol similar to as described in Procedure E to afford 25.2 mg of (±) 9-(3,4-dihydroxy-3-methylbut-1-yn-1-yl)-10-fluoro-3-N-methyl-2,5-diazatetracyclo[11.1.1.0[2,6].0[7,12]]pentadeca-3,5,7,9,11-pentaene-3,4-dicarboxamide [MS (Q1) 413 (M)+, 1H NMR (400 MHz, DMSO) δ 10.56 (q, J=4.6 Hz, 1H), 8.83 (d, J=7.5 Hz, 1H), 8.24 (s, 1H), 7.75 (s, 1H), 7.29 (d, J=10.0 Hz, 1H), 6.16-6.02 (m, 1H), 5.43 (s, 1H), 4.99 (t, J=6.1 Hz, 1H), 3.74-3.60 (m, 1H), 3.54-3.37 (m, 2H), 3.20-3.02 (m, 2H), 2.78 (d, J=4.5 Hz, 3H), 1.76-1.62 (m, 2H), 1.44 (s, 3H)] and 14.3 mg of (±) 9-(3,4-dihydroxy-3-methylbut-1-yn-1-yl)-10-fluoro-2,5 diazatetracyclo[11.1.1.0[2,6].0[7,12]]pentadeca-3,5,7,9,11-pentaene-4-carboxamide [MS (Q1) 356 (M)+. 1H NMR (400 MHz, DMSO) δ 8.65 (d, J=7.6 Hz, 1H), 7.82 (s, 1H), 7.51 (s, 1H), 7.27 (d, J=10.2 Hz, 1H), 7.09 (s, 1H), 5.45 (s, 1H), 5.01 (s, 1H), 4.91 (q, J=10.6, 1H), 3.75-3.67 (m, 1H), 3.44 (q, J=10.6 Hz, 2H), 3.14-3.03 (m, 2H), 1.68 (d, J=12.2 Hz, 2H), 1.43 (s, 3H).] following reverse phase hplc purification.
Reaction SMILES: [OH-].[Na+].Cl[C:4]([O:6][CH2:7][CH3:8])=[O:5].O.[NH2:10][CH2:11][C@H:12]([OH:14])[CH3:13]>O1CCOCC1>[CH2:7]([O:6][C:4]([NH:10][CH2:11][C@H:12]([OH:14])[CH3:13])=[O:5])[CH3:8]
Reactant: C[C@@H](O)CN
Reactant: CCOC(=O)Cl
Agent: [Na+]
Agent: [OH-]
Solvent: C1COCCO1
Solvent: O
Product: CCOC(=O)NC[C@@H](C)O
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
In an amount of 246 mg of (R)-1-amino-2-propanol was dissolved in 5 ml of 1,4-dioxane, added with 722 ml of 5 N aqueous sodium hydroxide, then added with 345 μl of ethyl chloroformate, and stirred at room temperature for 30 minutes. The reaction mixture was added with water, and extracted with ethyl acetate, and the organic layer was dried over anhydrous magnesium sulfate, and then filtered. The filtrate was concentrated under reduced pressure to obtain 465 mg of (R)-1-ethoxycarbonylamino-2-propanol. Physicochemical Properties of this Compound
Reaction SMILES: C[O:2][C:3]([C:5]1[C:6]([O:22][CH3:23])=[N:7][C:8]([C:12]2[C:17]([CH2:18][CH3:19])=[CH:16][CH:15]=[CH:14][C:13]=2[CH2:20][CH3:21])=[N:9][C:10]=1[CH3:11])=O.[CH2:24]([Mg]Cl)[CH2:25][CH3:26].[CH2:29]1[CH2:33][O:32][CH2:31][CH2:30]1>>[CH2:20]([C:13]1[CH:14]=[CH:15][CH:16]=[C:17]([CH2:18][CH3:19])[C:12]=1[C:8]1[N:7]=[C:6]([O:22][CH3:23])[C:5]([C:3]([OH:2])([CH2:30][CH2:29][CH3:33])[CH2:24][CH2:25][CH3:26])=[C:10]([CH3:11])[N:9]=1)[CH3:21].[CH2:20]([C:13]1[CH:14]=[CH:15][CH:16]=[C:17]([CH2:18][CH3:19])[C:12]=1[C:8]1[N:7]=[C:6]([O:22][CH3:23])[C:5]([CH:31]([OH:32])[CH2:30][CH2:29][CH3:33])=[C:10]([CH3:11])[N:9]=1)[CH3:21]
Reactant: CCc1cccc(CC)c1-c1nc(C)c(C(=O)OC)c(OC)n1
Reactant: CCC[Mg]Cl
Reactant: C1CCOC1
Product: CCCC(O)(CCC)c1c(C)nc(-c2c(CC)cccc2CC)nc1OC
Product: CCCC(O)c1c(C)nc(-c2c(CC)cccc2CC)nc1OC
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a solution of 2-(2,6-diethyl-phenyl)-4-methoxy-6-methyl-pyrimidine-5-carboxylic acid methyl ester (3.3 g, 0.01 mol) at 0° C. in dry THF (50 mL) under nitrogen with magnetic stirring is added n-propyl magnesium chloride (26 mL, 2.0 M, 0.05 mol) in dropwise fashion. The reaction mixture is allowed to warm to room temperature and stirred for 2 h. The reaction mixture is quenched with a saturated aqueous NH4Cl solution (20 mL) and extracted with DCM (100 mL). The DCM layer is dried over sodium sulfate, filtered and evaporated to obtain a residue. Purification by chromatography over silica gel eluting with 10% EtOAc-hexanes affords the title compound as a colorless oil and 1-[2-(2,6-diethylphenyl)-4-methoxy-6-methylpyrimidin-5-yl]butan-1-ol as a colorless oil. Title compound 1H NMR (300 MHz, CDCl3): δ 7.23-7.29 (m, 1H), 7.13 (d, J=9 Hz, 2H), 3.95 (s, 3H), 2.72 (s, 3H), 2.41 (q, J=7.5 Hz, 4H), 2.18-2.30 (m, 2H), 1.66-1.81 (m, 2H), 1.42-1.54 (m, 2H), 1.05-1.18 (m, 8H), 0.91 (t, J=7.2 Hz, 6H); LC-MS found 371 (MH+). 1-[2-(2,6-Diethylphenyl)-4-methoxy-6-methylpyrimidin-5-yl]butan-1-ol NMR (300 MHz, CDCl3): δ 7.23-7.28 (m, 1H), 7.1 (d, J=9 Hz, 2H), 4.81-5.11 (m, 1H), 4.01(s, 3H), 2.45 (s, 3H), 2.55 (q, J=7.5 Hz, 4H), 1.88-2.00 (m, 1H), 1.30-1.81 (m, 4H), 1.10 (q, J=7.8, 4.8 Hz, 6H), 0.91 (t, J=7.2 Hz, 6H); LC-MS found 328 (MH+).
Reaction SMILES: Cl[C:2]1[N:25]=[C:5]2[C:6]([C:10]3[CH:15]=[C:14]([S:16]([CH3:19])(=[O:18])=[O:17])[CH:13]=[CH:12][C:11]=3[O:20][CH2:21][CH:22]([F:24])[F:23])=[CH:7][CH:8]=[CH:9][N:4]2[N:3]=1.[C:26]([O:30][C:31]([N:33]1[CH2:39][CH2:38][C:37]2[CH:40]=[CH:41][C:42]([NH2:44])=[CH:43][C:36]=2[CH2:35][CH2:34]1)=[O:32])([CH3:29])([CH3:28])[CH3:27]>>[C:26]([O:30][C:31]([N:33]1[CH2:39][CH2:38][C:37]2[CH:40]=[CH:41][C:42]([NH:44][C:2]3[N:25]=[C:5]4[C:6]([C:10]5[CH:15]=[C:14]([S:16]([CH3:19])(=[O:18])=[O:17])[CH:13]=[CH:12][C:11]=5[O:20][CH2:21][CH:22]([F:24])[F:23])=[CH:7][CH:8]=[CH:9][N:4]4[N:3]=3)=[CH:43][C:36]=2[CH2:35][CH2:34]1)=[O:32])([CH3:29])([CH3:27])[CH3:28]
Reactant: CC(C)(C)OC(=O)N1CCc2ccc(N)cc2CC1
Reactant: CS(=O)(=O)c1ccc(OCC(F)F)c(-c2cccn3nc(Cl)nc23)c1
Product: CC(C)(C)OC(=O)N1CCc2ccc(Nc3nc4c(-c5cc(S(C)(=O)=O)ccc5OCC(F)F)cccn4n3)cc2CC1

Procedure:
7-{8-[2-(2,2-Difluoro-ethoxy)-5-methanesulfonyl-phenyl]-[1,2,4]triazolo[1,5-a]pyridin-2-ylamino}-1,2,4,5-tetrahydro-3-benzazepine-3-carboxylic acid tert-butyl ester was prepared from 2-chloro-8-[2-(2,2-difluoro-ethoxy)-5-methanesulfonyl-phenyl]-[1,2,4]-triazolo[1,5-a]pyridine (0.282 g, 727 mmol) and 7-amino-1,2,4,5-tetrahydro-3-benzazepine-3-carboxylic acid tert-butyl ester (0.286 g, 1.09 mmol) in a manner analogous to Example 311a and 311b to give product (0.340 g, 76%): 1H NMR (400 MHz, (D3C)2SO, δ, ppm): 9.54 (s, 1H), 8.80 (d, 1H), 8.22 (s, 1H), 8.00 (d, 1H), 7.69 (d, 1H), 7.48 (m, 2H), 7.38 (s, 1H), 7.10 (t, 1H), 7.00 (d, 1H), 6.28 (br m, 1H), 4.54 (m, 2H), 3.44 (m, 4H), 3.23 (s, 3H), 2.76 (m, 4H), 1.41 (s, 9H). MS=614 (MH)+.
Reaction SMILES: F[C:2]1[CH:9]=[CH:8][C:7]([CH:10]=[O:11])=[CH:6][C:3]=1[C:4]#[N:5].[Cl:12][C:13]1[CH:18]=[CH:17][C:16]([OH:19])=[CH:15][C:14]=1[C:20]([F:23])([F:22])[F:21]>>[Cl:12][C:13]1[CH:18]=[CH:17][C:16]([O:19][C:2]2[CH:9]=[CH:8][C:7]([CH:10]=[O:11])=[CH:6][C:3]=2[C:4]#[N:5])=[CH:15][C:14]=1[C:20]([F:21])([F:22])[F:23]
Reactant: N#Cc1cc(C=O)ccc1F
Reactant: Oc1ccc(Cl)c(C(F)(F)F)c1
Product: N#Cc1cc(C=O)ccc1Oc1ccc(Cl)c(C(F)(F)F)c1

Procedure:
The title compound was prepared by a procedure similar to that described for D4 starting from 2-fluoro-5-formylbenzonitrile and 4-chloro-3-(trifluoromethyl)phenol.
Reaction SMILES: [CH3:1][O:2][C:3]([C@@:5]1([CH3:18])[C@@H:9]([OH:10])[CH2:8][CH2:7][N:6]1[C:11]([O:13][C:14]([CH3:17])([CH3:16])[CH3:15])=[O:12])=[O:4].N1C=CN=C1.[Si:24](Cl)([C:27]([CH3:30])([CH3:29])[CH3:28])([CH3:26])[CH3:25]>C(Cl)Cl>[CH3:1][O:2][C:3]([C@@:5]1([CH3:18])[C@@H:9]([O:10][Si:24]([C:27]([CH3:30])([CH3:29])[CH3:28])([CH3:26])[CH3:25])[CH2:8][CH2:7][N:6]1[C:11]([O:13][C:14]([CH3:17])([CH3:16])[CH3:15])=[O:12])=[O:4]
Reactant: CC(C)(C)[Si](C)(C)Cl
Reactant: COC(=O)[C@@]1(C)[C@@H](O)CCN1C(=O)OC(C)(C)C
Agent: c1c[nH]cn1
Solvent: ClCCl
Product: COC(=O)[C@@]1(C)[C@@H](O[Si](C)(C)C(C)(C)C)CCN1C(=O)OC(C)(C)C
Reaction time: 8 h
Yield: 61.2 %

Procedure:
To a solution of compound 3A (0.591 g, 2.27 mmol) in CH2Cl2 (6.5 mL) at rt was added imidazole (0.464 g, 6.81 mmol) followed by tert-butydimethylsilyl chloride (1.71 g, 11.4 mmol). After stirring overnight, the reaction mixture was partitioned between H2O and CH2Cl2. The CH2Cl2 layer was washed with 1 M H3PO4 and water, then dried (MgSO4), filtered and concentrated under reduced pressure. The residue was chromatographed (silica gel) eluting with 30% EtOAc/hexane to yield compound 3B (0.519 g). LC/MS m/z 396 [M+Na]+.
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][CH2:9][CH2:10][OH:11])=[CH:4][CH:3]=1.[H-].[Na+].I[CH2:15][CH3:16]>CN(C=O)C.O>[CH2:15]([O:1][C:2]1[CH:3]=[CH:4][C:5]([CH2:8][CH2:9][CH2:10][OH:11])=[CH:6][CH:7]=1)[CH3:16]
Reactant: CCI
Reactant: OCCCc1ccc(O)cc1
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: CCOc1ccc(CCCO)cc1
Reaction time: 0.25 h
Yield: 81.7 %

Procedure:
To a solution of 3-(4-hydroxyphenyl)-1-propanol (3.00 g, 19.7 mmol, 1 equiv) in DMF (100 ml) was added portion wise NaH (0.45 g, 18.8 mmol, 0.95 equiv) at rt, and the resulting mixture was stirred for 15 min. Iodoethane (1.37 ml, 20.0 mmol, 1 equiv) was added drop wise and the mixture was stirred for 2.5 h. The reaction mixture was diluted with water and extracted with EtOAc. The extract was washed with water, dried over MgSO4, and concentrated under vacuum to give the title compound (2.90 g, 81.7%) that was used as such for the next step.