Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([C:5]1[N:6]([CH2:13][C:14]2[CH:19]=[CH:18][C:17]([C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][C:21]=3[C:26]3[NH:30][N:29]=[N:28][N:27]=3)=[CH:16][CH:15]=2)[C:7]([CH2:11][OH:12])=[C:8]([Cl:10])[N:9]=1)[CH2:2][CH2:3][CH3:4].FC1C([O:38][C:39](=O)[CH2:40][CH2:41][CH2:42][O:43][N+:44]([O-:46])=[O:45])=C(F)C(F)=C(F)C=1F>CN(C1C=CN=CC=1)C.CN(C=O)C>[CH2:1]([C:5]1[N:6]([CH2:13][C:14]2[CH:19]=[CH:18][C:17]([C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][C:21]=3[C:26]3[NH:30][N:29]=[N:28][N:27]=3)=[CH:16][CH:15]=2)[C:7]([CH2:11][O:12][C:39]([CH2:40][CH2:41][CH2:42][O:43][N+:44]([O-:46])=[O:45])=[O:38])=[C:8]([Cl:10])[N:9]=1)[CH2:2][CH2:3][CH3:4]
Reactant: O=C(CCCO[N+](=O)[O-])Oc1c(F)c(F)c(F)c(F)c1F
Reactant: CCCCc1nc(Cl)c(CO)n1Cc1ccc(-c2ccccc2-c2nnn[nH]2)cc1
Agent: CN(C)c1ccncc1
Solvent: CN(C)C=O
Product: CCCCc1nc(Cl)c(COC(=O)CCCO[N+](=O)[O-])n1Cc1ccc(-c2ccccc2-c2nnn[nH]2)cc1

Procedure:
Using the same procedure described in Example 1 but starting from 2-butyl-4-chloro-1-[[2′-(1H-tetrazol-5-yl)[1,1′-biphenyl]-4-yl]methyl]-1H-imidazole-5-methanol (Losartan)(2.13 g, 5.04 mmol) and 4-(nitrooxy)butanoic acid pentafluorophenyl ester (1.59 g, 5.04 mmol) TEA (0.7 ml, 5.04 mmol), DMAP (0.615 g, 5.04 mmol) and using DMF as solvent. Then the mixture was diluted with buffer solution (pH=3); the pH was adjusted to 2-3 and the mixture was extracted with EtOAc. The organic phase washed with brine, dried over Na2SO4 and evaporated. The residue was purified with Flash chromatography of the residue (CH2Cl2/MeOH 98:2) and the title compound was obtained as a white solid (1.48 g, 53%).
Reaction SMILES: [Cl:1][C:2]1([Cl:13])[CH2:4][CH:3]1[O:5][C:6]1[CH:12]=[CH:11][C:9]([NH2:10])=[CH:8][CH:7]=1.[CH3:14][C:15]1[CH:25]=[CH:24][CH:23]=[CH:22][C:16]=1[C:17]([N:19]=[C:20]=[O:21])=[O:18]>O1CCCC1>[Cl:1][C:2]1([Cl:13])[CH2:4][CH:3]1[O:5][C:6]1[CH:12]=[CH:11][C:9]([NH:10][C:20]([NH:19][C:17](=[O:18])[C:16]2[CH:22]=[CH:23][CH:24]=[CH:25][C:15]=2[CH3:14])=[O:21])=[CH:8][CH:7]=1
Reactant: Cc1ccccc1C(=O)N=C=O
Reactant: Nc1ccc(OC2CC2(Cl)Cl)cc1
Solvent: C1CCOC1
Product: Cc1ccccc1C(=O)NC(=O)Nc1ccc(OC2CC2(Cl)Cl)cc1

Procedure:
6.54 g (0.03 Mol) of 4-(2,2-dichlorcyclopropyloxy)-aniline, dissolved in 50 ml dry tetrahydrofuran, are added dropwise with 4.84 g (0.03 Mol) of 2-methylbenzoyl-isocyanate, with stirring. The temperature increases mildly therewith. After cooling, the product is precipitated with pentane, withdrawn by suction, after-washed with pentane and dried.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][C:9](=O)[C:10]([F:13])([F:12])[F:11])=[CH:4][CH:3]=1.C(O)C.Cl.[NH2:19][OH:20].C([O-])(=O)C.[Na+]>O>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][C:9](=[N:19][OH:20])[C:10]([F:13])([F:12])[F:11])=[CH:4][CH:3]=1
Reactant: NO
Reactant: O=C(Cc1ccc(Cl)cc1)C(F)(F)F
Agent: CC(=O)[O-]
Agent: Cl
Agent: [Na+]
Solvent: CCO
Solvent: O
Product: ON=C(Cc1ccc(Cl)cc1)C(F)(F)F
Temperature: 25 °C
Yield: 110.7 %

Procedure:
A solution of 3-(p-Chlorophenyl)-1,1,1-trifluoro-2-propanone (10.0 g, 0.045 mol) and ethanol (60 mL) is treated with a solution of hydroxylamine hydrochloride (4.68 g, 0.067 mol) and water (20 mL) and then with a solution of sodium acetate (5.53 g, 0.067 mol) and water (20 mL). The reaction mixture is then refluxed for 2 hours, cooled to room temperature, diluted with water and extracted with ether. The combined organic extracts are washed sequentially with water and brine, dried over anhydrous sodium sulfate and concentrated in vacuo to give a liquid which solidifies upon standing to give the title product as white needles (11.84 g). Identified by IR and NMR spectral analyses.
Reaction SMILES: O.[OH-].[Li+].C[O:5][C:6](=[O:34])[CH2:7][C:8]1[C:17]([CH3:18])=[C:16]([C:19]2[CH:24]=[CH:23][C:22]([S:25]([N:28]3[CH2:32][CH2:31][CH2:30][CH2:29]3)(=[O:27])=[O:26])=[CH:21][CH:20]=2)[C:15]2[C:10](=[CH:11][CH:12]=[C:13]([Cl:33])[CH:14]=2)[CH:9]=1.C1COCC1.O>CCCCCC>[Cl:33][C:13]1[CH:14]=[C:15]2[C:10](=[CH:11][CH:12]=1)[CH:9]=[C:8]([CH2:7][C:6]([OH:34])=[O:5])[C:17]([CH3:18])=[C:16]2[C:19]1[CH:20]=[CH:21][C:22]([S:25]([N:28]2[CH2:32][CH2:31][CH2:30][CH2:29]2)(=[O:26])=[O:27])=[CH:23][CH:24]=1
Reactant: COC(=O)Cc1cc2ccc(Cl)cc2c(-c2ccc(S(=O)(=O)N3CCCC3)cc2)c1C
Agent: [Li+]
Agent: [OH-]
Solvent: CCCCCC
Solvent: O
Solvent: C1CCOC1
Product: Cc1c(CC(=O)O)cc2ccc(Cl)cc2c1-c1ccc(S(=O)(=O)N2CCCC2)cc1
Temperature: 25 °C
Reaction time: 16 h
Yield: 95.9 %

Procedure:
Lithium hydroxide monohydrate (0.046 g, 1.09 mmol) was added to a stirred solution of {6-chloro-3-methyl-4-[4-(pyrrolidine-1-sulfonyl)-phenyl]-naphthalen-2-yl}-acetic acid methyl ester (0.125 g, 0.27 mmol) in a 3:1 mixture of THF—H2O mixture (15 mL). The reaction mixture was stirred for 16 hours at room temperature. The reaction mixture was concentrated to remove THF, and the crude material was diluted with water, acidified [pH˜2] with a 6 N aqueous solution of hydrochloric acid. The mixture was extracted twice with ethyl acetate. The collected organic layers were washed with water and brine, dried over anhydrous Na2SO4, and concentrated under reduced pressure to give the crude product. Trituration with hexane afforded {6-chloro-3-methyl-4-[4-(pyrrolidine-1-sulfonyl)-phenyl]-naphthalen-2-yl}-acetic acid (0.115 g, 95%) as a solid. 1H NMR (DMSO-d6) δ: 12.50 (br. s, 1H), 7.80-8.21 (m, 4H), 7.42-7.69 (m, 3H), 6.98 (d, J=5.4 Hz, 1H), 3.86 (d, J=3.9 Hz, 2H), 3.26 (d, J=3.9 Hz, 4H), 2.07 (d, J=3.9 Hz, 3H), 1.69 (d, J=3.9 Hz, 4H). MS calcd. for C23H21ClNO4S [(M−H)−] 442, obsd. 442.3.
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([NH:8][C@H:9]([C:11]2[CH:16]=[CH:15][C:14]([O:17][CH3:18])=[CH:13][CH:12]=2)[CH3:10])[CH:5]=[N:4][CH:3]=1.[N:19]1[C:23]2[CH:24]=[CH:25][CH:26]=[CH:27][C:22]=2[NH:21][CH:20]=1>>[N:19]1([C:2]2[N:7]=[C:6]([NH:8][C@H:9]([C:11]3[CH:16]=[CH:15][C:14]([O:17][CH3:18])=[CH:13][CH:12]=3)[CH3:10])[CH:5]=[N:4][CH:3]=2)[C:23]2[CH:24]=[CH:25][CH:26]=[CH:27][C:22]=2[N:21]=[CH:20]1
Reactant: COc1ccc([C@H](C)Nc2cncc(Cl)n2)cc1
Reactant: c1ccc2[nH]cnc2c1
Product: COc1ccc([C@H](C)Nc2cncc(-n3cnc4ccccc43)n2)cc1
Yield: 41.3 %

Procedure:
In a procedure analogous to example 25, reaction of 6-chloro-N-[(1S)-1-(4-methoxyphenyl)ethyl]pyrazin-2-amine (105 mg, 0.40 mmol) and benzimidazole (52 mg, 0.44 mmol) furnished the product (57 mg, 41%).
Reaction SMILES: [Br:1][C:2]1[CH:6]=[C:5]([C:7](O)=[O:8])[N:4]([C:10]2[C:15]([Cl:16])=[CH:14][CH:13]=[CH:12][N:11]=2)[N:3]=1.S(Cl)([Cl:19])=O.CN(C=O)C>C(Cl)(Cl)Cl>[Br:1][C:2]1[CH:6]=[C:5]([C:7]([Cl:19])=[O:8])[N:4]([C:10]2[C:15]([Cl:16])=[CH:14][CH:13]=[CH:12][N:11]=2)[N:3]=1
Reactant: O=S(Cl)Cl
Reactant: O=C(O)c1cc(Br)nn1-c1ncccc1Cl
Solvent: ClC(Cl)Cl
Solvent: CN(C)C=O
Product: O=C(Cl)c1cc(Br)nn1-c1ncccc1Cl

Procedure:
1.52 g of 3-bromo-1-(3-chloropyridin-2-yl)-1H-pyrazole-5-carboxylic acid was dissolved in 10 ml of chloroform, 0.55 ml of thionyl chloride was dropwise added, and 0.05 ml of DMF was added, followed by reflux for 30 minutes. After the reaction liquid was stood to cool, the solvent was distilled off under reduced pressure to obtain crude product of 3-bromo-1-(3-chloropyridin-2-yl)-1H-pyrazole-5-carbonyl chloride. Then, a mixed solution comprising the above crude product and 5 ml of toluene was dropwise added to a mixed solution comprising 0.5 ml of ethanethiol, 1.11 ml of triethylamine and 20 ml of chloroform under cooling with ice, followed by stirring for 5 minutes and reaction at room temperature for 14 hours. The reaction solvent was distilled off under reduced pressure, and 50 ml of water was added, followed by extraction with ethyl acetate. The organic layer was washed with a saturated sodium chloride aqueous solution and dried over sodium sulfate. The solvent was distilled off under reduced pressure, and the residue was purified by silica gel column chromatography (eluent: n-hexane/ethyl acetate=1/0 to 3/1) to obtain 1.4 g of the desired product in the form of light red crystals (melting point: 94° C.).
Reaction SMILES: [OH:1][C:2]1[CH:9]=[CH:8][C:5]([CH:6]=[O:7])=[CH:4][CH:3]=1.[CH2:10]([O:12][C:13](=[O:20])[CH2:14][CH2:15][CH2:16][CH2:17][CH2:18]Br)[CH3:11].C([O-])([O-])=O.[K+].[K+]>CN(C=O)C>[CH2:10]([O:12][C:13](=[O:20])[CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][O:1][C:2]1[CH:9]=[CH:8][C:5]([CH:6]=[O:7])=[CH:4][CH:3]=1)[CH3:11]
Reactant: CCOC(=O)CCCCCBr
Reactant: O=Cc1ccc(O)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CCOC(=O)CCCCCOc1ccc(C=O)cc1
Temperature: 50 °C
Reaction time: 20 h

Procedure:
A mixture of 4-hydroxybenzaldehyde 1 (3, 0.60 kg, 4.91 mol), ethyl-6-bromohexanoate 2 (4, 1.10 kg, 4.91 mol), and K2CO3 (1.36 kg, 9.83 mol) in DMF (2 L) was stirred at 50° C. for 20 h. The mixture was filtered to remove remaining K2CO3. The resulting solution was concentrated in vacuo, diluted with EtOAc (3 L) and subsequently washed with saturated aqueous NaCl (3×1.5 L). The organic layer was dried (MgSO4), filtered and concentrated in vacuo to give an off white solid (3, 1.23 kg, 4.66 mol, 95%) with no need for further purification: M.p.: 33-35 ° C. 1H NMR (400 MHz, CDCl3) δ=9.87 (s, 1H), 7.81 (d, J=8.7, 2H), 6.97 (d, J=8.7, 2H), 4.12 (q, J=7.1, 2H), 4.04 (t, J=6.4, 2H), 2.33 (t, J=7.4, 2H), 1.82 (m, 2H), 1.69 (m, 2H), 1.53 (m, 2H), 1.25 (t, J=7.1, 3H); 13C NMR (400 MHz, CDCl3) δ=191.0, 173.7, 164.3, 132.1 (2C), 130.1, 114.9 (2C), 68.3, 60.5, 34.4, 29.0, 25.8, 24.8, 14.4; IR (film) ν=2941, 1719, 1688, 1595, 1579, 1509, 1466, 1392, 1307, 1252, 1213, 1155, 1108, 1030, 999, 832 cm−1; HRMS (MALDI-FTMS) m/z 287.1254 (287.1254 calculated for C15H20O4Na, (M+Na)+).
Reaction SMILES: [N:1]([CH2:4][C:5]1[CH:6]=[C:7]([C:11]2[N:15]=[C:14]([C:16]3[CH:21]=[CH:20][C:19]([O:22][CH3:23])=[CH:18][CH:17]=3)[NH:13][N:12]=2)[CH:8]=[CH:9][CH:10]=1)=[N+]=[N-].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.O.[ClH:44].CCOCC>C(#N)C>[ClH:44].[CH3:23][O:22][C:19]1[CH:18]=[CH:17][C:16]([C:14]2[NH:13][N:12]=[C:11]([C:7]3[CH:6]=[C:5]([CH:10]=[CH:9][CH:8]=3)[CH2:4][NH2:1])[N:15]=2)=[CH:21][CH:20]=1
Reactant: COc1ccc(-c2nc(-c3cccc(CN=[N+]=[N-])c3)n[nH]2)cc1
Agent: Cl
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: O
Solvent: CCOCC
Solvent: CC#N
Product: COc1ccc(-c2nc(-c3cccc(CN)c3)n[nH]2)cc1
Reaction time: 0.5 h
Yield: 69.1 %

Procedure:
A solution of 3-(3-azidomethyl-phenyl)-5-(4-methoxy-phenyl)-1H-[1,2,4]triazole (980 mg, 3.2 mmol) in acetonitrile (40 ml) was treated with triphenyl phosphine (839 mg, 3.2 mmol) and water (288 mg, 16 mmol) at 20° C. for 20 min, then for 30 min. at 60° C. Upon cooling the product mixture was filtered, the solvent was evaporated and the residue chromatographed over 20 g SiO2 (Merck 230-400 mesh) with CH2Cl2-MeOH (2M NH3) 97:3 affording a solid after evaporation of the solvent. This material was dissolved in ethanol at r.t. and an excess 2N HCl/ether solution (2.0 ml, 4 mmol) was added. After 30 min. the precipitate was filtered off, washed with ether and dried under high vacuum at 60° C. overnight affording the title compound (700 mg, 69% yield) as a white solid. MS: m/e=281.3 (M+H+).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[C:13](=[O:14])[C:12]([O:15][C:16]3[CH:21]=[CH:20][C:19]([C:22]4[CH:27]=[CH:26][C:25]([F:28])=[CH:24][CH:23]=4)=[CH:18][CH:17]=3)=[C:11]([N:29]3[CH2:34][CH2:33][CH:32](O)[CH2:31][CH2:30]3)[CH:10]=[N:9]2)=[CH:4][CH:3]=1.S(Cl)([Cl:38])=O>>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([N:8]2[C:13](=[O:14])[C:12]([O:15][C:16]3[CH:21]=[CH:20][C:19]([C:22]4[CH:23]=[CH:24][C:25]([F:28])=[CH:26][CH:27]=4)=[CH:18][CH:17]=3)=[C:11]([N:29]3[CH2:34][CH2:33][CH:32]([Cl:38])[CH2:31][CH2:30]3)[CH:10]=[N:9]2)=[CH:6][CH:7]=1
Reactant: O=c1c(Oc2ccc(-c3ccc(F)cc3)cc2)c(N2CCC(O)CC2)cnn1-c1ccc(Cl)cc1
Reactant: O=S(Cl)Cl
Product: O=c1c(Oc2ccc(-c3ccc(F)cc3)cc2)c(N2CCC(Cl)CC2)cnn1-c1ccc(Cl)cc1

Procedure:
A suspension of 150 mg (0.305 mmol) of 2-(4-chlorophenyl)-4-(4′-fluorobiphenyl-4-yloxy)-5-(4-hydroxypiperidin-1-yl)-2H-pyridazin-3-one (obtainable in analogy to Example 15) is heated under reflux with 4 ml of thionyl chloride for 60 min. After cooling, the reaction solution is concentrated under high vacuum, the residue is partitioned between 50 ml of ethyl acetate and 20 ml of saturated sodium bicarbonate solution, the organic phase is separated off, and the aqueous phase is extracted three times with ethyl acetate. The combined organic phases are dried over sodium sulfate, and the solvent is removed in vacuo. The product is purified by chromatography on silica gel with toluene/ethyl acetate from 9:1 to 8:2 as mobile phase.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[S:9][C:10]([CH:13]([OH:15])[CH3:14])=[CH:11][N:12]=2)=[C:4]([CH3:16])[CH:3]=1.Cl[C:18]1[CH:26]2[CH:21]([CH:22]3[O:27][CH:25]2[CH2:24][CH2:23]3)[C:20](=[O:28])[CH:19]=1.[H-].[Na+].COCCOCCOCCOC>O1CCCC1>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[S:9][C:10]([CH:13]([O:15][C:18]3[CH:26]4[CH:21]([CH:22]5[O:27][CH:25]4[CH2:24][CH2:23]5)[C:20](=[O:28])[CH:19]=3)[CH3:14])=[CH:11][N:12]=2)=[C:4]([CH3:16])[CH:3]=1
Reactant: O=C1C=C(Cl)C2C3CCC(O3)C12
Reactant: Cc1cc(Br)ccc1-c1ncc(C(C)O)s1
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: COCCOCCOCCOC
Product: Cc1cc(Br)ccc1-c1ncc(C(C)OC2=CC(=O)C3C4CCC(O4)C23)s1
Temperature: 25 °C
Reaction time: 24 h
Yield: 73.2 %

Procedure:
To a solution of [2-(4-bromo-2-methyl-phenyl)-thiazol-5-yl]-ethanol (450 mg, 1.5 mmol) and 5-chloro-10-oxa-tricyclo[5.2.1.0*2,6*]dec-4-en-3-one (277 mg, 1.5 mmol) in tetrahydrofuran (10 ml) is added in one portion the sodium hydride (60% dispersion in mineral oil, 60 mg, 1.5 mmol). The reaction mixture is stirred at room temperature for 24 hours. The crude reaction mixture is vacced down under reduced pressure and 10 ml of triglyme are added. The reaction mixture is therefore heated to reflux for 30 minutes. The crude reaction mixture is vacced down and purified by flash chromatography on silica gel to give a yellow solid. The solid is washed with iso-hexane to give 5-{1-[2-(4-bromo-2-methyl-phenyl)-thiazol-5-yl]-ethoxy}-10-oxa-tricyclo[5.2.1.0*2,6*]dec-4-en-3-one (490 mg).
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][CH:6]=[C:5]2[CH:11]1[CH2:16][CH2:15][N:14]([CH3:17])[CH2:13][CH2:12]1.[NH:18]1[CH:22]=[CH:21][CH:20]=[C:19]1[C:23](O)=[O:24]>>[NH:18]1[CH:22]=[CH:21][CH:20]=[C:19]1[C:23]([NH:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][CH:6]=[C:5]2[CH:11]1[CH2:16][CH2:15][N:14]([CH3:17])[CH2:13][CH2:12]1)=[O:24]
Reactant: CN1CCC(c2c[nH]c3ccc(N)cc23)CC1
Reactant: O=C(O)c1ccc[nH]1
Product: CN1CCC(c2c[nH]c3ccc(NC(=O)c4ccc[nH]4)cc23)CC1
Yield: 88.8 %

Procedure:
Beginning with 10.0 mg (0.044 mMol) 5-amino-3-(1-methylpiperidin-4-yl)-1H-indole and 21.1 mg (0.131 mmol) pyrrole-2-carboxylic acid, 12.6 mg (78%) of the title compound were recovered.
Reaction SMILES: C1(NC2CCCCC2)CCCCC1.[C:14]([O:18][C:19]([NH:21][CH:22]([CH2:26][CH2:27][CH2:28][O:29][CH2:30][C:31]1[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=1)[C:23]([OH:25])=O)=[O:20])([CH3:17])([CH3:16])[CH3:15].[NH2:37][CH:38]([C:44](=[O:46])[CH3:45])[C:39]([O:41][CH2:42][CH3:43])=[O:40].Cl.C(N=C=NCCCN(C)C)C.ON1C2C=CC=CC=2N=N1.C(N(CC)CC)C>C(OCC)(=O)C.CO.C(Cl)(Cl)Cl.O>[CH2:30]([O:29][CH2:28][CH2:27][CH2:26][C@@H:22]([C:23]([NH:37][CH:38]([C:44](=[O:46])[CH3:45])[C:39]([O:41][CH2:42][CH3:43])=[O:40])=[O:25])[NH:21][C:19]([O:18][C:14]([CH3:15])([CH3:16])[CH3:17])=[O:20])[C:31]1[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=1
Reactant: CC(C)(C)OC(=O)NC(CCCOCc1ccccc1)C(=O)O
Reactant: CCOC(=O)C(N)C(C)=O
Agent: C1CCC(NC2CCCCC2)CC1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Solvent: O
Solvent: CCOC(C)=O
Solvent: CCN(CC)CC
Product: CCOC(=O)C(NC(=O)[C@H](CCCOCc1ccccc1)NC(=O)OC(C)(C)C)C(C)=O

Procedure:
(S)-2-(tert-butoxycarbonylamino-5-benzyloxypentanoic acid dicyclohexylamine salt (10.0 g, 19.8 mmol) was purified by silica gel column chromatography (ethyl acetate to ethyl acetate:methanol=19:1) in order to remove dicyclohexylamine. The resulting oil, ethyl 2-amino-3-oxobutanoate (3.60 g, 19.8 mmol), ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (5.69 g, 29.7 mmol), 1-hydroxybenzotriazole (4.01 g, 29.7 mmol), triethylamine (6.87 mL, 49.5 mmol), in chloroform (40 mL) was stirred for 6 h at room temperature, and then reaction mixture was poured into water. The organic layer was separated, washed with saturated brine, dried over sodium sulfate, filtrated and concentrated in vacuo. The crude was purified by silica gel column chromatography (hexane:ethyl acetate=9:1 to 3:2) to give ethyl 2-{[5-(benzyloxy)-N-(tert-butoxycarbonyl)-L-norvalyl]amino}-3-oxobutanoate. MS (APCI): m/z 468 (M+NH4).
Reaction SMILES: [NH:1]([C:13]([O:15][C:16]([CH3:19])([CH3:18])[CH3:17])=[O:14])[C@H:2]([C:10]([OH:12])=O)[CH2:3][CH:4]1[CH2:9][CH2:8][CH2:7][CH2:6][CH2:5]1.CCN(C(C)C)C(C)C.F[P-](F)(F)(F)(F)F.N1(O[P+](N(C)C)(N(C)C)N(C)C)C2C=CC=CC=2N=N1.[S:56]1[CH:60]=[CH:59][N:58]=[C:57]1[NH2:61]>CN(C=O)C.O>[C:16]([O:15][C:13](=[O:14])[NH:1][C@H:2]([C:10](=[O:12])[NH:61][C:57]1[S:56][CH:60]=[CH:59][N:58]=1)[CH2:3][CH:4]1[CH2:5][CH2:6][CH2:7][CH2:8][CH2:9]1)([CH3:19])([CH3:18])[CH3:17]
Reactant: Nc1nccs1
Reactant: CC(C)(C)OC(=O)N[C@@H](CC1CCCCC1)C(=O)O
Agent: CN(C)[P+](On1nnc2ccccc21)(N(C)C)N(C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: O
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)N[C@@H](CC1CCCCC1)C(=O)Nc1nccs1
Temperature: 25 °C
Reaction time: 1 h
Yield: 74 %

Procedure:
A solution of Boc-Cha-OH (9.2 g, 34 mmol), DIEA (15 ml, 85 mmol) and BOP (16.5 g, 37 mmol) in DMF (80 ml) was maintained at ambient temperature for 40 minutes followed by the addition of thiazol-2-ylamine (3.4 g, 34 mmol). Reaction was maintained at ambient temperature for 2 hours. Reaction mixture was diluted with water (200 ml) and extracted with EtOAc (2×150 ml). Organic layer was washed with brine (100 ml), dried over anh. MgSO4 and evaporated in vacuum. Residue was subjected to flash chromatography on CombiFlash® Companion unit equipped with RediSep® flash column (normal phase, 35-60 micron average particle size silicagel, 40 g, Teledyne Isco); flow rate=35 ml/min; injection volume 2 ml; mobile phase A: hexane; mobile phase B: EtOAc; gradient 0-70% B in 1 h. Fractions containing the desired product were combined and concentrated in vacuum to provide target compound (8.89 g, 74%) as yellow oil. LC-MS [M+H] 354.4 (C17H27N3O3S+H, requires 354.49).
Reaction SMILES: C([O:3][C:4](=O)[CH2:5][O:6][CH2:7][C:8]1[S:9][C:10]([CH2:13][N:14]([CH3:16])[CH3:15])=[CH:11][CH:12]=1)C.[NH3:18]>C(O)C>[CH3:15][N:14]([CH2:13][C:10]1[S:9][C:8]([CH2:7][O:6][CH2:5][C:4]([NH2:18])=[O:3])=[CH:12][CH:11]=1)[CH3:16]
Reactant: N
Reactant: CCOC(=O)COCc1ccc(CN(C)C)s1
Solvent: CCO
Product: CN(C)Cc1ccc(COCC(N)=O)s1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
A solution of [[5-(N,N-dimethylaminomethyl)2-thienyl]methoxy] acetic acid ethyl ester (4.0 g) in a mixture of 0.88 ammonia solution (75 ml) and ethanol (75 ml) was stirred for 1 hr at room temperature. The solvent was removed and the residue recrystallised from a 1:1 mixture of benzene and petroleum spirit (b.p. 60°-80°) to afford a white crystalline solid (3.2 g) m.p. 86.5°-95°. NMR (CDCl3) 7.71, s, (6H); 6.38, s, (2H); 6.00, s, (2H); 5.30, s, (2H); 3.5, br, (2H); 3.12, q, (2H).
Reaction SMILES: [C:1]([C:3]1[CH:12]=[CH:11][C:6]([C:7]([O:9][CH3:10])=[O:8])=[CH:5][CH:4]=1)#[N:2].Cl.C(N(CC)CC)C.[N-:21]=[N+:22]=[N-:23].[Na+].O>C1(C)C=CC=CC=1>[NH:21]1[C:1]([C:3]2[CH:12]=[CH:11][C:6]([C:7]([O:9][CH3:10])=[O:8])=[CH:5][CH:4]=2)=[N:2][N:23]=[N:22]1
Reactant: COC(=O)c1ccc(C#N)cc1
Reactant: [N-]=[N+]=[N-]
Agent: Cl
Agent: [Na+]
Solvent: O
Solvent: CCN(CC)CC
Solvent: Cc1ccccc1
Product: COC(=O)c1ccc(-c2nnn[nH]2)cc1
Temperature: 25 °C
Yield: 96 %

Procedure:
1.16 g (10 mmol) of methyl 4-cyanobenzoate, 2.06 g (15 mmol) of triethylamine hydrochloride and 0.98 g (15 mmol) of sodium azide in toluene (20 ml) was allowed to react at 100° C. for 16 hours, and after cooling to room temperature, water (20 ml) was added, and the reaction solution was allowed to separate. Concentrated hydrochloric acid was added to the aqueous layer, and the precipitated colorless solid was collected by filtration through a Kiriyama funnel and dried under reduced pressure to obtain methyl 4-(1H-tetrazol-5-yl)benzoate (1.96 g, yield 96%).
Reaction SMILES: [C:1]([C:3]1[CH:11]=[C:10]2[C:6]([C:7]([CH3:19])=[N:8][N:9]2[C:12]2[CH:17]=[CH:16][N:15]=[C:14]([NH2:18])[N:13]=2)=[CH:5][CH:4]=1)#[CH:2].[Li+].CC([N-]C(C)C)C.[C:28]1([C:34]([C:49]2[CH:54]=[CH:53][CH:52]=[CH:51][CH:50]=2)([C:43]2[CH:48]=[CH:47][CH:46]=[CH:45][CH:44]=2)[N:35]2[CH:39]=[C:38]([C:40](=[O:42])[CH3:41])[N:37]=[CH:36]2)[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1>C1COCC1>[NH2:18][C:14]1[N:13]=[C:12]([N:9]2[C:10]3[C:6](=[CH:5][CH:4]=[C:3]([C:1]#[C:2][C:40]([C:38]4[N:37]=[CH:36][N:35]([C:34]([C:43]5[CH:48]=[CH:47][CH:46]=[CH:45][CH:44]=5)([C:28]5[CH:29]=[CH:30][CH:31]=[CH:32][CH:33]=5)[C:49]5[CH:54]=[CH:53][CH:52]=[CH:51][CH:50]=5)[CH:39]=4)([OH:42])[CH3:41])[CH:11]=3)[C:7]([CH3:19])=[N:8]2)[CH:17]=[CH:16][N:15]=1
Reactant: C#Cc1ccc2c(C)nn(-c3ccnc(N)n3)c2c1
Reactant: CC(=O)c1cn(C(c2ccccc2)(c2ccccc2)c2ccccc2)cn1
Agent: CC(C)[N-]C(C)C
Agent: [Li+]
Solvent: C1CCOC1
Product: Cc1nn(-c2ccnc(N)n2)c2cc(C#CC(C)(O)c3cn(C(c4ccccc4)(c4ccccc4)c4ccccc4)cn3)ccc12
Temperature: 25 °C
Reaction time: 0.33 h

Procedure:
To a solution of 4-(6-ethynyl-3-methylindazol-1-yl)pyrimidin-2-amine (180 mg at 90% purity, 0.65 mmol) in THF (2.5 mL) at −78° C. under nitrogen was added 2M LDA in THF (0.81 mL, 1.63 mmol). After 5 minutes 1-[1-(triphenylmethyl)imidazol-4-yl]ethanone (458.08 mg, 1.3 mmol) in THF (1.5 mL) was added. After 20 minutes, the mixture was allowed to warm up to RT and stirred for a further 1 hr. The reaction mixture was quenched by addition of saturated aqueous NH4Cl (1 mL). The volatiles were removed in vacuo and the mixture was diluted with DCM (10 ml) and washed with water (2 mL), dried (Na2SO4), filtered and concentrated in vacuo. The crude product was purified by flash chromatography (Biotage, 2-12% methanol gradient in DCM) to give the title intermediate as a yellow oil: 1H NMR (500 MHz, CDCl3) delta 1.96 (3H, s), 2.58 (3H, s), 4.41 (1H, s), 5.36 (2H, s), 6.96 (1H, d, J=1.0), 7.19-7.09 (6H, m), 7.24 (1H, d, J=5.7 Hz), 7.35-7.30 (10H, m), 7.44 (1H, d, J=1.0 Hz), 7.53 (1H, d, J=8.2), 8.24 (1H, d, J=5.7), 8.83 (1H, s); LC-MS: m/z=+360.35 (M-C(C6H5)3)+.
Reaction SMILES: Br[C:2]1[CH:3]=[CH:4][C:5]2=[C:6]([CH:29]=1)[N:7]=[C:8]([NH:21][C:22](=[O:28])[O:23][C:24]([CH3:27])([CH3:26])[CH3:25])[CH2:9][C:10]([C:12](=[O:20])[N:13]([CH2:17][CH2:18][CH3:19])[CH2:14][CH2:15][CH3:16])=[CH:11]2.[OH:30][C:31]1[CH:36]=[CH:35][C:34](B(O)O)=[CH:33][CH:32]=1.O.[K].[K].C1(P(C2C=CC(S(O)(=O)=O)=CC=2)C2C=CC(S(O)(=O)=O)=CC=2)C=CC=CC=1.C(=O)([O-])[O-].[Na+].[Na+]>C(O)C.CC([O-])=O.CC([O-])=O.[Pd+2]>[CH2:14]([N:13]([CH2:17][CH2:18][CH3:19])[C:12]([C:10]1=[CH:11][C:5]2[CH:4]=[CH:3][C:2]([C:34]3[CH:35]=[CH:36][C:31]([OH:30])=[CH:32][CH:33]=3)=[CH:29][C:6]=2[N:7]=[C:8]([NH:21][C:22](=[O:28])[O:23][C:24]([CH3:27])([CH3:26])[CH3:25])[CH2:9]1)=[O:20])[CH2:15][CH3:16]
Reactant: CCCN(CCC)C(=O)C1=Cc2ccc(Br)cc2N=C(NC(=O)OC(C)(C)C)C1
Reactant: OB(O)c1ccc(O)cc1
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: O=C([O-])[O-]
Solvent: O
Solvent: CCO
Product: CCCN(CCC)C(=O)C1=Cc2ccc(-c3ccc(O)cc3)cc2N=C(NC(=O)OC(C)(C)C)C1
Temperature: 65 °C
Yield: 40.9 %

Procedure:
tert-Butyl (1E,4E)-8-bromo-4-(dipropylcarbamoyl)-3H-benzo[b]azepin-2-ylcarbamate (0.095 g, 0.205 mmol), 4-hydroxyphenylboronic acid (0.040 g, 0.286 mmol), Pd(OAc)2 (0.0045 g, 0.020 mmol), 4,4′-(phenylphosphinidene)bisbenzenesulfonic acid dipotassium hydrate (0.022 g, 0.041 mmol), 2M sodium carbonate solution (0.307 mls, 0.614 mmol) were combined in 2 mls of ethanol and this mixture was purged with Argon for 5 minutes and then warmed to 65° C. under argon for 1.5 hours. The mixture was then diluted with citric acid, extracted with EtOAc (2×), extracts washed with saturated sodium carbonate solution, dried over sodium sulfate and concentrated under reduced pressure. Flash 40 Biotage (40S cartridge, 30% EtOAc/Hexane) afforded 0.040 g of tert-butyl (1E,4E)-4-(dipropylcarbamoyl)-8-(4-hydroxyphenyl)-3H-benzo[b]azepin-2-ylcarbamate (41%). m/z (APCI-pos) M+1=478.0.