Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([CH:8]=[CH:9][CH:10]=1)[C:5]([OH:7])=[O:6].C(N(C(C)C)C(C)C)C.[C:20]([NH:37][CH2:38][C:39](Cl)=[O:40])([O:22][CH2:23][CH:24]1[C:36]2[C:31](=[CH:32][CH:33]=[CH:34][CH:35]=2)[C:30]2[C:25]1=[CH:26][CH:27]=[CH:28][CH:29]=2)=[O:21].Cl>C1COCC1.C(Cl)Cl>[CH:26]1[C:25]2[CH:24]([CH2:23][O:22][C:20]([NH:37][CH2:38][C:39]([NH:1][C:2]3[CH:3]=[C:4]([CH:8]=[CH:9][CH:10]=3)[C:5]([OH:7])=[O:6])=[O:40])=[O:21])[C:36]3[C:31](=[CH:32][CH:33]=[CH:34][CH:35]=3)[C:30]=2[CH:29]=[CH:28][CH:27]=1
Reactant: O=C(Cl)CNC(=O)OCC1c2ccccc2-c2ccccc21
Reactant: Nc1cccc(C(=O)O)c1
Agent: Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: C1CCOC1
Solvent: ClCCl
Product: O=C(CNC(=O)OCC1c2ccccc2-c2ccccc21)Nc1cccc(C(=O)O)c1
Yield: 43 %

Procedure:
A solution of 3-aminobenzoic acid (0.5 g; 3.8 mmol) and N-ethyldiisopropylamine (DIEA) (0.64 mL; 3.8 mmol) in THF (20 mL) was added dropwise to a solution of Fmoc-glycine chloride (1.2 g; 4.0 mmol) (3) in THF (10 mL) and CH2Cl2 (10 mL). After 24 h stirring at room temperature 1 M HCl (50 mL) was added (final pH: 1.5). The precipitate was filtered, washed with H2O (2×100 mL), vacuum dried and crystallised from CHCl3/CH3OH (1:1) to give B as a white solid (0.7 g; 1.6 mmol). Yield 43%.
Reaction SMILES: C([NH:9][C:10]([NH:12][CH2:13][CH2:14][S:15][CH2:16][C:17]1[O:18][C:19]([CH2:22][N:23]([CH3:25])[CH3:24])=[CH:20][CH:21]=1)=[S:11])(=O)C1C=CC=CC=1.C(=O)([O-])[O-].[K+].[K+]>C(O)C.O>[CH3:25][N:23]([CH2:22][C:19]1[O:18][C:17]([CH2:16][S:15][CH2:14][CH2:13][NH:12][C:10]([NH2:9])=[S:11])=[CH:21][CH:20]=1)[CH3:24]
Reactant: CN(C)Cc1ccc(CSCCNC(=S)NC(=O)c2ccccc2)o1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CCO
Product: CN(C)Cc1ccc(CSCCNC(N)=S)o1
Temperature: 65 °C

Procedure:
A mixture of 24.76 g (65.6 mmol) of N-benzoyl-N'-(2-(((5-(dimethylamino)methyl-2-furanyl)methyl)thio)ethyl)-thiourea and 5.6 g (40.5 mmol) of potassium carbonate in 160 ml ethanol and 100 ml water is heated under stirring at 65° C. An additional amount of 3.45 g (25 mmol) potassium carbonate is added after 30 and 75 minutes respectively. After 90 minutes the ethanol is eliminated by vacuum distillation. A reaction mixture is diluted with 200 ml 5% sodium carbonate and extracted with dichloromethane (3×250 ml). The organic compound is washed with 5% sodium carbonate (2×500 ml), dried over anhydrous magnesium sulfate and concentrated to a brown oil. After chromatography on 500 g silica gel in dichloromethane/methanol 9:1, 16.8 g of N-(2-(((5-(dimethylamino)methyl-2-furanyl)methyl)thio)ethylthiourea oil is obtained.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([Cl:8])=[CH:4][C:3]=1[C:9]([C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1)=[O:10].[C:17]([C:21]1[CH:26]=[CH:25][C:24]([S:27](Cl)(=[O:29])=[O:28])=[CH:23][CH:22]=1)([CH3:20])([CH3:19])[CH3:18]>>[C:9]([C:3]1[CH:4]=[C:5]([Cl:8])[CH:6]=[CH:7][C:2]=1[NH:1][S:27]([C:24]1[CH:25]=[CH:26][C:21]([C:17]([CH3:20])([CH3:19])[CH3:18])=[CH:22][CH:23]=1)(=[O:29])=[O:28])(=[O:10])[C:11]1[CH:12]=[CH:13][CH:14]=[CH:15][CH:16]=1
Reactant: Nc1ccc(Cl)cc1C(=O)c1ccccc1
Reactant: CC(C)(C)c1ccc(S(=O)(=O)Cl)cc1
Product: CC(C)(C)c1ccc(S(=O)(=O)Nc2ccc(Cl)cc2C(=O)c2ccccc2)cc1

Procedure:
The title compound was prepared according to the general procedure for the synthesis of N-Aryl-benzenesulfonamides previously described using 115 mg of (2-amino-5-chloro-phenyl)-phenyl-methanone and 116 mg of 4-tert-Butyl-benzenesulfonyl chloride. 1H-NMR (400 MHz, CDCl3): δ 1.21 (s, 9H), 7.28–7.34 (m, 3H), 7.37–7.44 (m, 4H), 7.48 (dd, 1H, J=8.8, 2.4 Hz), 7.54–7.62 (m, 3H), 7.78 (d, 1H, J=8.8 Hz), 9.89 (s, 1H). MS: m/z 428.9 (M++1).
Reaction SMILES: C[Si]([N-][Si](C)(C)C)(C)C.[Li+].[C:11]([O:16][CH2:17][CH3:18])(=[O:15])[CH:12]([CH3:14])[CH3:13].Cl[CH2:20][C:21]1[CH:30]=[CH:29][C:28]2[C:23](=[CH:24][CH:25]=[CH:26][CH:27]=2)[CH:22]=1>O1CCCC1>[CH3:13][C:12]([CH3:14])([CH2:20][C:21]1[CH:30]=[CH:29][C:28]2[C:23](=[CH:24][CH:25]=[CH:26][CH:27]=2)[CH:22]=1)[C:11]([O:16][CH2:17][CH3:18])=[O:15]
Reactant: ClCc1ccc2ccccc2c1
Reactant: CCOC(=O)C(C)C
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Li+]
Solvent: C1CCOC1
Product: CCOC(=O)C(C)(C)Cc1ccc2ccccc2c1
Yield: 169.6 %

Procedure:
Lithium bis(trimethylsilyl)amide (1 M in tetrahydrofuran, 25.3 mL, 25.3 mmol) was added to a mixture of ethyl isobutyrate (2.67 g, 23.0 mmol) in tetrahydrofuran (25 mL) at −78° C. After stirring for 30 m, a solution of 2-(chloromethyl)naphthalene (400 mg, 2.30 mmol) in tetrahydrofuran (10 mL) was added to the reaction mixture dropwise. The mixture was stirred at −78° C. for another hour and then at room temperature overnight. The mixture was quenched by the addition of water and extracted with ethyl acetate. The combined organic fractions were washed with water, dried over sodium sulfate and concentrated under vacuum to give ethyl 2,2-dimethyl-3-(naphthalene-2-yl)propanoate (1.00 g) as a yellow oil, which was used without further purification.
Reaction SMILES: [F:1][C:2]([C:5]1[N:6]=[C:7]([CH2:10][N:11]2[N:15]=[C:14]([NH2:16])[CH:13]=[N:12]2)[S:8][CH:9]=1)([F:4])[CH3:3].[CH:17]1([C:20]2[O:21][C:22]([C:28]3[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=3)=[C:23]([C:25](O)=[O:26])[N:24]=2)[CH2:19][CH2:18]1>>[F:1][C:2]([C:5]1[N:6]=[C:7]([CH2:10][N:11]2[N:15]=[C:14]([NH:16][C:25]([C:23]3[N:24]=[C:20]([CH:17]4[CH2:18][CH2:19]4)[O:21][C:22]=3[C:28]3[CH:29]=[CH:30][CH:31]=[CH:32][CH:33]=3)=[O:26])[CH:13]=[N:12]2)[S:8][CH:9]=1)([F:4])[CH3:3]
Reactant: O=C(O)c1nc(C2CC2)oc1-c1ccccc1
Reactant: CC(F)(F)c1csc(Cn2ncc(N)n2)n1
Product: CC(F)(F)c1csc(Cn2ncc(NC(=O)c3nc(C4CC4)oc3-c3ccccc3)n2)n1

Procedure:
Following general procedure Z2, starting from 2-[4-(1,1-difluoro-ethyl)-thiazol-2-ylmethyl]-2H-[1,2,3]triazol-4-ylamine and 2-cyclopropyl-5-phenyl-oxazole-4-carboxylic acid.
Reaction SMILES: CC(CC(O)=O)=O.N=O.CC1(C)CCCC(C)(C)N1.[CH3:20][O:21][C:22]1[C:23]([O:55][CH3:56])=[CH:24][C:25]2[N:31]([C:32]([O:34][CH2:35][C:36]([Cl:39])([Cl:38])[Cl:37])=[O:33])[C@H:30]([CH2:40][O:41][Si:42]([C:45]([CH3:48])([CH3:47])[CH3:46])([CH3:44])[CH3:43])[C@@H:29]3[CH2:49][C@@H:50]([OH:52])[CH2:51][N:28]3[C:27](=[O:53])[C:26]=2[CH:54]=1>C(Cl)Cl>[CH3:20][O:21][C:22]1[C:23]([O:55][CH3:56])=[CH:24][C:25]2[N:31]([C:32]([O:34][CH2:35][C:36]([Cl:39])([Cl:37])[Cl:38])=[O:33])[C@H:30]([CH2:40][O:41][Si:42]([C:45]([CH3:48])([CH3:47])[CH3:46])([CH3:44])[CH3:43])[C@@H:29]3[CH2:49][C:50](=[O:52])[CH2:51][N:28]3[C:27](=[O:53])[C:26]=2[CH:54]=1
Reactant: COc1cc2c(cc1OC)N(C(=O)OCC(Cl)(Cl)Cl)[C@H](CO[Si](C)(C)C(C)(C)C)[C@@H]1C[C@@H](O)CN1C2=O
Agent: CC(=O)CC(=O)O
Agent: CC1(C)CCCC(C)(C)N1
Agent: N=O
Solvent: ClCCl
Product: COc1cc2c(cc1OC)N(C(=O)OCC(Cl)(Cl)Cl)[C@H](CO[Si](C)(C)C(C)(C)C)[C@@H]1CC(=O)CN1C2=O
Temperature: 25 °C
Reaction time: 18 h

Procedure:
Diodobenzene diacetate (2.44 g, 7.58 mmol, 1.78 Equiv.) and 2,2,6,6-tetramethylpiperidine nitroxyl (TEMPO) (133 mg, 0.85 mmol, 0.2 Equiv.) were added to a stirred solution of 25 (2.49 g, 4.26 mmol; 1.0 Equiv.) in dry DCM (40 mL). The mixture was stirred at room temperature for 18 h and the reaction mixture was diluted with DAM (50 mL). The organic phase was washed with said sodium bisulphite (2×25 mL), brine (40 mL), dried (MgSO4) and concentrated in vacuo. Purification by flash chromatography (EtOAc/Petroleum ether 6:4) afforded 26 as a white glass. (2.26 g, 91%): [α]D22=+95.0° (c=0.795, CHCl3); 1H NMR (CDCl3, 500 MHz) δ 0.22, 0.23 (two s, 6H, Si(CH3)2), 0.86 (s, 9H, C(CH3)3), 2.56 (dd, 1H, J=3.12, 19.60, H1b), 2.96 (dd, 1H, J=10.29, 18.9, H1a), 3.90 (s, 3H, CH3O8), 3.95-3.99 (m, 5H, H3b, H11a and CH3O7), 4.21 (d, 1H, J=12.02 Hz, Cl3CCH2), 4.32 (d, 1H, J=20.93 Hz, H3a), 5.24 (d, 1H, J=12.03 Hz, Cl3CCH2), 5.83 (d, 1H, J=9.26 Hz, H11), 6.77 (s, 1H, H9), 7.25 (s, 1H, H6); 13C NMR (CDCl3, 125 MHz) δ 207.8 (C2), 168.0 (C5), 153.7 (OC═ONH), 151.4 (C8), 149.2 (C7), 128.0 (C9-10), 124.5 (C5-6), 113.0 (C9), 110.4 (C6), 95.1 (Cl3C), 87.4 (C11), 74.8 (Cl3CCH2), 58.9 (C11a), 56.2 (CH3O7), 56.0 (CH3O8), 52.8 (C3), 40.3 (C1), 25.5 (C(CH3)3), 17.8 (Cquat), −4.2 and −5.3 (Si(CH3)2); IR (film) 2934, 1763 (C═O), 1720 (OC═ON), 1649 (NC═O), 1604, 1515, 1402, 1274, 1217, 1120, 1075, 1002, 866, 834, 756, 712 cm−1; MS (EI) m/z (relative intensity) 615 ([M+MeOH]+., 100).
Reaction SMILES: C([N-]C(C)C)(C)C.[Li+].C(NC(C)C)(C)C.C([Li])CCC.[C:21]1([CH3:30])[C:22]([C:27]([OH:29])=[O:28])=[CH:23][CH:24]=[CH:25][CH:26]=1.[CH2:31](Br)[CH2:32][CH2:33][CH2:34][CH2:35][CH2:36][CH2:37][CH2:38][CH2:39][CH2:40][CH3:41]>O1CCCC1>[CH2:30]([C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][C:22]=1[C:27]([OH:29])=[O:28])[CH2:41][CH2:40][CH2:39][CH2:38][CH2:37][CH2:36][CH2:35][CH2:34][CH2:33][CH2:32][CH3:31]
Reactant: CCCCCCCCCCCBr
Reactant: Cc1ccccc1C(=O)O
Agent: CC(C)[N-]C(C)C
Agent: [Li+]
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: CC(C)NC(C)C
Product: CCCCCCCCCCCCc1ccccc1C(=O)O
Reaction time: 0.08 h

Procedure:
A solution containing lithium diisopropylamide (0.1 mole) was prepared by treating a solution of diisopropylamine (14.1 ml, 0.1 mole) in tetrahydrofuran (200 ml) at 0° C. with n-butyl lithium (41.2 ml of a 2.43M solution, 0.1 mole), and stirring for 5 minutes. To this was added a solution of o-toluic acid (6.8 g, 0.05 mole) in tetrahydrofuran (50 ml). The ice bath was removed and the intense red solution was stirred for 30 minutes. This solution was slowly pipetted into a solution of undecylbromide (11.8 g, 0.05 mole) in tetrahydrofuran (50 ml) at -20° C. After the addition, the cooling bath was removed and the solution stirred for 30 minutes. A small amount of water was added and most of the tetrahydrofuran was removed under reduced pressure. The residue was poured into water, acidified with 3N hydrochloric acid and extracted with ether. The ether was dried, evaporated and the residue was recrystallized from acetonitrile, then from hexane, to give the product.
Reaction SMILES: [NH2:1][C:2]1[N:6]([CH:7]([CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH3:15])[CH2:8][CH3:9])[N:5]=[C:4]([CH3:16])[C:3]=1[C:17]([NH2:19])=[O:18].[CH2:20]1[O:28][C:27]2[CH:26]=[CH:25][C:24]([CH2:29][C:30](OC)=O)=[CH:23][C:22]=2[O:21]1.[O-]CC.[Na+].C(=O)([O-])O.[Na+]>ClCCl>[CH2:20]1[O:28][C:27]2[CH:26]=[CH:25][C:24]([CH2:29][C:30]3[NH:19][C:17](=[O:18])[C:3]4[C:4]([CH3:16])=[N:5][N:6]([CH:7]([CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH3:15])[CH2:8][CH3:9])[C:2]=4[N:1]=3)=[CH:23][C:22]=2[O:21]1
Reactant: COC(=O)Cc1ccc2c(c1)OCO2
Reactant: CCCCCCC(CC)n1nc(C)c(C(N)=O)c1N
Agent: CC[O-]
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Product: CCCCCCC(CC)n1nc(C)c2c(=O)[nH]c(Cc3ccc4c(c3)OCO4)nc21
Yield: 52.3 %

Procedure:
15 mg (0.055 mmol) of 5-amino-3-methyl-1-(3-nonyl)-1H-pyrazole-4-carboxamide and 53 mg (0.274 mmol) of methyl 3,4-methylenedioxyphenylacetate are refluxed for 6 hours in 0.5 ml of a 0.5M ethanolic sodium ethoxide solution. After dichloromethane and saturated aqueous sodium hydrogen carbonate solution have been added, the phases are separated. Purification by chromatography gives 11.8 mg (52%) of a solid, Rf=0.65 (dichloromethane/methanol=15:1).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:8]([C:16]2([OH:22])[CH2:21][CH2:20][CH2:19][CH2:18][CH2:17]2)[CH2:9][N:10]2[CH2:15][CH2:14][NH:13][CH2:12][CH2:11]2)[CH:5]=[CH:6][CH:7]=1.[O:23]([C:30]1[CH:31]=[C:32]([CH:35]=[CH:36][CH:37]=1)[CH:33]=O)[C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1.[ClH:38]>>[ClH:1].[ClH:38].[Cl:1][C:2]1[CH:3]=[C:4]([CH:8]([C:16]2([OH:22])[CH2:17][CH2:18][CH2:19][CH2:20][CH2:21]2)[CH2:9][N:10]2[CH2:15][CH2:14][N:13]([CH2:33][C:32]3[CH:35]=[CH:36][CH:37]=[C:30]([O:23][C:24]4[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=4)[CH:31]=3)[CH2:12][CH2:11]2)[CH:5]=[CH:6][CH:7]=1
Reactant: OC1(C(CN2CCNCC2)c2cccc(Cl)c2)CCCCC1
Reactant: O=Cc1cccc(Oc2ccccc2)c1
Agent: Cl
Product: OC1(C(CN2CCN(Cc3cccc(Oc4ccccc4)c3)CC2)c2cccc(Cl)c2)CCCCC1

Procedure:
In an analogous manner to Example 117, 1-{1-(3-chlorophenyl)-2-[4-(3-phenoxnbenzyl)piperazin-1-yl]ethyl}cyclohexanol dihydrochloride was prepared from 1-[1-(3-chlorophenyl)-2-piperazin-1-ylethyl]cyclohexanol (see Example 1) and 3-phenoxybenzaldehyde. MS (ESI) m/z 505/507 ([M+H]+); HRMS: calcd for C31H37ClN2O2. 2.00 HCl, 576.2077; found (ESI_FT), 505.26266.
Reaction SMILES: Cl[C:2]1[N:3]=[C:4]2[C:9](=[N:10][C:11]=1[N:12]1[CH2:17][CH2:16][S:15](=[O:18])[CH2:14][CH2:13]1)[N:8]=[C:7]([N:19]1[CH2:24][CH2:23][NH:22][CH2:21][CH2:20]1)[N:6]=[C:5]2[N:25]1[CH2:30][CH2:29][O:28][CH2:27][CH2:26]1.[CH2:31]([SH:34])[CH2:32][CH3:33]>>[O:28]1[CH2:29][CH2:30][N:25]([C:5]2[C:4]3[C:9](=[N:10][C:11]([N:12]4[CH2:17][CH2:16][S:15](=[O:18])[CH2:14][CH2:13]4)=[C:2]([S:34][CH2:31][CH2:32][CH3:33])[N:3]=3)[N:8]=[C:7]([N:19]3[CH2:24][CH2:23][NH:22][CH2:21][CH2:20]3)[N:6]=2)[CH2:26][CH2:27]1
Reactant: O=S1CCN(c2nc3nc(N4CCNCC4)nc(N4CCOCC4)c3nc2Cl)CC1
Reactant: CCCS
Product: CCCSc1nc2c(N3CCOCC3)nc(N3CCNCC3)nc2nc1N1CCS(=O)CC1

Procedure:
This compound was prepared analogous to Example 2 from 6-chloro-4-morpholino-7-(1-oxido-thiomorpholino)-2-piperazino-pteridine and propylmercaptan.
Reaction SMILES: [BH4-].[Na+].[CH3:3][O:4][C:5]1[CH:10]=[CH:9][C:8]([C:11](=[O:29])[CH:12]([CH2:18][C:19]2[CH:24]=[CH:23][C:22]([C:25]([F:28])([F:27])[F:26])=[CH:21][CH:20]=2)[C:13]([O:15][CH2:16][CH3:17])=[O:14])=[CH:7][CH:6]=1.Cl>C(OCC)C.[Cl-].[Zn+2].[Cl-]>[OH:29][CH:11]([C:8]1[CH:9]=[CH:10][C:5]([O:4][CH3:3])=[CH:6][CH:7]=1)[CH:12]([CH2:18][C:19]1[CH:24]=[CH:23][C:22]([C:25]([F:27])([F:28])[F:26])=[CH:21][CH:20]=1)[C:13]([O:15][CH2:16][CH3:17])=[O:14]
Reactant: CCOC(=O)C(Cc1ccc(C(F)(F)F)cc1)C(=O)c1ccc(OC)cc1
Agent: Cl
Agent: [BH4-]
Agent: [Cl-]
Solvent: CCOCC
Product: CCOC(=O)C(Cc1ccc(C(F)(F)F)cc1)C(O)c1ccc(OC)cc1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 87.4 %

Procedure:
To a solution of zinc chloride (12.3 g, 90.4 mmol) in diethyl ether (150 ml) was added sodium borohydride (6.85 g, 181 mmol) and the mixture was stirred at room temperature for 30 min. The insoluble material was filtered off. To the filtrate was added a solution of ethyl 3-(4-methoxyphenyl)-3-oxo-2-((4-(trifluoromethyl)phenyl)methyl)propionate (17.2 g, 45.2 mmol) in diethyl ether (50 ml) and the mixture was stirred at room temperature for 30 min. 1N Hydrochloric acid was added to the reaction solution under ice-cooling for quenching, water (200 ml) was added, and the mixture was extracted with ethyl acetate (300 ml×2). The extract was washed with water and saturated brine, dried over anhydrous magnesium sulfate and evaporated under reduced pressure. The residue was purified by silica gel column chromatography (hexane:ethyl acetate=4:1-2:1) to give ethyl (2RS,3RS)-3-hydroxy-3-(4-methoxyphenyl)-2-((4-(trifluoromethyl)phenyl)methyl)propionate (15.1 g, 87%) as a colorless oil.
Reaction SMILES: ClC(Cl)(Cl)C[O:4][C:5]([C@@H:7]1[CH2:12][CH2:11][CH2:10][N:9]([C:13](=[O:66])[C@@H:14]([NH:35][C:36](=[O:65])[C@@H:37]([NH:41][C:42](=[O:64])[C:43]([CH3:63])([CH3:62])/[CH:44]=[CH:45]/[C:46]2[CH:55]=[C:54]3[C:49]([CH:50]=[CH:51][C:52]([C@H:56]([O:58]C(=O)C)[CH3:57])=[N:53]3)=[CH:48][CH:47]=2)[CH:38]([CH3:40])[CH3:39])[C@H:15]([O:17][Si:18]([C:31]([CH3:34])([CH3:33])[CH3:32])([C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=2)[C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)[CH3:16])[NH:8]1)=[O:6].O.[OH-].[Li+].Cl>O1CCCC1.O>[C:31]([Si:18]([C:25]1[CH:26]=[CH:27][CH:28]=[CH:29][CH:30]=1)([C:19]1[CH:20]=[CH:21][CH:22]=[CH:23][CH:24]=1)[O:17][C@H:15]([CH3:16])[C@H:14]([NH:35][C:36](=[O:65])[C@@H:37]([NH:41][C:42](=[O:64])[C:43]([CH3:62])([CH3:63])/[CH:44]=[CH:45]/[C:46]1[CH:55]=[C:54]2[C:49]([CH:50]=[CH:51][C:52]([C@H:56]([OH:58])[CH3:57])=[N:53]2)=[CH:48][CH:47]=1)[CH:38]([CH3:40])[CH3:39])[C:13]([N:9]1[CH2:10][CH2:11][CH2:12][C@@H:7]([C:5]([OH:6])=[O:4])[NH:8]1)=[O:66])([CH3:34])([CH3:33])[CH3:32]
Reactant: CC(=O)O[C@H](C)c1ccc2ccc(/C=C/C(C)(C)C(=O)N[C@H](C(=O)N[C@H](C(=O)N3CCC[C@@H](C(=O)OCC(Cl)(Cl)Cl)N3)[C@@H](C)O[Si](c3ccccc3)(c3ccccc3)C(C)(C)C)C(C)C)cc2n1
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Product: CC(C)[C@H](NC(=O)C(C)(C)/C=C/c1ccc2ccc([C@@H](C)O)nc2c1)C(=O)N[C@H](C(=O)N1CCC[C@@H](C(=O)O)N1)[C@@H](C)O[Si](c1ccccc1)(c1ccccc1)C(C)(C)C
Temperature: 25 °C
Yield: 100 %

Procedure:
(S)-1-[(2S,3R)-2-((S)-2-{(E)-4-[2-((R)-1-Acetoxy-ethyl)-quinolin-7-yl]-2,2-dimethyl-but-3-enoylamino}-3-methyl-butyrylamino)-3-(tert-butyl-diphenyl-silanyloxy)-butyryl]-hexahydro-pyridazine-3-carboxylic acid 2,2,2-trichloro-ethyl ester (444 mg, 0.440 mmol) was taken up in a mixture of tetrahydrofuran (10 mL) and water (3 mL) and cooled using an ice bath. Lithium hydroxide monohydrate (148 mg, 3.52 mmol) was then added and the reaction was allowed to slowly warm to room temperature and left to stir for eighty minutes. The solution was then neutralised with hydrochloric acid (2 M) and concentrated until all volatiles had been removed to afford the title compound (368 mg, 100%) as a yellow solid. 1H NMR (300 MHz, CD3OD) δ 0.83 (d, J=6.5 Hz, 3H), 0.87-93 (m, 7H), 0.96 (s, 9H), 1.16-1.61 (m, 13H), 1.63-1.81 (m, 2H), 2.10-2.23 (m, 2H), 2.26-2.33 (m, 1H), 2.64-2.76 (m, 1H), 3.98-4.21 (m, 3H), 4.86 (d, J=11.8 Hz, 1H), 5.08 (d, J=9.6 Hz, 1H), 6.81 (ABq, Δδ=0.17, JAB=16.2 Hz, 2H), 7.13-7.19 (m, 1H), 7.22-7.29 (m, 1H), 7.32-7.47 (m, 6H), 7.52-7.63 (m, 4H), 7.72-8.12 (m, 3H). LCMS (m/z) 836.6 [M+H], Tr=3.03 min.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([F:8])[C:3]=1[F:9].[N:10]1[CH:15]=[CH:14][CH:13]=[C:12]2[CH2:16][C:17](=[O:21])[CH2:18][CH2:19][CH2:20][C:11]=12>C1COCC1>[F:9][C:3]1[C:4]([F:8])=[CH:5][CH:6]=[CH:7][C:2]=1[C:17]1([OH:21])[CH2:18][CH2:19][CH2:20][C:11]2=[N:10][CH:15]=[CH:14][CH:13]=[C:12]2[CH2:16]1
Reactant: Fc1cccc(Br)c1F
Reactant: O=C1CCCc2ncccc2C1
Solvent: C1CCOC1
Product: OC1(c2cccc(F)c2F)CCCc2ncccc2C1
Temperature: -78 °C
Reaction time: 0.33 h

Procedure:
In an oven-dried 500 mL round-bottomed flask was BuLi (17.19 mL, 43.0 mmol) in THF (100 mL) to give a colorless solution at −78° C. under nitrogen. 1-Bromo-2,3-difluorobenzene (4.81 mL, 43.0 mmol) was added dropwise via syringe. The mixture was stirred at −78° C. for 20 min, and 8,9-dihydro-5H-cyclohepta[b]pyridin-6(7H)-one (4.947 g, 30.7 mmol) (azeotroped with dry benzene and dried under high vac) dissolved in 10 ml THF was added dropwise via canuula (plus 10 ml THF rinse). The mixture was warmed up to rt in 1 h. TLC showed some conversion to a slightly more polar spot. After quenched with saturated NH4Cl solution, THF was stripped off. The remaining mixture was partitioned between water and EtOAc. The layers were separated and the organic layer was washed with brine, dried with Na2SO4, and concentrated to a dark oil. The residue was purified by FCC up to 10% MeOH/CH2Cl2 (very difficult separation). The impure fractions were pooled and purified by FCC with EtOAc/CH2Cl2 up to pure EtOAc. The recovered SM: 1.88 g (38%). The product fractions were pooled and concentrated to a tan solid, which were washed repeatedly with Et2O to a tan solid (1.79 g, 21%). 1H NMR (400 MHz, CHLOROFORM-d) δ ppm 8.27 (dd, J=4.91, 1.38 Hz, 1H) 7.38-7.47 (m, 1H) 7.30-7.35 (m, 1H) 6.97-7.12 (m, 3H) 3.93 (dd, J=14.60, 2.52 Hz, 1H) 3.06-3.20 (m, 2H) 2.86 (dd, J=14.60, 1.76 Hz, 1H) 2.37-2.68 (m, 2H) 1.68-1.94 (m, 2H) 1.17 (t, J=7.05 Hz, 1H).
Reaction SMILES: C(OC(=O)[NH:7][CH2:8][C:9]1[N:10]([CH2:30][CH:31]([CH3:33])[CH3:32])[C:11](=[O:29])[C:12]2[C:17]([C:18]=1[O:19][CH2:20][CH2:21][CH2:22][CH3:23])=[CH:16][C:15]([N:24]1[CH:28]=[N:27][N:26]=[N:25]1)=[CH:14][CH:13]=2)(C)(C)C.[ClH:35]>C(OCC)(=O)C>[ClH:35].[NH2:7][CH2:8][C:9]1[N:10]([CH2:30][CH:31]([CH3:32])[CH3:33])[C:11](=[O:29])[C:12]2[C:17]([C:18]=1[O:19][CH2:20][CH2:21][CH2:22][CH3:23])=[CH:16][C:15]([N:24]1[CH:28]=[N:27][N:26]=[N:25]1)=[CH:14][CH:13]=2
Reactant: CCCCOc1c(CNC(=O)OC(C)(C)C)n(CC(C)C)c(=O)c2ccc(-n3cnnn3)cc12
Agent: Cl
Solvent: CCOC(C)=O
Product: CCCCOc1c(CN)n(CC(C)C)c(=O)c2ccc(-n3cnnn3)cc12
Temperature: 25 °C
Reaction time: 1 h
Yield: 95 %

Procedure:
Tert-butyl[4-butoxy-2-isobutyl-1-oxo-6-(1H-tetrazol-1-yl)-1,2-dihydro-3-isoquinolinyl]methylcarbamate (0.24 g, 0.5 mmol) was dissolved in a solution of 4N hydrogen chloride in ethyl acetate (5 ml) and the mixture was stirred at room temperature for 1 h. The reaction mixture was concentrated under reduced pressure and the obtained crystals was crystallized from methanol-diethyl ether to give 3-(aminomethyl)-4-butoxy-2-isobutyl-6-(1H-tetrazol-1-yl)-1(2H)-isoquinolinone hydrochloride (0.19 g, 95.0%) as crystals.
Reaction SMILES: [Cl:1][C:2]1[C:11]([Cl:12])=[CH:10][C:9]([Cl:13])=[CH:8][C:3]=1[C:4]([C:6]#[N:7])=O.C(=O)(O)O.[NH2:18][NH:19][C:20]([NH2:22])=[NH:21].[N+]([O-])(O)=O>CS(C)=O>[NH2:21][C:20]1[N:19]=[N:18][C:4]([C:3]2[CH:8]=[C:9]([Cl:13])[CH:10]=[C:11]([Cl:12])[C:2]=2[Cl:1])=[C:6]([NH2:7])[N:22]=1
Reactant: N=C(N)NN
Reactant: N#CC(=O)c1cc(Cl)cc(Cl)c1Cl
Agent: O=C(O)O
Solvent: CS(C)=O
Solvent: O=[N+]([O-])O
Product: Nc1nnc(-c2cc(Cl)cc(Cl)c2Cl)c(N)n1
Reaction time: 3 h

Procedure:
A solution of 2,3,5-trichlorobenzoyl cyanide (38.5 g, 0.16M) in dimethylsulphoxide (80 ml) was added dropwise to a stirred suspension of aminoguanidine bicarbonate (65.76 g, 0.32M) which had been treated with 8N aqueous nitric acid (560 ml). The mixture was stirred for 3 hours and then was left to stand at room temperature for 21 days. The solid was filtered off, washed with water (2×100 ml) and dried in vacuo. A suspension of the dried solid in a 10% solution of potassium hydroxide pellets in methanol (320 ml) was heated to reflux for 1 hour, the mixture was cooled and evaporated down in vacuo. The residue was treated with ice/water (200 ml), the resultant solid was filtered off and dried in vacuo. This dried solid was put on top of a dry column (25 mm diameter, 200 g of MFC silica gel) and eluted with a solution of ethyl acetate/methanol/acetic acid (90:2.5:2.5). Fractions 50 to 80 (900 drops per fraction) were collected, combined and evaporated down in vacuo. The resultant solid was recrystallised from isopropanol to give 3,5-diamino-6-(2,3,5-trichlorophenyl)- 1,2,4-triazine. Yield 0.77 g (1.6%), m.p. 232°-235° C. (uncorrected).
Reaction SMILES: [F:1][C:2]1[C:31]([F:32])=[CH:30][CH:29]=[CH:28][C:3]=1[CH2:4][NH:5][C:6]1[C:11]([C:12]([NH2:14])=[O:13])=[CH:10][N:9]=[C:8]([NH:15][C:16]2[CH:21]=[CH:20][C:19]([CH:22]3[CH2:27][CH2:26][NH:25][CH2:24][CH2:23]3)=[CH:18][CH:17]=2)[CH:7]=1.O.[CH3:34][N:35]1[CH2:42][CH2:41][CH2:40][C@H:36]1[C:37](O)=[O:38].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>CN1C(=O)CCC1>[F:1][C:2]1[C:31]([F:32])=[CH:30][CH:29]=[CH:28][C:3]=1[CH2:4][NH:5][C:6]1[C:11]([C:12]([NH2:14])=[O:13])=[CH:10][N:9]=[C:8]([NH:15][C:16]2[CH:17]=[CH:18][C:19]([CH:22]3[CH2:23][CH2:24][N:25]([C:37]([C@@H:36]4[CH2:40][CH2:41][CH2:42][N:35]4[CH3:34])=[O:38])[CH2:26][CH2:27]3)=[CH:20][CH:21]=2)[CH:7]=1
Reactant: CN1CCC[C@H]1C(=O)O
Reactant: NC(=O)c1cnc(Nc2ccc(C3CCNCC3)cc2)cc1NCc1cccc(F)c1F
Agent: CN(C)[P+](On1nnc2ccccc21)(N(C)C)N(C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN1CCCC1=O
Solvent: CCN(C(C)C)C(C)C
Solvent: O
Product: CN1CCC[C@H]1C(=O)N1CCC(c2ccc(Nc3cc(NCc4cccc(F)c4F)c(C(N)=O)cn3)cc2)CC1
Temperature: 25 °C
Yield: 64.6 %

Procedure:
The mixture of compound 4-(2,3-difluorobenzylamino)-6-(4-(piperidin-4-yl)phenylamino)nicotinamide (Example 209) (50 mg, 0.11 mmol), N-methyl-L-proline monohydrate (33 mg, 0.22 mmol), DIEA (180 μL, 1.1 mmol) in 4 mL NMP was stirred at RT. To it was added BOP (210 mg, 0.55 mmol). The mixture was stirred for overnight, quenched with TFA, and subjected to reverse phase preparative HPLC to isolate the title compound (39 mg). MS found for C30H34F2N6O2 as (M+H)+ 549.5. UV: λ=259 nm. 1H NMR (a pair of rotomers): (CD3OD) δ 8.18 (1H, s), 7.32 (with 7.33, 2H, d, J=8.4 Hz), 7.25 (1H, m), 7.17 (1H, m), 7.13-7.07 (3H, m), 5.77 (with 5.79, 1H, s), 4.68 (2H, m), 4.57 (1H, m), 4.54 (2H, s), 3.90 (1H, m), 3.74 (1H, m), 3.27 (1H, m), 2.93 (with 2.97, 3H, s), 2.90 (2H, m), 2.68 (1H, m), 2.25 (1H, m), 2.11-1.95 (4H, m), 1.82-1.63 (2H, m) ppm.