Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [ClH:1].[CH3:2][C:3]1[NH:7][CH:6]=[N:5][C:4]=1[CH2:8][S:9][CH2:10][CH2:11][NH:12][C:13]([NH:15][CH2:16][CH2:17][S:18][CH2:19][C:20]1[N:21]=[CH:22][NH:23][C:24]=1[CH3:25])=[S:14].[CH3:26]O>>[ClH:1].[ClH:1].[ClH:1].[CH3:26][S:14][C:13](=[N:12][CH2:11][CH2:10][S:9][CH2:8][C:4]1[N:5]=[CH:6][NH:7][C:3]=1[CH3:2])[NH:15][CH2:16][CH2:17][S:18][CH2:19][C:20]1[N:21]=[CH:22][NH:23][C:24]=1[CH3:25]
Reactant: Cc1[nH]cnc1CSCCNC(=S)NCCSCc1nc[nH]c1C
Reactant: CO
Agent: Cl
Product: CSC(=NCCSCc1nc[nH]c1C)NCCSCc1nc[nH]c1C

Procedure:
Dry hydrogen chloride was passed into a solution of N,N'-bis-[2-((5-methyl-4-imidazolyl)methylthio)ethyl]thiourea (7.7 g) in methanol at 80° for 5 hours. Concentration and re-evaporation with isopropyl alcohol afforded S-methyl-N,N'-bis-[2-((5-methyl-4-imidazolyl)methylthio)ethyl]isothiourea trihydrochloride (9.0 g), m.p. 212°-215° (isopropyl alcohol).
Reaction SMILES: [Cl:1][C:2](=[CH2:12])[CH2:3][C:4]1[CH:11]=[CH:10][C:7]([CH2:8][OH:9])=[CH:6][CH:5]=1.[Br:13][C:14]([Br:24])=[CH:15][C@H:16]1[C@@H:18]([C:19](Cl)=[O:20])[C:17]1([CH3:23])[CH3:22].N1C=CC=CC=1>C1C=CC=CC=1>[Br:13][C:14]([Br:24])=[CH:15][C@H:16]1[C@@H:18]([C:19]([O:9][CH2:8][C:7]2[CH:10]=[CH:11][C:4]([CH2:3][C:2]([Cl:1])=[CH2:12])=[CH:5][CH:6]=2)=[O:20])[C:17]1([CH3:22])[CH3:23]
Reactant: C=C(Cl)Cc1ccc(CO)cc1
Reactant: CC1(C)[C@H](C(=O)Cl)[C@@H]1C=C(Br)Br
Solvent: c1ccncc1
Solvent: c1ccccc1
Product: C=C(Cl)Cc1ccc(COC(=O)[C@@H]2[C@H](C=C(Br)Br)C2(C)C)cc1
Reaction time: 16 h

Procedure:
The alcohol of Example 2 (0.078 g) in benzene (2 ml) is added to (IR)cis 3-(2,2-dibromovinyl)2,2-dimethylcyclopropane carbonyl chloride (0.135 g) in benzene (3 ml). Pyridine (0.06 ml) is then added and the mixture stirred at 20° for 16 hours. This is chromatographed on florisil and the fraction eluted by 7% ether in petrol evaporated to a residue of 0.19 g (96%) ester, nD20 1.5692.
Reaction SMILES: [CH3:1]/[C:2](/[O:8][Si:9]([CH3:12])([CH3:11])[CH3:10])=[N:3]\[Si](C)(C)C.O[C:14]1[CH:15]=[C:16]2[C:20](=[CH:21][C:22]=1O)NC=C2>ClCCl>[CH3:10][Si:9]([CH3:12])([CH3:11])[O:8][C:1]1[C:21]2[C:22](=[CH:14][CH:15]=[CH:16][CH:20]=2)[NH:3][C:2]=1[O:8][Si:9]([CH3:10])([CH3:11])[CH3:12]
Reactant: Oc1cc2cc[nH]c2cc1O
Reactant: C/C(=N\[Si](C)(C)C)O[Si](C)(C)C
Solvent: ClCCl
Product: C[Si](C)(C)Oc1[nH]c2ccccc2c1O[Si](C)(C)C
Temperature: 25 °C
Yield: 71 %

Procedure:
To 0.81 g (0.004 mole) of N,O-bis(trimethylsilyl) acetamide is added, stirring at room temperature, 0.3 g (0.002 mole) of 5,6-dihydroxy indole. When dissolution is completed, 2 ml dichloromethane are added and the solution is passed through a column of silica 60, eluating with dichloromethane. The first fraction obtained is concentrated in a rotavapor, then vacuum-dried. Thus are obtained 0.42 g (yield: 71%) of white crytal of 5,6[di(trimethylsilyloxy]indole.
Reaction SMILES: [OH:1][CH2:2][C:3]([C@H:5]([C@@H:7]([C@@H:9]([CH2:11][OH:12])[OH:10])O)O)=O.CN1[C:18](=[O:19])[CH2:17]CC1.C(OC(=O)C)(=O)C>CN(C1C=CN=CC=1)C.O>[C:18]([O:12][CH2:11][C:9]1[O:10][C:3]([CH:2]=[O:1])=[CH:5][CH:7]=1)(=[O:19])[CH3:17]
Reactant: CN1CCCC1=O
Reactant: O=C(CO)[C@@H](O)[C@H](O)[C@H](O)CO
Agent: CN(C)c1ccncc1
Solvent: CC(=O)OC(C)=O
Solvent: O
Product: CC(=O)OCc1ccc(C=O)o1
Temperature: 110 °C

Procedure:
39.4 kg (219 mol) of D-fructose and 5.9 kg of dried acidic Dowex® 50WX8-200 ion exchanger (styrene-divinylbenzene copolymer resin with SO3H groups, obtainable from The Dow Chemical Company, Midland, U.S.A.) in the H form were introduced with stirring into 90 l of NMP and heated to 110° C. for 6 h. After cooling, the reaction mixture was filtered and washed with 8 l of NMP. The filtrate was admixed with stirring with 390 g (3.2 mol) of 4-(N,N-dimethylamino)pyridine and 20.5 1 (217 mol) of acetic anhydride at 20-25° C. within 1 h. After continuing the reaction for 1 h, the brown reaction mixture was freed of the solvent at 90-100° C. under reduced pressure (of 50-10 mbar). After cooling, the residue was admixed with 160 l of MtBE, 60 1 of water and 4 kg of activated carbon. The suspension was filtered though Celite®. After the phase separation, the solvent of the filtrate was distilled off at 50° C. under reduced pressure (20 mbar) and the residue was fractionally distilled under reduced pressure at 106-110° C./5 mbar.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:37])[CH2:4][N:5]([C:11]1[CH:16]=[C:15]([O:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH3:35])[CH:14]=[C:13]([OH:36])[CH:12]=1)[CH2:6][C:7]([O:9][CH3:10])=[O:8].[Br:38][CH2:39][CH2:40][CH2:41]Br.C(=O)([O-])[O-].[K+].[K+]>CC(C)=O.CN(C=O)C>[CH3:1][O:2][C:3](=[O:37])[CH2:4][N:5]([C:11]1[CH:16]=[C:15]([O:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH3:35])[CH:14]=[C:13]([O:36][CH2:41][CH2:40][CH2:39][Br:38])[CH:12]=1)[CH2:6][C:7]([O:9][CH3:10])=[O:8]
Reactant: CCCCCCCCCCCCCCCCCCOc1cc(O)cc(N(CC(=O)OC)CC(=O)OC)c1
Reactant: BrCCCBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: CC(C)=O
Product: CCCCCCCCCCCCCCCCCCOc1cc(OCCCBr)cc(N(CC(=O)OC)CC(=O)OC)c1
Yield: 71 %

Procedure:
A mixture of 4.0 g (7.67 mmol) of N-[3-hydroxy-5-(octadecyloxy)phenyl]-N-(2-methoxy-2-oxoethyl)glycine methyl ester, 7.8 ml (76.7 mmol) of 1,3-dibromopropane and 5.3 g (38.3 mmol) of potassium carbonate in 75 ml of acetone and 15 ml of DMF was stirred at reflux under argon for 41 hours. The reaction mixture was filtered through a Celite pad and the filtrate was concentrated to a solidwhich was purified by HPLC using 5% ethyl acetate-toluene to give 3.5 g (72% yield, mp 67°-69°) of N-[3-(3-bromopropoxy)-5-(octadecyloxy)phenyl]-N-(2-methoxy-2-oxoethyl) glycine methyl ester. The structure was confirmed by the nmr spectrum.
Reaction SMILES: [C:1]([NH2:5])(=[O:4])[CH:2]=[CH2:3].[NH2:6][CH2:7][CH2:8][CH3:9]>CO>[CH2:7]([N:6]([CH2:3][CH2:2][C:1]([NH2:5])=[O:4])[CH2:3][CH2:2][C:1]([NH2:5])=[O:4])[CH2:8][CH3:9]
Reactant: C=CC(N)=O
Reactant: CCCN
Solvent: CO
Product: CCCN(CCC(N)=O)CCC(N)=O
Temperature: 80 °C
Yield: 97590.4 %

Procedure:
A mixture of 118.6 g (1.67 mol) of acrylamide and 49.3 g (0.83 mmol) of 1-aminopropane in 250 ml of methanol was heated at 80° C. for 1 hour. The solvent was evaporated and the solid crystallized from ethanol. There was obtained 162.3 g (0.81 mol, 97%) of 3,3'-(propylimino)bispropanamide as a white solid mp 101°-101.5° C.
Reaction SMILES: C[O:2][C:3](=[O:38])[CH:4]([C:14]1[N:15]=[CH:16][N:17]([C:19]([C:32]2[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=2)([C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=2)[C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)[CH:18]=1)[CH2:5][C:6]1[CH:11]=[CH:10][C:9]([C:12]#[N:13])=[CH:8][CH:7]=1.[OH-].[Li+].Cl>C1COCC1>[C:32]1([C:19]([C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)([C:26]2[CH:27]=[CH:28][CH:29]=[CH:30][CH:31]=2)[N:17]2[CH:18]=[C:14]([CH:4]([CH2:5][C:6]3[CH:11]=[CH:10][C:9]([C:12]#[N:13])=[CH:8][CH:7]=3)[C:3]([OH:38])=[O:2])[N:15]=[CH:16]2)[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=1
Reactant: COC(=O)C(Cc1ccc(C#N)cc1)c1cn(C(c2ccccc2)(c2ccccc2)c2ccccc2)cn1
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Product: N#Cc1ccc(CC(C(=O)O)c2cn(C(c3ccccc3)(c3ccccc3)c3ccccc3)cn2)cc1

Procedure:
A solution of the 2-{1-(triphenylmethyl)-1H-imidazol-4-yl}-2-(4-cyanobenzyl)-acetic acid methyl ester in THF was treated with 1 equivalent of 1M lithium hydroxide solution. Upon consumption of starting material as determined by t.l.c, 1 equivalent of hydrochloric acid was added and the solution evaporated to dryness in vacuo. The material obtained in this manner could be used without furthur purification.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[OH:8].C([Li])CCC.[CH3:14][O:15][CH2:16][C:17](=[O:19])[CH3:18]>>[OH:19][C:17]([C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[OH:8])([CH3:18])[CH2:16][O:15][CH3:14]
Reactant: COCC(C)=O
Reactant: Oc1ccccc1Br
Agent: [Li]CCCC
Product: COCC(C)(O)c1ccccc1O

Procedure:
2-(2-hydroxy-1-methoxypropan-2-yl)phenol was prepared according to the procedure described for 417a using 2-bromophenol (400 μL, 3.4 mmol), n-butyllithium in hexanes (1.6 M, 5.0 mL, 7.9 mmol) and methoxyacetone (412 uL, 4.48 mmol). 1H NMR (400 MHz, CDCl3) δppm 1.64 (s, 3H), 3.45 (d, J=9.3 Hz, 1H), 3.47 (s, 3H), 3.77 (d, J=9.3 Hz, 1H), 6.85 (m, 1H), 6.90 (m, 1H), 7.04 (m, 1H), 7.20 (m, 1H), 9.22 (s, 1H).
Reaction SMILES: Cl.[CH3:2][O:3][C:4]1[CH:5]=[CH:6][C:7]2[O:12][CH2:11][CH:10]([CH2:13][NH:14][CH2:15][CH2:16][CH2:17][O:18][C:19]3[CH:29]=[CH:28][C:22]4[CH:23]=[CH:24][C:25](=[O:27])[O:26][C:21]=4[CH:20]=3)[O:9][C:8]=2[CH:30]=1.CI.[CH:33](N(C(C)C)CC)(C)C>CN(C=O)C>[CH3:2][O:3][C:4]1[CH:5]=[CH:6][C:7]2[O:12][CH2:11][CH:10]([CH2:13][N:14]([CH3:33])[CH2:15][CH2:16][CH2:17][O:18][C:19]3[CH:29]=[CH:28][C:22]4[CH:23]=[CH:24][C:25](=[O:27])[O:26][C:21]=4[CH:20]=3)[O:9][C:8]=2[CH:30]=1
Reactant: CCN(C(C)C)C(C)C
Reactant: COc1ccc2c(c1)OC(CNCCCOc1ccc3ccc(=O)oc3c1)CO2
Agent: Cl
Solvent: CI
Solvent: CN(C)C=O
Product: COc1ccc2c(c1)OC(CN(C)CCCOc1ccc3ccc(=O)oc3c1)CO2
Temperature: 80 °C
Yield: 9.7 %

Procedure:
7-[3-[[(2,3-Dihydro-7-methoxy-1,4-benzodioxin-2-yl)methyl]amino]propoxy]-2H-1-benzopyran-2-one hydrochloride (2.2 g, 5.0 mmole) was dissolved in 100 ml of DMF and 700 mg (5.0 mmole) of methyl iodide added, followed by 2.6 g (20 mmole) of diisopropylethylamine. The mixture was heated at 80° C. for 24 hours under a nitrogen atmosphere. The solvent was then removed in vacuum and replaced with 300 ml of dichloromethane. The mixture was washed with 300 ml portions of saturated aqueous sodium bicarbonate, saturated sodium chloride solution, dried over sodium sulfate, filtered and concentrated in vacuum. The residue was purified by column chromatography on 100 g of silica gel using chloroform as eluant and crystallized from isopropanol with addition of 2.5 ml of 4N isopropanolic HCl to give 0.20 g of the title compound as a monohydrochloride, m.p. 176°-178° C.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([OH:11])[C:5]([OH:10])=[C:6]([CH:9]=1)[CH:7]=[O:8].[H-].[Na+].[CH2:14]([O:21][CH2:22][CH2:23][CH2:24]Br)[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1>CS(C)=O>[CH2:14]([O:21][CH2:22][CH2:23][CH2:24][O:11][C:4]1[C:5]([OH:10])=[C:6]([CH:9]=[C:2]([Cl:1])[CH:3]=1)[CH:7]=[O:8])[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1
Reactant: BrCCCOCc1ccccc1
Reactant: O=Cc1cc(Cl)cc(O)c1O
Agent: [H-]
Agent: [Na+]
Solvent: CS(C)=O
Product: O=Cc1cc(Cl)cc(OCCCOCc2ccccc2)c1O
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 93.8 %

Procedure:
To a solution of 5-chloro-2,3-dihydroxy-benzaldehyde (3.1 g, 17.7 mmol) in anhydrous DMSO (20 mL) was added NaH (60% in mineral oil, 1.50 g, 35.4 mmol) portion-wise and the mixture was stirred for 30 minutes. The solution was cooled to 0° C. and a solution of 3-benzyloxy-1-bromopropane (3.1 mL, 17.7 mmol) in DMSO (3 mL) was added dropwise over 10 minutes period. The ice bath was removed. After overnight, the solution was diluted with EtOAc (100 mL), washed with water, brine, dried over Na2SO4, filtered and concentrated under reduced pressure. The product was purified by silica gel column chromatography (2:1 hexanes-EtOAc mobile phase) generating the title compound (5.3 g, 16.6 mmol, 94%) as a light yellow oil. 1H NMR (400 MHz, CHLOROFORM-d) δ ppm 10.81 (s, 1H), 9.87 (s, 1H), 7.42-7.28 (m, 5H), 7.17 (s, 1H), 7.08 (s, 1H), 4.53 (s, 2H), 4.17 (t, J=6.2 Hz, 2H), 3.69 (t, J=5.8 Hz, 2H), 2.15 (t, J=6.2 Hz, 2H).
Reaction SMILES: [Br:1][C:2]1[C:3]([F:11])=[C:4]([C:7]([Cl:10])=[CH:8][CH:9]=1)[CH:5]=[O:6].[BH4-].[Na+]>C(O)C.O>[Br:1][C:2]1[C:3]([F:11])=[C:4]([CH2:5][OH:6])[C:7]([Cl:10])=[CH:8][CH:9]=1
Reactant: O=Cc1c(Cl)ccc(Br)c1F
Agent: [BH4-]
Agent: [Na+]
Solvent: CCO
Solvent: O
Product: OCc1c(Cl)ccc(Br)c1F
Temperature: 25 °C
Reaction time: 1 h
Yield: 51.2 %

Procedure:
To a solution of 3-bromo-6-chloro-2-fluorobenzaldehyde (20.0 g, 0.084 mol) in ethanol (250 mL) was added sodium borohydride (6.4 g, 0.168 mol) and the reaction mixture was stirred at ambient temperature for 1 hour. The mixture was diluted with water (300 mL) and extracted with ethyl acetate (2×200 mL), dried (sodium sulfate) and concentrated. The crude solid was recrystallized from hexanes to give (3-bromo-6-chloro-2-fluorophenyl) methanol (10.4 g, 0.043 mol): 1H NMR (CDCl3): δ 7.50 (m, 1H), 7.15 (dt, 1H), 4.90 (s, 2H), 2.10 (bs, 1H).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]([CH3:15])=[CH:9][PH:10](=[O:14])[O:11][CH2:12][CH3:13])=[CH:4][CH:3]=1.B(F)(F)F.CCOCC.C(=O)([O-])O.[Na+].[CH:30](OCC)([O:34][CH2:35][CH3:36])[O:31][CH2:32][CH3:33]>>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]([CH3:15])=[CH:9][P:10]([CH:30]([O:34][CH2:35][CH3:36])[O:31][CH2:32][CH3:33])(=[O:14])[O:11][CH2:12][CH3:13])=[CH:6][CH:7]=1
Reactant: CCO[PH](=O)C=C(C)c1ccc(Cl)cc1
Reactant: CCOC(OCC)OCC
Agent: FB(F)F
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCOCC
Product: CCOC(OCC)P(=O)(C=C(C)c1ccc(Cl)cc1)OCC
Temperature: 25 °C
Reaction time: 168 h

Procedure:
A solution of 1.68 g of ethyl 2-(4-chlorophenyl)prop-1-enylphosphinate in 20 ml of triethyl orthoformate is treated with 0.1 g of boron trifluoride diethyl etherate and the resulting solution stirred for 7 days at room temperature. The reaction mixture is then treated with 20 ml 10% aqueous sodium hydrogen carbonate solution and extracted twice with dichloromethane. The organic layer is removed, dried and concentrated to give an oil. Chromatography on silica gel gives ethyl 2-(4-chlorophenyl)prop-1-enyl-(diethoxymethyl)phosphinate as a colourless oil. 1H-NMR (CDCl3): δ(ppm)=7.38 (4H, m; Ph), 5.51 (1H, d, CH), 4.62 (1H, d, CH--P), 4.05 (2H, q, CH2OP), 3.88-3.56 (CH, m, 2×CH2OC), 2.07 (2H, d, d, CH2P), 1.28-1.14 (9H, m, 3×CH3).
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4]([CH:17]=[C:18]([CH3:20])[CH:19]=1)[C:5]([N:7]([CH3:16])[C@H:8]([C:13]([OH:15])=O)[C@H:9]([CH2:11][CH3:12])[CH3:10])=[O:6].Cl.C[O:23][C:24](=[O:37])[C@H:25]([CH2:27][C:28]1[C:36]2[C:31](=[CH:32][CH:33]=[CH:34][CH:35]=2)[NH:30][CH:29]=1)[NH2:26]>>[CH3:20][C:18]1[CH:17]=[C:4]([CH:3]=[C:2]([CH3:1])[CH:19]=1)[C:5]([N:7]([CH3:16])[C@H:8]([C:13]([NH:26][C@H:25]([C:24]([OH:37])=[O:23])[CH2:27][C:28]1[C:36]2[C:31](=[CH:32][CH:33]=[CH:34][CH:35]=2)[NH:30][CH:29]=1)=[O:15])[C@H:9]([CH2:11][CH3:12])[CH3:10])=[O:6]
Reactant: COC(=O)[C@@H](N)Cc1c[nH]c2ccccc12
Reactant: CC[C@H](C)[C@@H](C(=O)O)N(C)C(=O)c1cc(C)cc(C)c1
Agent: Cl
Product: CC[C@H](C)[C@@H](C(=O)N[C@@H](Cc1c[nH]c2ccccc12)C(=O)O)N(C)C(=O)c1cc(C)cc(C)c1

Procedure:
Coupling of N-(3,5-dimethylbenzoyl)-N-methyl-(L)-isoleucine (prepared following the procedure described in example 78) with (L)-tryptophan methyl ester hydrochloride according to example 12 followed by hydrolysis of the methyl ester moiety according to example 1 gives N-(3,5-dimethylbenzoyl)-N-methyl-(L)-isoleucinyl-(L)-tryptophan; FAB-MS m/e 464 (M+H)+.
Reaction SMILES: [NH2:1][C:2]1[C:17]([O:18][CH3:19])=[CH:16][C:5]2[CH:6]([CH2:14][CH3:15])[C:7](=[O:13])[N:8]([CH2:11][CH3:12])[CH2:9][CH2:10][C:4]=2[CH:3]=1.Cl[C:21]1[N:26]=[C:25]([NH:27][C@@H:28]2[CH2:33][CH2:32][CH2:31][CH2:30][C@H:29]2[NH:34][S:35]([CH3:38])(=[O:37])=[O:36])[C:24]([Cl:39])=[CH:23][N:22]=1.C12(CS(O)(=O)=O)C(C)(C)C(CC1)CC2=O.C(O)(C)C.C(=O)(O)[O-].[Na+]>O>[Cl:39][C:24]1[C:25]([NH:27][C@@H:28]2[CH2:33][CH2:32][CH2:31][CH2:30][C@H:29]2[NH:34][S:35]([CH3:38])(=[O:37])=[O:36])=[N:26][C:21]([NH:1][C:2]2[C:17]([O:18][CH3:19])=[CH:16][C:5]3[CH:6]([CH2:14][CH3:15])[C:7](=[O:13])[N:8]([CH2:11][CH3:12])[CH2:9][CH2:10][C:4]=3[CH:3]=2)=[N:22][CH:23]=1
Reactant: CCC1C(=O)N(CC)CCc2cc(N)c(OC)cc21
Reactant: CS(=O)(=O)N[C@@H]1CCCC[C@H]1Nc1nc(Cl)ncc1Cl
Agent: CC1(C)C2CCC1(CS(=O)(=O)O)C(=O)C2
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Solvent: CC(C)O
Product: CCC1C(=O)N(CC)CCc2cc(Nc3ncc(Cl)c(N[C@@H]4CCCC[C@H]4NS(C)(=O)=O)n3)c(OC)cc21
Temperature: 120 °C

Procedure:
7-Amino-1,3-diethyl-8-methoxy-1,3,4,5-tetrahydro-3-benzazepin-2-one (85 mg, 0.32 mmol;), N-[(1R,2R)-2-(2,5-dichloro-pyrimidin-4-ylamino)-cyclohexyl]-methanesulfonamide (120 mg, 0.36 mmol), and 10-camphorsulfonic acid (82.5 mg, 0.355 mmol) were charged to isopropyl alcohol (3 ml, 40 mmol) in a microwave reaction tube. The reaction was heated in microwave at 120° C. for 40 minutes. The resulting solution was poured into a mixture of 20 ml saturated sodium bicarbonate solution and 40 ml water and the aqueous solution was extracted with methylene chloride (4×10 ml portions). The combined organic extracts were dried over magnesium sulfate, filtered and evaporated under reduced pressure to yield a clear yellow oil. The oil was evaporated onto celite and the celite placed on silica gel (12 g Isco column) and eluted with 0-70% EtOAc in Hexanes to obtain N-{(1R,2R)-2-[5-Chloro-2-(1,3-diethyl-8-methoxy-2-oxo-2,3,4,5-tetrahydro-1H-benzo[d]azepin-7-ylamino)-pyrimidin-4-ylamino]-cyclohexyl}-methanesulfonamide as a beige powder. MP: 126-127° C.; 1H-NMR (CDCl3) δ 8.01 (d, J=7.1 Hz, 1H), 7.35 (s, 1H), 6.72 (s, 1H), 5.35 (d, J=7.8 Hz, 1H), 5.29 (d, J=7.8 Hz, 1H), 4.00-3.82 (m, 5H), 3.57 (p, J=7 Hz, 1H), 3.45 (m, 2H), 3.28-3.07 (m, 3H), 2.80 (d, J=2.8 Hz, 3H), 2.30-2.10 (m, 3H), 1.98-1.80 (m, 3H), 1.47-1.30 (m, 4H), 1.10 (t, J=7 Hz, 3H), 1.03 (t, J=7 Hz, 3H); LC/MS (ESI+): 565 (M+H).
Reaction SMILES: C([O:3][C:4](=[O:25])/[CH:5]=[C:6](\[O:8][C:9]1[CH:14]=[CH:13][C:12]([C:15]23[CH2:24][CH:19]4[CH2:20][CH:21]([CH2:23][CH:17]([CH2:18]4)[CH2:16]2)[CH2:22]3)=[CH:11][CH:10]=1)/[CH3:7])C>C(O)C.[OH-].[Na+]>[C:15]12([C:12]3[CH:11]=[CH:10][C:9]([O:8]/[C:6](/[CH3:7])=[CH:5]\[C:4]([OH:25])=[O:3])=[CH:14][CH:13]=3)[CH2:22][CH:21]3[CH2:23][CH:17]([CH2:18][CH:19]([CH2:20]3)[CH2:24]1)[CH2:16]2
Reactant: CCOC(=O)/C=C(/C)Oc1ccc(C23CC4CC(CC(C4)C2)C3)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: C/C(=C/C(=O)O)Oc1ccc(C23CC4CC(CC(C4)C2)C3)cc1

Procedure:
A solution of 12.2 g of 3-[4-(1-adamantyl)-phenoxy]-crotonic acid ethyl ester in 120 ml of ethanol and 24 ml of 2 N sodium hydroxide solution is stirred for 5 days at about 25° C. It is then evaporated in vacuo to a volume of approx. 20 ml and the residue is partitioned between twice 200 ml of methylene chloride and 200 ml of 2 N hydrochloric acid. The organic phases are washed until neutral, treated with active charcoal, dried over sodium sulphate and evaporated in vacuo. Crystallisation of the evaporation residue from ethanol gives 3-[4-(1-adamantyl)-phenoxy]-crotonic acid of melting point 215°-218° C (decomposition).
Reaction SMILES: [Br:1][C:2]1[CH:10]=[C:9]([C:11]([F:14])([F:13])[F:12])[CH:8]=[C:7]2[C:3]=1[CH:4]=[CH:5][NH:6]2.[H-].[Na+].Br[CH:18]([CH3:20])[CH3:19]>CN(C=O)C>[Br:1][C:2]1[CH:10]=[C:9]([C:11]([F:12])([F:13])[F:14])[CH:8]=[C:7]2[C:3]=1[CH:4]=[CH:5][N:6]2[CH:18]([CH3:20])[CH3:19]
Reactant: FC(F)(F)c1cc(Br)c2cc[nH]c2c1
Reactant: CC(C)Br
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CC(C)n1ccc2c(Br)cc(C(F)(F)F)cc21
Reaction time: 8 h
Yield: 39.6 %

Procedure:
To a solution of 4-bromo-6-(trifluoromethyl)-1H-indole (1 g, 3.79 mmol) in DMF (6 mL) was added 60% sodium hydride (0.182 g, 4.54 mmol), and the mixture was stirred for 30 min 2-bromopropane (0.533 mL, 5.68 mmol) was added and the mixture was stirred overnight. The reaction was then quenched with 10% NaHCO3 and extracted with EtOAc (3×). The extract was dried over Na2SO4 and concentrated. The residue was purified using column chromatography (Silica gel, 0 to 100% EtOAc/hexanes) to give the title compound (460 mg, 40%) as white solid. 1H NMR (400 MHz, CHLOROFORM-d) δ ppm 1.56-1.61 (m, 6H), 4.66-4.79 (m, 1H), 6.65 (d, J=3.03 Hz, 1H), 7.27-7.31 (m, 1H), 7.45 (d, J=3.03 Hz, 1H), 7.54 (s, 1H), 7.63 (s, 1H). MS: (M+H)+=306.2.
Reaction SMILES: Cl.[NH:2]1[CH2:7][CH2:6][CH:5]([C:8]2[NH:12][N:11]=[C:10]([C:13]3[CH:18]=[CH:17][C:16]([Cl:19])=[CH:15][CH:14]=3)[C:9]=2[C:20]2[CH:25]=[CH:24][N:23]=[CH:22][CH:21]=2)[CH2:4][CH2:3]1.C(OC)(OC)OC.[S:33]1[CH:37]=[CH:36][N:35]=[C:34]1[CH:38]=O.[OH-].[Na+]>CO>[CH3:38][C:34]1[S:33][CH:37]=[C:36]([N:2]2[CH2:3][CH2:4][CH:5]([C:8]3[NH:12][N:11]=[C:10]([C:13]4[CH:14]=[CH:15][C:16]([Cl:19])=[CH:17][CH:18]=4)[C:9]=3[C:20]3[CH:25]=[CH:24][N:23]=[CH:22][CH:21]=3)[CH2:6][CH2:7]2)[N:35]=1
Reactant: Clc1ccc(-c2n[nH]c(C3CCNCC3)c2-c2ccncc2)cc1
Reactant: O=Cc1nccs1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: COC(OC)OC
Solvent: CO
Product: Cc1nc(N2CCC(c3[nH]nc(-c4ccc(Cl)cc4)c3-c3ccncc3)CC2)cs1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a suspension of 5-(4-piperidyl)-4-(4-pyridyl)-3-(4-chlorophenyl)pyrazole hydrochloride (Example C-74) in 12 mL of MeOH was added trimethyl orthoformate (2.6 g, 24.4 mmol) and 2-thiazolecarboxaldehyde (1.4 g, 12.2 mmol). The suspension was stirred at room temperature for 2 h. To this mixture was added NaCNBH (1.5 g, 24.4 mmol) and the resulting suspension was stirred at room temperature for 7 days. The mixture was poured onto 2.5 N NaOH and was extracted with ethyl acetate (2×100 mL). The combined extracts were washed with brine (1×100 mL), dried over Na2SO4, filtered and concentrated to leave a solid. This solid was triturated with ether and filtered to afford the title compound: MS (M+H): 436 (base peak).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([C:11]2[O:12][C:13]3[C:18]([C:19](=[O:21])[CH:20]=2)=[CH:17][CH:16]=[CH:15][CH:14]=3)[CH:5]=[C:6]([F:10])[C:7]=1[O:8]C.CC(O)=O.O>I>[F:10][C:6]1[CH:5]=[C:4]([C:11]2[O:12][C:13]3[C:18]([C:19](=[O:21])[CH:20]=2)=[CH:17][CH:16]=[CH:15][CH:14]=3)[CH:3]=[C:2]([F:1])[C:7]=1[OH:8]
Reactant: COc1c(F)cc(-c2cc(=O)c3ccccc3o2)cc1F
Agent: I
Solvent: CC(=O)O
Solvent: O
Product: O=c1cc(-c2cc(F)c(O)c(F)c2)oc2ccccc12
Temperature: 110 °C
Reaction time: 4 h
Yield: 73 %

Procedure:
To a solution of 2′-hydroxyacetophenone (0.68 g, 5 mmol) in 10 mL anhydrous pyridine was added 3,5-difluoro-4-methoxybenzoyl chloride (1.03 g, 5 mmol) and the reaction mixture was stirred at rt for 15 h under nitrogen atmosphere. The reaction mixture was poured into 100 mL 2N HCl. The solid was filtered off, washed with water and dried under vacuum to give a white solid (1.44 g, 94%). The compound (1.42 g, 4.63 mmol) was dissolved in 10 mL anhydrous pyridine. Powdered KOH (0.78 g, 13.9 mmol) was added and the reaction mixture was stirred at rt overnight under nitrogen. Water (50 mL) was added and the solid was isolated by filtration, and washed with water to give yellow solid (1.05 g, 74%). To a suspension of the yellow solid (0.82 g, 2.67 mmol) in 6 mL glacial AcOH was added 3 drops of conc. HCl and the reaction mixture was stirred at 110° C. for 2 h. The mixture was cooled to rt and 50 mL water was added. The solid was isolated by filtration, washed with water and dried under vacuum to give 2-(3,5-difluoro-4-methoxyphenyl)chromen-4-one as a white solid (0.61 g, 79%). 2-(3,5-Difluoro-4-methoxyphenyl)chromen-4-one was suspended in 15 mL hydroiodic acid. Glacial AcOH (6 mL) was added and the reaction mixture was stirred at 110° C. for 4 h. The mixture was cooled to rt. Water (100 mL) was added and the solid was isolated by filtration, washed with water and dried under vacuum. The crude compound was washed with 1:1 dichloromethane and MeOH (15 mL) to give 2-(3,5-difluoro-4-hydroxyphenyl)-4H-chromen-4-one (0.416 g, 73%) as a pale yellow solid. MS (ES) m/z: 275.04 (M+1); Mp. 275-276° C.
Reaction SMILES: Cl[C:2]1[CH:11]=[CH:10][N:9]=[C:8]2[C:3]=1[CH:4]=[CH:5][C:6]([CH2:12][CH2:13][CH3:14])=[N:7]2.[CH3:15][C:16]1[CH:21]=[CH:20][C:19]([C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)=[C:18]([NH2:28])[CH:17]=1>>[CH3:15][C:16]1[CH:21]=[CH:20][C:19]([C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)=[C:18]([NH:28][C:2]2[C:3]3[C:8](=[N:7][C:6]([CH2:12][CH2:13][CH3:14])=[CH:5][CH:4]=3)[N:9]=[CH:10][CH:11]=2)[CH:17]=1
Reactant: CCCc1ccc2c(Cl)ccnc2n1
Reactant: Cc1ccc(-c2ccccc2)c(N)c1
Product: CCCc1ccc2c(Nc3cc(C)ccc3-c3ccccc3)ccnc2n1

Procedure:
The product from Example 2g (0.106 g, 0.49 mmol) was reacted with the product from Example 213b (0.088 g, 0.49 mmol) for 65 h following the procedure of Example 1g giving the crude title compound which was purified by HPLC with TFA providing the product as a trifluoroacetic acid salt (0.122 g, 52%). 1H NMR (300 MHz, DMSO-d6) ppm: 0.96 (t, J=7.35 Hz, 3H) 1.81 (d, J=7.72 Hz, 2H) 2.43 (s, 3H) 2.89-3.02 (m, 2H) 6.31 (d, J=6.99 Hz, 1H) 7.14-7.58 (m, 8H) 7.77 (d, J=8.46 Hz, 1H) 8.32 (d, J=7.35 Hz, 1H) 8.91 (d, J=8.46 Hz, 1H) 10.91-11.08 (m, 1H); MS (ESI+) m/z 354.0 (M+H)+; (ESI−) m/z 351.9 (M−H)−.