Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C[C@]1(NC2C=NC(C(F)(F)F)=CN=2)CCC[C@@H]1NC(C1C(C2N=CC=CN=2)=CC=CN=1)=O.[CH3:33][C@:34]1([NH:40][C:41]2[CH:46]=[N:45][C:44]([C:47]([F:50])([F:49])[F:48])=[CH:43][N:42]=2)[CH2:38][CH2:37][CH2:36][C@@H:35]1[NH2:39].[CH3:51][C:52]1[N:56]=[C:55]([C:57]2[CH:65]=[CH:64][CH:63]=[CH:62][C:58]=2[C:59](O)=[O:60])[O:54][N:53]=1>>[CH3:51][C:52]1[N:56]=[C:55]([C:57]2[CH:65]=[CH:64][CH:63]=[CH:62][C:58]=2[C:59]([NH:39][C@H:35]2[CH2:36][CH2:37][CH2:38][C@:34]2([CH3:33])[NH:40][C:41]2[CH:46]=[N:45][C:44]([C:47]([F:50])([F:48])[F:49])=[CH:43][N:42]=2)=[O:60])[O:54][N:53]=1
Reactant: Cc1noc(-c2ccccc2C(=O)O)n1
Reactant: C[C@]1(Nc2cnc(C(F)(F)F)cn2)CCC[C@@H]1N
Agent: C[C@]1(Nc2cnc(C(F)(F)F)cn2)CCC[C@@H]1NC(=O)c1ncccc1-c1ncccn1
Product: Cc1noc(-c2ccccc2C(=O)N[C@H]2CCC[C@]2(C)Nc2cnc(C(F)(F)F)cn2)n1

Procedure:
Prepared according to the procedure for N-[(1S,2S)-2-methyl-2-{[5-(trifluoromethyl)pyrazin-2-yl]amino}cyclopentyl]-3-(pyrimidin-2-yl)pyridine-2-carboxamide (Example 144) from (1S,2S)-1-methyl-1-N-[5-(trifluoromethyl)pyrazin-2-yl]cyclopentane-1,2-diamine (Intermediate 25; 190 mg, 0.73 mmol) and 2-(3-methyl-1,2,4-oxadiazol-5-yl)benzoic acid (CAS number 475105-77-2; 179 mg, 0.88 mmol). After work-up, the crude material was loaded directly on to a cation/anion mixed mode cartridge, eluted with DCM and concentrated in vacuo. This was then recrystallised from MTBE to afford the title compound.
Reaction SMILES: [Cl:1][C:2]1[C:3](=[O:15])[N:4]([CH:9]2[CH2:14][CH2:13][CH2:12][CH2:11][O:10]2)[N:5]=[CH:6][C:7]=1Cl.[CH3:16][OH:17].[OH-].[K+]>CCCCCC.C(OCC)C>[Cl:1][C:2]1[C:3](=[O:15])[N:4]([CH:9]2[CH2:14][CH2:13][CH2:12][CH2:11][O:10]2)[N:5]=[CH:6][C:7]=1[O:17][CH3:16]
Reactant: O=c1c(Cl)c(Cl)cnn1C1CCCCO1
Reactant: CO
Agent: [K+]
Agent: [OH-]
Solvent: CCOCC
Solvent: CCCCCC
Product: COc1cnn(C2CCCCO2)c(=O)c1Cl
Temperature: 0 °C
Reaction time: 3 h
Yield: 77 %

Procedure:
4,5-Dichloro-2-(tetrahydro-2H-pyran-2-yl)-3(2H)-pyridazinone from the previous step and 17 L of methanol were added to a 50 L round bottomed flask equipped with a glycol cooling jacket and a mechanical stirrer. The resulting solution was cooled to 0° C. and 87% KOH (1172 g 18.17 moles) was added in portions over approximately 1 h. The mixture exothermed to 40° C. Following the addition the mixture was allowed to stir an additional 3 h at ambient temperature. The reaction mixture was partitioned with 12 L of ethyl acetate and 12 L of H2O. The aqueous layer was extracted with ethyl acetate (2×4 L). The combined organic layers were washed with brine (2×10 L) and dried (MgSO4). The organic solution was clarified by filtration and concentrated to give a dark semi-solid. The crude material was equally divided and added to two 22 L flasks. The material was suspended in 12 L hexane/diethyl ether (2:1 ratio). The washed material was vacuum filtered on a Buchner funnel and air dried overnight to give 3,406 g (77% over 2 steps) of 4-chloro-5-methoxy-2-(tetrahydro-2H-pyran-2-yl)-3(2H)-pyridazinone as a dark tan solid suitable for further transformations. The product was purified by recrystallization from ethyl acetate/cyclohexane to give a white solid, mp=118°-120° C.
Reaction SMILES: [N+:1]([C:4]1[N:9]=[CH:8][C:7]([N:10]2[CH2:15][CH2:14][N:13]([C:16]([O:18][C:19]([CH3:22])([CH3:21])[CH3:20])=[O:17])[CH2:12][CH2:11]2)=[CH:6][CH:5]=1)([O-:3])=[O:2].[CH3:23][C@@H]1NCCN(C(OC(C)(C)C)=O)C1.BrC1C=CC([N+]([O-])=O)=NC=1>>[CH3:23][C@@H:15]1[N:10]([C:7]2[CH:8]=[N:9][C:4]([N+:1]([O-:3])=[O:2])=[CH:5][CH:6]=2)[CH2:11][CH2:12][N:13]([C:16]([O:18][C:19]([CH3:22])([CH3:21])[CH3:20])=[O:17])[CH2:14]1
Reactant: C[C@H]1CN(C(=O)OC(C)(C)C)CCN1
Reactant: CC(C)(C)OC(=O)N1CCN(c2ccc([N+](=O)[O-])nc2)CC1
Agent: O=[N+]([O-])c1ccc(Br)cn1
Product: C[C@H]1CN(C(=O)OC(C)(C)C)CCN1c1ccc([N+](=O)[O-])nc1
Yield: 50 %

Procedure:
Following the procedure described for compound 101g and starting with (3S)-tert-butyl 3-methylpiperazine-1-carboxylate (10.0 g, 50 mmol) and 5-bromo-2-nitropyridine (10.5 g, 50 mmol) afforded 191e as a yellow solid (8.05 g, 50%). MS-ESI: [M+H]+ 323
Reaction SMILES: C12CC(CC1)CCO2.[CH3:9][C:10]1[CH2:14][C:13](C(OCC)=O)([C:15]([O:17]CC)=[O:16])[CH2:12][CH:11]=1>>[CH3:9][C:10]1[CH2:14][CH:13]([C:15]([OH:17])=[O:16])[CH2:12][CH:11]=1
Reactant: CCOC(=O)C1(C(=O)OCC)CC=C(C)C1
Agent: C1CC2CCC(C2)O1
Product: CC1=CCC(C(=O)O)C1

Procedure:
When m is 1, n is 2 and p is 1, the ring system is a 2-oxabicyclo[3.2.1]octane, another subclass of this invention. For example, compound XIIp ##STR26## in which R2, R5 and R6 are methyl, can be prepared by saponification and decarboxylation of diethyl 1-methylcyclopent-1-ene-4,4-dicarboxylate, prepared by the procedure of E. E. Schweiger and G. J. O'Neill, J. Org. Chem., 30, 2082 (1965), to provide 1-methylcyclopent-1-ene-4-carboxylic acid. The resulting carboxylic acid is homologated in the manner proscribed for the compounds XIp, and subsequently treated similarly to the acid of subclass IX.
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][C:4]2([C:15]3[N:16]=[CH:17][NH:18][C:14]=3[C:13]3[CH:12]=[CH:11][CH:10]=[CH:9][C:8]=3[O:7]2)[CH2:3][CH2:2]1.[CH:19]([O:22][C:23]1[CH:31]=[CH:30][C:26]([C:27](O)=[O:28])=[CH:25][C:24]=1[CH3:32])([CH3:21])[CH3:20].C(N(CC)CC)C.CCN=C=NCCCN(C)C>ClCCl>[CH:19]([O:22][C:23]1[CH:31]=[CH:30][C:26]([C:27]([N:1]2[CH2:6][CH2:5][C:4]3([C:15]4[N:16]=[CH:17][NH:18][C:14]=4[C:13]4[CH:12]=[CH:11][CH:10]=[CH:9][C:8]=4[O:7]3)[CH2:3][CH2:2]2)=[O:28])=[CH:25][C:24]=1[CH3:32])([CH3:21])[CH3:20]
Reactant: Cc1cc(C(=O)O)ccc1OC(C)C
Reactant: c1ccc2c(c1)OC1(CCNCC1)c1nc[nH]c1-2
Agent: CCN=C=NCCCN(C)C
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: Cc1cc(C(=O)N2CCC3(CC2)Oc2ccccc2-c2[nH]cnc23)ccc1OC(C)C
Reaction time: 16 h
Yield: 12 %

Procedure:
A mixture of 1H-spiro[chromeno[3,4-d]imidazole-4,4′-piperidine] (210 mg, 0.88 mmol), 4-isopropoxy-3-methyl-benzoic acid (170 mg, 0.89 mmol), triethylamine (370 μL, 2.6 mmol), and EDCI (170 mg, 0.89 mmol) in dichloromethane (5 mL) was stirred for 16 h. The reaction mixture was diluted with dichloromethane and was washed with 1M HCl, saturated solution of NaHCO3, and brine. The organics were dried over sodium sulfate and evaporated to dryness. The crude product was purified by silica gel chromatography eluting with 0-100% methanol in dichloromethane to yield (4-isopropoxy-3-methylphenyl)(1H-spiro[chromeno[3,4-d]imidazole-4,4′-piperidine]-1′-yl)methanone (44 mg, 12%). ESI-MS m/z calc. 417.5. found 418.5 (M+1)+; Retention time: 1.44 minutes (3 min run).
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([O:8][CH3:9])[N:5]=[C:4]([NH:10][CH2:11][C:12]2[CH:16]=[CH:15][S:14][CH:13]=2)[CH:3]=1.[C:17]([C:20]([C:23]1[CH:24]=[C:25](B(O)O)[CH:26]=[CH:27][CH:28]=1)([CH3:22])[CH3:21])([OH:19])=[O:18].C([O-])([O-])=O.[Cs+].[Cs+]>COCCOC.O.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[CH3:9][O:8][C:6]1[N:7]=[C:2]([C:25]2[CH:24]=[C:23]([C:20]([CH3:22])([CH3:21])[C:17]([OH:19])=[O:18])[CH:28]=[CH:27][CH:26]=2)[CH:3]=[C:4]([NH:10][CH2:11][C:12]2[CH:16]=[CH:15][S:14][CH:13]=2)[N:5]=1
Reactant: COc1nc(Cl)cc(NCc2ccsc2)n1
Reactant: CC(C)(C(=O)O)c1cccc(B(O)O)c1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: COCCOC
Solvent: O
Product: COc1nc(NCc2ccsc2)cc(-c2cccc(C(C)(C)C(=O)O)c2)n1
Temperature: 90 °C
Reaction time: 6 h
Yield: 4.7 %

Procedure:
Argon is bubbled through a mixture of (6-chloro-2-methoxy-pyrimidin-4-yl)-thiophen-3-ylmethyl-amine (216 mg, 0.84 mmol), 3-(1-carboxy-1-methyl-ethyl)-phenyl boronic acid [312 mg, 1.5 mmol, see Example 49(b) step 2], Cs2CO3 (821 mg, 2.52 mmol), and tetrakis(triphenylphosphine)palladium (0) (92 mg, 0.08 mmol) in ethylene glycol dimethyl ether (2.5 mL) and water (0.5 mL), for a period of 10 minutes. The reaction vessel is sealed and heated to 90° C. After stirring for 6 hours the heating is turned off and the mixture is allowed to cool to ambient temperature upon standing for 24 hours. The mixture is diluted with water (40 mL) and extracted twice with EtOAc (25 mL). The organic extracts are combined and dried over magnesium sulfate, filtered and concentrated to afford 2-(3-{2-methoxy-6-[(thiophen-3-ylmethyl)-amino]-pyrimidin-4-yl}-phenyl)-2-methyl-propionic acid [15 mg, 4.6%, Example 71] as a solid. LCMS RT=1.94 minutes, MS: 384 (M+H). IC50=393 nM
Reaction SMILES: [F:1][C:2]([F:20])([F:19])[C:3]1[CH:4]=[C:5]([C:9]2[CH:10]=[C:11]3[C:15](=[CH:16][CH:17]=2)[C:14](=[O:18])[CH2:13][CH2:12]3)[CH:6]=[CH:7][CH:8]=1.[BrH:21].BrBr.C(=O)([O-])O.[Na+]>C(O)(=O)C.O>[Br:21][CH:13]1[CH2:12][C:11]2[C:15](=[CH:16][CH:17]=[C:9]([C:5]3[CH:6]=[CH:7][CH:8]=[C:3]([C:2]([F:19])([F:20])[F:1])[CH:4]=3)[CH:10]=2)[C:14]1=[O:18]
Reactant: Br
Reactant: O=C1CCc2cc(-c3cccc(C(F)(F)F)c3)ccc21
Agent: BrBr
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CC(=O)O
Solvent: O
Product: O=C1c2ccc(-c3cccc(C(F)(F)F)c3)cc2CC1Br
Temperature: 25 °C
Reaction time: 3 h

Procedure:
1.79 g of 5-(3-trifluoromethylphenyl)indan-1-one are dissolved in 10 ml of glacial acetic acid. 5.5 μl of a 48% strength solution of hydrobromic acid in water are added and a solution of 0.362 ml of bromine in 5 ml of glacial acetic acid is then slowly added dropwise. The reaction mixture is stirred at room temperature for 3 hours and then poured into a mixture of 50 ml of water with 50 g of ice and 86 mg of sodium hydrogencarbonate. The aqueous suspension is extracted by shaking with 100 ml of dichloromethane, the organic phase is washed three times with 50 ml of water, dried over magnesium sulfate and concentrated, and the residue is chromatographed on silica gel using toluene/ethyl acetate 25/1. 2-Bromo-5(3-trifluoromethylphenyl)indan-1-one of melting point 96° C. is obtained. 2,2-Dibromo-5-(3-trifluoromethylphenyl)indan-1-one of melting point 210° C. (dec.) is isolated as a by-product.
Reaction SMILES: C([Li])CCC.CN(C[N:10]1[CH:14]=[CH:13][N:12]=[CH:11]1)C.[I:15][C:16]1[CH:23]=[CH:22][CH:21]=[CH:20][C:17]=1[CH:18]=[O:19].Cl>O1CCCC1>[NH:10]1[CH:14]=[CH:13][N:12]=[C:11]1[CH:18]([C:17]1[CH:20]=[CH:21][CH:22]=[CH:23][C:16]=1[I:15])[OH:19]
Reactant: O=Cc1ccccc1I
Reactant: CN(C)Cn1ccnc1
Agent: Cl
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: OC(c1ncc[nH]1)c1ccccc1I
Reaction time: 8 h
Yield: 38 %

Procedure:
n-Butyl lithium solution (2.5M in hexanes, 0.84 mL, 2.10 mmol) was added to 1-(dimethylaminomethyl)imidazole (prepared by the method detailed in JOC 1988, 53, 5685-5689; 0.25 g, 2.0 mmol) in tetrahydrofuran (8 mL) at ≦−65° C. with stirring under nitrogen. After 1 hour at this temperature a solution of 2-iodobenzaldehyde (0.50 g, 2.09 mmol) in tetrahydrofuran (1 mL) was added and the mixture allowed to return to ambient temperature overnight. Dilute hydrochloric acid (2N, 10 mL) was then added and organic solvent removed in vacuo before neutralising with sodium bicarbonate. Dichloromethane (3×30 mL) extracts were washed with saturated brine then dried (MgSO4), filtered and concentrated in vacuo to give a yellow oil. Purification by flash column chromatography eluting with 50% ethyl acetate/isohexane gave a white solid of 1H-imidazol-2-yl(2-iodophenyl)methanol (0.22 g, 38%). 1H NMR (500 MHz, d6-DMSO) δ 11.94 (1H, s), 7.80 (1H, dd, J=1.0, 7.8 Hz), 7.53 (1H, dd, J=1.7, 7.8 Hz), 7.41-7.37 (1H, m), 7.04-7.00 (2H, m), 6.74 (1H, s), 6.20 (1H, d, J=4.7 Hz), 5.83 (1H, d, J=4.7 Hz); m/z (ES+) 301 [MH+].
Reaction SMILES: [Cl:1][C:2]1[NH:3][C:4]2[C:9]([C:10]=1[CH:11]=[O:12])=[CH:8][CH:7]=[CH:6][CH:5]=2.[H-].[Na+].[CH3:15]I.O>CN(C=O)C>[Cl:1][C:2]1[N:3]([CH3:15])[C:4]2[C:9]([C:10]=1[CH:11]=[O:12])=[CH:8][CH:7]=[CH:6][CH:5]=2
Reactant: CI
Reactant: O=Cc1c(Cl)[nH]c2ccccc12
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: Cn1c(Cl)c(C=O)c2ccccc21
Reaction time: 0.5 h
Yield: 108.9 %

Procedure:
A solution of 2-chloro-1H-indole-3-carboxaldehyde (1.0 g, 5.5 mmol) in DMF (30 mL) is treated portionwise over 10 min with 60% sodium hydride (440 mg, 11 mmol). After stirring for 30 min, methyl iodide (685 μL, 11 mmol) is slowly added and the resulting mixture is stirred 3 hr at room temperature. Water (5 mL) is cautiously added and the solvents are removed. The residue is dissolved in ethyl acetate and washed with water, with brine, dried, filtered and concentrated to give 2-chloro-1-methyl-1H-indole-3-carboxaldehyde (1.16 g, 105%), mp 94.5-95.5° C., as a white solid. MS 194 (M+H).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:9]=[CH:10][C:11]=1[O:12][CH3:13])[CH2:6][CH2:7][OH:8].C(O[CH:17](OCC)[CH2:18][NH2:19])C.Cl>O1CCOCC1>[CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:9](=[CH:10][C:11]=1[O:12][CH3:13])[CH:17]([CH2:18][NH2:19])[O:8][CH2:7][CH2:6]2
Reactant: COc1ccc(CCO)cc1OC
Reactant: CCOC(CN)OCC
Agent: Cl
Solvent: C1COCCO1
Product: COc1cc2c(cc1OC)C(CN)OCC2
Reaction time: 48 h

Procedure:
A solution of the starting material of formula II, 3,4-dimethoxyphenethyl alcohol (108 g), described by E. Z. Khafagy and J. P. Lambooy, J. Med. Chem., 9, 936 (1966), and the starting material of formula III, aminoacetaldehyde diethyl acetal (78 g), in dry dioxane (250 ml) is stirred and cooled (ice bath) while being saturated with hydrogen chloride over a period of 1 hour. The mixture is kept at room temperature for 2 days. The crystalline precipitate is collected, washed with dry dioxane and then ether to yield the hydrochloric acid addition salt (hydrochloride) of the title compound, m.p. 250°-255° C. (dec.), after recrystallization from methanol.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][CH:5]=[C:6]2[C:11]=1[N:10]([CH3:12])[CH:9]=[C:8]([OH:13])[C:7]2=[O:14].C(=O)([O-])[O-].[K+].[K+].Cl[CH2:22][C:23]1[CH:28]=[CH:27][C:26]([O:29][CH3:30])=[CH:25][CH:24]=1.[I-].[K+]>CN(C)C=O>[Br:1][C:2]1[CH:3]=[CH:4][CH:5]=[C:6]2[C:11]=1[N:10]([CH3:12])[CH:9]=[C:8]([O:13][CH2:22][C:23]1[CH:28]=[CH:27][C:26]([O:29][CH3:30])=[CH:25][CH:24]=1)[C:7]2=[O:14]
Reactant: COc1ccc(CCl)cc1
Reactant: Cn1cc(O)c(=O)c2cccc(Br)c21
Agent: O=C([O-])[O-]
Agent: [I-]
Agent: [K+]
Solvent: CN(C)C=O
Product: COc1ccc(COc2cn(C)c3c(Br)cccc3c2=O)cc1
Temperature: 90 °C
Yield: 77.5 %

Procedure:
A suspension of 8-bromo-3-hydroxy-1-methylquinolin-4(1H)-one (2.4 g, 8.97 mmol) and potassium carbonate (1.488 g, 10.77 mmol) in N,N-dimethylformamide (50 mL) was heated at 90° C. for 0.5 h. Then 1-(chloromethyl)-4-methoxybenzene (1.442 mL, 9.87 mmol) and potassium iodide (0.149 g, 0.897 mmol) were added, and the mixture was heated at the same temperature for another 2 h. After cooling. N,N-dimethylformamide was removed in vacuo and the residue was partitioned between dichloromethane and brine. The organic phase was separated, the aqueous phase was extracted with dichloromethane for several times. The combined organic extracts were dried over sodium sulfate, filtered and concentrated, The residue was purified by automatic silica gel column chromatography (Combiflash RF), eluting with ethyl acetate/hexanes (0-100%) to afford 8-bromo-3-((4-methoxybenzyl)oxy)-1-methylquinolin-4(1H)-one (2.6 g, 6.95 mmol, 77% yield) as a light brown solid. LCMS: (M+H)+: 374.0.
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[CH:5]=[C:4]([NH:12][C:13]2[CH:17]=[CH:16][NH:15][N:14]=2)[N:3]=1.[S:18]1[CH:22]=[CH:21][C:20](B(O)O)=[CH:19]1>>[NH:15]1[CH:16]=[CH:17][C:13]([NH:12][C:4]2[N:3]=[C:2]([C:20]3[CH:21]=[CH:22][S:18][CH:19]=3)[C:11]3[C:6]([CH:5]=2)=[CH:7][CH:8]=[CH:9][CH:10]=3)=[N:14]1
Reactant: OB(O)c1ccsc1
Reactant: Clc1nc(Nc2cc[nH]n2)cc2ccccc12
Product: c1ccc2c(-c3ccsc3)nc(Nc3cc[nH]n3)cc2c1

Procedure:
Similar procedure as described in example 131 was used, starting from (1-chloro-isoquinolin-3-yl)-(1H-pyrazol-3-yl)-amine and 3-thiophene boronic acid to give (1H-pyrazol-3-yl)-(1-thiophen-3-yl-isoquinolin-3-yl)-amine. LC-MS m/e 293(MH+).
Reaction SMILES: [CH:1](O)=[O:2].CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C.[NH2:37][C@H:38]([CH2:47][C:48]1[CH:53]=[CH:52][C:51]([C:54]2[CH:59]=[CH:58][CH:57]=[C:56]([Cl:60])[CH:55]=2)=[CH:50][CH:49]=1)[CH2:39][C@:40]([CH2:45][OH:46])([CH3:44])[C:41]([OH:43])=[O:42]>CN(C=O)C>[Cl:60][C:56]1[CH:55]=[C:54]([C:51]2[CH:52]=[CH:53][C:48]([CH2:47][C@@H:38]([NH:37][CH:1]=[O:2])[CH2:39][C@:40]([CH2:45][OH:46])([CH3:44])[C:41]([OH:43])=[O:42])=[CH:49][CH:50]=2)[CH:59]=[CH:58][CH:57]=1
Reactant: O=CO
Reactant: C[C@@](CO)(C[C@H](N)Cc1ccc(-c2cccc(Cl)c2)cc1)C(=O)O
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: C[C@@](CO)(C[C@@H](Cc1ccc(-c2cccc(Cl)c2)cc1)NC=O)C(=O)O
Reaction time: 0.08 h
Yield: 4.2 %

Procedure:
Formic acid (3 mg, 32 μmol) was combined with HATU (12 mg, 32 μmol) and DMF (0.2 mL) and stirred for 5 minutes. DIPEA (17 μl, 96 μmol) was added, followed by (2S,4R)-4-amino-5-(3′-chlorobiphenyl-4-yl)-2-hydroxymethyl-2-methyl-pentanoic acid (79 mg, 38 μmol) pre-dissolved in DMF (0.5 mL) and DIPEA (17 μl, 96 μmol). The resulting mixture was stirred for 15 minutes. The solvent was removed in vacuo and the residue was dissolved in AcOH and purified by preparative HPLC to yield the title compound (0.5 mg). MS m/z [M+H]+ calc'd for C20H22ClNO4, 376.12. found 376.2.
Reaction SMILES: [H-].[Na+].[S:3]1[C:7]2[CH:8]=[CH:9][CH:10]=[CH:11][C:6]=2[N:5]=[C:4]1[NH:12][C@H:13]1[CH2:18][CH2:17][C@H:16]([OH:19])[CH2:15][CH2:14]1.[Cl:20][C:21]1[C:26](Cl)=[N:25][CH:24]=[CH:23][N:22]=1.O>CN(C=O)C>[Cl:20][C:21]1[C:26]([O:19][C@H:16]2[CH2:15][CH2:14][C@H:13]([NH:12][C:4]3[S:3][C:7]4[CH:8]=[CH:9][CH:10]=[CH:11][C:6]=4[N:5]=3)[CH2:18][CH2:17]2)=[N:25][CH:24]=[CH:23][N:22]=1
Reactant: O[C@H]1CC[C@H](Nc2nc3ccccc3s2)CC1
Reactant: Clc1nccnc1Cl
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: Clc1nccnc1O[C@H]1CC[C@H](Nc2nc3ccccc3s2)CC1
Temperature: 60 °C
Reaction time: 0.75 h

Procedure:
Sodium hydride (60% dispersion, 0.41 g, 10.2 mmol) was added to a solution of trans-4-(benzo[d]thiazol-2-ylamino)cyclohexanol (as prepared according to Scheme 5) (1.10 g, 4.43 mmol) in DMF (20 mL) under argon. The mixture was stirred for 45 min and then 2,3-dichloropyrazine (0.66 g, 4.43 mmol) was added via syringe. This mixture was heated to 60° C. for 16 h, cooled to room temperature, then water was added slowly. The resulting suspension was filtered and the collected solid was purified by silica gel chromatography to give N-(trans-4-(3-chloropyrazin-2-yloxy)cyclohexyl)benzo[d]thiazol-2-amine (0.92 g, 2.54 mmol, 57% yield) as a white solid.
Reaction SMILES: [C:1](Cl)(=[O:19])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[S:8][S:9][C:10]1[CH:18]=[CH:17][CH:16]=[CH:15][C:11]=1[C:12](Cl)=[O:13].[F:21][C:22]([F:35])([F:34])[C:23]1[CH:24]=[C:25]([CH:27]=[C:28]([C:30]([F:33])([F:32])[F:31])[CH:29]=1)[NH2:26]>ClCCl.N1C=CC=CC=1>[F:21][C:22]([F:34])([F:35])[C:23]1[CH:24]=[C:25]([NH:26][C:1](=[O:19])[C:2]2[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=2[S:8][S:9][C:10]2[CH:18]=[CH:17][CH:16]=[CH:15][C:11]=2[C:12]([NH:26][C:25]2[CH:27]=[C:28]([C:30]([F:31])([F:32])[F:33])[CH:29]=[C:23]([C:22]([F:21])([F:34])[F:35])[CH:24]=2)=[O:13])[CH:27]=[C:28]([C:30]([F:31])([F:32])[F:33])[CH:29]=1
Reactant: Nc1cc(C(F)(F)F)cc(C(F)(F)F)c1
Reactant: O=C(Cl)c1ccccc1SSc1ccccc1C(=O)Cl
Solvent: c1ccncc1
Solvent: ClCCl
Product: O=C(Nc1cc(C(F)(F)F)cc(C(F)(F)F)c1)c1ccccc1SSc1ccccc1C(=O)Nc1cc(C(F)(F)F)cc(C(F)(F)F)c1
Yield: 8 %

Procedure:
This compound was prepared according to the general method of Example 77 using 2,2'-dithiobisbenzoyl chloride (2.00 g, 5.83 mmol) in 50 mL of dichloromethane and 3,5 -bis (trifluoromethyl) aniline (2.66 g, 11.6 mmol) in 21 mL of pyridine. The crude product was recrystallized from ethyl acetate-hexanes (1:9) to yield 0.34 g of the title compound, mp 213°-214° C.
Reaction SMILES: C(N(CC)CC)C.[NH2:8][C:9]1[C:14]2[CH2:15][CH:16]([CH3:18])[O:17][C:13]=2[C:12]([Cl:19])=[CH:11][CH:10]=1.Cl[C:21](OC(Cl)(Cl)Cl)=[O:22]>O1CCOCC1>[Cl:19][C:12]1[C:13]2[O:17][CH:16]([CH3:18])[CH2:15][C:14]=2[C:9]([N:8]=[C:21]=[O:22])=[CH:10][CH:11]=1
Reactant: CC1Cc2c(N)ccc(Cl)c2O1
Reactant: O=C(Cl)OC(Cl)(Cl)Cl
Solvent: C1COCCO1
Solvent: CCN(CC)CC
Product: CC1Cc2c(N=C=O)ccc(Cl)c2O1

Procedure:
6.07 g of triethylamine was added to a mixture of 9.18 g of 32A, 11.87 g of trichloromethyl chloroformate and 250 mL of dioxane, and the mixture was refluxed for 6 hours. The mixture was cooled, filtered, and the filtrate was stripped of solvent, to give 7-chloro-2,3-dihydro-4-isocyanato-2-methylbenzofuran (34A), as a brown liquid.
Reaction SMILES: C([O:3][C:4]([C:6]1[CH:7]=[N:8][N:9]([C:11]2[N:20](COCC[Si](C)(C)C)[C:19](=[O:29])[C:18]3[C:13](=[CH:14][CH:15]=[C:16](I)[CH:17]=3)[N:12]=2)[CH:10]=1)=[O:5])C.[F:31][C:32]1[CH:33]=[C:34](B(O)O)[CH:35]=[CH:36][CH:37]=1>>[F:31][C:32]1[CH:37]=[C:36]([C:16]2[CH:17]=[C:18]3[C:13](=[CH:14][CH:15]=2)[N:12]=[C:11]([N:9]2[CH:10]=[C:6]([C:4]([OH:3])=[O:5])[CH:7]=[N:8]2)[NH:20][C:19]3=[O:29])[CH:35]=[CH:34][CH:33]=1
Reactant: OB(O)c1cccc(F)c1
Reactant: CCOC(=O)c1cnn(-c2nc3ccc(I)cc3c(=O)n2COCC[Si](C)(C)C)c1
Product: O=C(O)c1cnn(-c2nc3ccc(-c4cccc(F)c4)cc3c(=O)[nH]2)c1

Procedure:
The titled compound was prepared in a manner analogous to Example 69, steps C-E, using 1-[6-iodo-4-oxo-3-(2-trimethylsilanyl-ethoxymethyl)-3,4-dihydro-quinazolin-2-yl]-1H-pyrazole-4-carboxylic acid ethyl ester (Example 69 product from step B) and 3-fluorophenylboronic acid in step C. MS (ESI): mass calcd. for C18H11FN4O3, 350.1; m/z found, 351.1 [M+H]+. 1H NMR (600 MHz, DMSO-d6): 13.01 (br s, 2H), 8.98 (s, 1H), 8.38 (d, J=2.0 Hz, 1H), 8.29 (s, 1H), 8.22-8.20 (m, 1H), 7.80 (d, J=8.0 Hz, 1H), 7.68-7.64 (m, 2H), 7.58-7.54 (m, 1H), 7.28-7.24 (m, 1H).
Reaction SMILES: [Br:1][C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][C:10]=2[N+:12]([O-])=O)[C:5]([Cl:15])=[N:4][CH:3]=1.O1CCCC1>C(O)C.[Pt].[S]>[NH2:12][C:10]1[CH:9]=[CH:8][CH:7]=[C:6]2[C:11]=1[C:2]([Br:1])=[CH:3][N:4]=[C:5]2[Cl:15]
Reactant: O=[N+]([O-])c1cccc2c(Cl)ncc(Br)c12
Agent: [Pt]
Agent: [S]
Solvent: C1CCOC1
Solvent: CCO
Product: Nc1cccc2c(Cl)ncc(Br)c12
Temperature: 25 °C
Reaction time: 15 h
Yield: 102.1 %

Procedure:
A solution of 4-bromo-1-chloro-5-nitroisoquinoline (14.0 g) prepared according to the method described in a known literature (Nair et al., Indian J. Chem., 1967, 5, 403) in ethanol (75 ml) and tetrahydrofuran (75 ml) was added with 3% platinum-sulfur/activated carbon (3% Pt-S/C, NE Chemcat, CM011, 14.0 g), and the mixture was stirred at room temperature for 15 hours under a hydrogen gas atmosphere. The atmosphere was replaced with nitrogen gas, and then the insoluble matters were removed by filtration through Celite, and the solvent was evaporated under reduced pressure to obtain the title compound (12.8 g).
Reaction SMILES: CO[C:3]([C:5]1[C:9]([CH3:10])=[C:8]([C:11]2[CH:16]=[C:15]([C:17]([F:20])([F:19])[F:18])[CH:14]=[C:13]([C:21]([F:24])([F:23])[F:22])[CH:12]=2)[N:7]([CH2:25][CH:26]2[CH2:31][CH2:30][CH2:29][CH2:28][CH2:27]2)[C:6]=1[CH3:32])=[O:4].[C@@H:33]([NH2:37])([CH2:35][CH3:36])[CH3:34]>>[C@@H:33]([NH:37][C:3]([C:5]1[C:9]([CH3:10])=[C:8]([C:11]2[CH:12]=[C:13]([C:21]([F:22])([F:23])[F:24])[CH:14]=[C:15]([C:17]([F:20])([F:18])[F:19])[CH:16]=2)[N:7]([CH2:25][CH:26]2[CH2:31][CH2:30][CH2:29][CH2:28][CH2:27]2)[C:6]=1[CH3:32])=[O:4])([CH2:35][CH3:36])[CH3:34]
Reactant: CC[C@H](C)N
Reactant: COC(=O)c1c(C)c(-c2cc(C(F)(F)F)cc(C(F)(F)F)c2)n(CC2CCCCC2)c1C
Product: CC[C@H](C)NC(=O)c1c(C)c(-c2cc(C(F)(F)F)cc(C(F)(F)F)c2)n(CC2CCCCC2)c1C

Procedure:
The title compound was synthesized in analogy to example 203, from 5-(3,5-bis-trifluoromethyl-phenyl)-1-cyclohexylmethyl-2,4-dimethyl-1H-pyrrole-3-carboxylic acid methyl ester and (S)-sec-butylamine as R1R2NH, MS (ISP) 503.4 (M+H)+.