Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:40]=[CH:39][C:6]([CH2:7][N:8]([CH2:30][C:31]2[CH:36]=[CH:35][C:34]([O:37][CH3:38])=[CH:33][CH:32]=2)[C:9]2[N:14]=[CH:13][C:12]([C:15]3[C:16]4[CH2:29][CH2:28][NH:27][C:17]=4[N:18]=[C:19]([N:21]4[CH2:26][CH2:25][O:24][CH2:23][CH2:22]4)[N:20]=3)=[CH:11][N:10]=2)=[CH:5][CH:4]=1.[C:41]1([N:47]=[C:48]=[S:49])[CH:46]=[CH:45][CH:44]=[CH:43][CH:42]=1.NC(N)=S>>[C:41]1([NH:47][C:48]([N:27]2[C:17]3[N:18]=[C:19]([N:21]4[CH2:26][CH2:25][O:24][CH2:23][CH2:22]4)[N:20]=[C:15]([C:12]4[CH:11]=[N:10][C:9]([N:8]([CH2:7][C:6]5[CH:5]=[CH:4][C:3]([O:2][CH3:1])=[CH:40][CH:39]=5)[CH2:30][C:31]5[CH:32]=[CH:33][C:34]([O:37][CH3:38])=[CH:35][CH:36]=5)=[N:14][CH:13]=4)[C:16]=3[CH2:29][CH2:28]2)=[S:49])[CH:46]=[CH:45][CH:44]=[CH:43][CH:42]=1
Reactant: S=C=Nc1ccccc1
Reactant: COc1ccc(CN(Cc2ccc(OC)cc2)c2ncc(-c3nc(N4CCOCC4)nc4c3CCN4)cn2)cc1
Agent: NC(N)=S
Product: COc1ccc(CN(Cc2ccc(OC)cc2)c2ncc(-c3nc(N4CCOCC4)nc4c3CCN4C(=S)Nc3ccccc3)cn2)cc1
Yield: 155.2 %

Procedure:
Using bis-(4-methoxy-benzyl)-[5-(2-morpholin-4-yl-6,7-dihydro-5H-pyrrolo[2,3-d]pyrimidin-4-yl)-pyrimidin-2-yl]-amine (80.0 mg, 0.148 mmol) and phenyl isothiocyanate (53.0 μl, 0.447 mmol) instead of o-tolyl isothiocyanate, thiourea was formed in the same manner as Example 1-D-210, to obtain a crude product of 4-{2-[bis-(4-methoxy-benzyl)-amino]-pyrimidin-5-yl}-2-morpholin-4-yl-5,6-dihydro-pyrrolo[2,3-d]pyrimidine-7-carbothioic acid phenylamide as a brown solid (155 mg), and then the PMB groups were removed according to the above Deprotection method 3, to obtain the desired compound (D-216) as a yellow powder (34.5 mg, 55%).
Reaction SMILES: [CH3:1][C:2]1[C:3]([CH2:12][CH2:13][C:14](O)=O)=[N:4][C:5]2[C:10]([N:11]=1)=[CH:9][CH:8]=[CH:7][CH:6]=2.[C:17]1([NH2:24])[C:18]([NH2:23])=[CH:19][CH:20]=[CH:21][CH:22]=1.C([O-])([O-])=O.[Na+].[Na+]>Cl.O1CCOCC1>[NH:23]1[C:18]2[CH:19]=[CH:20][CH:21]=[CH:22][C:17]=2[N:24]=[C:14]1[CH2:13][CH2:12][C:3]1[C:2]([CH3:1])=[N:11][C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[N:4]=1
Reactant: Nc1ccccc1N
Reactant: Cc1nc2ccccc2nc1CCC(=O)O
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: C1COCCO1
Product: Cc1nc2ccccc2nc1CCc1nc2ccccc2[nH]1
Temperature: 150 °C
Yield: 6.2 %

Procedure:
3-(3-Methylquinoxalin-2-yl)propanoic acid (98 mg, 0.45 mmol) and benzene-1,2-diamine (98 mg, 0.45 mmol) were suspended in 4 M HCl in 1,4-dioxane (6 mL) and heated in the microwave (150° C., 2.5 h). The crude reaction was poured into saturated aqueous Na2CO3 solution (30 mL) and extracted with EtOAc (3×50 mL). The organic layers were combined, washed with brine (1×50 mL), dried (Na2SO4), filtered and concentrated. The crude material was purified by RPLC (Gilson). Fractions containing the compound were combined, diluted with EtOAc and washed with saturated aqueous Na2CO3, dried (Na2SO4), filtered and concentrated to give 2-(2-(1H-benzo[d]imidazol-2-yl)ethyl)-3-methylquinoxaline (8 mg) as an orange oil. LC-MS m/z 289 (M+H+).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([CH:8]=[CH:9][CH:10]=1)[C:5]([OH:7])=[O:6].[C:11](Br)([CH3:14])([CH3:13])[CH3:12]>C(=O)([O-])[O-].[Ag+2]>[C:11]([O:6][C:5](=[O:7])[C:4]1[CH:8]=[CH:9][CH:10]=[C:2]([Br:1])[CH:3]=1)([CH3:14])([CH3:13])[CH3:12]
Reactant: CC(C)(C)Br
Reactant: O=C(O)c1cccc(Br)c1
Agent: [Ag+2]
Agent: O=C([O-])[O-]
Product: CC(C)(C)OC(=O)c1cccc(Br)c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 54.4 %

Procedure:
To a mixture of 3-bromo benzoic acid (10 g, 0.5 mol), silver carbonate (276 g, 1 mol) and dry molecular sieves (100 g) taken in dry CH2Cl2 (2 L), tert-butylbromide (115 mL, 1 mol) was added dropwise at 0° C. and the reaction mixture was stirred overnight at RT. The solid was filtered and washed with dichloromethane. Organic layer was washed with 10% aqueous solution of NaHCO3 (2×500 mL), water (2×500 mL), brine and dried. The solvent was removed under vacuum to give tert-butyl-3-bromobenzoate (70 g, 57%).
Reaction SMILES: [CH2:1]([N:8]1[CH2:14][C:13]2[N:15]=[CH:16][C:17](Cl)=[N:18][C:12]=2[O:11][CH2:10][CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH2:20]([C@@H:22]1[CH2:27][O:26][CH2:25][CH2:24][NH:23]1)[CH3:21].CC(C1C=C(C(C)C)C(C2C=CC=CC=2P(C2CCCCC2)C2CCCCC2)=C(C(C)C)C=1)C.CC(C)([O-])C.[Na+]>C1(C)C=CC=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd].O>[CH2:1]([N:8]1[CH2:14][C:13]2[N:15]=[CH:16][C:17]([N:23]3[CH2:24][CH2:25][O:26][CH2:27][C@H:22]3[CH2:20][CH3:21])=[N:18][C:12]=2[O:11][CH2:10][CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CC[C@@H]1COCCN1
Reactant: Clc1cnc2c(n1)OCCN(Cc1ccccc1)C2
Agent: [Pd]
Agent: CC(C)(C)[O-]
Agent: CC(C)c1cc(C(C)C)c(-c2ccccc2P(C2CCCCC2)C2CCCCC2)c(C(C)C)c1
Solvent: Cc1ccccc1
Solvent: O
Product: CC[C@@H]1COCCN1c1cnc2c(n1)OCCN(Cc1ccccc1)C2
Temperature: 100 °C
Yield: 33.3 %

Procedure:
A suspension of 8-benzyl-3-chloro-6,7,8,9-tetrahydropyrazino[2,3-f][1,4]oxazepine (308 mg), (3R)-3-ethylmorpholine (193 mg), Pd2(dba)3 (31 mg), XPhos (64 mg) and sodium tert-butoxide (216 mg) in toluene (6 mL) was stirred under an argon atmosphere with heating at 100° C. for 2 hr. Water was added to the reaction mixture, the aqueous layer was extracted with ethyl acetate, and the organic layer was washed with saturated brine, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The obtained residue was purified by basic silica gel column chromatography (solvent gradient: 5→33% ethyl acetate/hexane) to give the title compound (132 mg, 33%) as a pale-yellow oil.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:8]2[C:17]3[C:12](=[CH:13][CH:14]=[C:15]([CH:18]([C:25]4[CH:30]=[CH:29][C:28]([Cl:31])=[CH:27][CH:26]=4)[C:19]4[N:23]([CH3:24])[CH:22]=[N:21][N:20]=4)[CH:16]=3)[N:11]([CH3:32])[C:10](=[O:33])[CH:9]=2)[CH:5]=[CH:6][CH:7]=1.CC([OH:38])(C)C.[K].O>CN(C)C=O>[Cl:1][C:2]1[CH:3]=[C:4]([C:8]2[C:17]3[C:12](=[CH:13][CH:14]=[C:15]([C:18]([C:25]4[CH:26]=[CH:27][C:28]([Cl:31])=[CH:29][CH:30]=4)([OH:38])[C:19]4[N:23]([CH3:24])[CH:22]=[N:21][N:20]=4)[CH:16]=3)[N:11]([CH3:32])[C:10](=[O:33])[CH:9]=2)[CH:5]=[CH:6][CH:7]=1
Reactant: Cn1cnnc1C(c1ccc(Cl)cc1)c1ccc2c(c1)c(-c1cccc(Cl)c1)cc(=O)n2C
Reactant: CC(C)(C)O
Agent: [K]
Solvent: CN(C)C=O
Solvent: O
Product: Cn1cnnc1C(O)(c1ccc(Cl)cc1)c1ccc2c(c1)c(-c1cccc(Cl)c1)cc(=O)n2C
Temperature: 25 °C
Reaction time: 1 h
Yield: 77 %

Procedure:
Air was bubbled in a mixture of 4-(3-chlorophenyl)-6-[(4-chlorophenyl)(4-methyl-4H-1,2,4-triazol-3-yl)methyl]-1-methyl-2(1H)-quinolinone (see Example B7) (0.0018 mol) in N,N-dimethylformamide (8 ml) at 5° C. for 30 minutes. 2-methyl-2-propanol, potassium salt (0.0036 mol) was added portionwise. The mixture was stirred at room temperature for 1 hour, poured out into water, filtered and washed several times with water. The precipitate was taken up in CH2Cl2. The organic layer was separated dried (MgSO4), filtered and the solvent was evaporated till dryness. The residue (1.1 g) was purified by column chromatography over silica gel (eluent: CH2Cl2/CH3OH/NH4OH 92/8/0.1; 15–40 μm). The pure fractions were collected and the solvent was evaporated. The residue (0.75 g, 85%) was crystallized from 2 propanone/DIPE. The precipitate was filtered off and dried, yielding 0.68 g (77%) of 4-(3-chlorophenyl)-6-[(4-chlorophenyl)hydroxy(4-methyl-4H-1,2,4-triazol-3-yl)methyl]-1-methyl-2(1H)-quinolinone, mp. 182° C.
Reaction SMILES: [CH3:1][C:2]1[N:3]([C:17]2[CH:22]=[CH:21][NH:20][C:19](=[O:23])[CH:18]=2)[C:4]([CH3:16])=[C:5]([C:7]#[C:8][C:9]2[CH:10]=[C:11]([CH3:15])[CH:12]=[CH:13][CH:14]=2)[N:6]=1.Br[CH2:25][CH2:26][O:27][CH3:28]>>[CH3:1][C:2]1[N:3]([C:17]2[CH:22]=[CH:21][N:20]([CH2:25][CH2:26][O:27][CH3:28])[C:19](=[O:23])[CH:18]=2)[C:4]([CH3:16])=[C:5]([C:7]#[C:8][C:9]2[CH:10]=[C:11]([CH3:15])[CH:12]=[CH:13][CH:14]=2)[N:6]=1
Reactant: COCCBr
Reactant: Cc1cccc(C#Cc2nc(C)n(-c3cc[nH]c(=O)c3)c2C)c1
Product: COCCn1ccc(-n2c(C)nc(C#Cc3cccc(C)c3)c2C)cc1=O

Procedure:
The title compound, light brown solid, MS: m/e=362.3 (M+H+), was prepared in accordance with the general method of example 3 from 4-[2,5-dimethyl-4-m-tolylethynyl-imidazol-1-yl]-1H-pyridin-2-one and 2-bromoethyl-methylether.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([CH:7]=[C:8]([F:10])[CH:9]=1)[C:5]#[N:6].[CH3:11][S-:12].[Na+].C(N(CC)C(C)C)(C)C.Cl>C1(C)C=CC=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd].CC1(C)C2C(=C(P(C3C=CC=CC=3)C3C=CC=CC=3)C=CC=2)OC2C(P(C3C=CC=CC=3)C3C=CC=CC=3)=CC=CC1=2>[F:10][C:8]1[CH:7]=[C:4]([CH:3]=[C:2]([S:12][CH3:11])[CH:9]=1)[C:5]#[N:6]
Reactant: C[S-]
Reactant: N#Cc1cc(F)cc(Br)c1
Agent: [Pd]
Agent: CC1(C)c2cccc(P(c3ccccc3)c3ccccc3)c2Oc2c(P(c3ccccc3)c3ccccc3)cccc21
Agent: Cl
Solvent: Cc1ccccc1
Solvent: CCN(C(C)C)C(C)C
Product: CSc1cc(F)cc(C#N)c1
Yield: 74.2 %

Procedure:
(Step 1) A mixture of 3-bromo-5-fluorobenzonitrile (10.0 g), sodium methanethiolate (3.85 g), Pd2(dba)3 (229 mg), Xantphos (289 mg) and N,N-diisopropylethylamine (12.9 g) was stirred in toluene (100 ml) at 90° C. for 9 hr. The reaction mixture was treated with 1N hydrochloric acid, and extracted with ethyl acetate. The organic layer was washed with saturated brine, and dried over magnesium sulfate. The solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate:hexane=1:19) to give 3-fluoro-5-(methylsulfanyl)benzonitrile (6.2 g) as a solid.
Reaction SMILES: F[C:2]1[CH:9]=[CH:8][CH:7]=[CH:6][C:3]=1[C:4]#[N:5].[NH:10]1[CH2:15][CH2:14][O:13][CH2:12][CH2:11]1>C(#N)C>[O:13]1[CH2:14][CH2:15][N:10]([C:2]2[CH:9]=[CH:8][CH:7]=[CH:6][C:3]=2[C:4]#[N:5])[CH2:11][CH2:12]1
Reactant: N#Cc1ccccc1F
Reactant: C1COCCN1
Solvent: CC#N
Product: N#Cc1ccccc1N1CCOCC1
Temperature: 110 °C
Yield: 956.3 %

Procedure:
2-Fluorobenzonitrile (1.21 g, 1.00 mmol) was dissolved in acetonitrile (50 ml), and morpholine (33 ml, 377 mmol) was added thereto followed by stirring at 110° C. for 2 nights. After the reaction was completed, the reaction mixture was concentrated to give oily substances which were then purified by silica gel chromatography (eluent: chloroform) to give the title compound (1.80 g, 95%) as oily substances.
Reaction SMILES: [OH-].[Na+].[Cl:3][C:4]1[CH:26]=[C:25]([C:27]([NH:29][CH2:30][C:31]2[CH:36]=[CH:35][CH:34]=[C:33]([O:37]C(C3C=CSC=3)=O)[CH:32]=2)=[O:28])[CH:24]=[C:23]([Cl:45])[C:5]=1[C:6]([NH:8][C@H:9]([C:19]([O:21]C)=[O:20])[CH2:10][NH:11][C:12]([C:14]1[CH:18]=[CH:17][S:16][CH:15]=1)=[O:13])=[O:7].[OH-].S1C=CC(C(NC[C@@H](C(OC)=O)N)=O)=C1>CO>[Cl:3][C:4]1[CH:26]=[C:25]([C:27]([NH:29][CH2:30][C:31]2[CH:36]=[CH:35][CH:34]=[C:33]([OH:37])[CH:32]=2)=[O:28])[CH:24]=[C:23]([Cl:45])[C:5]=1[C:6]([NH:8][C@H:9]([C:19]([OH:21])=[O:20])[CH2:10][NH:11][C:12]([C:14]1[CH:18]=[CH:17][S:16][CH:15]=1)=[O:13])=[O:7]
Reactant: COC(=O)[C@H](CNC(=O)c1ccsc1)NC(=O)c1c(Cl)cc(C(=O)NCc2cccc(OC(=O)c3ccsc3)c2)cc1Cl
Agent: COC(=O)[C@@H](N)CNC(=O)c1ccsc1
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: O=C(NCc1cccc(O)c1)c1cc(Cl)c(C(=O)N[C@@H](CNC(=O)c2ccsc2)C(=O)O)c(Cl)c1
Reaction time: 8 h
Yield: 130.4 %

Procedure:
An aqueous solution of sodium hydroxide (1 M; 0.305 mL, 0.305 mmol) was added to a solution of N-[2,6-dichloro-4-[[[[3-[(thiophene-3-carbonyl)oxy]phenyl]methy]amino]carbonyl]benzoyl]-3-[(thiophene-3-carbonyl)amino]-L-alanine, methyl ester (101 mg, 0.153 mmol) in methanol (2 mL). The solution was allowed to stir overnight and then concentrated. An aqueous solution of odium hydroxide (1 M; 0.210 mL, 0.210 mmol) was added to a solution of N-[2,6-dichloro-4-[[(3-hydroxyphenyl)methyl]amino]carbonyl]benzoyl]-3-[(thiophene-3-carbonyl)amino]-L-alanine, methyl ester (58 mg, 0.105 mmol) in methanol (2 mL). The solution was allowed to stir overnight and then concentrated. The residues from the two reactions were purified by HPLC and lyophilized to give N-[2,6-dichloro-4-[[[(3-hydroxyphenyl)methyl]amino]carbonyl)benzoyl]-3-[(thiophene-3-carbonyl)amino]-L-alanine (107 mg, 78%) as a white solid.
Reaction SMILES: [C:1]([NH:5][S:6]([CH3:9])(=[O:8])=[O:7])([CH3:4])([CH3:3])[CH3:2].C([Li])CCC.[F:15][C:16]1[CH:25]=[CH:24][C:19]([C:20](OC)=[O:21])=[CH:18][CH:17]=1.C(O)(=O)C>C1COCC1.C(OCC)(=O)C>[C:1]([NH:5][S:6]([CH2:9][C:20]([C:19]1[CH:24]=[CH:25][C:16]([F:15])=[CH:17][CH:18]=1)=[O:21])(=[O:8])=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: COC(=O)c1ccc(F)cc1
Reactant: CC(C)(C)NS(C)(=O)=O
Agent: [Li]CCCC
Solvent: CCOC(C)=O
Solvent: CC(=O)O
Solvent: C1CCOC1
Product: CC(C)(C)NS(=O)(=O)CC(=O)c1ccc(F)cc1
Temperature: 0 °C
Yield: 36.6 %

Procedure:
N-tert-Butylmethanesulfonamide (1.00 g) was initially charged in THF (10 ml) and cooled to −78° C. n-Butyllithium (1.6 N in hexane, 9.00 ml) was added dropwise. Subsequently, the mixture was warmed up to 0° C. within 5 minutes, stirred for 5 further minutes and cooled again to −78° C. Methyl 4-fluorobenzoate (1.56 g) in THF (10 ml) dissolved and to −78° C. cooled. The solution prepared above was added dropwise at low temperature. After the addition had ended, the mixture was allowed to come to room temperature and stirred for a further 1 hour. After the addition of acetic acid (0.82 ml) and ethyl acetate (50 ml), the mixture was washed with saturated sodium hydrogencarbonate solution (50 ml) and saturated sodium chloride solution (50 ml). The organic phase was dried over magnesium sulfate, filtered and concentrated by rotary evaporation. Purification was effected via normal phase with an n-heptane/ethyl acetate gradient. The fractions of value were combined, concentrated by rotary evaporation and dried under reduced pressure. This gave the product (661 mg) with a molecular weight of 273.3 g/mol (C12H16FNO3S), MS (EST): m/e=296 (M+Na+).
Reaction SMILES: [C:1]([NH:4][C:5]1[S:6][C:7]([S:10](Cl)(=[O:12])=[O:11])=[N:8][N:9]=1)(=[O:3])[CH3:2].Cl.[CH3:15][NH:16][CH3:17]>>[C:1]([NH:4][C:5]1[S:6][C:7]([S:10]([N:16]([CH3:17])[CH3:15])(=[O:12])=[O:11])=[N:8][N:9]=1)(=[O:3])[CH3:2]
Reactant: CNC
Reactant: CC(=O)Nc1nnc(S(=O)(=O)Cl)s1
Agent: Cl
Product: CC(=O)Nc1nnc(S(=O)(=O)N(C)C)s1
Temperature: 20 °C
Reaction time: 2 h

Procedure:
A 40% aqueous solution of dimethylamine (400 ml) was charged into a glass reaction vessel fitted with a mechanical stirrer and thermometer. The solution was cooled to 20° C. and stirred while 2-acetamido-5-chlorosulfonyl-1,3,4-thiadiazole (250 grams) was slowly added. Ther temperature of the reaction mixture was kept between 0° and 20° C. during this addition. Stirring was then continued at room temperature for a period of about 2 hours. The reaction mixture was then treated with 6N hydrochloric acid. Solids were filtered out, water washed and air dried to yield the desired product 2-acetamido-5-(N,N-dimethylaminosulfonyl)-1,3,4-thiadiazole.
Reaction SMILES: [C:1]1([N:7]=[C:8]=[O:9])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C[NH:11]S(C1C=CC(C)=CC=1)(=O)=O>ClC1C=CC=CC=1Cl>[C:1]1([NH:7][C:8]([NH2:11])=[O:9])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: CNS(=O)(=O)c1ccc(C)cc1
Reactant: O=C=Nc1ccccc1
Solvent: Clc1ccccc1Cl
Product: NC(=O)Nc1ccccc1

Procedure:
Phenyl isocyanate (1.19 g, 0.01 mol) and N-methyl-4-methylbenzene sulfonamide (1.85 g, 0.01 mol) were dissolved in 1,2-dichlorobenzene (20 ml) and refluxed for 40 hrs. After cooling, the solvent was evaporated in vacuo to give a viscous oil that crystallized on standing to give N-methyl-N-4-methylphenyl-N*-phenyl urea mp 63–65° C. MS m/z 304. (M+ calcd for C15H16N2O3S=304). H NMR (300 Mhz, CDCl3) d 2.43 (s, 3, CH3), 2.65 (s, 3, CH3), 7.33 (m, 5, aromatic), 7.48 (m, 1, aromatic), 7.75 (m, 3, aromatic).
Reaction SMILES: [NH2:1][CH2:2][C@@H:3]1[C@H:8]([CH3:9])[CH2:7][CH2:6][CH2:5][N:4]1[C:10]([C:12]1[CH:17]=[CH:16][C:15]([F:18])=[CH:14][C:13]=1[C:19]1[N:24]=[CH:23][CH:22]=[CH:21][N:20]=1)=[O:11].Cl[C:26]1[N:31]=[CH:30][C:29]([Cl:32])=[CH:28][N:27]=1>>[Cl:32][C:29]1[CH:28]=[N:27][C:26]([NH:1][CH2:2][C@@H:3]2[C@H:8]([CH3:9])[CH2:7][CH2:6][CH2:5][N:4]2[C:10]([C:12]2[CH:17]=[CH:16][C:15]([F:18])=[CH:14][C:13]=2[C:19]2[N:20]=[CH:21][CH:22]=[CH:23][N:24]=2)=[O:11])=[N:31][CH:30]=1
Reactant: Clc1cnc(Cl)nc1
Reactant: C[C@@H]1CCCN(C(=O)c2ccc(F)cc2-c2ncccn2)[C@@H]1CN
Product: C[C@@H]1CCCN(C(=O)c2ccc(F)cc2-c2ncccn2)[C@@H]1CNc1ncc(Cl)cn1

Procedure:
The title compound was prepared following the same general protocol as described for Example A44 using ((2S,3R)-2-(aminomethyl)-3-methylpiperidin-1-yl)(4-fluoro-2-(pyrimidin-2-yl)phenyl)methanone and 2,5-dichloropyrimidine. ESI-MS (m/z): 441 [M+1]+.
Reaction SMILES: [CH2:1]([N:5]([CH2:23][C:24]1[CH:36]=[CH:35][C:27]([O:28][CH2:29][C:30]([O:32]CC)=[O:31])=[C:26]([CH3:37])[CH:25]=1)[C:6]1[C:7]([CH3:22])=[C:8]([C:12]2[CH:17]=[CH:16][C:15]([C:18]([F:21])([F:20])[F:19])=[CH:14][CH:13]=2)[CH:9]=[CH:10][CH:11]=1)[CH2:2][CH2:3][CH3:4].[OH-].[Na+]>CO.C1COCC1>[CH2:1]([N:5]([CH2:23][C:24]1[CH:36]=[CH:35][C:27]([O:28][CH2:29][C:30]([OH:32])=[O:31])=[C:26]([CH3:37])[CH:25]=1)[C:6]1[C:7]([CH3:22])=[C:8]([C:12]2[CH:13]=[CH:14][C:15]([C:18]([F:21])([F:20])[F:19])=[CH:16][CH:17]=2)[CH:9]=[CH:10][CH:11]=1)[CH2:2][CH2:3][CH3:4]
Reactant: CCCCN(Cc1ccc(OCC(=O)OCC)c(C)c1)c1cccc(-c2ccc(C(F)(F)F)cc2)c1C
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CO
Product: CCCCN(Cc1ccc(OCC(=O)O)c(C)c1)c1cccc(-c2ccc(C(F)(F)F)cc2)c1C
Yield: 101 %

Procedure:
To a solution of ethyl [4-({butyl[2-methyl-4′-(trifluoromethyl)-1,1′-biphenyl-3-yl]amino}methyl)-2-methylphenoxy]acetate (110 mg, 0.21 mmol) in MeOH (2 mL) and THF (2 mL) at room temperature was added 2M NaOH (1 mL, 2 mmol). The resultant mixture was stirred for 2 h. The solvents were removed in vacuo and the residue was partitioned between CH2Cl2 (2×20 mL) and 2M HCl (20 mL). The organic solution was passed through a hydrophobic frit and the solvent was removed in vacuo affording the title compound as a white solid (103 mg).
Reaction SMILES: C([O:3][C:4](=[O:34])[CH2:5][O:6][C:7]1[CH:16]=[CH:15][C:14]2[C:9](=[CH:10][CH:11]=[C:12]([C:17]3[S:21][C:20]4[CH:22]=[CH:23][CH:24]=[CH:25][C:19]=4[C:18]=3[C:26](=[O:32])[CH2:27][C:28]([CH3:31])([CH3:30])[CH3:29])[CH:13]=2)[C:8]=1[Br:33])C.[OH-].[K+].Cl>C1COCC1.O>[Br:33][C:8]1[C:9]2[C:14](=[CH:13][C:12]([C:17]3[S:21][C:20]4[CH:22]=[CH:23][CH:24]=[CH:25][C:19]=4[C:18]=3[C:26](=[O:32])[CH2:27][C:28]([CH3:31])([CH3:29])[CH3:30])=[CH:11][CH:10]=2)[CH:15]=[CH:16][C:7]=1[O:6][CH2:5][C:4]([OH:34])=[O:3]
Reactant: CCOC(=O)COc1ccc2cc(-c3sc4ccccc4c3C(=O)CC(C)(C)C)ccc2c1Br
Agent: Cl
Agent: [K+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Product: CC(C)(C)CC(=O)c1c(-c2ccc3c(Br)c(OCC(=O)O)ccc3c2)sc2ccccc12
Temperature: 25 °C
Reaction time: 4 h
Yield: 68.3 %

Procedure:
A mixture of {1-bromo-6-[3-(3,3-dimethyl-butyryl)-benzo[b]thiophen-2-yl]-naphthalen-2-yloxy}-acetic acid ethyl ester (0.360 g, 0.667 mmol) and potassium hydroxide (0.125 g, 2.23 mmol) in THF (5 mL) and water (5 mL) was stirred at ambient temperature for four hours. It was then poured in excess water and acidified with 2N hydrochloric acid. This was then extracted with ethyl acetate and washed with water and brine. The organic phase was dried with anhydrous magnesium sulfate, filtered, solvent evaporated dried in vacuo at 78° C. for 12 hours to yield {1-bromo-6-[3-(3,3-dimethyl-butyryl)-benzo[b]thiophen-2-yl]-naphthalen-2-yloxy}-acetic acid as a light yellow solid (0.233 g, 68.3%): MP: 206–7° C.; mass spectrum (+EI, [M+H]+) m/z 511/513. 1H NMR (500 MHz, DMSO-d6): δ12.9–13.4 (br, 1H), 8.24 (d, 1H, J=9.01 Hz), 8.11–8.13(m, 2H), 8.07–8.09 (m, 1H), 7.74 (dd, 1H, J=8.78 Hz and 1.76 Hz), 7.46–7.51 (m, 3H), 5.02 (s, 2H), 2.33 (s, 2H), 0.76 ppm (s, 9H). Elemental Analysis for C26H23BrNO4S: Calcd: C, 61.06; H, 4.53; N, 0.00; Found: C, 61.17; H,4.64; N, 0.00.
Reaction SMILES: [CH2:1]([CH:3]1[O:5][CH2:4]1)Cl.[CH2:6]([C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=1[OH:15])[CH:7]=[CH2:8].[OH-].[Na+]>C(C1C=CC=CC=1O)C=C.O>[CH2:1]([O:15][C:10]1[CH:11]=[CH:12][CH:13]=[CH:14][C:9]=1[CH2:6][CH:7]=[CH2:8])[CH:3]1[O:5][CH2:4]1
Reactant: ClCC1CO1
Reactant: C=CCc1ccccc1O
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: C=CCc1ccccc1OCC1CO1
Temperature: 100 °C
Reaction time: 1 h

Procedure:
This allyl phenyl ether was introduced into an autoclave and held at 200° C. for 5 hours with stirring. In this stage, a rearrangement reaction occurred to obtain 2-allylphenol. Into a reaction vessel, 134 g (1 mol) of the 2-allylphenol and 1.3 g of a boron trifluoride ether complex as a catalyst were introduced. In a nitrogen atmosphere, the contents were heated to 100° C. with stirring, and epichlorohydrin was added dropwise thereto in an amount of 1 mol per mole of the 2-allylphenol, with stirring the contents and maintaining that temperature. Thereafter, 100 g of 48% aqueous sodium hydroxide solution was added dropwise thereto at 60° C., and the resultant mixture was aged at 60° C. for 2 hours. Subsequently, 400 g of water was added thereto, and this mixture was stirred at 80° C. for 30 minutes and then allowed to stand still at 80° C. for 1 hour. The lower layer (aqueous layer) which had separated was removed, followed by dehydration at 100° C. under vacuum to obtain 2-allylphenyl glycidyl ether.
Reaction SMILES: [CH:1]([NH:4][C:5]([C:7]1[C:15]2[C:10](=[N:11][CH:12]=[C:13]([C:16]3[C:24]4[C:19](=[CH:20][CH:21]=[C:22]([C:25](C)(C)[O:26][SiH2]C(C)(C)C)[CH:23]=4)[N:18]([CH3:34])[N:17]=3)[N:14]=2)[N:9]([CH2:35][O:36][CH2:37][CH2:38][Si:39]([CH3:42])([CH3:41])[CH3:40])[CH:8]=1)=[O:6])([CH3:3])[CH3:2].[F-].C([N+](CCCC)(CCCC)CCCC)CCC>C1COCC1>[CH:1]([NH:4][C:5]([C:7]1[C:15]2[C:10](=[N:11][CH:12]=[C:13]([C:16]3[C:24]4[C:19](=[CH:20][CH:21]=[C:22]([CH2:25][OH:26])[CH:23]=4)[N:18]([CH3:34])[N:17]=3)[N:14]=2)[N:9]([CH2:35][O:36][CH2:37][CH2:38][Si:39]([CH3:41])([CH3:40])[CH3:42])[CH:8]=1)=[O:6])([CH3:3])[CH3:2]
Reactant: CC(C)NC(=O)c1cn(COCC[Si](C)(C)C)c2ncc(-c3nn(C)c4ccc(C(C)(C)O[SiH2]C(C)(C)C)cc34)nc12
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: C1CCOC1
Product: CC(C)NC(=O)c1cn(COCC[Si](C)(C)C)c2ncc(-c3nn(C)c4ccc(CO)cc34)nc12
Temperature: 0 °C

Procedure:
In a round-bottomed flask, 2-[5-(tert-butyl-dimethyl-silanyloxymethyl)-1-methyl-1H-indazol-3-yl]-5-(2-trimethylsilanyl-ethoxymethyl)-5H-pyrrolo[2,3-b]pyrazine-7-carboxylic acid isopropylamide (425 mg, 0.66 mmol) was dissolved in THF (6 ml). The light yellow solution was cooled to 0° C. and tetrabutylammonium fluoride (1.0 M in THF, 0.24 ml, 0.240 mmol) was added dropwise. The reaction mixture was allowed to warm slowly to room temperature over 2 h then quenched with water and extracted with EtOAc (2×). The combined organic layers were washed with water and brine then concentrated. The residue was triturated with diethyl ether to afford 2-(5-hydroxymethyl-1-methyl-1H-indazol-3-yl)-5-(2-trimethylsilanyl-ethoxymethyl)-5H-pyrrolo[2,3-b]pyrazine-7-carboxylic acid isopropylamide as a yellow powder which was used without further purification.
Reaction SMILES: FC(F)(F)C([NH:5][C@H:6]([C:11]1[CH:16]=[CH:15][C:14]([F:17])=[CH:13][CH:12]=1)[C:7]([OH:10])([CH3:9])[CH3:8])=O.[OH-].[K+].O.ClCCl>CO>[NH2:5][C@H:6]([C:11]1[CH:12]=[CH:13][C:14]([F:17])=[CH:15][CH:16]=1)[C:7]([CH3:9])([OH:10])[CH3:8]
Reactant: CC(C)(O)[C@H](NC(=O)C(F)(F)F)c1ccc(F)cc1
Agent: [K+]
Agent: [OH-]
Solvent: CO
Solvent: ClCCl
Solvent: O
Product: CC(C)(O)[C@H](N)c1ccc(F)cc1
Temperature: 60 °C
Reaction time: 20 h
Yield: 87.1 %

Procedure:
5.6 g of 2,2,2-trifluoro-N—[(R)-1-(4-fluoro-phenyl)-2-hydroxy-2-methyl-propyl]-acetamide and 2.27 g KOH are suspended in 61.1 ml of methanol. The reaction mixture is stirred for 20 hours at 60° C. and then combined with water and dichloromethane, the organic phase is dried and evaporated to dryness. 3.2 g of the product are obtained as an oil.