Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[N:7]([CH2:30][C:31]([O:33][CH2:34][CH3:35])=[O:32])[C:8]([C:10]1[CH:29]=[CH:28][C:13]2[N:14]([CH3:27])[C:15]([CH2:17][O:18][C:19]3[CH:24]=[CH:23][C:22]([C:25]#[N:26])=[CH:21][CH:20]=3)=[N:16][C:12]=2[CH:11]=1)=[O:9].[ClH:36].C(O)C.C(=O)([O-])[O-].[NH4+:44].[NH4+]>ClCCl.C(O)C>[ClH:36].[ClH:36].[N:1]1[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[N:7]([CH2:30][C:31]([O:33][CH2:34][CH3:35])=[O:32])[C:8]([C:10]1[CH:29]=[CH:28][C:13]2[N:14]([CH3:27])[C:15]([CH2:17][O:18][C:19]3[CH:24]=[CH:23][C:22]([C:25](=[NH:44])[NH2:26])=[CH:21][CH:20]=3)=[N:16][C:12]=2[CH:11]=1)=[O:9]
Reactant: [NH4+]
Reactant: CCOC(=O)CN(C(=O)c1ccc2c(c1)nc(COc1ccc(C#N)cc1)n2C)c1ccccn1
Agent: Cl
Agent: O=C([O-])[O-]
Solvent: ClCCl
Solvent: CCO
Product: CCOC(=O)CN(C(=O)c1ccc2c(c1)nc(COc1ccc(C(=N)N)cc1)n2C)c1ccccn1
Yield: 44 %

Procedure:
Prepared analogously to Example 25d from 1-methyl-2-[(4-cyanophenyl)oxymethyl]benzimidazol-5-yl-carboxylic acid-N-(2-pyridyl)-N-(ethoxycarbonylmethyl)amide and ethanolic hydrochloric acid, ethanol, and ammonium carbonate. Yield: 44% of theory, C26H26N6O4 (486.5); Rf value: 0.12 (silica gel; dichloromethane/ethanol=4:1); EKA mass spectrum: (M+H)+=487; (M+2H)++=244; (M+H+Na)++=255.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[O:9][C:10]([CH3:13])=[N:11][N:12]=2)=[CH:4][C:3]=1[C:14]1[CH:19]=[CH:18][C:17]([C:20](O)=[O:21])=[CH:16][CH:15]=1.[OH:23][C:24]1[CH:31]=[CH:30][C:27]([CH2:28][NH2:29])=[CH:26][CH:25]=1>>[OH:23][C:24]1[CH:31]=[CH:30][C:27]([CH2:28][NH:29][C:20]([C:17]2[CH:18]=[CH:19][C:14]([C:3]3[CH:4]=[C:5]([C:8]4[O:9][C:10]([CH3:13])=[N:11][N:12]=4)[CH:6]=[CH:1][C:2]=3[CH3:7])=[CH:15][CH:16]=2)=[O:21])=[CH:26][CH:25]=1
Reactant: NCc1ccc(O)cc1
Reactant: Cc1nnc(-c2ccc(C)c(-c3ccc(C(=O)O)cc3)c2)o1
Product: Cc1nnc(-c2ccc(C)c(-c3ccc(C(=O)NCc4ccc(O)cc4)cc3)c2)o1

Procedure:
N-(4-Hydroxybenzyl)-2′-methyl-5′-(5-methyl-1,3,4-oxadiazol-2-yl)-1,1′-biphenyl-4-carboxamide was prepared from 2′-methyl-5′-(5-methyl-1,3,4-oxadiazol-2-yl)-1,1′-biphenyl-4-carboxylic acid and 4-hydroxybenzylamine using method H. NMR; δH [2H6]—DMSO 9.27,(1H, s), 9.02,(1H, t), 7.98,(2H, d), 7.89,(1H, dd), 7.76,(1H, d), 7.54,,(1H, d), 7.51,(2H, d), 7.13,(2H, d), 6.71,(2H, d), 4.39,(2H, d), 2.56,(3H, s), 2.31,(3H, s), LCMS; retention time 3.03 min, MH+ 400.
Reaction SMILES: [CH3:1][N:2]1[CH2:7][CH2:6][CH:5]([C:8]2[C:16]3[C:11](=[CH:12][CH:13]=[C:14](B(O)O)[CH:15]=3)[NH:10][CH:9]=2)[CH2:4][CH2:3]1.Br[C:21]1[CH:26]=[CH:25][C:24]([NH:27][C:28](=[O:36])[C:29]2[CH:34]=[CH:33][C:32]([F:35])=[CH:31][CH:30]=2)=[CH:23][CH:22]=1.C(=O)([O-])[O-].[Na+].[Na+]>O1CCCC1.CO.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>[F:35][C:32]1[CH:33]=[CH:34][C:29]([C:28]([NH:27][C:24]2[CH:25]=[CH:26][C:21]([C:14]3[CH:15]=[C:16]4[C:11](=[CH:12][CH:13]=3)[NH:10][CH:9]=[C:8]4[CH:5]3[CH2:6][CH2:7][N:2]([CH3:1])[CH2:3][CH2:4]3)=[CH:22][CH:23]=2)=[O:36])=[CH:30][CH:31]=1
Reactant: O=C(Nc1ccc(Br)cc1)c1ccc(F)cc1
Reactant: CN1CCC(c2c[nH]c3ccc(B(O)O)cc23)CC1
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: [Na+]
Solvent: CO
Solvent: C1CCOC1
Product: CN1CCC(c2c[nH]c3ccc(-c4ccc(NC(=O)c5ccc(F)cc5)cc4)cc23)CC1
Yield: 29.4 %

Procedure:
The title compound was prepared by the procedure of Example 10, beginning with 3-(1-methylpiperidin-4-yl)-1H-indole-5-boronic acid (0.200 g, 0.77 mmol), 1-bromo-4-(4-fluorobenzamido)benzene (0.217 g, 0.74 mmol), tetrakis(triphenylphosphine)palladium(0) (0.045 g, 0.039 mol), and 2M aqueous sodium carbonate solution (2 mL) in 15 mL of tetrahydrofuran:methanol (1:1) to give the title compound (0.093 g, 29%) as an amorphous solid. FDMS m/e=427 (M+). EA calculated for C27H26N3OF: C, 75.85; H, 6.13; N, 9.83. Found: C, 75.55; H, 6.18; N, 9.73.
Reaction SMILES: C[O:2][C:3](=[O:22])[CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][N:11]1[C:15]2[CH:16]=[C:17]([Cl:20])[CH:18]=[CH:19][C:14]=2[O:13][C:12]1=[O:21].[OH-].[Na+]>>[Cl:20][C:17]1[CH:18]=[CH:19][C:14]2[O:13][C:12](=[O:21])[N:11]([CH2:10][CH2:9][CH2:8][CH2:7][CH2:6][CH2:5][CH2:4][C:3]([OH:22])=[O:2])[C:15]=2[CH:16]=1
Reactant: COC(=O)CCCCCCCn1c(=O)oc2ccc(Cl)cc21
Agent: [Na+]
Agent: [OH-]
Product: O=C(O)CCCCCCCn1c(=O)oc2ccc(Cl)cc21

Procedure:
The product is produced as described in example 22 from 10.9 g. of 8-(5-chloro-2-oxo-benzoxazolin-3-yl)-caprylic acid methyl ester and 1.6 g. of NaOH. Eluant in chromatographic purification: chloroform.
Reaction SMILES: [OH:1][C:2]1[CH:9]=[CH:8][C:5]([CH2:6][OH:7])=[CH:4][CH:3]=1.[OH-].[K+].[CH3:12][CH2:13][CH2:14]Br.O>CS(C)=O>[CH2:12]([O:1][C:2]1[CH:9]=[CH:8][C:5]([CH2:6][OH:7])=[CH:4][CH:3]=1)[CH2:13][CH3:14]
Reactant: CCCBr
Reactant: OCc1ccc(O)cc1
Agent: [K+]
Agent: [OH-]
Solvent: O
Solvent: CS(C)=O
Product: CCCOc1ccc(CO)cc1
Reaction time: 24 h
Yield: 95.2 %

Procedure:
4-hydroxybenzyl alcohol (12.4 g: 100.0 mmol) was dissolved in 100 ml of dimethylsulfoxide (DMSO), and an aqueous solution of potassium hydroxide (KOH/H2O: 6.6 g/15 ml) was added to the mixture. After the resultant mixture was dissolved homogeneously by stirring, n-propyl bromide (12.3 g:100.0 mmol) was added thereto, and the reaction was carried out at a room temperature for 24 hours. The reaction mixture was poured into 1 L of an iced water and a solid was formed by stirring. The resultant solid was collected by filtration, dried, and recrystallized from toluene to provide 15.8 g (95.2 mmol) of 4-n-propyloxybenzyl alcohol.
Reaction SMILES: [OH:1][C:2]1[CH:38]=[CH:37][C:5]([C:6]([N:8]([CH:34]([CH3:36])[CH3:35])[C:9]2[CH:14]=[C:13]([O:15][CH3:16])[CH:12]=[CH:11][C:10]=2[CH:17]2[CH2:26][CH2:25][C:24]3[CH:23]=[C:22]([O:27]C(=O)C(C)(C)C)[CH:21]=[CH:20][C:19]=3[CH2:18]2)=O)=[CH:4][CH:3]=1.Cl[CH2:40][C:41]([NH:43][CH2:44][CH3:45])=O>>[CH2:41]([NH:43][CH2:44][CH2:45][O:1][C:2]1[CH:38]=[CH:37][C:5]([CH2:6][N:8]([CH:34]([CH3:36])[CH3:35])[C:9]2[CH:14]=[C:13]([O:15][CH3:16])[CH:12]=[CH:11][C:10]=2[CH:17]2[CH2:26][CH2:25][C:24]3[CH:23]=[C:22]([OH:27])[CH:21]=[CH:20][C:19]=3[CH2:18]2)=[CH:4][CH:3]=1)[CH3:40]
Reactant: CCNC(=O)CCl
Reactant: COc1ccc(C2CCc3cc(OC(=O)C(C)(C)C)ccc3C2)c(N(C(=O)c2ccc(O)cc2)C(C)C)c1
Product: CCNCCOc1ccc(CN(c2cc(OC)ccc2C2CCc3cc(O)ccc3C2)C(C)C)cc1
Yield: 7.5 %

Procedure:
Synthesized from pivalic acid 6-{2-[(4-hydroxybenzoyl)isopropylamino]-4-methoxyphenyl}-5,6,7,8-tetrahydronaphthalen-2-yl ester (31 mg) and 2-chloro-N-ethylacetamide (22 mg) according to an analogous synthetic method to Example 404 and purified by LC-MS, the title compound (2.2 mg) was obtained.
Reaction SMILES: Cl.[NH2:2][CH2:3][CH:4]([C:7]1[C:16]2[C:11](=[CH:12][CH:13]=[C:14]([O:17][CH3:18])[CH:15]=2)[CH:10]=[CH:9][CH:8]=1)[CH2:5][OH:6].C(=O)([O-])[O-].[K+].[K+].[Cl-].[CH2:26]([OH:29])[CH2:27][CH3:28]>O.C(OCC)(=O)C>[OH:6][CH2:5][CH:4]([C:7]1[C:16]2[C:11](=[CH:12][CH:13]=[C:14]([O:17][CH3:18])[CH:15]=2)[CH:10]=[CH:9][CH:8]=1)[CH2:3][NH:2][C:26](=[O:29])[CH2:27][CH3:28]
Reactant: COc1ccc2cccc(C(CN)CO)c2c1
Reactant: CCCO
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [Cl-]
Solvent: CCOC(C)=O
Solvent: O
Product: CCC(=O)NCC(CO)c1cccc2ccc(OC)cc12
Temperature: 0 °C
Reaction time: 0.25 h

Procedure:
The compound obtained in Step B (3.73 mmol) is dissolved in 100 ml of a mixture of water and ethyl acetate (50/50). Potassium carbonate (11.2 mmol) is added and the reaction mixture is cooled to 0° C. Using an ice bath. Propanol chloride (4.6 mmol) is added dropwise and the mixture is stirred for 15 minutes in the cold state. When the reaction is complete, the organic phase is washed with hydrochloric acid solution (1M), washed with water, dried and evaporated under reduced pressure. The solution obtained is recrystallized from acetonitrile to yield the title product in the form of a white solid.
Reaction SMILES: [CH2:1]([C:4]1[N:17]([CH2:18][C:19]2[CH:24]=[CH:23][C:22]([C:25]3[CH:30]=[CH:29][CH:28]=[CH:27][C:26]=3[C:31]3[N:35]([C:36]([C:49]4[CH:54]=[CH:53][CH:52]=[CH:51][CH:50]=4)([C:43]4[CH:48]=[CH:47][CH:46]=[CH:45][CH:44]=4)[C:37]4[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=4)[N:34]=[N:33][N:32]=3)=[CH:21][CH:20]=2)[C:7]2[CH:8]([C:12]([O:14][CH2:15][CH3:16])=[O:13])[NH:9][CH2:10][CH2:11][C:6]=2[N:5]=1)[CH2:2][CH3:3].C(=O)([O-])[O-].[K+].[K+].[CH2:61](Br)[CH3:62].CN(C)C=O>C(OCC)(=O)C>[CH2:61]([N:9]1[CH2:10][CH2:11][C:6]2[N:5]=[C:4]([CH2:1][CH2:2][CH3:3])[N:17]([CH2:18][C:19]3[CH:20]=[CH:21][C:22]([C:25]4[CH:30]=[CH:29][CH:28]=[CH:27][C:26]=4[C:31]4[N:35]([C:36]([C:43]5[CH:44]=[CH:45][CH:46]=[CH:47][CH:48]=5)([C:37]5[CH:38]=[CH:39][CH:40]=[CH:41][CH:42]=5)[C:49]5[CH:54]=[CH:53][CH:52]=[CH:51][CH:50]=5)[N:34]=[N:33][N:32]=4)=[CH:23][CH:24]=3)[C:7]=2[CH:8]1[C:12]([O:14][CH2:15][CH3:16])=[O:13])[CH3:62]
Reactant: CCCc1nc2c(n1Cc1ccc(-c3ccccc3-c3nnnn3C(c3ccccc3)(c3ccccc3)c3ccccc3)cc1)C(C(=O)OCC)NCC2
Reactant: CCBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: CCCc1nc2c(n1Cc1ccc(-c3ccccc3-c3nnnn3C(c3ccccc3)(c3ccccc3)c3ccccc3)cc1)C(C(=O)OCC)N(CC)CC2
Temperature: 25 °C
Reaction time: 8 h
Yield: 53.9 %

Procedure:
A mixture of ethyl 2-n-propyl-3-[2'-(1-trityl- 1H-tetrazol-5-yl)biphenyl-4-yl]methyl-4,5,6,7-tetrahydroimidazo[4,5-c]pyridine-4-carboxylate (2.00 g), potassium carbonate (1.16 g), ethyl bromide (0.61 g) and dimethylformamide (10 ml) is stirred overnight at room temperature. The mixture is diluted with ethyl acetate, and the solution is washed with water, dried and evaporated. The residue is purified by silica gel column chromatography (solvent; chloroform/methanol) to give ethyl 5-ethyl-2-n-propyl-3-[2'-(1-trityl-1H-tetrazol-5-yl)biphenyl-4-yl]methyl-4,5,6,7-tetrahydroimidazo[4,5-c]pyridine-4-carboxylate (1.12 g) as a white foam.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:7]=[CH:8][C:9]=1[C:10]([F:13])([F:12])[F:11])[CH:5]=O.[N+:14]([CH3:17])([O-:16])=[O:15].[OH-].[Na+]>>[F:1][C:2]1[CH:3]=[C:4]([CH:5]=[CH:17][N+:14]([O-:16])=[O:15])[CH:7]=[CH:8][C:9]=1[C:10]([F:13])([F:12])[F:11]
Reactant: O=Cc1ccc(C(F)(F)F)c(F)c1
Reactant: C[N+](=O)[O-]
Agent: [Na+]
Agent: [OH-]
Product: O=[N+]([O-])C=Cc1ccc(C(F)(F)F)c(F)c1
Yield: 46 %

Procedure:
3-Fluoro-4-trifluoromethyl-benzaldehyde (5 g, 25.9 mmol) was reacted with nitro methane (1.58 g, 25.9 mmol), 10N NaOH (1.08 g, 27.20 mmol) to afford 2.8 g of the product (46.6% yield).
Reaction SMILES: [C:1]([CH2:3][CH:4]([N:8]1[CH:12]=[C:11]([C:13]2[C:18]([O:19][CH3:20])=[CH:17][N:16]=[C:15]([NH:21][C:22]3[CH:23]=[C:24]([CH:28]=[CH:29][CH:30]=3)[C:25]([OH:27])=O)[N:14]=2)[CH:10]=[N:9]1)[CH:5]1[CH2:7][CH2:6]1)#[N:2].[O:31]1[CH2:36][CH2:35][CH:34]([NH2:37])[CH2:33][CH2:32]1.F[P-](F)(F)(F)(F)F.N1(O[P+](N(C)C)(N(C)C)N(C)C)C2C=CC=CC=2N=N1.CN(C)C=O.C(N(CC)C(C)C)(C)C>>[C:1]([CH2:3][CH:4]([N:8]1[CH:12]=[C:11]([C:13]2[C:18]([O:19][CH3:20])=[CH:17][N:16]=[C:15]([NH:21][C:22]3[CH:23]=[C:24]([CH:28]=[CH:29][CH:30]=3)[C:25]([NH:37][CH:34]3[CH2:35][CH2:36][O:31][CH2:32][CH2:33]3)=[O:27])[N:14]=2)[CH:10]=[N:9]1)[CH:5]1[CH2:7][CH2:6]1)#[N:2]
Reactant: COc1cnc(Nc2cccc(C(=O)O)c2)nc1-c1cnn(C(CC#N)C2CC2)c1
Reactant: NC1CCOCC1
Agent: CN(C)[P+](On1nnc2ccccc21)(N(C)C)N(C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: COc1cnc(Nc2cccc(C(=O)NC3CCOCC3)c2)nc1-c1cnn(C(CC#N)C2CC2)c1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a mixture of 3-({4-[1-(2-cyano-1-cyclopropylethyl)-1H-pyrazol-4-yl]-5-methoxypyrimidin-2-yl}amino)benzoic acid (30 mg, 0.00007 mol), tetrahydro-2H-pyran-4-amine (7.5 mg, 0.000074 mol) and benzotriazol-1-yloxytris(dimethylamino)phosphonium hexafluorophosphate (39 mg, 0.000089 mol) in N,N-dimethylformamide (0.5 mL, 0.006 mol) was added N,N-diisopropylethylamine (31 μL, 0.00018 mol). The reaction was stirred at room temperature for 1 h, quenched with water, purified on HPLC to give the desired product as a diastereomeric mixture (free base). LCMS (M+H) 488.2.
Reaction SMILES: CO[C:3]([C:5]1[N:6]=[C:7]([C:23]#[N:24])[C:8]2[C:13]([C:14]=1[OH:15])=[CH:12][CH:11]=[C:10]([O:16][C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1)[CH:9]=2)=[O:4].[NH2:25][CH:26]([C:31]1[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=1)[CH2:27][C:28]([OH:30])=[O:29].C[O-].[Na+]>CN(C=O)C>[C:23]([C:7]1[C:8]2[C:13](=[CH:12][CH:11]=[C:10]([O:16][C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=3)[CH:9]=2)[C:14]([OH:15])=[C:5]([C:3]([NH:25][CH:26]([C:31]2[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=2)[CH2:27][C:28]([OH:30])=[O:29])=[O:4])[N:6]=1)#[N:24]
Reactant: COC(=O)c1nc(C#N)c2cc(Oc3ccccc3)ccc2c1O
Reactant: NC(CC(=O)O)c1ccccc1
Agent: C[O-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: N#Cc1nc(C(=O)NC(CC(=O)O)c2ccccc2)c(O)c2ccc(Oc3ccccc3)cc12
Yield: 73.2 %

Procedure:
To a mixture of 1-cyano-4-hydroxy-7-phenoxy-isoquinoline-3-carboxylic acid methyl ester (100 mg, 0.31 mmol) and 3-amino-3-phenyl-propionic acid (257 mg, 1.56 mmol) (Sigma-Aldrich) in 3 mL of DMF was added NaOMe solid (67 mg, 1.25 mmol). The resultant mixture was heated in a 150° C. oil bath for 3 h. After cooled, insoluble was filtered off. Filtrate was diluted with water (100 mL). This suspension mixture was brought to clear by adding 1 N NaOH (pH=ca. 10). It was then acidified by 1 N HCl to pH=3-4 and extracted with EtOAc. Organic layer was washed with brine, dried over MgSO4, filtered and concentrated to provide the title compound 103 mg (0.227 mmol) in 73% yield. LC-MS ESI−: 451.95 (M−1)−.
Reaction SMILES: C([Li])CCC.CCCCCC.[CH3:12][S:13][C:14]1[N:15]=[CH:16][N:17]2[CH:21]=[CH:20][S:19][C:18]=12.[CH3:22][Si:23](Cl)([CH3:25])[CH3:24].[Cl-].[NH4+]>C1COCC1>[CH3:12][S:13][C:14]1[N:15]=[CH:16][N:17]2[CH:21]=[C:20]([Si:23]([CH3:25])([CH3:24])[CH3:22])[S:19][C:18]=12
Reactant: C[Si](C)(C)Cl
Reactant: CSc1ncn2ccsc12
Agent: [Cl-]
Agent: [Li]CCCC
Agent: [NH4+]
Solvent: C1CCOC1
Solvent: CCCCCC
Product: CSc1ncn2cc([Si](C)(C)C)sc12
Temperature: -30 °C
Reaction time: 0.42 h

Procedure:
A 1.59 N n-butyllithium/n-hexane solution (9.91 ml) was added dropwise in an argon atmosphere at −50° C. to a solution of 2.55 g of 7-methylthioimidazo[5,1-b]thiazole in 100 ml of THF. The mixture was stirred at the same temperature for 25 min. Trimethylsilyl chloride (2.08 ml) was added thereto, and the mixture was stirred for 30 min. The temperature of the system was raised to −30° C. A 1.59 N n-butyllithium/n-hexane solution (5.72 ml) was added dropwise thereto, and the mixture was stirred at the same temperature for 30 min. An aqueous ammonium chloride solution was added to the reaction solution. The mixture was extracted with ethyl acetate. The extract was dried over anhydrous magnesium sulfate and then filtered. The solvent was removed by distillation under the reduced pressure. The residue was purified by column chromatography on silica gel (hexane:ethyl acetate=1:2) to give 2.58 g of 7-methylthio-2-trimethylsilylimidazo[5,1-b]-thiazole.
Reaction SMILES: C(OC([N:8]1[CH2:14][CH2:13][C:12]2([C:15]([OH:17])=[O:16])[CH:10]([CH2:11]2)[CH2:9]1)=O)(C)(C)C.[ClH:18].[CH3:19]O>O1CCOCC1>[ClH:18].[CH:10]12[CH2:11][C:12]1([C:15]([O:17][CH3:19])=[O:16])[CH2:13][CH2:14][NH:8][CH2:9]2
Reactant: CO
Reactant: CC(C)(C)OC(=O)N1CCC2(C(=O)O)CC2C1
Agent: Cl
Solvent: C1COCCO1
Product: COC(=O)C12CCNCC1C2
Temperature: 60 °C
Yield: 101 %

Procedure:
3-[(tert-Butoxy)carbonyl]-3-azabicyclo[4.1.0]heptane-6-carboxylic acid (5 g, 20.72 mmol) was dissolved in MeOH (200 mL) and 4M HCl in 1,4-dioxane (25.9 mL) was added. The reaction mixture was heated at 60° C. for 4 h. The reaction mixture was cooled to room temperature, then concentrated, to afford the title compound (4.0 g, 101%) as a pale yellow solid. δH (250 MHz, CDCl3) 3.69 (s, 3H), 3.42 (br s, 1H), 2.11 (br s, 5H), 1.84 (br s, 1H), 1.62 (d, J 4.2 Hz, 1H), 1.29 (br s, 1H).
Reaction SMILES: [F:1][C:2]1[C:7]([F:8])=[CH:6][CH:5]=[CH:4][C:3]=1[CH2:9][CH2:10][C:11]1[N:12]([CH2:22][C:23]([OH:25])=O)[C:13]2[C:18]([C:19](=[O:21])[N:20]=1)=[CH:17][CH:16]=[CH:15][CH:14]=2.[CH3:26][C:27]([N:33]1[CH2:38][CH2:37][CH:36]([NH:39][CH2:40][C:41]2[CH:46]=[CH:45][C:44]([C:47]3[CH:52]=[CH:51][C:50]([C:53]([F:56])([F:55])[F:54])=[CH:49][CH:48]=3)=[CH:43][CH:42]=2)[CH2:35][CH2:34]1)([CH3:32])[C:28]([O:30][CH3:31])=[O:29].CCN(C(C)C)C(C)C.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F>C(#N)C>[F:1][C:2]1[C:7]([F:8])=[CH:6][CH:5]=[CH:4][C:3]=1[CH2:9][CH2:10][C:11]1[N:12]([CH2:22][C:23]([N:39]([CH2:40][C:41]2[CH:46]=[CH:45][C:44]([C:47]3[CH:48]=[CH:49][C:50]([C:53]([F:56])([F:54])[F:55])=[CH:51][CH:52]=3)=[CH:43][CH:42]=2)[CH:36]2[CH2:37][CH2:38][N:33]([C:27]([CH3:26])([CH3:32])[C:28]([O:30][CH3:31])=[O:29])[CH2:34][CH2:35]2)=[O:25])[C:13]2[C:18]([C:19](=[O:21])[N:20]=1)=[CH:17][CH:16]=[CH:15][CH:14]=2
Reactant: COC(=O)C(C)(C)N1CCC(NCc2ccc(-c3ccc(C(F)(F)F)cc3)cc2)CC1
Reactant: O=C(O)Cn1c(CCc2cccc(F)c2F)nc(=O)c2ccccc21
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CC#N
Solvent: CCN(C(C)C)C(C)C
Product: COC(=O)C(C)(C)N1CCC(N(Cc2ccc(-c3ccc(C(F)(F)F)cc3)cc2)C(=O)Cn2c(CCc3cccc(F)c3F)nc(=O)c3ccccc32)CC1
Temperature: 25 °C
Reaction time: 1 h
Yield: 57.9 %

Procedure:
A mixture of [2-[2-(2,3-difluorophenyl)ethyl]-4-oxo-1 (4H)-quinazolinyl]acetic acid (Int. C1) (100 mg, 1 equiv), methyl 2-methyl-2-[4-({[4′-(trifluoromethyl)-4-biphenylyl]methyl}amino)-1-piperidinyl]propanoate (Int. B1) (130 mg, 1.03 equiv), DIPEA (0.1 ml, 3.6 equiv), acetonitrile (2 ml) and HATU (130 mg, 1.4 equiv) was stirred at room temperature for 1 h, then evaporated and redissolved in acetonitrile. Purification by reverse phase HPLC (Preparative Method A) gave methyl 2-[4-({[2-[2-(2,3-difluoro-phenyl)ethyl]-4-oxo-1 (4H)-quinazolinyl]acetyl} {[4′-(trifluoromethyl)-4-biphenylyl]-methyl}amino)-1-piperidinyl]-2-methylpropanoate (128 mg).
Reaction SMILES: C([N:8]1[CH2:13][CH2:12][CH:11]([N:14]([CH3:16])[CH3:15])[C:10]([CH3:18])([CH3:17])[CH2:9]1)C1C=CC=CC=1>CO.[H][H].[OH-].[OH-].[Pd+2]>[CH3:15][N:14]([CH3:16])[CH:11]1[CH2:12][CH2:13][NH:8][CH2:9][C:10]1([CH3:17])[CH3:18]
Reactant: CN(C)C1CCN(Cc2ccccc2)CC1(C)C
Reactant: [H][H]
Agent: [Pd+2]
Agent: [OH-]
Solvent: CO
Product: CN(C)C1CCNCC1(C)C

Procedure:
A mixture of 20% Pd(OH)2 on carbon (0.3 g) and 1-benzyl-4-dimethylamino-3,3-dimethylpiperidine (4.5 g, 6.0 mmol) in methanol (20 ml) was stirred in hydrogen atmosphere (1 atm.) for 48 hr at room temperature. The catalyst was filtered off, washed with methanol and filtrate was concentrated to afford 4-dimethylamino-3,3-dimethylpiperidine. Yield 1.6 g (95%), C9H20N2, m/z 157 (M+1).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH2:11][C@@H:10]([C:14]2[CH:19]=[CH:18][C:17]([N:20]3[CH:28]=[C:27]4[C:22]([C:23]([C:29](O)=[O:30])=[CH:24][CH:25]=[CH:26]4)=[N:21]3)=[CH:16][CH:15]=2)[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].C(=O)(OC(C)(C)C)OC(C)(C)C.[N:44]1C=CC=CC=1.C(=O)(O)[O-].[NH4+].Cl>C(Cl)Cl>[NH2:44][C:29]([C:23]1[C:22]2[C:27](=[CH:28][N:20]([C:17]3[CH:18]=[CH:19][C:14]([C@@H:10]4[CH2:11][CH2:12][CH2:13][N:8]([C:6]([O:5][C:1]([CH3:3])([CH3:4])[CH3:2])=[O:7])[CH2:9]4)=[CH:15][CH:16]=3)[N:21]=2)[CH:26]=[CH:25][CH:24]=1)=[O:30]
Reactant: c1ccncc1
Reactant: CC(C)(C)OC(=O)N1CCC[C@@H](c2ccc(-n3cc4cccc(C(=O)O)c4n3)cc2)C1
Agent: CC(C)(C)OC(=O)OC(C)(C)C
Agent: Cl
Agent: O=C([O-])O
Solvent: ClCCl
Product: CC(C)(C)OC(=O)N1CCC[C@@H](c2ccc(-n3cc4cccc(C(N)=O)c4n3)cc2)C1
Reaction time: 20 h

Procedure:
F2 was dissolved in DCM (0.35M) and di tert-butyl carbonate (1.3 eq) and pyridine (1.0 eq) added at RT. After 30 minutes ammonium bicarbonate (1.3 eq) was added and stirring continued for 20 hours. 1M HCl (5 mL/g) was added and the phases separated, the organic layer was washed twice with water and concentrated to a low volume. The crude compound (F3) was filtered through a pad of silica and then crystallised from methyl tert-butyl ether.
Reaction SMILES: [C:1]([O:5][C:6](=[O:20])[NH:7][C@H:8]1[C:14](=[O:15])[NH:13][C:12]2[CH:16]=[CH:17][CH:18]=[CH:19][C:11]=2[CH2:10][CH2:9]1)([CH3:4])([CH3:3])[CH3:2].C(O)(=O)C.[Br:25]Br>C(OCC)(=O)C>[C:1]([O:5][C:6](=[O:20])[NH:7][C@@H:8]1[CH2:9][CH2:10][C:11]2[CH:19]=[C:18]([Br:25])[CH:17]=[CH:16][C:12]=2[NH:13][C:14]1=[O:15])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)N[C@@H]1CCc2ccccc2NC1=O
Reactant: BrBr
Solvent: CC(=O)O
Solvent: CCOC(C)=O
Product: CC(C)(C)OC(=O)N[C@@H]1CCc2cc(Br)ccc2NC1=O
Temperature: 25 °C
Reaction time: 1.5 h

Procedure:
A round-bottom flask containing ((R)-2-oxo-2,3,4,5-tetrahydro-1H-benzo[b]azepin-3-yl)-carbamic acid tert-butyl ester (0.338 g, 1.20 mmol) was fitted with a stirbar and septa. Acetic acid (glacial, 5 mL) and bromine (0.37 g, 2.3 mmol) were added, in that order, giving a solution that was stirred at room temperature for 1.5 hours. The reaction was then poured into ethyl acetate (50 mL) and washed with saturated aqueous NaHCO3 solution (2×50 mL). The organic layer was dried over MgSO4, filtered and concentrated in vacuo to give an oil that was purified via flash chromatography on silica gel (10% to 50% ethyl acetate/hexanes linear gradient) to give the desired product.
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH3:21])=[CH:4][C:3]=1[C:22](=O)[CH3:23].Cl.O>[Pd].C(O)(=O)C>[CH2:22]([C:3]1[CH:4]=[C:5]([CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH3:21])[CH:6]=[CH:7][C:2]=1[OH:1])[CH3:23]
Reactant: CCCCCCCCCCCCCCc1ccc(O)c(C(C)=O)c1
Agent: [Pd]
Agent: Cl
Solvent: CC(=O)O
Solvent: O
Product: CCCCCCCCCCCCCCc1ccc(O)c(CC)c1
Temperature: 50 °C
Reaction time: 24 h
Yield: 72.6 %

Procedure:
A mixture of 23 g of 1-(2-hydroxy-5-tetradecylphenyl)ethanone, 5 g of 5% palladium on carbon catalyst, 10 ml of concentrated hydrochloric acid, 100 ml of water and 100 ml of glacial acetic acid was warmed to 50° C. and then hydrogenated in a Parr apparatus for 24 hours. This mixture was filtered, the solvent removed ad the residue dissolved in ether. The ether solution was washed with water, then a small amount of dilute aqueous sodium bicarbonate and dried. The residue was purified by HPLC, giving 16 g of the desired compound, mp 45.5°-46.5° C.
Reaction SMILES: [NH2:1][CH2:2][CH2:3][CH2:4][N:5]([C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][N:8]=1)[CH3:6].CS[C:15]1[NH:20][C:19](=[O:21])[C:18]([CH2:22][C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][C:24]=2[Cl:29])=[CH:17][N:16]=1>N1C=CC=CC=1>[CH3:6][N:5]([CH2:4][CH2:3][CH2:2][NH:1][C:15]1[NH:20][C:19](=[O:21])[C:18]([CH2:22][C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][C:24]=2[Cl:29])=[CH:17][N:16]=1)[C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][N:8]=1
Reactant: CSc1ncc(Cc2ccccc2Cl)c(=O)[nH]1
Reactant: CN(CCCN)c1ccccn1
Solvent: c1ccncc1
Product: CN(CCCNc1ncc(Cc2ccccc2Cl)c(=O)[nH]1)c1ccccn1

Procedure:
2-[N-(3-aminopropyl)-N-methylamino]pyridine (0.74 g) and 2-methylthio-5-(2-chlorobenzyl)pyrimid-4-one (1.0 g) were heated together under reflux in pyridine (2.5 ml) for 28 hr. After stripping, the residue was recrystallised twice from ethanol/water to give 2-[3-(N-methyl-N-pyrid-2-ylamino)propylamino]-5-(2-chlorobenzyl)pyrimid-4-one 0.5H2O, 0.87 g (59%) mp 47°-49° C.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([CH:8]=[CH:9][C:10]=1[C:11]([N:13]1[CH2:17][CH:16]=[CH:15][CH2:14]1)=[O:12])[C:5]([OH:7])=O.CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.[B-](F)(F)(F)F.C(N(C(C)C)CC)(C)C.[Br:49][C:50]1[CH:63]=[CH:62][C:53]2[NH:54][C:55]([C@@H:57]([NH2:61])[CH2:58][O:59][CH3:60])=[N:56][C:52]=2[CH:51]=1.ClCl>O1CCCC1.ClCCl.C(O)C>[Br:1][C:2]1[CH:3]=[C:4]([CH:8]=[CH:9][C:10]=1[C:11]([N:13]1[CH2:17][CH:16]=[CH:15][CH2:14]1)=[O:12])[C:5]([NH:61][C@H:57]([C:55]1[NH:54][C:53]2[CH:62]=[CH:63][C:50]([Br:49])=[CH:51][C:52]=2[N:56]=1)[CH2:58][O:59][CH3:60])=[O:7]
Reactant: O=C(O)c1ccc(C(=O)N2CC=CC2)c(Br)c1
Reactant: COC[C@H](N)c1nc2cc(Br)ccc2[nH]1
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: ClCl
Agent: F[B-](F)(F)F
Solvent: ClCCl
Solvent: C1CCOC1
Solvent: CCO
Product: COC[C@H](NC(=O)c1ccc(C(=O)N2CC=CC2)c(Br)c1)c1nc2cc(Br)ccc2[nH]1
Yield: 62 %

Procedure:
Prepared analogously to Example 1g from 3-bromo-4-(2,5-dihydropyrrol-1-ylcarbonyl)benzoic acid, TBTU, diisopropylethylamine, and (1R)-1-(5-bromo-1H-benzimidazol-2-yl)-2-methoxyethylamine in tetrahydrofuran. Yield: 62%; Rf value: 0.45 (silica gel: dichloromethane/ethanol=95:5); C22H20Br2N4O3 (548.233); mass spectrum: (M+H)+=547/549/551 (chlorine isotope).