Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: N(OCC(C)C)=O.[Br:8][C:9]1[CH:15]=[CH:14][C:12](N)=[C:11]([Cl:16])[CH:10]=1.S(=O)(=O)(O)O.[CH:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1>>[Br:8][C:9]1[CH:15]=[CH:14][C:12]([C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)=[C:11]([Cl:16])[CH:10]=1
Reactant: Nc1ccc(Br)cc1Cl
Reactant: c1ccccc1
Agent: CC(C)CON=O
Agent: O=S(=O)(O)O
Product: Clc1cc(Br)ccc1-c1ccccc1
Temperature: 52.5 °C

Procedure:
Isobutyl nitrite (121 g, 1.17 mol) and cupric chloride (21.2 g, 0.16 mol) are added to a solution of 4-bromo-2-chloroaniline (200 g, 0.97 mol) in benzene (500 mL) at 60-65° C. temperature. The reaction mixture is refluxed for 2 hrs. The reaction mixture is cooled to 50-55° C. temperature and to it a solution of aqueous sulfuric acid (92 mL conc. Sulfuric acid in 453 mL demineralized water). After refluxing for 1 hr the reaction mixture is cooled to room temperature and organic layer is separated. It is treated with an aqueous solution of urea (41 g in 127 mL water) and refluxed for 1 hr. Organic layer is separated, washed with demineralized water (2×200 mL) and dried over sodium sulfate. After removing the solvent under reduced pressure the residue is fractionally distilled to get 4-bromo-2-chlorobiphenyl.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:16])[C:4]([C:7]1[CH:12]=[CH:11][C:10]([C:13](Cl)=[O:14])=[CH:9][CH:8]=1)([CH3:6])[CH3:5].[NH2:17][C:18]1[CH:33]=[CH:32][C:31]([Cl:34])=[CH:30][C:19]=1[C:20]([NH:22][C:23]1[CH:28]=[CH:27][C:26]([Cl:29])=[CH:25][N:24]=1)=[O:21]>C(Cl)Cl.CN(C1C=CN=CC=1)C>[CH3:1][O:2][C:3](=[O:16])[C:4]([C:7]1[CH:12]=[CH:11][C:10]([C:13](=[O:14])[NH:17][C:18]2[CH:33]=[CH:32][C:31]([Cl:34])=[CH:30][C:19]=2[C:20](=[O:21])[NH:22][C:23]2[CH:28]=[CH:27][C:26]([Cl:29])=[CH:25][N:24]=2)=[CH:9][CH:8]=1)([CH3:6])[CH3:5]
Reactant: COC(=O)C(C)(C)c1ccc(C(=O)Cl)cc1
Reactant: Nc1ccc(Cl)cc1C(=O)Nc1ccc(Cl)cn1
Agent: CN(C)c1ccncc1
Solvent: ClCCl
Product: COC(=O)C(C)(C)c1ccc(C(=O)Nc2ccc(Cl)cc2C(=O)Nc2ccc(Cl)cn2)cc1
Temperature: 0 °C
Reaction time: 1 h

Procedure:
To a solution of 2-(4-chlorocarbonyl-phenyl)-2-methyl-propionic acid methyl ester (240.0 mg, 1.0 mmol) in CH2Cl2 at 0° C. was added TEA (3.0 mmol) followed by addition of 2-amino-5-chloro-N-(5-chloro-pyridin-2-yl)-benzamide (281 mg, 1.0 mmol) and DMAP (cat. 10 mg). The resulted mixture was stirred at 0° C. for 1 hr and rt over night. Solvent was evaporated and HPLC purification gave 2{4-[4-Chloro-2-(5-chloro-pyridin-2-ylcarbamoyl)-phenylcarbamoyl]-phenyl}-2-methyl-propionic acid methyl ester as white solid. MS found: (M+1)+=486.2.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:12]=[CH:11][C:10]2[NH:9][C:8](=[O:13])[C:7]3[S:14][CH:15]=[CH:16][C:6]=3[C:5]=2[C:4]=1[C:17]1[CH:22]=[CH:21][C:20]([N:23]2[CH2:28][CH2:27][NH:26][CH2:25][CH2:24]2)=[CH:19][CH:18]=1.C(N(CC)C(C)C)(C)C.[CH3:38][S:39](Cl)(=[O:41])=[O:40]>C(Cl)Cl>[CH3:1][O:2][C:3]1[CH:12]=[CH:11][C:10]2[NH:9][C:8](=[O:13])[C:7]3[S:14][CH:15]=[CH:16][C:6]=3[C:5]=2[C:4]=1[C:17]1[CH:18]=[CH:19][C:20]([N:23]2[CH2:28][CH2:27][N:26]([S:39]([CH3:38])(=[O:41])=[O:40])[CH2:25][CH2:24]2)=[CH:21][CH:22]=1
Reactant: CS(=O)(=O)Cl
Reactant: COc1ccc2[nH]c(=O)c3sccc3c2c1-c1ccc(N2CCNCC2)cc1
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: COc1ccc2[nH]c(=O)c3sccc3c2c1-c1ccc(N2CCN(S(C)(=O)=O)CC2)cc1
Reaction time: 1 h
Yield: 66.7 %

Procedure:
To a solution of 8-methoxy-9-[4-(piperazin-1-yl)phenyl]thieno[2,3-c]quinolin-4(5H)-one (89 mg, 0.23 mmol) in methylene chloride (2 mL) was added N,N-diisopropylethylamine (0.42 mL, 0.68 mmol) and methanesulfonyl chloride (45 μL, 0.27 mmol) and the reaction mixture was stirred for 1 h. The reaction mixture was quenched with water and the layers were separated. The aqueous layer was extracted with ethyl acetate and the combined organic layers were dried over Na2SO4, filtered, concentrated and the residue was purified by preparatory HPLC (C18 silica, acetonitrile/water w/0.05% TFA gradient) to afford the desired product (72 mg, 68%) as a brown solid: ESI MS m/z 470 [C23H23N3O4S2+H]+.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[CH:4][C:5]2[CH2:11][CH2:10][N:9]([CH3:12])[C:8](=[O:13])[CH2:7][C:6]=2[CH:14]=1.[CH3:15][NH:16][C:17]([C:19]1[C:24]([NH:25][C:26]2[C:31]([Cl:32])=[CH:30][N:29]=[C:28](Cl)[N:27]=2)=[CH:23][CH:22]=[CH:21][N:20]=1)=[O:18]>>[CH3:15][NH:16][C:17]([C:19]1[C:24]([NH:25][C:26]2[C:31]([Cl:32])=[CH:30][N:29]=[C:28]([NH:1][C:2]3[CH:3]=[CH:4][C:5]4[CH2:11][CH2:10][N:9]([CH3:12])[C:8](=[O:13])[CH2:7][C:6]=4[CH:14]=3)[N:27]=2)=[CH:23][CH:22]=[CH:21][N:20]=1)=[O:18]
Reactant: CN1CCc2ccc(N)cc2CC1=O
Reactant: CNC(=O)c1ncccc1Nc1nc(Cl)ncc1Cl
Product: CNC(=O)c1ncccc1Nc1nc(Nc2ccc3c(c2)CC(=O)N(C)CC3)ncc1Cl

Procedure:
Following a procedure analogous to Example 1742a, 8-amino-3-methyl-1,3,4,5-tetrahydro-benzo[d]azepin-2-one and 3-(2,5-dichloro-pyrimidin-4-ylamino)-pyridine-2-carboxylic acid methylamide were converted to 3-[5-chloro-2-(3-methyl-4-oxo-2,3,4,5-tetrahydro-1H-benzo[d]azepin-7-ylamino)-pyrimidin-4-ylamino]-pyridine-2-carboxylic acid methylamide. TFA salt: 1H NMR (300 MHz, CD3OD) δ 8.58 (d, 1H), 8.18 (s, 1H), 7.69 (m, 3H), 7.44 (m, 2H), 7.23 (m, 2H), 6.29 (d, 1H), 4.29 (s, 2H), 3.39 (m, 2H), 3.26 (m, 2H), 3.04 (s, 3H), 2.94 (s, 3H); MS (m/e) 452 (M+1).
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:13]=[CH:12][C:11]([C:14]([C:16]3[CH:21]=[CH:20][C:19]([Cl:22])=[C:18]([Cl:23])[CH:17]=3)=[O:15])=[CH:10][CH:9]=2)=[CH:4][CH:3]=1.[Br:24]N1C(=O)CCC1=O.C(#N)N(C)C>C(Cl)(Cl)(Cl)Cl>[Br:24][CH2:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[CH:9]=[CH:10][C:11]([C:14]([C:16]3[CH:21]=[CH:20][C:19]([Cl:22])=[C:18]([Cl:23])[CH:17]=3)=[O:15])=[CH:12][CH:13]=2)=[CH:6][CH:7]=1
Reactant: O=C1CCC(=O)N1Br
Reactant: Cc1ccc(-c2ccc(C(=O)c3ccc(Cl)c(Cl)c3)cc2)cc1
Solvent: ClC(Cl)(Cl)Cl
Solvent: CN(C)C#N
Product: O=C(c1ccc(-c2ccc(CBr)cc2)cc1)c1ccc(Cl)c(Cl)c1

Procedure:
A mixture of 5.0 g of 3,4-dichlorophenyl 4'-methyl-4-biphenylyl ketone, 2.7 g of N-bromosuccinimide and 20 mg of azaisobutyronitrile in 70 ml of carbon tetrachloride is heated to boiling under reflux. The precipitated material is filtered and the filtrate is evaporated. The residue is recrystallized from toluene/cyclohexane. 3,4-Dichlorophenyl 4'-bromomethyl-4-biphenylyl ketone is obtained.
Reaction SMILES: [NH2:1][C:2]1[C:7]([NH2:8])=[CH:6][C:5]([Br:9])=[CH:4][N:3]=1.[CH3:10][CH2:11][C:12](=O)[CH2:13][CH3:14].CC(O)=O>ClC(Cl)C>[Br:9][C:5]1[CH:6]=[C:7]([NH:8][CH:12]([CH2:13][CH3:14])[CH2:11][CH3:10])[C:2]([NH2:1])=[N:3][CH:4]=1
Reactant: CCC(=O)CC
Reactant: Nc1cc(Br)cnc1N
Solvent: CC(=O)O
Solvent: CC(Cl)Cl
Product: CCC(CC)Nc1cc(Br)cnc1N
Reaction time: 8 h

Procedure:
To a solution of 2,3-diamino-5-bromopyridine (10.0 g, 53.2 mmol, 1.0 equiv) and 3-pentanone (6.18 mL, 58.5 mmol, 1.1 equiv) in dichloroethane (150 mL) was added AcOH (3.0 mL, 53.2 mmol, 1.0 equiv) followed by NaHB(OAc)3 (16.9 g, 79.8 mmol, 1.5 equiv), added as a solid in several portions over ˜5 min. The reaction was allowed to stir overnight. The reaction mixture was then washed with satd. aq. NaHCO3 and brine, and the resulting organic layer was dried over anhydrous sodium sulfate, filtered and concentrated in vacuo. Purification by silica gel MPLC (10%-40% EtOAc/Hexanes) provided 5-bromo-N3-(pentan-3-yl)pyridine-2,3-diamine as an off white solid (2.0 g, 14%). m/z=240.1 [M+H]+
Reaction SMILES: [Br-:1].O[C@@H]1C2CC[N+](CC(=O)NC3C=CON=3)(CC2)C1.[Br-].[OH:21][C@@H:22]1[CH:27]2[CH2:28][CH2:29][N+:24]([CH2:30][C:31](=[O:39])[NH:32][C:33]3[CH:38]=[N:37][CH:36]=[CH:35][N:34]=3)([CH2:25][CH2:26]2)[CH2:23]1.[CH:40]1([C:46]([OH:56])([C:50]2[CH:55]=[CH:54][CH:53]=[CH:52][CH:51]=2)[C:47](O)=[O:48])[CH2:45][CH2:44][CH2:43][CH2:42][CH2:41]1>>[Br-:1].[CH:50]1([C:46]([OH:56])([C:40]2[CH:41]=[CH:42][CH:43]=[CH:44][CH:45]=2)[C:47]([O:21][C@@H:22]2[CH:27]3[CH2:28][CH2:29][N+:24]([CH2:30][C:31](=[O:39])[NH:32][C:33]4[CH:38]=[N:37][CH:36]=[CH:35][N:34]=4)([CH2:25][CH2:26]3)[CH2:23]2)=[O:48])[CH2:55][CH2:54][CH2:53][CH2:52][CH2:51]1
Reactant: O=C(O)C(O)(c1ccccc1)C1CCCCC1
Reactant: O=C(C[N+]12CCC(CC1)[C@@H](O)C2)Nc1cnccn1
Agent: O=C(C[N+]12CCC(CC1)[C@@H](O)C2)Nc1ccon1
Agent: [Br-]
Product: O=C(C[N+]12CCC(CC1)[C@@H](OC(=O)C(O)(c1ccccc1)C1CCCCC1)C2)Nc1cnccn1

Procedure:
This compound is prepared as a diastereomeric mixture using an method analogous to Example 4, by replacing (R)-3-hydroxy-1-(isoxazol-3-ylcarbamoylmethyl)-1-azonia-bicyclo[2.2.2]octane bromide (Intermediate A) with (R)-3-Hydroxy-1-(pyrazin-2-ylcarbamoylmethyl)-1-azonia-bicyclo[2.2.2]octane bromide (Intermediate H) and 2,2′-diphenylpropionic acid with cyclohexyl-hydroxy-phenyl-acetic acid.
Reaction SMILES: C[N:2](C)/[CH:3]=[CH:4]/[C:5]([C:7]1[C:12](=[O:13])[CH:11]=[CH:10][N:9]([C:14]2[CH:19]=[CH:18][CH:17]=[C:16]([O:20][C:21]([F:24])([F:23])[F:22])[CH:15]=2)[N:8]=1)=O.[O:26]1[C:31]2[CH:32]=[CH:33][C:34]([NH:36]N)=[CH:35][C:30]=2[O:29][CH2:28][CH2:27]1>>[O:26]1[C:31]2[CH:32]=[CH:33][C:34]([N:36]3[C:5]([C:7]4[C:12](=[O:13])[CH:11]=[CH:10][N:9]([C:14]5[CH:19]=[CH:18][CH:17]=[C:16]([O:20][C:21]([F:24])([F:23])[F:22])[CH:15]=5)[N:8]=4)=[CH:4][CH:3]=[N:2]3)=[CH:35][C:30]=2[O:29][CH2:28][CH2:27]1
Reactant: CN(C)/C=C/C(=O)c1nn(-c2cccc(OC(F)(F)F)c2)ccc1=O
Reactant: NNc1ccc2c(c1)OCCO2
Product: O=c1ccn(-c2cccc(OC(F)(F)F)c2)nc1-c1ccnn1-c1ccc2c(c1)OCCO2

Procedure:
Reaction of 3-((E)-3-dimethylamino-acryloyl)-1-(3-trifluoromethoxy-phenyl)-1H-pyridazin-4-one (A-6) and (2,3-dihydro-benzo[1,4]dioxin-6-yl)-hydrazine according to example 43 gave the desired product. MS: M=456.9 (M+H)+
Reaction SMILES: [Br:1][C:2]1[CH:7]=[C:6]([C:8]2[C:9]([C:14]3[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=3)=[N:10][O:11][C:12]=2[CH3:13])[CH:5]=[CH:4][N:3]=1.[Br:20]N1C(=O)CCC1=O>C(Cl)(Cl)(Cl)Cl.C(Cl)Cl.CC(N=NC(C#N)(C)C)(C#N)C>[Br:1][C:2]1[CH:7]=[C:6]([C:8]2[C:9]([C:14]3[CH:15]=[CH:16][CH:17]=[CH:18][CH:19]=3)=[N:10][O:11][C:12]=2[CH2:13][Br:20])[CH:5]=[CH:4][N:3]=1
Reactant: O=C1CCC(=O)N1Br
Reactant: Cc1onc(-c2ccccc2)c1-c1ccnc(Br)c1
Agent: CC(C)(C#N)N=NC(C)(C)C#N
Solvent: ClCCl
Solvent: ClC(Cl)(Cl)Cl
Product: BrCc1onc(-c2ccccc2)c1-c1ccnc(Br)c1
Reaction time: 18 h
Yield: 56.9 %

Procedure:
A stirred solution of the above Compound 17a (404 mg, 1.28 mmol), N-bromosuccinimide (239 mg, 1.35 mmol) and AIBN (11 mg, 0.064 mmol) in CCl4 (3 mL) was heated to reflux and placed under a 300 W lamp for 18 h. The solution was diluted with CH2Cl2 (15 mL), extracted with H2O (3×10 mL), brine (40 mL), dried (MgSO4), filtered and concentrated. Flash chromatography (SiO2, 15-20% EtOAc-hexanes) provided the title compound (287 mg, 0.728 mmol, 57%).
Reaction SMILES: [SH:1][C:2]1[S:3][C:4]2[C:9]([N:10]=1)=[CH:8][CH:7]=[CH:6][N:5]=2.C(=O)([O-])[O-].[K+].[K+].[CH2:17]([O:21][C:22](=[O:25])[CH2:23]Cl)[CH2:18][CH2:19][CH3:20].C(OCC)(=O)C>CN(C)C=O>[CH2:17]([O:21][C:22]([CH2:23][S:1][C:2]1[S:3][C:4]2[C:9]([N:10]=1)=[CH:8][CH:7]=[CH:6][N:5]=2)=[O:25])[CH2:18][CH2:19][CH3:20]
Reactant: CCCCOC(=O)CCl
Reactant: Sc1nc2cccnc2s1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: CCCCOC(=O)CSc1nc2cccnc2s1
Temperature: 25 °C
Yield: 99 %

Procedure:
Twenty-four (24) g of 2-mercaptothiazolo[5,4-b]pyridine was dissolved in 300 ml of N,N-dimethylformamide, and 43.3 g of potassium carbonate and 23.65 g of chloroacetic acid n-butyl ester were added to the solution, followed by one-hour stirring at room temperature. Seven hundred (700) ml of ethyl acetate was added to the solution, which was then washed with water three times, dehydrated over magnesium sulfate, dried and distilled to remove the solvent to obtain the title compound (39.9 g, 99%).
Reaction SMILES: I[C:2]1[CH:7]=[CH:6][C:5]([C:8]#[C:9][CH2:10][N:11]2[CH2:15][CH2:14][CH2:13][CH2:12]2)=[CH:4][CH:3]=1.[Cl:16][C:17]1[CH:22]=[CH:21][C:20]([C:23]2[CH:24]=[CH:25][C:26]([C:29]#[CH:30])=[N:27][CH:28]=2)=[CH:19][CH:18]=1>>[Cl:16][C:17]1[CH:18]=[CH:19][C:20]([C:23]2[CH:24]=[CH:25][C:26]([C:29]#[C:30][C:2]3[CH:7]=[CH:6][C:5]([C:8]#[C:9][CH2:10][N:11]4[CH2:15][CH2:14][CH2:13][CH2:12]4)=[CH:4][CH:3]=3)=[N:27][CH:28]=2)=[CH:21][CH:22]=1
Reactant: C#Cc1ccc(-c2ccc(Cl)cc2)cn1
Reactant: Ic1ccc(C#CCN2CCCC2)cc1
Product: Clc1ccc(-c2ccc(C#Cc3ccc(C#CCN4CCCC4)cc3)nc2)cc1

Procedure:
Prepared according to general working method I from 1-[3-(4-iodo-phenyl)-prop-2-ynyl]-pyrrolidine (230 mg, 75%, 0.55 mmol) and 5-(4-chloro-phenyl)-2-ethynyl-pyridine (118 mg, 0.55 mmol).
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([CH:35]=[CH:36][CH:37]=1)[CH2:5][N:6]1[CH:10]=[C:9]([C:11]2[CH:20]=[CH:19][CH:18]=[C:17]3[C:12]=2[CH2:13][CH2:14][CH2:15][N:16]3[C:21](=[O:34])[CH2:22][CH2:23][CH2:24][O:25][C:26]2[CH:31]=[CH:30][CH:29]=[C:28]([CH3:32])[C:27]=2[CH3:33])[CH:8]=[N:7]1.Br[CH2:39]C1C=C(NC(=O)OC(C)(C)C)C=CC=1.BrC(C1C=C(NC(=O)OC(C)(C)C)C=CC=1)C>>[NH2:1][C:2]1[CH:3]=[C:4]([CH:5]([N:6]2[CH:10]=[C:9]([C:11]3[CH:20]=[CH:19][CH:18]=[C:17]4[C:12]=3[CH2:13][CH2:14][CH2:15][N:16]4[C:21](=[O:34])[CH2:22][CH2:23][CH2:24][O:25][C:26]3[CH:31]=[CH:30][CH:29]=[C:28]([CH3:32])[C:27]=3[CH3:33])[CH:8]=[N:7]2)[CH3:39])[CH:35]=[CH:36][CH:37]=1
Reactant: CC(C)(C)OC(=O)Nc1cccc(CBr)c1
Reactant: Cc1cccc(OCCCC(=O)N2CCCc3c(-c4cnn(Cc5cccc(N)c5)c4)cccc32)c1C
Agent: CC(Br)c1cccc(NC(=O)OC(C)(C)C)c1
Product: Cc1cccc(OCCCC(=O)N2CCCc3c(-c4cnn(C(C)c5cccc(N)c5)c4)cccc32)c1C

Procedure:
The title compound was prepared using a procedure analogous to 1-(5-(1-(3-aminobenzyl)-1H-pyrazol-4-yl)-3,4-dihydroquinolin-1(2H)-yl)-4-(2,3-dimethylphenoxy)butan-1-one except that tert-butyl 3-(bromomethyl)phenylcarbamate was replaced with tert-butyl 3-(1-bromoethyl)phenylcarbamate. LCMS, [M+H]+=509.5.
Reaction SMILES: [C:1]([NH:3][C:4](=[N:7][CH2:8][CH2:9][S:10][CH2:11][C:12]1[O:13][C:14]2[CH:20]=[C:19]([CH2:21][N:22]([CH3:24])[CH3:23])[CH:18]=[CH:17][C:15]=2[CH:16]=1)SC)#[N:2].[CH2:25]([NH2:28])[C:26]#[CH:27]>C(#N)C>[C:1]([NH:3][C:4]([NH:7][CH2:8][CH2:9][S:10][CH2:11][C:12]1[O:13][C:14]2[CH:20]=[C:19]([CH2:21][N:22]([CH3:24])[CH3:23])[CH:18]=[CH:17][C:15]=2[CH:16]=1)=[N:28][CH2:25][C:26]#[CH:27])#[N:2]
Reactant: CSC(=NCCSCc1cc2ccc(CN(C)C)cc2o1)NC#N
Reactant: C#CCN
Solvent: CC#N
Product: C#CCN=C(NC#N)NCCSCc1cc2ccc(CN(C)C)cc2o1

Procedure:
A solutiion of N-cyano-N'-[2-(6-dimethylaminomethyl)-2-benzofuranylmethylthio)ethyl]-S-methylisothiourea (Example 1, Step F) (6.55 g., 0.018 mole) and propargylamine (4.0 g., 0.073 mole) in acetonitrile (100 ml.) is heated in a sealed pressure vessel at 110°-120° C. for 36 hours. The reaction solution is then evaporated at reduced pressure. N-cyano-N'-[2-(6-dimethylaminomethyl-2-benzofuranylmethylthio)ethyl]-N"-(2-propynyl)guanidine is obtained when the residual oil is chromatographed on silica gel with elution by an 8% solution of methanol in chloroform.
Reaction SMILES: [C:1]1([P:7](C2C=CC=CC=2)[C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[Cl:20]P(Cl)C1C=CC=CC=1>>[Cl:20][P:7]([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[C:1]1[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: ClP(Cl)c1ccccc1
Reactant: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Product: ClP(c1ccccc1)c1ccccc1

Procedure:
At virtually the same temperature, triphenylphosphine also reacts with dichloro(phenyl)phosphine to give chloro(diphenyl)phosphine (German Pat. No. A-3,215,379):
Reaction SMILES: Cl.[CH3:2][O:3][C:4](=[O:27])[C@@H:5]([NH:8][C:9]([C:11]1[CH:16]=[CH:15][C:14]([C:17]2[CH:22]=[CH:21][C:20]([C:23]([F:26])([F:25])[F:24])=[CH:19][CH:18]=2)=[CH:13][CH:12]=1)=[O:10])[CH2:6][NH2:7].[C:28]1([C:36]2[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=2)[CH:33]=[CH:32][C:31]([CH:34]=O)=[CH:30][CH:29]=1.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>>[CH3:2][O:3][C:4](=[O:27])[C@@H:5]([NH:8][C:9]([C:11]1[CH:16]=[CH:15][C:14]([C:17]2[CH:22]=[CH:21][C:20]([C:23]([F:25])([F:24])[F:26])=[CH:19][CH:18]=2)=[CH:13][CH:12]=1)=[O:10])[CH2:6][NH:7][CH2:34][C:31]1[CH:32]=[CH:33][C:28]([C:36]2[CH:37]=[CH:38][CH:39]=[CH:40][CH:41]=2)=[CH:29][CH:30]=1
Reactant: COC(=O)[C@H](CN)NC(=O)c1ccc(-c2ccc(C(F)(F)F)cc2)cc1
Reactant: O=Cc1ccc(-c2ccccc2)cc1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: Cl
Agent: [Na+]
Product: COC(=O)[C@H](CNCc1ccc(-c2ccccc2)cc1)NC(=O)c1ccc(-c2ccc(C(F)(F)F)cc2)cc1

Procedure:
3-Amino-(2S)-[(4′-trifluoromethyl-biphenyl-4-carbonyl)-amino]-propionic acid methyl ester hydrochloride (0.200 g, 0.493 mmol) was subjected to reductive amination as per general procedure E with biphenyl-4-carbaldehyde (0.080 g, 0.444 mmol) and sodium triacetoxyborohydride (0.208 g, 0.986 mmol) to yield the 3-[(biphenyl-4-ylmethyl)-amino]-(2S)-[(4′-trifluoromethyl-biphenyl-4-carbonyl)-amino]-propionic acid methyl ester which was further hydrolyzed as per general procedure C to yield 3-[(biphenyl-4-ylmethyl)-amino]-(2S)-[(4′-trifluoromethyl-biphenyl-4-carbonyl)-amino]-propionic acid (0.190 g, 70%).
Reaction SMILES: C(O[CH:4]=[C:5]([C:19]#[N:20])[CH2:6][CH2:7][CH2:8][C:9]1[C:18]2[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=2)[CH:12]=[CH:11][CH:10]=1)C.Cl.[NH2:22][C:23]([NH2:25])=[NH:24].C(=O)([O-])[O-].[K+].[K+].O>CN(C)C=O>[NH2:24][C:23]1[N:25]=[C:19]([NH2:20])[C:5]([CH2:6][CH2:7][CH2:8][C:9]2[C:18]3[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=3)[CH:12]=[CH:11][CH:10]=2)=[CH:4][N:22]=1
Reactant: N=C(N)N
Reactant: CCOC=C(C#N)CCCc1cccc2ccccc12
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: Nc1ncc(CCCc2cccc3ccccc23)c(N)n1
Temperature: 125 °C
Reaction time: 6 h
Yield: 35.9 %

Procedure:
Under a nitrogen atmosphere a stirred solution of 0.85 gram (0.003 mole) of 1-ethoxy-2-cyano-5-(naphth-1-yl)-1-pentene, 1.22 grams (0.013 mole) of guanidine hydrochloride, and 2.65 grams (0.01 9 mole) of potassium carbonate in 20 mL of N,N-dimethylformamide was heated at 110° C. for 20 hours. After this time the reaction mixture was analyzed by thin layer chromatography (TLC) which indicated the reaction was not complete. The reaction mixture was warmed to 125° C. where it was stirred for six hours. TLC analysis of the reaction mixture after this time indicated that the reaction was still not complete. An additional 10 mL of dimethylformamide was added, and the reaction mixture was stirred at 125° C. for an additional 64 hours. The reaction mixture was then poured into water, and the mixture was extracted with two 100 mL portions of ethyl acetate. The combined extracts were concentrated under reduced pressure, yielding a yellow solid. The solid was triturated with dichloromethane. The solid was collected by filtration and subjected to column chromatography on silica gel. Elution was accomplished with 10:1 methylene chloride and methanol. The eluate was concentrated under reduced pressure, yielding 0.30 gram of 2,4-diamino-5-[3-(naphth-1-yl)propyl]pyrimidine, mp 179°-181° C. The NMR spectrum was consistent with the proposed structure.
Reaction SMILES: [CH2:1]([O:3][C:4]([N:6]1[CH2:11][CH2:10][N:9]([C:12](=[O:37])[C@@H:13]([NH:22][C:23]([C:25]2[CH:29]=[C:28]([OH:30])[N:27]([C:31]3[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=3)[N:26]=2)=[O:24])[CH2:14][C:15]([O:17][C:18]([CH3:21])([CH3:20])[CH3:19])=[O:16])[CH2:8][CH2:7]1)=[O:5])[CH3:2].Br[CH2:39][C:40]([O:42][CH2:43][C:44]1[CH:49]=[CH:48][CH:47]=[CH:46][CH:45]=1)=[O:41].C(=O)([O-])[O-].[Cs+].[Cs+]>CN(C=O)C.C(OCC)(=O)C>[CH2:1]([O:3][C:4]([N:6]1[CH2:11][CH2:10][N:9]([C:12](=[O:37])[C@@H:13]([NH:22][C:23]([C:25]2[CH:29]=[C:28]([O:30][CH2:39][C:40]([O:42][CH2:43][C:44]3[CH:49]=[CH:48][CH:47]=[CH:46][CH:45]=3)=[O:41])[N:27]([C:31]3[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=3)[N:26]=2)=[O:24])[CH2:14][C:15]([O:17][C:18]([CH3:21])([CH3:20])[CH3:19])=[O:16])[CH2:8][CH2:7]1)=[O:5])[CH3:2]
Reactant: CCOC(=O)N1CCN(C(=O)[C@H](CC(=O)OC(C)(C)C)NC(=O)c2cc(O)n(-c3ccccc3)n2)CC1
Reactant: O=C(CBr)OCc1ccccc1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: CCOC(=O)N1CCN(C(=O)[C@H](CC(=O)OC(C)(C)C)NC(=O)c2cc(OCC(=O)OCc3ccccc3)n(-c3ccccc3)n2)CC1
Temperature: 25 °C
Reaction time: 12 h

Procedure:
To a solution of 8.0 g 4-{(S)-3-tert-Butoxycarbonyl-2-[(5-hydroxy-1-phenyl-1H-pyrazole-3-carbonyl)-amino]propionyl}-piperazine-1-carboxylic acid ethyl ester in 50 ml DMF were added 2.5 ml benzyl bromoacetate and 10.1 g cesium carbonate. After stirring at RT for 12 h the solution was reduced to a volume of 50 ml, diluted with 400 ml ethyl acetate and extracted with aqueous LiCl (4% w/w) and aqueous NaHCO3. The crude product obtained after evaporation of the solvent was used in the subsequent reaction.
Reaction SMILES: Cl.[C:2]([C:6]1[CH:11]=[CH:10][C:9]([C@@H:12]([NH2:14])[CH3:13])=[CH:8][CH:7]=1)([CH3:5])([CH3:4])[CH3:3].[Cl:15][C:16]1[CH:36]=[CH:35][C:19]([CH2:20][N:21]2[C:29]3[C:24](=[CH:25][C:26]([C:30](O)=[O:31])=[CH:27][CH:28]=3)[C:23]([CH3:33])=[C:22]2[CH3:34])=[CH:18][C:17]=1[O:37][C@@H:38]([CH3:43])[C:39]([O:41][CH3:42])=[O:40]>>[C:2]([C:6]1[CH:7]=[CH:8][C:9]([C@@H:12]([NH:14][C:30]([C:26]2[CH:25]=[C:24]3[C:29](=[CH:28][CH:27]=2)[N:21]([CH2:20][C:19]2[CH:35]=[CH:36][C:16]([Cl:15])=[C:17]([CH:18]=2)[O:37][C@@H:38]([CH3:43])[C:39]([O:41][CH3:42])=[O:40])[C:22]([CH3:34])=[C:23]3[CH3:33])=[O:31])[CH3:13])=[CH:10][CH:11]=1)([CH3:5])([CH3:3])[CH3:4]
Reactant: C[C@H](N)c1ccc(C(C)(C)C)cc1
Reactant: COC(=O)[C@H](C)Oc1cc(Cn2c(C)c(C)c3cc(C(=O)O)ccc32)ccc1Cl
Agent: Cl
Product: COC(=O)[C@H](C)Oc1cc(Cn2c(C)c(C)c3cc(C(=O)N[C@@H](C)c4ccc(C(C)(C)C)cc4)ccc32)ccc1Cl

Procedure:
The title compound was prepared following the same protocol as described in Step 5, Example 36, using the (S)-1-(4-(tert-butyl)phenyl)ethanamine hydrochloride instead of the (S)-1-(3-cyclopropylphenyl)ethanamine hydrochloride the (S)-1-(4-chloro-3-((1-methoxy-1-oxopropan-2-yl)oxy)benzyl)-2,3-dimethyl-1H-indole-5-carboxylic acid instead of the 1-(4-(2-methoxy-2-oxoethoxy)benzyl)-2,3-dimethyl-1H-indole-5-carboxylic acid.
Reaction SMILES: II.C(=O)([O-])[O-].[K+].[K+].[CH3:9][O:10][C:11]1[N:16]=[C:15]([O:17][CH3:18])[C:14]([CH:19]=O)=[CH:13][N:12]=1.[Cl:21][C:22]1[CH:27]=[CH:26][C:25]([C:28]([NH2:40])([C:30]([C:33]2[CH:38]=[CH:37][C:36]([Cl:39])=[CH:35][CH:34]=2)([NH2:32])[CH3:31])[CH3:29])=[CH:24][CH:23]=1>C(O)(C)(C)C.C(OCC)C>[Cl:21][C:22]1[CH:27]=[CH:26][C:25]([C@@:28]2([CH3:29])[C@:30]([C:33]3[CH:34]=[CH:35][C:36]([Cl:39])=[CH:37][CH:38]=3)([CH3:31])[NH:32][C:19]([C:14]3[C:15]([O:17][CH3:18])=[N:16][C:11]([O:10][CH3:9])=[N:12][CH:13]=3)=[N:40]2)=[CH:24][CH:23]=1
Reactant: CC(N)(c1ccc(Cl)cc1)C(C)(N)c1ccc(Cl)cc1
Reactant: COc1ncc(C=O)c(OC)n1
Agent: II
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOCC
Solvent: CC(C)(C)O
Product: COc1ncc(C2=N[C@@](C)(c3ccc(Cl)cc3)[C@@](C)(c3ccc(Cl)cc3)N2)c(OC)n1
Temperature: 65 °C

Procedure:
The title compound was prepared using the procedure described by Ishihara, M. and Togo, H. Synlett 2006, 2, 227-230 and ibid Tetrahedron 2007, 63,1474-1480. Iodine (172 mg, 0.68 mg) was dissolved in tert-butanol (20 mL) and potassium carbonate (300 mg, 2.2 mmol) was added. 2,4-Dimethoxy-5-formylpyrimidine (100 mg, 0.6 mmol, Frontier) and (rac)-2,3-Bis(4-chloro-phenyl)-butane-2,3-diamine (200 mg, 0.65 mmol) was added to the mixture. This was warmed to 65° C. for 2 h. This was cooled, diluted with ethyl ether (50 mL) and filtered through Celite. After evaporating to dryness, the residue was purified by flash column chromatography (silica gel, eluting with 2-5% methanol/methylene chloride) to give rac-5-[(4S*,5R*)-4,5-bis-(4-chloro-phenyl)-4,5-dimethyl-4,5-dihydro-1H-imidazol-2-yl]-2,4-dimethoxy-pyrimidine.
Reaction SMILES: [C:1]([O:5][C:6]([C@@H:8]1[CH2:12][C@@H:11]([OH:13])[CH2:10][C@H:9]1[C:14](=[O:26])[NH:15][C@:16]1([C:21]([O:23][CH2:24][CH3:25])=[O:22])[CH2:18][C@H:17]1[CH:19]=[CH2:20])=[O:7])([CH3:4])([CH3:3])[CH3:2].[F:27][C:28]1[CH:29]=[C:30]([C:35]2[N:44]=[C:43](O)[C:42]3[C:37](=[C:38]([CH3:48])[C:39]([O:46][CH3:47])=[CH:40][CH:41]=3)[N:36]=2)[CH:31]=[C:32]([F:34])[CH:33]=1>>[C:1]([O:5][C:6]([CH:8]1[CH2:12][CH:11]([O:13][C:43]2[C:42]3[C:37](=[C:38]([CH3:48])[C:39]([O:46][CH3:47])=[CH:40][CH:41]=3)[N:36]=[C:35]([C:30]3[CH:31]=[C:32]([F:34])[CH:33]=[C:28]([F:27])[CH:29]=3)[N:44]=2)[CH2:10][CH:9]1[C:14](=[O:26])[NH:15][C:16]1([C:21]([O:23][CH2:24][CH3:25])=[O:22])[CH2:18][CH:17]1[CH:19]=[CH2:20])=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: COc1ccc2c(O)nc(-c3cc(F)cc(F)c3)nc2c1C
Reactant: C=C[C@@H]1C[C@]1(NC(=O)[C@@H]1C[C@H](O)C[C@H]1C(=O)OC(C)(C)C)C(=O)OCC
Product: C=CC1CC1(NC(=O)C1CC(Oc2nc(-c3cc(F)cc(F)c3)nc3c(C)c(OC)ccc23)CC1C(=O)OC(C)(C)C)C(=O)OCC

Procedure:
The alcohol 15 and the quinazolinol 128 was reacted according to same procedure described in example 155 which gave the title compound as a white solid slightly contaminated by triphenyl phosphine oxide (1.245 g, >100%), LRMS (M+H) 652.