Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [S:1]1[CH:5]=[CH:4][C:3]2[C:6]([O:8][C:9]([C:11]3[CH:15]=[CH:14][S:13][C:12]=3[C:2]1=2)=[O:10])=O.C1(C)C=CC=CC=1.[CH2:23]([CH:31]([CH2:34][CH2:35][CH2:36][CH2:37][CH2:38][CH2:39][CH2:40][CH2:41][CH2:42][CH3:43])[CH2:32][NH2:33])[CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH3:30]>CN(C)C1C=CN=CC=1.C(OCC)C>[CH2:23]([CH:31]([CH2:34][CH2:35][CH2:36][CH2:37][CH2:38][CH2:39][CH2:40][CH2:41][CH2:42][CH3:43])[CH2:32][N:33]1[C:6](=[O:8])[C:3]2[CH:4]=[CH:5][S:1][C:2]=2[C:12]2[S:13][CH:14]=[CH:15][C:11]=2[C:9]1=[O:10])[CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH3:30]
Reactant: O=c1oc(=O)c2ccsc2c2sccc12
Reactant: CCCCCCCCCCC(CN)CCCCCCCC
Agent: CN(C)c1ccncc1
Solvent: CCOCC
Solvent: Cc1ccccc1
Product: CCCCCCCCCCC(CCCCCCCC)Cn1c(=O)c2ccsc2c2sccc2c1=O
Reaction time: 0.25 h
Yield: 187.4 %

Procedure:
A dry 8 mL microwave reaction tube was charged with a micro-stirbar, anhydride (4) (354 mg, 1.50 mmol), 4-(dimethylamino)pyridine (61 mg, 0.50 mmol), and 5 mL of toluene. Next, 2-octyldodecylamine (446 mg, 1.5 mmol) was added dropwise to the suspension over 15 minutes and the reaction was allowed to stir for an additional 15 minutes until no solid remained. The reaction tube was then irradiated with microwaves (PMAX=300 W) for 2 hours at a constant temperature of 220° C. This procedure was repeated four more times and the five reaction mixtures were combined in 250 mL of diethyl ether, washed six times with 150 mL of water, one time with 100 mL of brine, and the organics dried over Mg2SO4. After filtration, the solvent was removed by evaporation to afford a yellow oil (90% pure by 1H NMR) that was purified by column chromatography on silica gel with a mixture of diethyl ether (10%) and hexane (90%) as the eluent. A light yellow oil (1.45 g, 37% yield) was obtained upon concentration of the main fractions.
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[O:6][C:7]([CH3:27])=[C:8]([CH2:10][O:11][C:12]2[CH:17]=[CH:16][C:15](B3OC(C)(C)C(C)(C)O3)=[CH:14][CH:13]=2)[CH:9]=1)=[O:4].[F:28][CH:29]([F:38])[O:30][C:31]1[CH:36]=[CH:35][C:34](I)=[CH:33][CH:32]=1.C(=O)([O-])[O-].[Cs+].[Cs+].ClCCl>O1CCOCC1>[CH3:1][O:2][C:3]([C:5]1[O:6][C:7]([CH3:27])=[C:8]([CH2:10][O:11][C:12]2[CH:13]=[CH:14][C:15]([C:34]3[CH:35]=[CH:36][C:31]([O:30][CH:29]([F:38])[F:28])=[CH:32][CH:33]=3)=[CH:16][CH:17]=2)[CH:9]=1)=[O:4]
Reactant: FC(F)Oc1ccc(I)cc1
Reactant: COC(=O)c1cc(COc2ccc(B3OC(C)(C)C(C)(C)O3)cc2)c(C)o1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: ClCCl
Solvent: C1COCCO1
Product: COC(=O)c1cc(COc2ccc(-c3ccc(OC(F)F)cc3)cc2)c(C)o1
Temperature: 80 °C
Reaction time: 4 h
Yield: 57.2 %

Procedure:
A degassed mixture of 5-methyl-4-[4-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-phenoxymethyl]-furan-2-carboxylic acid methyl ester (119) (200 mg, 0.54 mmoles), 4-difluoromethoxy-1-iodo-benzene (175 mg, 0.65 mmoles), 2M aqueous cesium carbonate (0.81 ml) and), [1,1′-bis(diphenylphosphino)ferrocene]dichloropalladium(II) complex with dichloromethane (1:1) (20 mg) in 1,4-dioxan (10 ml), under an argon atmosphere was heated at 80° C. for 20 h. Further quantities of 4-difluoromethoxy-1-iodo-benzene (87.5 mg, 0.0.27 mmoles) and [1,1′-bis(diphenylphosphino) ferrocene]dichloropalladium(II) complex with dichloromethane (1:1) (10 mg) were added and heating at 80° C. was continued for 4 hours. After cooling, the mixture was concentrated. The residue was dissolved in dichloromethane and washed with water and brine, and dried. The solvent was evaporated and the residue was purified by flash chromatography using petrol (40-60°)/diethyl ether 9:1 v/v as eluent to afford compound 128 (120 mg) as a wax. LC/MS System A; Rt=4.14 mins.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([CH:16]=[CH:17][CH:18]=1)[C:5]([N:7]([CH2:12][CH2:13][O:14][CH3:15])[CH2:8][CH2:9][O:10][CH3:11])=[O:6].[OH-].[Na+].Cl[C:22]([O:24][C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1)=[O:23]>O1CCOCC1>[CH3:15][O:14][CH2:13][CH2:12][N:7]([CH2:8][CH2:9][O:10][CH3:11])[C:5]([C:4]1[CH:3]=[C:2]([NH:1][C:22](=[O:23])[O:24][C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=2)[CH:18]=[CH:17][CH:16]=1)=[O:6]
Reactant: O=C(Cl)Oc1ccccc1
Reactant: COCCN(CCOC)C(=O)c1cccc(N)c1
Agent: [Na+]
Agent: [OH-]
Solvent: C1COCCO1
Product: COCCN(CCOC)C(=O)c1cccc(NC(=O)Oc2ccccc2)c1
Temperature: 0 °C
Reaction time: 1 h

Procedure:
To a stirred solution of 3-amino-N,N-bis(2-methoxyethyl)benzamide (1.01 g) in 1,4-dioxane (10 ml) was added 1N sodium hydroxide solution (5.2 ml) and phenyl chloroformate (0.55 ml) successively in an ice-cooled bath. The bath was removed and the reaction mixture was stirred vigorously for 1 hour, during which time phenyl chloroformate (0.25 ml) was further added. The mixture was extracted with dichloromethane and the organic layer was washed with water twice and brine, dried over anhydrous magnesium sulfate, and evaporated in vacuo. The residue was crystallized from diisopropyl ether to give phenyl 3-[N,N-bis(2-methoxyethyl)carbamoyl]phenylcarbamate (1.30 g) as a colorless powder.
Reaction SMILES: [C:1]([CH2:9][N:10]1[C:14]([S:15][C:16]2[CH:21]=[C:20]([Cl:22])[CH:19]=[C:18]([Cl:23])[CH:17]=2)=[C:13]([CH:24]([CH3:26])[CH3:25])[N:12]=[C:11]1[CH2:27][O:28]CC1C=CC(OC)=CC=1)(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.N(CC1N(CC)C(C(C)C)=C(SC2C=C(F)C=C(F)C=2)N=1)=[N+]=[N-]>>[C:1]([CH2:9][N:10]1[C:14]([S:15][C:16]2[CH:17]=[C:18]([Cl:23])[CH:19]=[C:20]([Cl:22])[CH:21]=2)=[C:13]([CH:24]([CH3:26])[CH3:25])[N:12]=[C:11]1[CH2:27][OH:28])(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: COc1ccc(COCc2nc(C(C)C)c(Sc3cc(Cl)cc(Cl)c3)n2CC(=O)c2ccccc2)cc1
Agent: CCn1c(CN=[N+]=[N-])nc(Sc2cc(F)cc(F)c2)c1C(C)C
Product: CC(C)c1nc(CO)n(CC(=O)c2ccccc2)c1Sc1cc(Cl)cc(Cl)c1

Procedure:
Compound I-31 was obtained from 1-benzoylmethyl-5-(3,5-dichlorophenylthio)-4-isopropyl-2-(p-methoxybenzyloxymethyl)-1H-imidazole (17u) by the same synthetic process as that for Compound I-16 in Example 16 (yield 75%). mp 205-211° C.
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:14]=[CH:13][C:12]([C:15]2[CH:20]=[CH:19][C:18]([CH2:21][CH2:22][CH2:23][OH:24])=[CH:17][CH:16]=2)=[CH:11][CH:10]=1)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH3:7].C1C=C[NH+]=CC=1.[O-][Cr](Cl)(=O)=O.CCOCC>C(Cl)Cl>[CH2:1]([O:8][C:9]1[CH:14]=[CH:13][C:12]([C:15]2[CH:20]=[CH:19][C:18]([CH2:21][CH2:22][CH:23]=[O:24])=[CH:17][CH:16]=2)=[CH:11][CH:10]=1)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH3:7]
Reactant: CCCCCCCOc1ccc(-c2ccc(CCCO)cc2)cc1
Agent: O=[Cr](=O)([O-])Cl
Agent: c1cc[nH+]cc1
Solvent: ClCCl
Solvent: CCOCC
Product: CCCCCCCOc1ccc(-c2ccc(CCC=O)cc2)cc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 109.1 %

Procedure:
To a cold (0° C.) stirred solution of 3-(4′-heptyloxybiphenyl-4-yl)propan-1-ol (2.26 g, 6.92 mmol) in CH2Cl2 (60 ml) were added molecular sieves 4A powder (5.17 g) and PCC (5.25 g, 24.4 mmol). After being stirred for 2 h at room temperature, Et2O (20 ml) was added to the mixture. The reaction mixture was transferred to a short silica gel column and eluted with CH2Cl2. The eluate was concentrated in vacuo to give 3-(4′-heptyloxybiphenyl-4-yl)propionaldehyde (crude, 2.45 g) which was used for the next step without further purification.
Reaction SMILES: C1([C:7]2[C:20]3[C:11](=[C:12]4[C:17](=[CH:18][CH:19]=3)[C:16](C3C=CC=CC=3)=[CH:15][CH:14]=[N:13]4)[N:10]=[CH:9][CH:8]=2)C=CC=CC=1.BrBr.O.Cl.BrBr>C(O)C>[N:10]1[C:11]2[C:20](=[CH:19][CH:18]=[C:17]3[C:12]=2[N:13]=[CH:14][CH:15]=[CH:16]3)[CH:7]=[CH:8][CH:9]=1
Reactant: c1ccc(-c2ccnc3c2ccc2c(-c4ccccc4)ccnc23)cc1
Agent: BrBr
Agent: Cl
Solvent: CCO
Solvent: O
Product: c1cnc2c(c1)ccc1cccnc12

Procedure:
Bis (4,7-diphenyl-1,10-phenanthroline)cobalt(III) chloride, (DIP)2Co(III)Cl2, was prepared as follows: 4,7-diphenyl-1,10-phenanthroline (Aldrich) was dissolved in a minimum volume of ethanol to which one half stoichiometric CoCl2.6H2O was added. The green-brown solution was oxidized by using Br2 /H2O, and a heavy orange precipitate formed immediately. The solution was refluxed for 1 h, and concentrated hydrochloride was added. The bromine oxidation was then repeated. The crude complex was recrystallized in aqueous ethanol. Other cobalt(III) complexes of this invention may be prepared by this method by substituting the appropriate ligand for 4,7-diphenyl-1,10-phenanthroline.
Reaction SMILES: [CH3:1][N:2]([CH3:6])[CH2:3][CH2:4][NH2:5].Cl[C:8]1[N:9]([CH2:30][CH:31]2[CH2:33][CH2:32]2)[C:10]2[C:15]([N:16]=1)=[C:14]([N:17]1[CH2:22][CH2:21][O:20][CH2:19][CH2:18]1)[N:13]=[C:12]([C:23]1[CH:24]=[N:25][C:26]([NH2:29])=[N:27][CH:28]=1)[N:11]=2>CS(C)=O>[NH2:29][C:26]1[N:25]=[CH:24][C:23]([C:12]2[N:11]=[C:10]3[C:15]([N:16]=[C:8]([NH:5][CH2:4][CH2:3][N:2]([CH3:6])[CH3:1])[N:9]3[CH2:30][CH:31]3[CH2:33][CH2:32]3)=[C:14]([N:17]3[CH2:22][CH2:21][O:20][CH2:19][CH2:18]3)[N:13]=2)=[CH:28][N:27]=1
Reactant: Nc1ncc(-c2nc(N3CCOCC3)c3nc(Cl)n(CC4CC4)c3n2)cn1
Reactant: CN(C)CCN
Solvent: CS(C)=O
Product: CN(C)CCNc1nc2c(N3CCOCC3)nc(-c3cnc(N)nc3)nc2n1CC1CC1
Temperature: 150 °C
Reaction time: 4 h
Yield: 74.5 %

Procedure:
N,N-Dimethylethylenediamine (113 mg, 1.3 mmol) and dimethyl sulfoxide (1 ml) were added to 5-[8-chloro-9-(cyclopropylmethyl)-6-morpholin-4-yl-9H-purin-2-yl]pyrimidin-2-amine (100 mg, 0.26 mmol) and the resulting mixture was stirred at 150° C. for 4 hours. The reaction mixture was purified by preparative HPLC (column, NOMURA Develosil Combi-RP-5; mobile phase, acetonitrile/water/formic acid) to give the title compound (85 mg, 68%) as a pale yellow solid.
Reaction SMILES: [CH2:1]([CH:5]1[C:9]2[CH:10]=[CH:11][CH:12]=[C:13]([O:14][C:15]3[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=3[CH3:21])[C:8]=2[O:7][C:6]1=[O:22])[CH2:2][CH2:3][CH3:4].[OH-:23].[K+]>CO>[OH:7][C:8]1[C:13]([O:14][C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=2[CH3:21])=[CH:12][CH:11]=[CH:10][C:9]=1[CH:5]([CH2:1][CH2:2][CH2:3][CH3:4])[C:6]([OH:22])=[O:23]
Reactant: CCCCC1C(=O)Oc2c(Oc3ccccc3C)cccc21
Reactant: [OH-]
Agent: [K+]
Solvent: CO
Product: CCCCC(C(=O)O)c1cccc(Oc2ccccc2C)c1O

Procedure:
3-(n-Butyl)-7-(o-tolyloxy)-2,3-dihydrobenzofuran-2-one was treated with potassium hydroxide in methanol in a similar manner to that of Example 21-(10) to give 2-[2-hydroxy-3-(o-tolyloxy)-phenyl]-n-hexanoic acid, mp. 83°-84° C.
Reaction SMILES: [H-].[Na+].[F:3][C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=1[OH:10].[Cl:11][C:12]1[CH:17]=[C:16](Cl)[N:15]=[CH:14][N:13]=1.O>C1COCC1.C(OCC)(=O)C>[Cl:11][C:12]1[CH:17]=[C:16]([O:10][C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[F:3])[N:15]=[CH:14][N:13]=1
Reactant: Oc1ccccc1F
Reactant: Clc1cc(Cl)ncn1
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Solvent: O
Product: Fc1ccccc1Oc1cc(Cl)ncn1
Temperature: 70 °C
Reaction time: 0.33 h
Yield: 65 %

Procedure:
NaH (80 mg, 60%, 3.0 mmol) was added to a solution of 2-fluorophenol (112 mg, 1 mmol) in 10 ml of anhydrous THF, the mixture was stirred for 20 minutes, 4,6-dichloro-pyrimidine (149 mg, 1 mmol) was added and then the reaction mixture was heated at 70° C. for 1 hour. After cooling, 5 ml water was added and ethyl acetate (20 ml) was used to extract the product. The organic layer was dried over sodium sulfate. The solvent was removed by rotovap to give 146 mg of 4-chloro-6-(2-fluorophenoxy)-pyrimidine, yield 65%.
Reaction SMILES: [C:1]([NH2:5])(=[O:4])[CH:2]=[CH2:3].C1(C)C=CC(S(O)(=O)=O)=CC=1.[Cl:17][C:18]1[CH:19]=[C:20]2[C:25](=[C:26]([Cl:28])[CH:27]=1)[CH2:24][CH:23](N1CCCC1)[CH2:22][CH2:21]2>C(Cl)(Cl)Cl.C(OCC)(=O)C>[Cl:17][C:18]1[CH:27]=[C:26]([Cl:28])[C:25]2[C:24]3[CH2:3][CH2:2][C:1](=[O:4])[NH:5][C:23]=3[CH2:22][CH2:21][C:20]=2[CH:19]=1
Reactant: Clc1cc(Cl)c2c(c1)CCC(N1CCCC1)C2
Reactant: C=CC(N)=O
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: ClC(Cl)Cl
Solvent: CCOC(C)=O
Product: O=C1CCC2=C(CCc3cc(Cl)cc(Cl)c32)N1

Procedure:
16.2 g of acrylamide and 0.9 g of anhydrous p-toluenesulphonic acid were added to 30.6 g of 1-(6,8-dichloro-3,4-dihydro-2(1H)-naphthyl)pyrrolidine. The mixture was heated under nitrogen to 100° for 2 hours and to 150° for 2 hours. After cooling, the reaction mixture was stirred at room temperature in 80 ml of a mixture of chloroform-ethyl acetate (1:1). There was obtained 8,10-dichloro-1,4,5,6-tetrahydrobenzo[f]quinolin-3(2H)-one which melts at 212°-214° after recrystallization from ethyl acetate.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[O:12][N:11]=[C:10]([CH3:13])[C:9]=2[NH2:14])=[CH:4][CH:3]=1.[F:15][C:16]([F:29])([F:28])[C:17]1[CH:18]=[C:19]([CH2:23][CH2:24][C:25](=O)[CH3:26])[CH:20]=[CH:21][CH:22]=1>>[Br:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[O:12][N:11]=[C:10]([CH3:13])[C:9]=2[NH:14][CH:25]([CH3:26])[CH2:24][CH2:23][C:19]2[CH:20]=[CH:21][CH:22]=[C:17]([C:16]([F:15])([F:28])[F:29])[CH:18]=2)=[CH:6][CH:7]=1
Reactant: Cc1noc(-c2ccc(Br)cc2)c1N
Reactant: CC(=O)CCc1cccc(C(F)(F)F)c1
Product: Cc1noc(-c2ccc(Br)cc2)c1NC(C)CCc1cccc(C(F)(F)F)c1

Procedure:
Prepared according to the procedure described in Example 24, Step 1, using 5-(4-bromo-phenyl)-3-methyl-isoxazol-4-ylamine and 4-(3-trifluoromethyl-phenyl)-butan-2-one. After silica gel chromatography the crude material was purified via preparatory chiral HPLC (Chiralcel-AD column, 2% EtOH in hexanes, 35 minutes) to afford two separate enantiomers. The first enantiomer eluted from the column is the title compound.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4](N)[C:5]([NH2:8])=[CH:6][CH:7]=1.[C:10]([S-:15])(=[S:14])OCC.[K+].O.Cl>CN(C=O)C>[F:1][C:2]1[CH:7]=[CH:6][C:5]2[N:8]=[C:10]([SH:15])[S:14][C:4]=2[CH:3]=1
Reactant: CCOC(=S)[S-]
Reactant: Nc1ccc(F)cc1N
Agent: Cl
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: Fc1ccc2nc(S)sc2c1
Temperature: 95 °C
Reaction time: 1 h

Procedure:
4-Fluorobenzene-1,2-diamine (10.0 g, 0.077 mol) and potassium O-ethyl carbonodithioate (37.1 g, 0.234 mol) were dissolved in dry DMF (150 mL) under nitrogen and heated to 95° C. for 12 h. The reaction was cooled to RT and 200 mL water was added followed by addition of 5N HCl to get precipitates. After stirring for 1 h, the precipitates were collected by filtration, washed with water and dried under vacuum for 2 h. The crude compound was then washed with chloroform and dried to give 6-fluorobenzo[d]thiazole-2-thiol as yellow solid.
Reaction SMILES: [Cl:1][C:2]1[CH:18]=[CH:17][C:5]2[CH2:6][CH2:7][N:8]([C:11](=[O:16])[C:12]([F:15])([F:14])[F:13])[CH2:9][CH2:10][C:4]=2[C:3]=1OS(C(F)(F)F)(=O)=O.[CH3:27][C:28]([CH3:43])([CH3:42])[C:29]([NH:31][CH2:32][CH2:33][C:34]1[CH:41]=[CH:40][C:37]([CH2:38][NH2:39])=[CH:36][CH:35]=1)=[O:30]>>[Cl:1][C:2]1[CH:18]=[CH:17][C:5]2[CH2:6][CH2:7][N:8]([C:11](=[O:16])[C:12]([F:15])([F:14])[F:13])[CH2:9][CH2:10][C:4]=2[C:3]=1[NH:39][CH2:38][C:37]1[CH:40]=[CH:41][C:34]([CH2:33][CH2:32][NH:31][C:29](=[O:30])[C:28]([CH3:42])([CH3:27])[CH3:43])=[CH:35][CH:36]=1
Reactant: CC(C)(C)C(=O)NCCc1ccc(CN)cc1
Reactant: O=C(N1CCc2ccc(Cl)c(OS(=O)(=O)C(F)(F)F)c2CC1)C(F)(F)F
Product: CC(C)(C)C(=O)NCCc1ccc(CNc2c(Cl)ccc3c2CCN(C(=O)C(F)(F)F)CC3)cc1
Yield: 70.3 %

Procedure:
Use a method similar to the General Procedure 1-2 to couple 7-chloro-3-(2,2,2-trifluoroacetyl)-6-trifluoromethanesulfonyloxy-2,3,4,5-tetrahydro-1H-benzo[d]azepine (106 mg, 0.251 mmol) and 4-[2-(2,2-dimethyl-propionylamino)-ethyl]-benzylamine (110 mg, 0.427 mmol). Purify the crude mixture by chromatography on silica gel eluting with hexane/EtOAc (6:4) to obtain 7-chloro-6-{4-[2-(2,2-dimethyl-propionylamino)-ethyl]-benzylamino}-3-(2,2,2-trifluoroacetyl)-2,3,4,5-tetrahydro-1H-benzo[d]azepine as a yellow oil (90 mg, 70%). MS (ES+) m/z: 510 (M+H)+.
Reaction SMILES: [C:1]([C:3]1[CH:8]=[CH:7][C:6](I)=[CH:5][C:4]=1[F:10])#[N:2].[CH2:11]([C:14]1[CH:19]=[CH:18][C:17]([C:20]#[CH:21])=[CH:16][CH:15]=1)[CH2:12][CH3:13].Cl>CN(C)C=O.[Pd](Cl)Cl.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>[CH2:11]([C:14]1[CH:15]=[CH:16][C:17]([C:20]#[C:21][C:6]2[CH:7]=[CH:8][C:3]([C:1]#[N:2])=[C:4]([F:10])[CH:5]=2)=[CH:18][CH:19]=1)[CH2:12][CH3:13]
Reactant: C#Cc1ccc(CCC)cc1
Reactant: N#Cc1ccc(I)cc1F
Agent: Cl[Pd]Cl
Agent: Cl
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CN(C)C=O
Product: CCCc1ccc(C#Cc2ccc(C#N)c(F)c2)cc1
Yield: 22.8 %

Procedure:
2.1 g of this 1-cyano-2-fluoro-4-iodobenzene was dissolved in 14 ml of N,N-dimethylformamide to which was added 3 mg of bis(triphenylphosphine) palladium (II) chloride and 13 mg of cuprous iodide. Next, 1.2 g of the 4-propylphenylacetylene obtained in step 2 was added and allowed to react at 50 to 60° C for 0.5 hour. After completion of the reaction, 35 ml of 9% hydrochloric acid was added to the reaction solution. After being extracted with chloroform, the crystals were washed with water three times to distill off the chloroform. The residue was purified by silica gel-chloroform column chromatography, followed by recrystallization with a mixed solvent of acetone and methanol to obtain 0.5 g of 4-propyl-3'-fluoro-4'-cyanotolan. The melting point of this compound (hereinafter referred to as the C-I point) was 67.2° C.
Reaction SMILES: [Cl:1][C:2]1[CH:13]=[C:6]2[C:7]([O:9][C:10](=[O:12])[NH:11][C:5]2=[CH:4][CH:3]=1)=O.[NH:14]1[CH2:17][CH2:16][C@H:15]1C(O)=O>CN(C)C=O.C(O)(=O)C>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[NH:11][C:10](=[O:12])[C@@H:15]3[CH2:16][CH2:17][N:14]3[C:7](=[O:9])[C:6]=2[CH:13]=1
Reactant: O=C(O)[C@@H]1CCN1
Reactant: O=c1[nH]c2ccc(Cl)cc2c(=O)o1
Solvent: CN(C)C=O
Solvent: CC(=O)O
Product: O=C1Nc2ccc(Cl)cc2C(=O)N2CC[C@@H]12
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 86.3 %

Procedure:
59.3 g (0.3 mol) of 5-chloro-isatoic anhydride and 30.3 g (0.3 mol) of (S)-azetidine-2-carboxylic acid were suspended in 400 ml of N,N-dimethylformamide/acetic acid 5:1 and heated to 87°-90° in an oil bath under argon for 64 hrs. The solvent was removed in a vacuum and the residue was taken up in 500 ml of methanol, whereupon the mixture was stirred at room temperature for 30 min. The white, pure crystals were filtered off under suction. The solvent was removed in a vacuum and the semi-crystalline residue was recrystallized from 60 ml of methanol (hot filtration). The products were combined and dried in a vacuum. There were obtained 61.3 g (86%) of (S)-6-chloro-1,2,4,9,10,10a-hexahydro-azeto[2,1-c][1,4]benzodiazepine-4,10-dione of m.p. 229°-231° (dec.).
Reaction SMILES: N[C:2]1[CH:3]=[C:4]([C:14](=[O:20])[C:15]([O:17]CC)=[O:16])[CH:5]=[CH:6][C:7]=1[CH:8]1[CH2:13][CH2:12][CH2:11][CH2:10][CH2:9]1.N([O-])=O.[Na+].O.[BrH:26]>>[Br:26][C:2]1[CH:3]=[C:4]([C:14](=[O:20])[C:15]([OH:17])=[O:16])[CH:5]=[CH:6][C:7]=1[CH:8]1[CH2:13][CH2:12][CH2:11][CH2:10][CH2:9]1
Reactant: CCOC(=O)C(=O)c1ccc(C2CCCCC2)c(N)c1
Reactant: Br
Agent: O=N[O-]
Agent: [Na+]
Solvent: O
Product: O=C(O)C(=O)c1ccc(C2CCCCC2)c(Br)c1

Procedure:
To 11.1 g. (0.044 moles) of ethyl 3-amino-4-cyclohexylphenylglyoxylate suspension in 225 ml of 40% hydrobromic acid and cooled to 0° C. is added dropwise a solution of 2.34 g. of sodium nitrite in 30 ml. of water. To this mixture is added a solution of 20 g. of cuprous bromide in 350 ml. of 40% hydrobromic acid added portion wise and stirred for 15 hours. The reaction mixture is then poured onto ice water, extracted with chloroform, dried over sodium sulfate and concentrated in vacuo. The residue is then crystallized to obtain 3-bromo-4-cyclohexylphenylglyoxylic acid.
Reaction SMILES: Br[C:2]1[C:3]([N:22]2[CH2:26][CH2:25][C@H:24]([CH2:27][OH:28])[CH2:23]2)=[N:4][CH:5]=[C:6]([CH:21]=1)[C:7]([NH:9][C:10]1[CH:15]=[CH:14][C:13]([O:16][C:17]([Cl:20])([F:19])[F:18])=[CH:12][CH:11]=1)=[O:8].[F:29][C:30]1[CH:31]=[N:32][CH:33]=[C:34](B2OC(C)(C)C(C)(C)O2)[CH:35]=1>>[Cl:20][C:17]([F:19])([F:18])[O:16][C:13]1[CH:14]=[CH:15][C:10]([NH:9][C:7]([C:6]2[CH:21]=[C:2]([C:34]3[CH:33]=[N:32][CH:31]=[C:30]([F:29])[CH:35]=3)[C:3]([N:22]3[CH2:26][CH2:25][C@H:24]([CH2:27][OH:28])[CH2:23]3)=[N:4][CH:5]=2)=[O:8])=[CH:11][CH:12]=1
Reactant: CC1(C)OB(c2cncc(F)c2)OC1(C)C
Reactant: O=C(Nc1ccc(OC(F)(F)Cl)cc1)c1cnc(N2CC[C@H](CO)C2)c(Br)c1
Product: O=C(Nc1ccc(OC(F)(F)Cl)cc1)c1cnc(N2CC[C@H](CO)C2)c(-c2cncc(F)c2)c1

Procedure:
The title compound was prepared in an analogous fashion to that described in Example 169 using (S)-5-bromo-N-(4-(chlorodifluoromethoxy)phenyl)-6-(3-(hydroxymethyl)pyrrolidin-1-yl)nicotinamide (Stage 174.1) and 3-fluoro-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridine to afford an off-white solid. HPLC (Condition 4) tR=5.29 min, UPLC-MS (Condition 3) tR=1.06 min, m/z=493.3 [M+H]+; 1H-NMR (400 MHz, DMSO-d6) δ ppm 1.47-1.63 (m, 1H) 1.83 (m, J=5.90 Hz, 1H) 2.14-2.28 (m, 1H) 2.96 (dd, J=10.95, 7.04 Hz, 1H) 3.10-3.38 (m, 5H) 4.60 (t, J=5.08 Hz, 1H) 7.32 (d, J=8.21 Hz, 2H) 7.77-7.88 (m, 3H) 8.05 (d, J=1.00 Hz, 1H) 8.50 (s, 1H) 8.57 (d, J=1.96 Hz, 1H) 8.76 (d, J=1.00 Hz, 1H) 10.16 (s, 1H).
Reaction SMILES: Br[C:2]1[C:3]2[C:4]3[CH:17]=[CH:16][S:15][C:5]=3[C:6](=[O:14])[NH:7][C:8]=2[CH:9]=[CH:10][C:11]=1[O:12][CH3:13].[C:18]([O:22][C:23]([NH:25][CH2:26][C:27]1[S:31][C:30](B(O)O)=[CH:29][CH:28]=1)=[O:24])([CH3:21])([CH3:20])[CH3:19]>>[C:18]([O:22][C:23](=[O:24])[NH:25][CH2:26][C:27]1[S:31][C:30]([C:2]2[C:3]3[C:4]4[CH:17]=[CH:16][S:15][C:5]=4[C:6](=[O:14])[NH:7][C:8]=3[CH:9]=[CH:10][C:11]=2[O:12][CH3:13])=[CH:29][CH:28]=1)([CH3:21])([CH3:19])[CH3:20]
Reactant: CC(C)(C)OC(=O)NCc1ccc(B(O)O)s1
Reactant: COc1ccc2[nH]c(=O)c3sccc3c2c1Br
Product: COc1ccc2[nH]c(=O)c3sccc3c2c1-c1ccc(CNC(=O)OC(C)(C)C)s1
Yield: 14.1 %

Procedure:
Following General Procedure B, 9-bromo-8-methoxythieno[2,3-c]quinolin-4(5H)-one (150 mg, 0.48 mmol) was reacted with 5-[(tert-butoxycarbonylamino)methyl]thiophen-2-ylboronic acid (130 mg, 0.53 mmol) to afford the desired product (30 mg, 18%) as a off-white solid: 1H NMR (500 MHz, CD3OD) δ 7.74 (d, J=5.4 Hz, 1H), 7.56 (d, J=9.1 Hz, 1H), 7.36 (d, J=9.1 Hz, 1H), 6.49 (d, J=3.1 Hz, 1H), 6.40 (br s, 1H), 6.01 (d, J=5.4 Hz, 1H), 4.27 (s, 2H), 3.82 (s, 3H), 1.39 (s, 9H).
Reaction SMILES: [CH2:1]([NH2:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Cl.Cl.[CH2:11]([N:13]([CH2:35][CH3:36])[CH2:14][CH:15]([N:17]1[C:30]2[CH:29]=[C:28]([C:31](=[NH:34])OC)[CH:27]=[CH:26][C:25]=2[S:24][C:23]2[C:18]1=[CH:19][CH:20]=[CH:21][CH:22]=2)[CH3:16])[CH3:12].O>CO>[CH2:1]([NH:8][C:31]([C:28]1[CH:27]=[CH:26][C:25]2[S:24][C:23]3[C:18](=[CH:19][CH:20]=[CH:21][CH:22]=3)[N:17]([CH:15]([CH3:16])[CH2:14][N:13]([CH2:35][CH3:36])[CH2:11][CH3:12])[C:30]=2[CH:29]=1)=[NH:34])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: NCc1ccccc1
Reactant: CCN(CC)CC(C)N1c2ccccc2Sc2ccc(C(=N)OC)cc21
Agent: Cl
Solvent: O
Solvent: CO
Product: CCN(CC)CC(C)N1c2ccccc2Sc2ccc(C(=N)NCc3ccccc3)cc21
Temperature: 5 °C
Reaction time: 2 h

Procedure:
A solution of benzylamine (3.18 cc) in methanol (5 cc) is added dropwise in the course of 5 minutes to a solution, cooled to 0°-5° C., of methyl 10-[(2RS)-1-diethylamino-2-propyl]-2-phenothiazinecarboximidate dihydrochloride (3.49 g) in methanol (21 cc). The mixture is stirred for 2 hours at 5° C. and is then concentrated to dryness at 50° C. under reduced pressure (30 mm Hg; 4 kPa) to give a residue which is taken up with distilled water (50 cc). The solution is washed with distilled water (50 cc) alkalinized to a pH in the region of 9 with N sodium hydroxide. The two phases are allowed to settle and the organic phase is separated and washed with half-saturated sodium chloride solution (50 cc), dried over magnesium sulphate, filtered and then concentrated to dryness under reduced pressure (30 mm Hg; 4 kPa) at 50° C. The residue is purified by chromatography on a column of neutral alumina (height: 24 cm; diameter: 2.1 cm), eluting successively with mixtures of cyclohexane and ethyl acetate in proportions of 50:50 (500 cc) and 25:75 (500 cc), then with pure ethyl acetate (500 cc) and finally with mixtures of ethyl acetate and methanol in proportions of 95:5 (500 cc) and 90:10 (500 cc) and collecting 50-cc fractions. Fractions 35 to 53 are combined and concentrated to dryness under reduced pressure (30 mm Hg; 4 kPa) at 50° C. to give N-benzyl-10-[ (2RS)-1-diethylamino-2-propyl]-2-phenothiazinecarboxamidine (0.96 g) in the form of a yellow product of meringue-like consistency.