Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([OH:8])=[CH:4][CH:3]=1.C(N(CC)CC)C.Cl[C:17]1[N:22]=[CH:21][C:20]([N+:23]([O-:25])=[O:24])=[CH:19][N:18]=1.O>O1CCCC1>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([O:8][C:17]2[N:22]=[CH:21][C:20]([N+:23]([O-:25])=[O:24])=[CH:19][N:18]=2)=[CH:4][CH:3]=1
Reactant: Oc1ccc(Br)cc1
Reactant: O=[N+]([O-])c1cnc(Cl)nc1
Solvent: O
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: O=[N+]([O-])c1cnc(Oc2ccc(Br)cc2)nc1
Temperature: 25 °C
Reaction time: 3 h
Yield: 85.9 %

Procedure:
To a solution of 4-bromophenol (200 mg) in tetrahydrofuran were added triethylamine (193 μL) and 2-chloro-5-nitropyrimidine (204 mg). The reaction mixture was stirred at room temperature for 3 hours. The reaction mixture was added to water (20 mL) and extracted with ethyl acetate (20 mL). The obtained organic layer was washed with a saturated sodium chloride aqueous solution, dried over anhydrous sodium sulfate and then concentrated under reduced pressure to give the titled compound (294 mg) having the following physical data.
Reaction SMILES: C(OC([N:8]1[CH2:12][CH2:11][CH2:10][CH:9]1[C:13]([O:15][CH2:16][CH2:17][CH2:18][C:19]1[CH:20]=[N:21][CH:22]=[CH:23][CH:24]=1)=[O:14])=O)(C)(C)C.C(=O)([O-])[O-].[K+].[K+]>C(Cl)Cl.FC(F)(F)C(O)=O>[NH:8]1[CH2:12][CH2:11][CH2:10][CH:9]1[C:13]([O:15][CH2:16][CH2:17][CH2:18][C:19]1[CH:20]=[N:21][CH:22]=[CH:23][CH:24]=1)=[O:14]
Reactant: CC(C)(C)OC(=O)N1CCCC1C(=O)OCCCc1cccnc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: O=C(OCCCc1cccnc1)C1CCCN1
Yield: 76.7 %

Procedure:
A solution of 3-(3-pyridyl)-1-propyl N-(tert-butyloxycarbonyl)pyrrolidine-2-carboxylate (3.0 g; 8.9 mmol) in methylene chloride (40 mL) and trifluoroacetic acid (8 mL) was stirred at room temperature for three hours. Saturated potassium carbonate was added until the pH was basic, and the reaction mixture was extracted with methylene chloride (3x). The combined organic extracts were dried and concentrated to yield 1.60 g (77%) of the free amine as a thick oil. 1H NMR (300 MHz, CDCl3) δ 1.71-2.09 (m, 6H); 2.63 (m, 2H); 2.86 (m, 1H); 2.94 (m, 1H) 3.71 (m, 1H); 4.11 (m, 2H); 7.18 (m, 1H); 7.45 (m, 1H); 8.41 (m, 2H).
Reaction SMILES: [CH3:1][C:2]1[C:6]([CH2:7][N:8]2[CH:12]=[C:11]([N:13]3[C:17](=[O:18])[CH2:16][NH:15][C:14]3=[O:19])[CH:10]=[N:9]2)=[C:5]([CH3:20])[O:4][N:3]=1.[Cl:21][C:22]1[CH:30]=[CH:29][CH:28]=[CH:27][C:23]=1[CH2:24][CH2:25]Br>>[Cl:21][C:22]1[CH:30]=[CH:29][CH:28]=[CH:27][C:23]=1[CH2:24][CH2:25][N:15]1[CH2:16][C:17](=[O:18])[N:13]([C:11]2[CH:10]=[N:9][N:8]([CH2:7][C:6]3[C:2]([CH3:1])=[N:3][O:4][C:5]=3[CH3:20])[CH:12]=2)[C:14]1=[O:19]
Reactant: Cc1noc(C)c1Cn1cc(N2C(=O)CNC2=O)cn1
Reactant: Clc1ccccc1CCBr
Product: Cc1noc(C)c1Cn1cc(N2C(=O)CN(CCc3ccccc3Cl)C2=O)cn1
Yield: 25 %

Procedure:
Prepared as in example 10-52 from 3-(1-((3,5-dimethylisoxazol-4-yl)methyl)-1H-pyrazol-4-yl)imidazolidine-2,4-dione (example 10-1) and 2-chlorophenethyl bromide. Yield: 25%. MS M+H calculated 414.13. found 414.2. The title compound was shown to inhibit hT2R08 bitter receptor and had an IC50 of 0.250M.
Reaction SMILES: [Br:1]C1C(C(OC)=O)=NC(N[C@@H]2C3C(=CC=CC=3)C[C@@H]2O)=CN=1.[Cl:23][C:24]1[CH:29]=[C:28]([Cl:30])[CH:27]=[CH:26][C:25]=1[C:31]1[N:32]=[CH:33][C:34]([NH:39][C@@H:40]2[C:48]3[C:43](=[CH:44][CH:45]=[CH:46][CH:47]=3)[CH2:42][C@@H:41]2[OH:49])=[N:35][C:36]=1[O:37][CH3:38]>>[Br:1][C:33]1[C:34]([NH:39][C@@H:40]2[C:48]3[C:43](=[CH:44][CH:45]=[CH:46][CH:47]=3)[CH2:42][C@@H:41]2[OH:49])=[N:35][C:36]([O:37][CH3:38])=[C:31]([C:25]2[CH:26]=[CH:27][C:28]([Cl:30])=[CH:29][C:24]=2[Cl:23])[N:32]=1
Reactant: COc1nc(N[C@@H]2c3ccccc3C[C@@H]2O)cnc1-c1ccc(Cl)cc1Cl
Reactant: COC(=O)c1nc(N[C@@H]2c3ccccc3C[C@@H]2O)cnc1Br
Product: COc1nc(N[C@@H]2c3ccccc3C[C@@H]2O)c(Br)nc1-c1ccc(Cl)cc1Cl

Procedure:
Following the procedure for the preparation of methyl 3-bromo-6-{[(1R,2S)-2-hydroxy-2,3-dihydro-1H-inden-1-yl]amino}pyrazine-2-carboxylate but substituting (1R,2S)-1-{[5-(2,4-dichlorophenyl)-6-methoxypyrazin-2-yl]amino}-2,3-dihydro-1H-inden-2-ol and making non-critical variations provided the title compound as a solid: 1H NMR (CDCl3) δ 3.09–3.13, 3.29–3.34, 3.92, 4.81, 5.60–5.63, 5.99, 7.33–7.42, 7.49; MS (ESI+) for C20H16BrCl2N3O2 m/z 479 (M+H)+.
Reaction SMILES: N([O-])=O.[Na+].[Cl:5][C:6]1[S:10][N:9]=[C:8]([Cl:11])[C:7]=1[C:12](N)=[O:13].S(=O)(=O)(O)[OH:16]>O>[Cl:5][C:6]1[S:10][N:9]=[C:8]([Cl:11])[C:7]=1[C:12]([OH:13])=[O:16]
Reactant: NC(=O)c1c(Cl)nsc1Cl
Reactant: O=S(=O)(O)O
Agent: O=N[O-]
Agent: [Na+]
Solvent: O
Product: O=C(O)c1c(Cl)nsc1Cl
Temperature: 50 °C
Reaction time: 0.5 h

Procedure:
NaNO2 (1 g, 14.49 mmol, 1.13 equiv), water (30 ml), dichloro-1,2-thiazole-4-carboxamide (2 g, 10.15 mmol, 1.00 equiv) was added to the sulfuric acid solution of the 3,5-dichloroisothiazole-4-carboxamide. The resulting solution was stirred for 30 min at 50° C. The resulting solution was extracted with 3×30 mL of dichloromethane and the organic layers combined and dried over anhydrous sodium sulfate and concentrated. This resulted in 400 mg (crude) of dichloro-1,2-thiazole-4-carboxylic acid as a brown solid.
Reaction SMILES: [CH:1]([N:4]1[CH2:9][CH2:8][N:7]([C:10]([C:12]2[CH:13]=[C:14]3[C:18](=[CH:19][CH:20]=2)[NH:17][C:16]([C:21](O)=[O:22])=[CH:15]3)=[O:11])[CH2:6][CH2:5]1)([CH3:3])[CH3:2].Cl.F[B-](F)(F)F.N1(OC(N(C)C)=[N+](C)C)C2C=CC=CC=2N=N1.[F:47][CH:48]1[CH2:53][CH2:52][CH2:51][NH:50][CH2:49]1.C(N(CC)C(C)C)(C)C>CN(C)C=O>[F:47][CH:48]1[CH2:53][CH2:52][CH2:51][N:50]([C:21]([C:16]2[NH:17][C:18]3[C:14]([CH:15]=2)=[CH:13][C:12]([C:10]([N:7]2[CH2:8][CH2:9][N:4]([CH:1]([CH3:2])[CH3:3])[CH2:5][CH2:6]2)=[O:11])=[CH:20][CH:19]=3)=[O:22])[CH2:49]1
Reactant: FC1CCCNC1
Reactant: CC(C)N1CCN(C(=O)c2ccc3[nH]c(C(=O)O)cc3c2)CC1
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: Cl
Agent: F[B-](F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: CC(C)N1CCN(C(=O)c2ccc3[nH]c(C(=O)N4CCCC(F)C4)cc3c2)CC1

Procedure:
The title compound was synthesized in analogy to example 1, from 5-(4-isopropyl-piperazine-1-carbonyl)-1H-indole-2-carboxylic acid 1:1 hydrochloride, O-(benzotriazol-1-yl)-N,N,N′,N′-tetramethyluronium tetrafluoroborate (commercially available), 3-fluoropiperidine (commercially available) and N,N-diisopropylethylamine in N,N-dimethylformamide to give the desired product after purification by preparative HPLC on reversed phase eluting with a gradient formed from acetonitrile/water/formic acid.
Reaction SMILES: ClC1C=C2C(C3N=C(N[C@H]4CCCN(CC(O)COC)C4)C(F)=CN=3)=CN(S(C3C=CC(C)=CC=3)(=O)=O)C2=NC=1.[Cl:41][C:42]1[CH:43]=[C:44]2[C:50]([C:51]3[N:56]=[C:55]([NH:57][CH:58]4[CH2:63][CH2:62][CH2:61][CH2:60][N:59]4[CH:64]([O:68][CH3:69])[C@@H:65]([OH:67])[CH3:66])[C:54]([F:70])=[CH:53][N:52]=3)=[CH:49][N:48](S(C3C=CC(C)=CC=3)(=O)=O)[C:45]2=[N:46][CH:47]=1.[Li+].[OH-]>C1COCC1.O>[Cl:41][C:42]1[CH:43]=[C:44]2[C:50]([C:51]3[N:56]=[C:55]([NH:57][CH:58]4[CH2:63][CH2:62][CH2:61][CH2:60][N:59]4[CH:64]([O:68][CH3:69])[C@@H:65]([OH:67])[CH3:66])[C:54]([F:70])=[CH:53][N:52]=3)=[CH:49][NH:48][C:45]2=[N:46][CH:47]=1
Reactant: COC([C@H](C)O)N1CCCCC1Nc1nc(-c2cn(S(=O)(=O)c3ccc(C)cc3)c3ncc(Cl)cc23)ncc1F
Agent: COCC(O)CN1CCC[C@H](Nc2nc(-c3cn(S(=O)(=O)c4ccc(C)cc4)c4ncc(Cl)cc34)ncc2F)C1
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Product: COC([C@H](C)O)N1CCCCC1Nc1nc(-c2c[nH]c3ncc(Cl)cc23)ncc1F
Temperature: 120 °C

Procedure:
To a solution of 1-[(3S)-3-[[2-[5-chloro-1-(p-tolylsulfonyl)pyrrolo[2,3-b]pyridin-3-yl]-5-fluoro-pyrimidin-4-yl]amino]-1-piperidyl]-3-methoxy-propan-2-ol, 1d, (0.15 g, 0.24 mmol) in THF was added 1N LiOH solution. The reaction mixture was heated in a microwave reactor at 120° C. for 5 minutes. The reaction mixture was diluted with water and the aqueous phase was extracted with EtOAc (twice). The combined organic phases were dried (MgSO4), filtered and concentrated under vacuo. The resulting solid was purified by silica gel chromatography (5-20% MeOH: CH2Cl2) to afford the desired product (537) as a white solid.
Reaction SMILES: [CH:1]1([O:6][C:7]2[CH:8]=[C:9]([CH:15]([CH3:18])[CH2:16][NH2:17])[CH:10]=[CH:11][C:12]=2[O:13][CH3:14])[CH2:5][CH2:4][CH2:3][CH2:2]1.Cl[CH2:20][C:21]#[N:22].C(=O)([O-])[O-].[Na+].[Na+]>CN(C=O)C>[CH:1]1([O:6][C:7]2[CH:8]=[C:9]([CH:15]([CH3:18])[CH2:16][NH:17][CH2:20][C:21]#[N:22])[CH:10]=[CH:11][C:12]=2[O:13][CH3:14])[CH2:2][CH2:3][CH2:4][CH2:5]1
Reactant: N#CCCl
Reactant: COc1ccc(C(C)CN)cc1OC1CCCC1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: COc1ccc(C(C)CNCC#N)cc1OC1CCCC1
Temperature: 60 °C
Reaction time: 5 h
Yield: 77 %

Procedure:
A mixture of (±)-3-(cyclopentyloxy)-4-methoxy-β-methylbenzeneethanamine (0.029 mol), chloroacetonitrile (0.0146 mol) and sodium carbonate (0.0219 mol) in DMF (200 ml) was stirred for 5 hours at 60° C. The reaction mixture was filtered and the filtrate was evaporated. The residue was washed with water, then extracted with 2-methoxy-2-methylpropane. The separated organic layer was dried, filtered, and the solvent was evaporated. The residue was purified by open column chromatography over silica gel (eluent: CH2Cl2 ; CH2Cl2 /2-propanone 96/4, and 90/10; then, CH2Cl2 /CH3OH 80/20). The pure fractions were collected and the solvent was evaporated, yielding 3.24 g (77%) of (±)-[[2-[3-(cyclopentyloxy)-4-methoxyphenyl]propyl]amino]acetonitrile (intermediate 21).
Reaction SMILES: [CH:1]1([N:6]2[CH2:12][C:11]([F:14])([F:13])[C:10](=[O:15])[N:9]([CH3:16])[C:8]3[CH:17]=[N:18][C:19]([NH:21][C:22]4[CH:30]=[CH:29][C:25]([C:26]([OH:28])=O)=[CH:24][C:23]=4[O:31][CH3:32])=[N:20][C:7]2=3)[CH2:5][CH2:4][CH2:3][CH2:2]1.C(N(C(C)C)C(C)C)C.[NH2:42][CH2:43][CH2:44][CH2:45][OH:46]>CN(C)C=O>[CH:1]1([N:6]2[CH2:12][C:11]([F:13])([F:14])[C:10](=[O:15])[N:9]([CH3:16])[C:8]3[CH:17]=[N:18][C:19]([NH:21][C:22]4[CH:30]=[CH:29][C:25]([C:26]([NH:42][CH2:43][CH2:44][CH2:45][OH:46])=[O:28])=[CH:24][C:23]=4[O:31][CH3:32])=[N:20][C:7]2=3)[CH2:2][CH2:3][CH2:4][CH2:5]1
Reactant: COc1cc(C(=O)O)ccc1Nc1ncc2c(n1)N(C1CCCC1)CC(F)(F)C(=O)N2C
Reactant: NCCCO
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: COc1cc(C(=O)NCCCO)ccc1Nc1ncc2c(n1)N(C1CCCC1)CC(F)(F)C(=O)N2C
Temperature: 25 °C
Reaction time: 1 h
Yield: 88.1 %

Procedure:
To a mixture of 0.08 g (0.18 mmole) of 4-(9-cyclopentyl-7,7-difluoro-5-methyl-6-oxo-6,7,8,9-tetrahydro-5H-pyrimido[4,5-b][1,4]diazepin-2-ylamino)-3-methoxy-benzoic acid (I-100), 0.16 mL (0.90 mmole) of ethyldiisopropyl amine and 0.016 mL (0.20 mmole) of 3-amino-propan-1-ol in 2.0 mL of dimethylformamide was added 0.085 g (0.20 mmole) of 1-(di-1-pyrrolidinylmethylene)-1H-benzotriazolium 3-oxide hexafluorophosphate. The mixture was stirred at room temperature for 1 hour, then diluted with 10 mL of ice water. The resulting solid was collected by filtration, washed with saturated sodium carbonate and water, and dried under vacuum. Purification by silica gel chromatography, eluting with dichloromethane-methanol (gradient, 100:0-90:10) gave 0.080 g of 4-(9-cyclopentyl-7,7-difluoro-5-methyl-6-oxo-6,7,8,9-tetrahydro-5H-pyrimido[4,5-b][1,4]diazepin-2-ylamino)-N-(3-hydroxy-propyl)-3-methoxy-benzamide (I-41) as a white solid.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([N+:8]([O-:10])=[O:9])=[CH:4][C:3]=1[CH3:11].[NH:12]1[CH2:17][CH2:16][CH2:15][CH2:14][C:13]1=[O:18].C(=O)([O-])[O-].[K+].[K+].[I-].[K+]>[Cu].O>[N+:8]([C:5]1[CH:6]=[CH:7][C:2]([N:12]2[CH2:17][CH2:16][CH2:15][CH2:14][C:13]2=[O:18])=[C:3]([CH3:11])[CH:4]=1)([O-:10])=[O:9]
Reactant: O=C1CCCCN1
Reactant: Cc1cc([N+](=O)[O-])ccc1Br
Agent: [Cu]
Agent: O=C([O-])[O-]
Agent: [I-]
Solvent: O
Product: Cc1cc([N+](=O)[O-])ccc1N1CCCCC1=O
Temperature: 140 °C

Procedure:
A mixture of 5.00 g (23.1 mmol) of 2-bromo-5-nitrotoluene, 2.28 g (23.0 mmol) of 2-piperidone, 2.56 g (40 mmol) of finely powdered copper, 4.98 g (36.0 mmol) of potassium carbonate and 5.98 g (36 mmol) of potassium iodide is heated at 140° C. for 48 hours. The reaction mixture is introduced into water, the mixture is filtered, and the residue is washed with water. The residue is taken up in ethyl acetate and re-filtered. The filtrate is dried and evaporated, giving 1-(4-nitro-2-methylphenyl)piperidin-2-one as a yellowish solid; ESI 235.
Reaction SMILES: [F:1][C:2]1[CH:16]=[CH:15][C:5]([CH2:6]P(=O)(OCC)OCC)=[CH:4][C:3]=1[O:17][C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1.[Cl:24][C:25]1[CH:38]=[CH:37][C:28]([C:29]([CH:34]2[CH2:36][CH2:35]2)=[C:30]([F:33])[CH:31]=O)=[CH:27][CH:26]=1.C[O-].[Na+]>O1CCCC1>[Cl:24][C:25]1[CH:26]=[CH:27][C:28]([C:29]([CH:34]2[CH2:36][CH2:35]2)=[C:30]([F:33])[CH:31]=[CH:6][C:5]2[CH:15]=[CH:16][C:2]([F:1])=[C:3]([O:17][C:18]3[CH:19]=[CH:20][CH:21]=[CH:22][CH:23]=3)[CH:4]=2)=[CH:37][CH:38]=1
Reactant: O=CC(F)=C(c1ccc(Cl)cc1)C1CC1
Reactant: CCOP(=O)(Cc1ccc(F)c(Oc2ccccc2)c1)OCC
Agent: C[O-]
Agent: [Na+]
Solvent: C1CCOC1
Product: FC(C=Cc1ccc(F)c(Oc2ccccc2)c1)=C(c1ccc(Cl)cc1)C1CC1
Temperature: 25 °C
Reaction time: 8 h
Yield: 87.6 %

Procedure:
A stirred solution of diethyl (4-fluoro-3-phenoxybenzyl)phosphonate (2.64 g, 7.8 mmol) and p-chloro-β-cyclopropyl-α-fluorocinnamaldehyde (1.35 g, 6 mmol) in tetrahydrofuran (20 mL) is treated with sodium methoxide (562 mg, 9.36 mmol) at 0° C., stirred at room temperature overnight, quenched with 2 N aqueous hydrochloric acid, and extracted with ethyl acetate. The organic extract is washed sequentially with water, 2 N aqueous hydrochloric acid and water, dried over anhydrous sodium sulfate, and concentrated in vacuo to obtain a residue. Flash chromatography of the residue on silica gel eluting with 1:9 ethyl acetate/hexanes gives the title product as a syrup (2.15 g, 87.7% yield) which is identified by NMR spectral analyses.
Reaction SMILES: ClC(Cl)(Cl)[C:3]([C:5]1[N:14]2[C:8]([CH2:9][N:10]([C:19](=[O:29])[CH2:20][S:21][C:22]3[CH:27]=[CH:26][C:25]([Br:28])=[CH:24][CH:23]=3)[C:11]3[CH:18]=[CH:17][CH:16]=[CH:15][C:12]=3[CH2:13]2)=[CH:7][CH:6]=1)=[O:4].[Cl:32][C:33]1[CH:34]=[C:35]([CH:38]=[CH:39][C:40]=1[Cl:41])[CH2:36][NH2:37].CS(C)=O>C(#N)C>[Br:28][C:25]1[CH:26]=[CH:27][C:22]([S:21][CH2:20][C:19]([N:10]2[C:11]3[CH:18]=[CH:17][CH:16]=[CH:15][C:12]=3[CH2:13][N:14]3[C:5]([C:3]([NH:37][CH2:36][C:35]4[CH:38]=[CH:39][C:40]([Cl:41])=[C:33]([Cl:32])[CH:34]=4)=[O:4])=[CH:6][CH:7]=[C:8]3[CH2:9]2)=[O:29])=[CH:23][CH:24]=1
Reactant: NCc1ccc(Cl)c(Cl)c1
Reactant: O=C(CSc1ccc(Br)cc1)N1Cc2ccc(C(=O)C(Cl)(Cl)Cl)n2Cc2ccccc21
Solvent: CC#N
Solvent: CS(C)=O
Product: O=C(NCc1ccc(Cl)c(Cl)c1)c1ccc2n1Cc1ccccc1N(C(=O)CSc1ccc(Br)cc1)C2
Temperature: 85 °C

Procedure:
To an 18×150 mm reaction vessel was added 2,2,2-trichloro-1-[10-{[(4-bromophenyl)thio]acetyl}-10,11-dihydro-5H-pyrrolo[2,1-c][1,4]benzodiazepine-3-yl]-ethanone of Example 80 (0.23 mmol), acetonitrile (2.5 mL), 3,4-dichlorobenzylamine (0.49 mmol), and dimethylsulfoxide (0.81 mmol). The stirred solution was heated to 85° C. for 20 hours. The solvent was evaporated and the residue was dissolved in 5 mL dichloromethane. The solution was washed twice with water, dried over anhydrous sodium sulfate, and evaporated. The crude product was purified using normal phase HPLC with a two phase solvent system (A=hexane, B=dichloromethane/methanol, 4:1) to give the title product, m.p. 150° C. MS [(+)ESI, m/z]: 614 [M+H]+ Anal. Calcd for C28H22BrCl2N3O2S: C, 54.65; H, 3.60; N, 6.83. Found: C, 54.68; H, 3.50; N, 6.73.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([CH3:8])=[CH:4][CH:3]=1.[CH2:9]([C:11]1[CH:18]=[CH:17][CH:16]=[CH:15][C:12]=1[C:13]#[N:14])[CH3:10].[Cl-].[Al+3].[Cl-].[Cl-].[OH-].[Na+]>O>[CH3:8][C:5]1[CH:6]=[CH:7][C:2]([NH:1][C:13](=[NH:14])[C:12]2[CH:15]=[CH:16][CH:17]=[CH:18][C:11]=2[CH2:9][CH3:10])=[CH:3][CH:4]=1
Reactant: Cc1ccc(N)cc1
Reactant: CCc1ccccc1C#N
Agent: [Al+3]
Agent: [Cl-]
Agent: [Na+]
Solvent: O
Product: CCc1ccccc1C(=N)Nc1ccc(C)cc1
Reaction time: 1 h
Yield: 92 %

Procedure:
5.0 g. of p-toluidine, 6.2 g. of o-ethylbenzonitrile and 6.3 g. of anhydrous aluminum chloride were heated at 120° C. with stirring for 1 hour. To the reaction mixture was added water and sodium hydroxide to make the mixture alkaline. The mixture was extracted with benzene and the extract was washed with water, dried and evaporated in vacuo to remove benzene. 10.2 g. (92% of theory) of N-(p-methylphenyl)-2-ethylbenzamidine was obtained.
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[C:6]2[C:7](Br)(Br)[C:8](=[O:15])[NH:9][C:10]=2[CH:11]=[C:12]([Br:14])[CH:13]=1)=[O:4]>C(O)(=O)C.C(OCC)(=O)C.[Zn]>[CH3:1][O:2][C:3]([C:5]1[C:6]2[CH2:7][C:8](=[O:15])[NH:9][C:10]=2[CH:11]=[C:12]([Br:14])[CH:13]=1)=[O:4]
Reactant: COC(=O)c1cc(Br)cc2c1C(Br)(Br)C(=O)N2
Agent: [Zn]
Solvent: CC(=O)O
Solvent: CCOC(C)=O
Product: COC(=O)c1cc(Br)cc2c1CC(=O)N2

Procedure:
3,3,6-Tribromo-2-oxo-2,3-dihydro-1H-indole-4-carboxylic acid methyl ester (5.90 g, 16.9 mmol) is suspended in glacial acetic acid (153 mL) and zinc dust (10 μM Mesh, 11.5 g, 169 mmol) is added over 5 minutes. The reaction is monitored by TLC and when complete (30 min) the reaction is filtered through celite and the filtrate washed with ethyl acetate. The combined filtrate and washings are evaporated in vacuo to yield an oil that is taken up in ethyl acetate (500 mL), washed with water (100 mL) and brine (100 mL). The organic layer is dried filtered and evaporated in vacuo to give the title compound that is recrystalized from ethyl acetate (2.2 g, 11.5 mmol 68%). LCMS (ESMS): m/z 271.3 (M+H+).
Reaction SMILES: [CH2:1]([CH:4]1[C:8](O)([CH3:9])[CH:7]=[CH:6][C:5]1=[O:11])[CH:2]=[CH2:3].[CH3:12][NH:13][CH3:14]>>[CH2:1]([C:4]1[C:5](=[O:11])[CH2:6][CH:7]([N:13]([CH3:14])[CH3:12])[C:8]=1[CH3:9])[CH:2]=[CH2:3]
Reactant: CNC
Reactant: C=CCC1C(=O)C=CC1(C)O
Product: C=CCC1=C(C)C(N(C)C)CC1=O
Reaction time: 0.5 h
Yield: 96.6 %

Procedure:
2-Allyl-3-hydroxy-3-methyl-4-cyclopentenone (15.2 g) was dropwise added to a 40% aqueous solution of dimethylamine (60 g) in the same flask as used in Example 1 at a temperature of 10° to 20° C. for 30 minutes. At the same temperature, the reaction mixture was kept for 1 hour. After completion of the reaction, the mixture was treated and purified in the same manner as in Example 1 to obtain 2-allyl-3-methyl-4-dimethylamino-2-cyclopentenone (17.3 g). Yield, 96.5%. nD20 1.4997.
Reaction SMILES: [O:1]1[C:6]2[CH:7]=[CH:8][CH:9]=[CH:10][C:5]=2[O:4][CH2:3][CH:2]1[CH2:11][C:12]#N.[H-].C([Al+]CC(C)C)C(C)C.C[OH:25].O>C1C=CC=CC=1>[O:1]1[C:6]2[CH:7]=[CH:8][CH:9]=[CH:10][C:5]=2[O:4][CH2:3][CH:2]1[CH2:11][CH:12]=[O:25]
Reactant: CO
Reactant: N#CCC1COc2ccccc2O1
Agent: CC(C)C[Al+]CC(C)C
Agent: [H-]
Solvent: O
Solvent: c1ccccc1
Product: O=CCC1COc2ccccc2O1

Procedure:
The starting material is prepared as follows: To the solution of 20 g of 1,4-benzodioxan-2-yl-acetonitrile in 200 ml of benzene is added dropwise 71 ml of a 1.6 N solution of diisobutyl aluminum hydride in benzene while stirring at 10°. After 6 hours 50 ml of methanol are added, followed by 200 ml of water. The organic layer is separated, dried and evaporated, to yield the 1,4-benzodioxan-2-yl-acetaldehyde.
Reaction SMILES: [CH:1]1([N:7]2[CH2:13][C@:12]([F:16])([CH:14]=[CH2:15])[C:11](=[O:17])[N:10]([CH3:18])[C:9]3[CH:19]=[N:20][C:21]([NH:23][C:24]4[CH:32]=[CH:31][C:27]([C:28](O)=[O:29])=[CH:26][C:25]=4[O:33][CH3:34])=[N:22][C:8]2=3)C[CH2:5][CH2:4][CH2:3][CH2:2]1.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.[NH2:59][CH:60]1[CH2:65][CH2:64][N:63]([CH3:66])[CH2:62][CH2:61]1>>[CH:1]1([N:7]2[CH2:13][C@:12]([F:16])([CH:14]=[CH2:15])[C:11](=[O:17])[N:10]([CH3:18])[C:9]3[CH:19]=[N:20][C:21]([NH:23][C:24]4[CH:32]=[CH:31][C:27]([C:28]([NH:59][CH:60]5[CH2:65][CH2:64][N:63]([CH3:66])[CH2:62][CH2:61]5)=[O:29])=[CH:26][C:25]=4[O:33][CH3:34])=[N:22][C:8]2=3)[CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: C=C[C@@]1(F)CN(C2CCCCC2)c2nc(Nc3ccc(C(=O)O)cc3OC)ncc2N(C)C1=O
Reactant: CN1CCC(N)CC1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Product: C=C[C@@]1(F)CN(C2CCCC2)c2nc(Nc3ccc(C(=O)NC4CCN(C)CC4)cc3OC)ncc2N(C)C1=O

Procedure:
The title compound was synthesized from (R)-4-(9-cyclohexyl-7-fluoro-7-vinyl-5-methyl-6-oxo-6,7,8,9-tetrahydro-5H-pyrimido[5,4-b][1,4]diazepin-2-ylamino)-3-methoxybenzoic acid as described in the General procedure for amide bond synthesis using HATU and 4-amino 1-N-methyl piperidine. 1H NMR (400 MHz, DMSO-d6) δ ppm 0.79-0.93 (m, 2 H) 1.18-1.31 (m, 2 H) 1.50-1.80 (m, 6 H) 1.83-2.00 (m, 4 H) 2.17 (s, 3 H) 2.71-2.95 (m, 2 H) 3.29 (s, 3 H) 3.67-3.87 (m, 3 H) 3.94 (s, 3 H) 4.89 (d, J=8.59 Hz, 1 H) 5.30-5.47 (m, 2 H) 6.01 (ddd, J=17.49, 12.69, 10.74 Hz, 1 H) 7.41-7.54 (m, 2 H) 7.82 (s, 1 H) 8.12 (s, 2 H) 8.30 (d, J=8.34 Hz, 1 H). [M+H] calc'd for C29H38FN7O3, 552; found 552.
Reaction SMILES: [NH2:1][C:2]1[C:7]([O:8][C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=2[F:15])=[CH:6][CH:5]=[CH:4][C:3]=1[CH2:16][C:17]([O:19]CC)=O.[Cl:22]N1C(=O)CCC1=O.Cl>O1CCOCC1>[O:19]=[C:17]1[CH2:16][C:3]2[C:2](=[C:7]([O:8][C:9]3[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=3[F:15])[CH:6]=[C:5]([Cl:22])[CH:4]=2)[NH:1]1
Reactant: O=C1CCC(=O)N1Cl
Reactant: CCOC(=O)Cc1cccc(Oc2ccccc2F)c1N
Agent: Cl
Solvent: C1COCCO1
Product: O=C1Cc2cc(Cl)cc(Oc3ccccc3F)c2N1
Temperature: 80 °C
Yield: 51.5 %

Procedure:
To a solution of ethyl 2-[2-amino-3-(2-fluorophenoxy)phenyl]acetate (8.5 g.) in dioxane (100 ml.) was added N-chlorosuccinimide (4.3 g.), and the mixture was stirred for an hour at 80° C. To the reaction mixture was added conc. hydrochloric acid (0.1 ml.), and the mixture was stirred for 10 minutes at ambient temperature. Dioxane was distilled off from the resulting mixture under reduced pressure. To the residue was added water and the mixture was extracted with ethyl acetate (200 ml.) twice. The extract was washed with a saturated aqueous solution of sodium chloride (100 ml.) twice, dried over magnesium sulfate and then evaporated under reduced pressure. The residue was washed with a mixture of diethyl ether and n-hexane (1:10) and recrystallized from ethanol to give crystals of 2-oxo-5-chloro-7-(2-fluorophenoxy)indoline (4.2 g.), mp 204° to 207° C.
Reaction SMILES: N[C:2]1[C:7]([C:8]2[CH:13]=[CH:12][C:11]([C:14]([F:17])([F:16])[F:15])=[CH:10][CH:9]=2)=[CH:6][C:5]([CH:18]([CH2:24][CH:25]2[CH2:27][CH2:26]2)[C:19]([O:21][CH2:22][CH3:23])=[O:20])=[CH:4][C:3]=1[O:28][CH2:29][CH:30]1[CH2:32][CH2:31]1.N([O-])=O.[Na+].CC#N.O.[ClH:41]>O.Cl[Cu]>[Cl:41][C:2]1[C:7]([C:8]2[CH:13]=[CH:12][C:11]([C:14]([F:17])([F:16])[F:15])=[CH:10][CH:9]=2)=[CH:6][C:5]([CH:18]([CH2:24][CH:25]2[CH2:27][CH2:26]2)[C:19]([O:21][CH2:22][CH3:23])=[O:20])=[CH:4][C:3]=1[O:28][CH2:29][CH:30]1[CH2:32][CH2:31]1
Reactant: CCOC(=O)C(CC1CC1)c1cc(OCC2CC2)c(N)c(-c2ccc(C(F)(F)F)cc2)c1
Reactant: Cl
Agent: Cl[Cu]
Agent: O=N[O-]
Agent: [Na+]
Solvent: O
Solvent: CC#N
Product: CCOC(=O)C(CC1CC1)c1cc(OCC2CC2)c(Cl)c(-c2ccc(C(F)(F)F)cc2)c1
Temperature: 90 °C
Reaction time: 0.67 h

Procedure:
Ethyl 2-(6-amino-5-(cyclopropylmethoxy)-4′-(trifluoromethyl)biphenyl-3-yl)-3-cyclopropylpropanoate (1 g, 2.2 mmol) was dissolved in a mixture of MeCN/H2O/HCl 30 mL/30 mL/2 mL at 0° C. A solution of NaNO2 (0.200 g, 2.9 mmol) in water (10 mL) was added drop wise at 0° C., and the reaction mixture was stirred for 40 min, at the same temperature. A solution of CuCl (1.1 g, 11.1 mmol) in water (10 mL) was added drop wise at 0° C. The reaction mixture was heated to 90° C. for 2.0 h and the mixture was concentrated under reduced pressure. The reaction mixture was extracted with EtOAc (3×50 mL), the combined organic layers were washed with water (50 mL) followed by brine (50 mL), was dried over Na2SO4, filtered and concentrated under reduced pressure to give a crude black oil. The oil was purified by chromatography over silica gel (hexane/EtOAc) to give ethyl 2-(6-chloro-5-(cyclopropylmethoxy)-4′-(trifluoromethyl)biphenyl-3-yl)-3-cyclopropylpropanoate (1.1 g) as a yellow oil.