Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([N:8]([CH2:21][C:22]1[CH:27]=[CH:26][C:25]([O:28][C:29]2[CH:34]=[CH:33][CH:32]=[C:31]([O:35][CH2:36][CH2:37][CH2:38]Br)[CH:30]=2)=[CH:24][CH:23]=1)[C:9]1[C:10]([CH3:20])=[C:11]([NH:15][S:16]([CH3:19])(=[O:18])=[O:17])[CH:12]=[CH:13][CH:14]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[NH:40]1[CH2:45][CH2:44][O:43][CH2:42][CH2:41]1>>[CH2:1]([N:8]([CH2:21][C:22]1[CH:27]=[CH:26][C:25]([O:28][C:29]2[CH:34]=[CH:33][CH:32]=[C:31]([O:35][CH2:36][CH2:37][CH2:38][N:40]3[CH2:45][CH2:44][O:43][CH2:42][CH2:41]3)[CH:30]=2)=[CH:24][CH:23]=1)[C:9]1[C:10]([CH3:20])=[C:11]([NH:15][S:16]([CH3:19])(=[O:18])=[O:17])[CH:12]=[CH:13][CH:14]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: C1COCCN1
Reactant: Cc1c(NS(C)(=O)=O)cccc1N(Cc1ccccc1)Cc1ccc(Oc2cccc(OCCCBr)c2)cc1
Product: Cc1c(NS(C)(=O)=O)cccc1N(Cc1ccccc1)Cc1ccc(Oc2cccc(OCCCN3CCOCC3)c2)cc1

Procedure:
The product from Example 72D and morpholine were processed as described in Example 72E to provide the title compound. 1H NMR (300 MHz, CDCl3) δ7.10-7.30 (m, 11 H), 6.86 (d, 2 H), 6.63 (d, 1 H), 6.55 (m, 2 H), 6.33 (t, 1 H), 4.31 (s, 2 H), 4.28 (s, 2 H), 4.00 (m, 6 H), 3.65 (m, 2 H), 3.25 (m, 2 H), 2.95 (m, 2 H), 2.85 (s, 3 H), 2.25 (m, 2 H), 2.17 (s, 3 H); MS (ESI+) m/z 616 (M+H)+.
Reaction SMILES: [F:1][C:2]1[C:7]([O:8][CH3:9])=[CH:6][CH:5]=[CH:4][C:3]=1[CH2:10]O.O.C(Cl)(Cl)(Cl)[Cl:14]>>[Cl:14][CH2:10][C:3]1[CH:4]=[CH:5][CH:6]=[C:7]([O:8][CH3:9])[C:2]=1[F:1]
Reactant: COc1cccc(CO)c1F
Reactant: ClC(Cl)(Cl)Cl
Solvent: O
Product: COc1cccc(CCl)c1F
Temperature: 90 °C
Reaction time: 1 h

Procedure:
To a solution of (2-fluoro-3-methoxyphenyl)methanol (13 g, 83.2 mmol) in CCl4 (75 mL), PClS (26 g, 128.7 mmol) was added. The resulting mixture was heated at 90° C. for 30 min and then stirred at room temperature for 1 h. The mixture was poured into water (160 mL) and extracted with dichloromethane (2×150 mL). The combined organic layers were washed with brine (200 mL), dried (Na2SO4), and concentrated in vacuo. The residue was purified by silica gel column chromatography (1:15 EtOAc/petroleum ether) to give the title compound (11.5 g). 1H NMR (CDCl3): δ 7.10-6.91 (m, 3H), 4.63 (s, 2H), 3.89 (s, 3H).
Reaction SMILES: [NH2:1][CH:2]1[C:12]2[C:7](=[N:8][CH:9]=[CH:10][CH:11]=2)[CH2:6][O:5][C:4]2[CH:13]=[CH:14][CH:15]=[CH:16][C:3]1=2.C(N(CC)CC)C.[Cl:24][CH2:25][C:26](Cl)=[O:27]>ClCCl>[Cl:24][CH2:25][C:26]([NH:1][CH:2]1[C:12]2[C:7](=[N:8][CH:9]=[CH:10][CH:11]=2)[CH2:6][O:5][C:4]2[CH:13]=[CH:14][CH:15]=[CH:16][C:3]1=2)=[O:27]
Reactant: O=C(Cl)CCl
Reactant: NC1c2ccccc2OCc2ncccc21
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: O=C(CCl)NC1c2ccccc2OCc2ncccc21
Reaction time: 2 h
Yield: 90 %

Procedure:
In this example, 1.9 g of 5-amino-5,11-dihydro[1]benzoxepino[3,4-b]pyridine prepared in a similar manner to that in Example 24 and 0.9 g of triethylamine were dissolved in 30 ml of dichloromethane. A solution of 1.0 g of chloroacetyl chloride in 5 ml of dichloromethane was added dropwise thereto under ice cooling. The mixture was stirred under ice cooling for 2 hours, and concentrated under reduced pressure to distill away about two thirds of the dichloromethane. Then, 40 ml of diisopropyl ether and 10 ml of water were added thereto, and the mixture was stirred and filtered. Drying the residue gave 2.3 g of 5-(chloroacetyl)amino-5,11-dihydro[1]benzoxepino[3,4-b]pyridine as crude crystals.
Reaction SMILES: [C:1]1([CH2:11][N:12]2[C:24]3[CH:23]=[CH:22][CH:21]=[C:20]([OH:25])[C:19]=3[C:18]3[C:13]2=[CH:14][CH:15]=[CH:16][C:17]=3[C:26]([O:28]C)=O)[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][CH:2]=1.Cl.[OH-].[NH4+:32]>C1COCC1.C(OCC)(=O)C>[C:1]1([CH2:11][N:12]2[C:24]3[CH:23]=[CH:22][CH:21]=[C:20]([OH:25])[C:19]=3[C:18]3[C:13]2=[CH:14][CH:15]=[CH:16][C:17]=3[C:26](=[O:28])[NH2:32])[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][CH:2]=1
Reactant: COC(=O)c1cccc2c1c1c(O)cccc1n2Cc1cccc2ccccc12
Reactant: [NH4+]
Agent: Cl
Agent: [OH-]
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: NC(=O)c1cccc2c1c1c(O)cccc1n2Cc1cccc2ccccc12
Yield: 40 %

Procedure:
A solution of the 9-[(1-naphthyl)methyl]-4-hydroxy-5-carbomethoxy carbazole (210 mg, 0.55 mM) in 10 mL THF and 30 mL concentrated aqueous ammonium hydroxide was sonicated for 20 hours at 40-50° C. The mixture was diluted with ethyl acetate and acidified to pH 1 with 5 N HCl. The aqueous layer was extracted three times with ethyl acetate. The combined organic extracts were washed with saturated brine, dried over magnesium sulfate, filtered, and concentrated. The residue was purified by column chromatography on silica gel (elution with gradient hexanes/ethyl acetate) to afford 80 mg (40%) of the 9-[(1-naphthyl)methyl]-4-hydroxy-5-carbamoyl carbazole as a white solid. 1H NMR (DMSO-d6) δ10.55 (s, 1H), 8.8 (br s, 1H), 8.4 (br s, 1H), 8.35 (d, 1H, J=8 Hz), 7.95 (d, 1H, J=8 Hz), 7.8 (d, 1H, J=8 Hz), 7.65 (m, 4H), 7.45 (m, 2H), 7.25 (t, 1H, J=8 Hz), 7.15 (t, 1H, J=8 Hz), 6.9 (d, 1H, J=8 Hz), 6.6 (d, 1H, J=8 Hz), and 6.2 (s, 2H). MS (ES) m/e 365, 367.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]([CH3:11])([CH3:10])[CH3:9].C([Li])CCC.[CH2:17]=[O:18]>C1COCC1>[C:8]([C:3]1[CH:4]=[CH:5][CH:6]=[CH:7][C:2]=1[CH2:17][OH:18])([CH3:11])([CH3:10])[CH3:9]
Reactant: C=O
Reactant: CC(C)(C)c1ccccc1Br
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: CC(C)(C)c1ccccc1CO
Temperature: 78 °C
Reaction time: 0.5 h
Yield: 75.3 %

Procedure:
To a solution of 1-bromo-2-tert-butylbenzene (2.88 g, 13.51 mmol) in anhydrous THF (45 mL) 2,2′-dipyridyl (ca 10 mg) was added under a nitrogen atmosphere. The mixture was cooled down minus 78° C., and a solution of n-butyllithium (2.5 M in hexanes, 5.94 mL, 14.86 mmol) was added dropwise via syringe within the period of ten minutes. Upon addition, the mixture was stirred for 30 minutes, then warmed up to minus 30° C., and a flow of formaldehyde (generated from 1.91 g of paraformaldehyde by heating at over 160° C.) was passed through the solution until the deep red color disappeared completely. The mixture was quenched with saturated ammonium chloride solution (5 mL), then poured into a mixture of dichloromethane (100 mL) and water (50 mL). The organic phase was separated and the aqueous phase was extracted with dichloromethane (20 mL) twice. The combined organic phase was dried over anhydrous Na2SO4, concentrated in vacuo, and purified by silica gel chromatography to yield 2-tert-butylbenzyl alcohol (1.67 g, 75%) as an oil. 1H NMR (400 MHz, CDCl3): δ 7.50 (m, 1H, Ph-H), 7.41 (m, 1H, Ph-H), 7.24 (m, 2H, Ph-H), 4.93 (d, J=4.8 Hz, 2H, CH2OH), 1.54 (br, 1H, CH2OH), 1.43 (s, 1H, C(CH3)3).
Reaction SMILES: [Cl:1][C:2]1[C:7]2[C:8](=[O:24])[N:9]([CH3:23])[CH2:10][C:11]3[N:12]([CH:13]=[N:14][C:15]=3[C:16]3[O:17][CH:18]=[C:19]([CH2:21]Cl)[N:20]=3)[C:6]=2[CH:5]=[CH:4][CH:3]=1.[CH:25]([NH:28][CH:29]([CH3:31])[CH3:30])([CH3:27])[CH3:26]>O1CCCC1>[Cl:1][C:2]1[C:7]2[C:8](=[O:24])[N:9]([CH3:23])[CH2:10][C:11]3[N:12]([CH:13]=[N:14][C:15]=3[C:16]3[O:17][CH:18]=[C:19]([CH2:21][N:28]([CH:29]([CH3:31])[CH3:30])[CH:25]([CH3:27])[CH3:26])[N:20]=3)[C:6]=2[CH:5]=[CH:4][CH:3]=1
Reactant: CN1Cc2c(-c3nc(CCl)co3)ncn2-c2cccc(Cl)c2C1=O
Reactant: CC(C)NC(C)C
Solvent: C1CCOC1
Product: CC(C)N(Cc1coc(-c2ncn3c2CN(C)C(=O)c2c(Cl)cccc2-3)n1)C(C)C
Yield: 31.3 %

Procedure:
0.30 g (0.00082 mol) of 7-chloro-3-(4-chloromethyl-oxazol-2-yl)-5-methyl-5,6-dihydro-4H-imidazo[1,5-a][1,4]-benzodiazepin-6-one was dissolved in 40 ml of tetrahydrofuran, treated with 2.3 ml (0.0165 mol) of diisopropylamine and boiled at 150° in an autoclave for 20 hrs. The solution was completely freed from the solvents, the residue was chromatographed over silica gel with ethyl acetate/ethanol 9:1 as the eluent and recrystallized from hot diisopropyl ether. There was obtained 0.11 g (31%) of 7-chloro-3-(4-diisopropylaminomethyl-oxazol-2-yl)-5-methyl-5,6-dihydro-4H-imidazo[1,5-a][1,4]benzodiazepin-6-one as white crystals; m.p. 164°-166°.
Reaction SMILES: [Zn:1].[C:2]([OH:7])(=[O:6])[C:3]([CH3:5])=[CH2:4].[O-2].[Zn+2]>>[C:2]([O-:7])(=[O:6])[C:3]([CH3:5])=[CH2:4].[C:2]([O-:7])(=[O:6])[C:3]([CH3:5])=[CH2:4].[Zn+2:1]
Reactant: [Zn]
Reactant: C=C(C)C(=O)O
Agent: [O-2]
Agent: [Zn+2]
Product: C=C(C)C(=O)[O-]

Procedure:
One hundred parts of cis-polybutadiene were blended on a mill with 17 parts of zinc oxice. 22.2 parts of methacryalic acid was slowly added and blended until thoroughly dispersed. After a few minutes there was very little odor of methacrylic acid from the stock, indicating that the acid had thoroughly reacted with the zinc oxide to form zinc dimethacrylate. 6.3 parts of Di-Cup 40-C was then blended into the rubber. Golf balls were molded as in Example 3.
Reaction SMILES: [C:1]([C:3]1[C:4]([C:17]([F:20])([F:19])[F:18])=[C:5]2[C:9](=[CH:10][CH:11]=1)[N:8]([CH2:12][C:13](=[NH:16])[NH:14][OH:15])[CH:7]=[CH:6]2)#[N:2].[Cl:21][C:22]1[CH:23]=[C:24]([CH:28]=[CH:29][CH:30]=1)[C:25](O)=O>>[Cl:21][C:22]1[CH:23]=[C:24]([C:25]2[O:15][N:14]=[C:13]([CH2:12][N:8]3[C:9]4[C:5](=[C:4]([C:17]([F:19])([F:20])[F:18])[C:3]([C:1]#[N:2])=[CH:11][CH:10]=4)[CH:6]=[CH:7]3)[N:16]=2)[CH:28]=[CH:29][CH:30]=1
Reactant: N#Cc1ccc2c(ccn2CC(=N)NO)c1C(F)(F)F
Reactant: O=C(O)c1cccc(Cl)c1
Product: N#Cc1ccc2c(ccn2Cc2noc(-c3cccc(Cl)c3)n2)c1C(F)(F)F

Procedure:
Synthesized as described in Example 72 from 2-[5-cyano-4-(trifluoromethyl)-1H-indol-1-yl]-N-hydroxyethanimidamide and 3-chlorobenzoic acid: MS (ESI): m/z 403 (M+1).
Reaction SMILES: Cl.[N:2]1[CH:7]=[CH:6][C:5]([N:8]2[CH2:13][CH2:12][CH:11]([C:14](Cl)=[O:15])[CH2:10][CH2:9]2)=[CH:4][CH:3]=1.Cl.[NH2:18][CH2:19][CH2:20][NH:21][C:22](=[O:38])[CH2:23][NH:24][S:25]([C:28]1[CH:37]=[CH:36][C:35]2[C:30](=[CH:31][CH:32]=[CH:33][CH:34]=2)[CH:29]=1)(=[O:27])=[O:26]>>[CH:29]1[C:30]2[C:35](=[CH:34][CH:33]=[CH:32][CH:31]=2)[CH:36]=[CH:37][C:28]=1[S:25]([NH:24][CH2:23][C:22]([NH:21][CH2:20][CH2:19][NH:18][C:14]([CH:11]1[CH2:12][CH2:13][N:8]([C:5]2[CH:6]=[CH:7][N:2]=[CH:3][CH:4]=2)[CH2:9][CH2:10]1)=[O:15])=[O:38])(=[O:27])=[O:26]
Reactant: O=C(Cl)C1CCN(c2ccncc2)CC1
Reactant: NCCNC(=O)CNS(=O)(=O)c1ccc2ccccc2c1
Agent: Cl
Product: O=C(CNS(=O)(=O)c1ccc2ccccc2c1)NCCNC(=O)C1CCN(c2ccncc2)CC1
Yield: 49 %

Procedure:
Using an analogous procedure to that described in Example 1, 1-(4-pyridyl)piperidine-4-carbonyl chloride hydrochloride salt was reacted with N-(2-aminoethyl)-2-(2-naphthalenesulphonamido)acetamide hydrochloride salt to give 2-(2-naphthalenesulphonamido)-N-{2-[1-(4-pyridyl)piperidin-4-ylcarbonylamino]ethyl}acetamide in 49% yield, m.p. 107-109° C.;
Reaction SMILES: [CH2:1]([C:4]1[N:9]=[C:8]([CH3:10])[N:7]2[N:11]=[C:12]([S:14](Cl)(=[O:16])=[O:15])[N:13]=[C:6]2[C:5]=1[CH2:18][C:19]1[CH:24]=[CH:23][C:22]([C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][C:26]=2[C:31]#[N:32])=[CH:21][CH:20]=1)[CH2:2][CH3:3].[CH3:33][NH:34][CH3:35]>>[CH3:33][N:34]([CH3:35])[S:14]([C:12]1[N:13]=[C:6]2[N:7]([C:8]([CH3:10])=[N:9][C:4]([CH2:1][CH2:2][CH3:3])=[C:5]2[CH2:18][C:19]2[CH:20]=[CH:21][C:22]([C:25]3[CH:30]=[CH:29][CH:28]=[CH:27][C:26]=3[C:31]#[N:32])=[CH:23][CH:24]=2)[N:11]=1)(=[O:15])=[O:16]
Reactant: CNC
Reactant: CCCc1nc(C)n2nc(S(=O)(=O)Cl)nc2c1Cc1ccc(-c2ccccc2C#N)cc1
Product: CCCc1nc(C)n2nc(S(=O)(=O)N(C)C)nc2c1Cc1ccc(-c2ccccc2C#N)cc1

Procedure:
Formula (XII): R1 =n-propyl, R2 =methyl, X=N, Y=C--SO2N(CH3)2X Y=double bond, ##STR122## 8 g of {7-n-propyl-5-methyl-8-[(2'-cyano-4-biphenylyl)methyl]-1,2,4-triazolo[1,5-c]pyrimidin-2-yl}sulphonyl chloride, prepared in Example 45, are stirred with 40 ml of a 40% aqueous solution of dimethylamine for one hour at 50° C. The mixture is then extracted with chloroform, and the organic phase is dried over magnesium sulphate and then concentrated under vacuum to give 5.5 g of N,N-dimethyl-{7-n-propyl-5-methyl-8-[(2'-cyano-4-biphenylyl)methyl]-1,2,4-triazolo[1,5-c]pyrimidin-2-yl}sulphonamide in the form of crystals of melting point 158° C. The following examples were prepared according to the same procedure:
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C:12](=[C:13]([NH:15][C:16]([C@@H:18]3[CH2:23][O:22][C:21]([CH3:25])([CH3:24])[CH2:20][NH:19]3)=[O:17])[CH:14]=1)[NH:11][C:10]1[CH:9]=[N:8][CH:7]=[CH:6][C:5]2=1.C(N(CC)CC)C.C([BH3-])#N.[Na+].[C:37]([OH:41])(=[O:40])[CH:38]=O>CO.O>[Cl:1][C:2]1[CH:3]=[C:4]2[C:12](=[C:13]([NH:15][C:16]([C@H:18]3[N:19]([CH2:38][C:37]([OH:41])=[O:40])[CH2:20][C:21]([CH3:25])([CH3:24])[O:22][CH2:23]3)=[O:17])[CH:14]=1)[NH:11][C:10]1[CH:9]=[N:8][CH:7]=[CH:6][C:5]2=1
Reactant: O=CC(=O)O
Reactant: CC1(C)CN[C@H](C(=O)Nc2cc(Cl)cc3c2[nH]c2cnccc23)CO1
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CO
Solvent: O
Solvent: CCN(CC)CC
Product: CC1(C)CN(CC(=O)O)[C@H](C(=O)Nc2cc(Cl)cc3c2[nH]c2cnccc23)CO1
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 72 %

Procedure:
To a suspension of (S)-6,6-Dimethyl-morpholine-3-carboxylic acid (6-chloro-9H-beta-carbolin-8-yl)-amide (2.6 g, 6.0 mmoles) in 60 ml of methanol was added 1.7 ml of triethylamine (2.0 eq.), sodium cyanoborohydride (575 mg, 9.1 mmoles) and glyoxylic acid (780 mg, 8.5 mmoles). The reaction mixture was stirred at ambient temperature for 1.5 hrs. Water was added (5 ml) and the mixture was concentrated to a thick yellow slurry. More water was then added (30 ml) and the resulting slurry was stirred at ambient temperature for 10 min. and was filtered. The collected yellow solid was washed with water and dried under high vacuum to give 1.80 g (71%) of the desired product.
Reaction SMILES: C[Si]([N-][Si](C)(C)C)(C)C.[K+].[N:11]12[CH2:18][CH2:17][CH:14]([CH2:15][CH2:16]1)[CH:13]([OH:19])[CH2:12]2.[NH2:20][C:21]1[CH:28]=[C:27](F)[C:24]([C:25]#[N:26])=[CH:23][N:22]=1>C1COCC1>[NH2:20][C:21]1[CH:28]=[C:27]([O:19][CH:13]2[CH:14]3[CH2:17][CH2:18][N:11]([CH2:16][CH2:15]3)[CH2:12]2)[C:24]([C:25]#[N:26])=[CH:23][N:22]=1
Reactant: OC1CN2CCC1CC2
Reactant: N#Cc1cnc(N)cc1F
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [K+]
Solvent: C1CCOC1
Product: N#Cc1cnc(N)cc1OC1CN2CCC1CC2
Temperature: 25 °C
Reaction time: 72 h

Procedure:
A solution of KHMDS in THF (1 M, 6.6 ml, 6.60 mmol) was added drop wise to a solution of racemic quinuclidin-3-ol (928 mg, 7.29 mmol) in THF (2 ml) at room temperature. After 55 min a solution of 6-amino-4-fluoronicotinonitrile (intermediate 21, 500 mg, 3.65 mmol) in THF (2 ml) was added and the reaction mixture stirred for 3 days at room temperature. The reaction mixture was partitioned between saturated aqueous NH4Cl and DCM, extracted with DCM (8×), the combined DCM layers were dried over Na2SO4 and evaporated. The residue was preabsorbed onto silica gel and purified by normal phase chromatography with a 12 g RediSep® silica column, eluting with a gradient from DCM to 20% MeOH in DCM. Product containing fractions were combined and evaporated to give the title compound as a beige solid. (UPLC-MS 6) tR 0.32; ESI-MS 245.2 [M+H]+.
Reaction SMILES: [Cl:1][C:2]1[C:7]([F:8])=[CH:6][CH:5]=[C:4]([Cl:9])[C:3]=1[C@H:10]([O:12][C:13]1[C:14]2[O:22][CH:21]=[C:20]([C:23]3[CH2:24][CH2:25][NH:26][CH2:27][CH:28]=3)[C:15]=2[CH:16]=[N:17][C:18]=1[NH2:19])[CH3:11].C(OC([N:36]1[CH2:40][CH2:39][CH2:38][C@@:37]1([CH3:44])[C:41](O)=[O:42])=O)(C)(C)C.CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.[B-](F)(F)(F)F.CCN(C(C)C)C(C)C.Cl>O1CCOCC1.CN(C=O)C>[NH2:19][C:18]1[N:17]=[CH:16][C:15]2[C:20]([C:23]3[CH2:24][CH2:25][N:26]([C:41]([C@:37]4([CH3:44])[CH2:38][CH2:39][CH2:40][NH:36]4)=[O:42])[CH2:27][CH:28]=3)=[CH:21][O:22][C:14]=2[C:13]=1[O:12][C@@H:10]([C:3]1[C:4]([Cl:9])=[CH:5][CH:6]=[C:7]([F:8])[C:2]=1[Cl:1])[CH3:11]
Reactant: C[C@@H](Oc1c(N)ncc2c(C3=CCNCC3)coc12)c1c(Cl)ccc(F)c1Cl
Reactant: CC(C)(C)OC(=O)N1CCC[C@@]1(C)C(=O)O
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: Cl
Agent: F[B-](F)(F)F
Solvent: CN(C)C=O
Solvent: C1COCCO1
Solvent: CCN(C(C)C)C(C)C
Product: C[C@@H](Oc1c(N)ncc2c(C3=CCN(C(=O)[C@]4(C)CCCN4)CC3)coc12)c1c(Cl)ccc(F)c1Cl
Temperature: 50 °C
Reaction time: 3 h

Procedure:
A mixture of 7-[(R)-1-(2,6-Dichloro-3-fluorophenyl)-ethoxy]-3-(1,2,3,6-tetrahydropyridin-4-yl)furo[3,2-c]pyridin-6-ylamine (150 mg, 0.36 mmol), (S)-2-Methylpyrrolidine-1,2-dicarboxylic acid 1-tert-butyl ester (98 mg, 0.43 mmol), TBTU (171 mg, 0.533 mmol), DIPEA (0.30 mL, 2.0 mmol) and DMF (10 mL) was stirred at 50° C. for 3 h. Reaction mixture was concentrated in vacuo, and the residue was taken up with DCM, washed with H2O, dried over sodium sulfate, filtered, and concentrated in vacuo. Purification of the residue by flash column chromatography using 1→4% NH3 in MeOH in DCM afforded an oil that was dissolved in 1,4-dioxane (2.0 mL). 4 M HCl in 1,4-Dioxane (0.9 mL) was added to the solution and the reaction mixture was stirred at 40° C. for 1 h and at 60° C. for 3 h. Purification of the crude material by prep TLC (eluting with NH3/MeOH/DCM) afforded the title compound as a light yellow solid. The compound was dissolved in DCM and 2 M of HCl in Et2O (4 mL) was added to the reaction mixture. The reaction mixture was concentrated in vacuo to afford the title compound as HCl salt. 1H NMR (400 MHz, CD3OD): δ=1.46 (s, 3H), 1.66-1.84 (m, 2H), 1.88 (d, J=6.8 Hz, 3H), 2.20 (br. s., 2H), 2.55 (br. s., 2H), 2.73-3.00 (m, 2H), 3.68-3.98 (m, 2H), 4.30 (br. s., 2H), 6.30 (br. s., 1H), 6.49 (q, J=6.7 Hz, 1H), 7.22 (t, J=8.7 Hz, 1H), 7.40 (dd, J=8.8, 4.8 Hz, 1H), 7.65 (s, 1H), 8.20 (s, 1H). MS (ES+): m/z 533.08/535.09 (100/69) [MH+]. HPLC: tR=2.45 min.
Reaction SMILES: Br[C:2]1[CH:3]=[CH:4][C:5]2[S:11](=[O:13])(=[O:12])[CH2:10][CH2:9][C:8]([C:14]([NH:16][C:17]3[CH:22]=[CH:21][C:20]([CH2:23][N:24]([CH3:31])[CH:25]4[CH2:30][CH2:29][O:28][CH2:27][CH2:26]4)=[CH:19][CH:18]=3)=[O:15])=[CH:7][C:6]=2[CH:32]=1.B([O-])([O-])O[C:35]1[CH:40]=[CH:39][C:38]([O:41][CH2:42][CH2:43][O:44][CH2:45][CH3:46])=[C:37]([Cl:47])[CH:36]=1.C(=O)([O-])[O-].[K+].[K+]>C1(C)C=CC=CC=1.C(O)C.O.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>[Cl:47][C:37]1[CH:36]=[C:35]([C:2]2[CH:3]=[CH:4][C:5]3[S:11](=[O:12])(=[O:13])[CH2:10][CH2:9][C:8]([C:14]([NH:16][C:17]4[CH:18]=[CH:19][C:20]([CH2:23][N:24]([CH3:31])[CH:25]5[CH2:26][CH2:27][O:28][CH2:29][CH2:30]5)=[CH:21][CH:22]=4)=[O:15])=[CH:7][C:6]=3[CH:32]=2)[CH:40]=[CH:39][C:38]=1[O:41][CH2:42][CH2:43][O:44][CH2:45][CH3:46]
Reactant: CCOCCOc1ccc(OB([O-])[O-])cc1Cl
Reactant: CN(Cc1ccc(NC(=O)C2=Cc3cc(Br)ccc3S(=O)(=O)CC2)cc1)C1CCOCC1
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: [K+]
Solvent: Cc1ccccc1
Solvent: CCO
Solvent: O
Product: CCOCCOc1ccc(-c2ccc3c(c2)C=C(C(=O)Nc2ccc(CN(C)C4CCOCC4)cc2)CCS3(=O)=O)cc1Cl
Temperature: 25 °C
Reaction time: 1 h
Yield: 72.9 %

Procedure:
Under argon atmosphere, a mixture of 7-bromo-N-[4-[[N-methyl-N-(tetrahydropyran-4-yl)amino]methyl]phenyl]-1,1-dioxo-2,3-dihydro-1-benzothiepine-4-carboxamide (300 mg), 3-chloro-4-(2-ethoxyethoxy)phenyl borate (156 mg) and potassium carbonate (160 mg) in toluene/ethanol/water (10/1/1 ml) was stirred at room temperature for 1 hour. To the mixture was added tetrakistriphenylphosphinepalladium (33 mg), and the mixture was refluxed for 6 hours, cooled, extracted with ethyl acetate, washed with saturated brine, dried with magnesium sulfate and concentrated under reduced pressure. The residue was purified with silica gel column chromatography (ethanol/ethyl acetate=1:3) and recrystallized from ethanol to give colorless crystals of 7-[3-chloro-4-(2-ethoxyethoxy)phenyl]-N-[4-[[N-methyl-N-(tetrahydropyran-4-yl)amino]methyl]phenyl]-1,1-dioxo-2,3-dihydro-1-benzothiepine-4-carboxamide (Compound 67) (269 mg).
Reaction SMILES: Cl[C:2]1[N:3]=[N:4][C:5]([Cl:21])=[C:6]([NH:8][C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=2[S:15]([CH:18]([CH3:20])[CH3:19])(=[O:17])=[O:16])[N:7]=1.[CH3:22][P:23]([C:26]1[CH:32]=[CH:31][C:29]([NH2:30])=[C:28]([F:33])[CH:27]=1)([CH3:25])=[O:24].C12(CS(O)(=O)=O)C(C)(C)C(CC1)CC2=O>CC(O)C.ClCCl>[Cl:21][C:5]1[N:4]=[N:3][C:2]([NH:30][C:29]2[CH:31]=[CH:32][C:26]([P:23]([CH3:22])([CH3:25])=[O:24])=[CH:27][C:28]=2[F:33])=[N:7][C:6]=1[NH:8][C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=1[S:15]([CH:18]([CH3:20])[CH3:19])(=[O:17])=[O:16]
Reactant: CC(C)S(=O)(=O)c1ccccc1Nc1nc(Cl)nnc1Cl
Reactant: CP(C)(=O)c1ccc(N)c(F)c1
Agent: CC1(C)C2CCC1(CS(=O)(=O)O)C(=O)C2
Solvent: ClCCl
Solvent: CC(C)O
Product: CC(C)S(=O)(=O)c1ccccc1Nc1nc(Nc2ccc(P(C)(C)=O)cc2F)nnc1Cl
Temperature: 25 °C

Procedure:
A mixture of 3,6-dichloro-N-[2-(propan-2-ylsulfonyl)phenyl]-1,2,4-triazin-5-amine (prepared as in Example 106: 0.7 mmol), 4-(Dimethylphosphoryl)-2-fluoroaniline (0.7 mmol) and camphorsulfonic acid (0.7 equiv.), is refluxed for 20-48 hours in 2-propanol. The reaction mixture is allowed to cool to room temperature, dissolved in dichloromethane and washed with an aqueous solution of Na2CO3. The dichloromethane extract is dried over MgSO4 and evaporated. The crude product is purified by Prep-HPLC.
Reaction SMILES: [CH3:1][C@@:2]1([C:5](=[O:38])[C@@H:6]([NH:14][C:15](=[O:37])[C@@H:16]([NH:24][C:25](=[O:36])[C@@H:26]([NH:28]C(=O)OC(C)(C)C)[CH3:27])[CH2:17][C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][N:19]=2)[CH2:7][C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)[CH2:4][O:3]1.[C:39]([OH:45])([C:41]([F:44])([F:43])[F:42])=[O:40]>C(Cl)Cl>[OH:45][C:39]([C:41]([F:44])([F:43])[F:42])=[O:40].[NH2:28][C@@H:26]([CH3:27])[C:25]([NH:24][C@@H:16]([CH2:17][C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][N:19]=1)[C:15]([NH:14][C@@H:6]([CH2:7][C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[C:5]([C@:2]1([CH3:1])[CH2:4][O:3]1)=[O:38])=[O:37])=[O:36]
Reactant: C[C@H](NC(=O)OC(C)(C)C)C(=O)N[C@@H](Cc1ccccn1)C(=O)N[C@@H](Cc1ccccc1)C(=O)[C@]1(C)CO1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: C[C@H](N)C(=O)N[C@@H](Cc1ccccn1)C(=O)N[C@@H](Cc1ccccc1)C(=O)[C@]1(C)CO1
Reaction time: 2 h

Procedure:
To tert-butyl ((S)-1-(((S)-1-(((S)-1-((S)-2-methyloxiran-2-yl)-1-oxo-3-phenylpropan-2-yl)amino)-1-oxo-3-(pyridin-2-yl)propan-2-yl)amino)-1-oxopropan-2-yl)carbamate (315 mg, 0.600 mmol) was added DCM (4 mL) followed by TFA (2 mL). The reaction mixture was allowed to stand for 2 h at which time it was concentrated to provide (S)-2-((S)-2-aminopropanamido)-N-((S)-1-((S)-2-methyloxiran-2-yl)-1-oxo-3-phenylpropan-2-yl)-3-(pyridin-2-yl)propanamide TFA salt as a yellow oil that was carried forward without further purification. MS (EI) for C25H28F3N4O5, found 425.3 [M-TFA]+.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2([C:18]3[CH:23]=[CH:22][C:21]([F:24])=[CH:20][CH:19]=3)[CH2:12][CH2:11][N:10]([CH2:13][C:14]([OH:16])=O)[C:9]2=[O:17])=[CH:4][CH:3]=1.C(Cl)(=O)C(Cl)=O.[F:31][C:32]([F:41])([F:40])[C:33]1[CH:34]=[CH:35][C:36]([NH2:39])=[N:37][CH:38]=1.CN1CCOCC1>ClCCl.CN(C)C=O>[F:24][C:21]1[CH:20]=[CH:19][C:18]([C:8]2([C:5]3[CH:4]=[CH:3][C:2]([F:1])=[CH:7][CH:6]=3)[CH2:12][CH2:11][N:10]([CH2:13][C:14]([NH:39][C:36]3[CH:35]=[CH:34][C:33]([C:32]([F:40])([F:31])[F:41])=[CH:38][N:37]=3)=[O:16])[C:9]2=[O:17])=[CH:23][CH:22]=1
Reactant: Nc1ccc(C(F)(F)F)cn1
Reactant: O=C(O)CN1CCC(c2ccc(F)cc2)(c2ccc(F)cc2)C1=O
Agent: O=C(Cl)C(=O)Cl
Solvent: CN1CCOCC1
Solvent: CN(C)C=O
Solvent: ClCCl
Product: O=C(CN1CCC(c2ccc(F)cc2)(c2ccc(F)cc2)C1=O)Nc1ccc(C(F)(F)F)cn1
Reaction time: 0.5 h

Procedure:
To a suspension of 2-(3,3-bis(4-fluorophenyl)-2-oxopyrrolidin-1-yl)acetic acid (0.158 g, 0.477 mmol; Example 58D) in dichloromethane (2 mL) was added a catalytic amount of N,N-dimethylformamide followed by oxalyl dichloride (2.0 Min dichloromethane) (0.358 mL, 0.715 mmol). After stirring for 30 minutes, the reaction was concentrated. The residue was dissolved in dichloromethane (2 mL) and 5-(trifluoromethyl)pyridin-2-amine (0.066 g, 0.405 mmol) and N-methylmorpholine (0.079 mL, 0.715 mmol) were added. After stirring for 2 hours, the reaction was loaded onto a GraceResolv™ 12 g silica gel column (Grace Davison Discovery Sciences) and the product eluted with a gradient of 5% ethyl acetate/hexanes to 75% ethyl acetate/hexanes (Flow=30 mL/minute) over 30 minutes to give the title compound. 1H NMR (300 MHz, CDCl3) δ 8.55 (d, J=12.2, 1H), 8.25 (d, J=8.8, 1H), 7.92 (dd, J=2.2, 8.8, 1H), 7.33 (ddd, J=2.7, 5.3, 7.1, 4H), 7.06-6.96 (m, 4H), 4.22 (s, 2H), 3.55 (t, J=6.5, 2H), 2.83 (t, J=6.5, 2H); MS (ESI+) m/z 467.1 (M+H)+.