Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][N:2]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[C:4]([CH2:11][C:12]2[C:13](=[O:19])[NH:14][C:15](=[S:18])[NH:16][CH:17]=2)=[CH:3]1.[Cl:20][C:21]1[CH:26]=[CH:25][C:24]([O:27][C:28]2[CH:33]=[CH:32][C:31]([CH2:34]Cl)=[CH:30][CH:29]=2)=[CH:23][C:22]=1[C:36]([F:39])([F:38])[F:37].C([O-])([O-])=O.[K+].[K+]>CN(C=O)C.CC(=O)OCC>[Cl:20][C:21]1[CH:26]=[CH:25][C:24]([O:27][C:28]2[CH:29]=[CH:30][C:31]([CH2:34][S:18][C:15]3[NH:16][CH:17]=[C:12]([CH2:11][C:4]4[C:5]5[C:10](=[CH:9][CH:8]=[CH:7][CH:6]=5)[N:2]([CH3:1])[CH:3]=4)[C:13](=[O:19])[N:14]=3)=[CH:32][CH:33]=2)=[CH:23][C:22]=1[C:36]([F:37])([F:38])[F:39]
Reactant: Cn1cc(Cc2c[nH]c(=S)[nH]c2=O)c2ccccc21
Reactant: FC(F)(F)c1cc(Oc2ccc(CCl)cc2)ccc1Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: Cn1cc(Cc2c[nH]c(SCc3ccc(Oc4ccc(Cl)c(C(F)(F)F)c4)cc3)nc2=O)c2ccccc21
Temperature: 80 °C
Yield: 25.8 %

Procedure:
A mixture of 5-[(1-methyl-1H-indol-3-yl)methyl]-2-thioxo-2,3-dihydro-4(1H)-pyrimidinone (95 mg, 0.349 mmol), 1-chloro-4-(4-(chloromethyl)phenoxy)-2-(trifluoromethyl)benzene (112 mg, 0.349 mmol), and K2CO3 (90 mg, 0.651 mmol) in DMF (2 mL) was heated at 80° C. for 3 h. The reaction mixture was diluted with EA (10 mL) and filtered through a silica pad to remove the solid suspension. The clear filtrate was concentrated under reduced pressure and purification via MDAP then afforded the title compound (50 mg, 24.75% yield). LCMS: rt=4.79 min, [M+H+]=556
Reaction SMILES: [F:1][CH:2]([F:6])[C:3](O)=[O:4].[Br:7][C:8]1[CH:13]=[C:12]([F:14])[CH:11]=[CH:10][C:9]=1[CH:15]([NH2:17])[CH3:16].Cl.CN(C)CCCN=C=NCC.O.ON1C2C=CC=CC=2N=N1.C(N(CC)CC)C>C(Cl)Cl>[Br:7][C:8]1[CH:13]=[C:12]([F:14])[CH:11]=[CH:10][C:9]=1[CH:15]([NH:17][C:3](=[O:4])[CH:2]([F:6])[F:1])[CH3:16]
Reactant: O=C(O)C(F)F
Reactant: CC(N)c1ccc(F)cc1Br
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: O
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CC(NC(=O)C(F)F)c1ccc(F)cc1Br
Temperature: 25 °C
Reaction time: 8 h
Yield: 66.3 %

Procedure:
Add difluoroacetic acid (777 mg, 8.1 mmol) to a mixture of 1-(2-bromo-4-fluorophenyl)ethanamine (1.18 g, 5.4 mmol), 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (1.55 g, 8.1 mmol), 1-hydroxybenzotriazole hydrate (1.24 g, 8.1 mmol), and triethylamine (2.26 mL, 16.2 mmol) in DCM (20 mL) at 0° C. Stir the mixture at RT overnight. Dilute the mixture with DCM, wash with water and aqueous saturated sodium chloride. Separate the organic layer and dry over sodium sulfate. Filter and concentrate in vacuo. Purify the residue by column chromatography [5% to 50% ethyl acetate in hexanes] to give the title compound (1.06 g, 44%). MS (ES) m/z 296 [M+1]+.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH3:9])[CH:5]=[C:6]([CH3:8])[CH:7]=1.C1C(=O)N([Br:17])C(=O)C1>C(Cl)(Cl)(Cl)Cl.CC(N=NC(C#N)(C)C)(C#N)C>[Cl:1][C:2]1[CH:7]=[C:6]([CH:5]=[C:4]([CH3:9])[CH:3]=1)[CH2:8][Br:17]
Reactant: Cc1cc(C)cc(Cl)c1
Reactant: O=C1CCC(=O)N1Br
Agent: CC(C)(C#N)N=NC(C)(C)C#N
Solvent: ClC(Cl)(Cl)Cl
Product: Cc1cc(Cl)cc(CBr)c1
Yield: 81.5 %

Procedure:
A solution of 5-chloro-m-xylene (14.06 g; 0.1 mol), NBS (17.8 g; 0.1 mol) and AIBN (1.1 g; 6.7 mmol) in CCl4 was refluxed for two hours. The resultant mixture was cooled, and the solid material formed was removed by filtration. Concentration yielded the sub-title compound (17.9 g; 80%).
Reaction SMILES: [Cl:1][C:2]1[CH:24]=[CH:23][C:5]([CH2:6][C:7]2[N:8]=[C:9]([C:17]3[CH:22]=[CH:21][N:20]=[CH:19][CH:18]=3)[S:10][C:11]=2[C:12]([O:14]CC)=[O:13])=[CH:4][CH:3]=1.[Li+].[OH-].Cl>C1COCC1.O>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([CH2:6][C:7]2[N:8]=[C:9]([C:17]3[CH:22]=[CH:21][N:20]=[CH:19][CH:18]=3)[S:10][C:11]=2[C:12]([OH:14])=[O:13])=[CH:23][CH:24]=1
Reactant: CCOC(=O)c1sc(-c2ccncc2)nc1Cc1ccc(Cl)cc1
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Product: O=C(O)c1sc(-c2ccncc2)nc1Cc1ccc(Cl)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 93.1 %

Procedure:
To a solution of ethyl 4-(4-chlorobenzyl)-2-(pyridin-4-yl)thiazole-5-carboxylate (12.8 g, 35.7 mmol) in THF (200 mL) and water (100 mL) was added 1.0 M LiOH (46.4 mL, 46.4 mmol) and the resulting solution was stirred at room temperature overnight. The mixture was acidified to pH 4 with 1 N HCl. The precipitated solids were filtered, washed with water and dried to give 11 g of the title compound as an a white solid. (93% yield). LC/MS (FA) ES+ 331. 1H NMR (400 MHz, d6-DMSO) δ: 13.86 (br s, 1H), 8.72-8.71 (m, 2H), 7.89-7.87 (m, 2H), 7.36-7.29 (m, 4H), 4.50 (s, 2H).
Reaction SMILES: [OH:1][C:2]1[C:11]([C:12](OCC)=[O:13])=[C:10]([OH:17])[C:9]2[C:4](=[C:5]([C:18]([F:21])([F:20])[F:19])[CH:6]=[CH:7][CH:8]=2)[N:3]=1.[NH2:22][C:23]1[S:24][CH:25]=[CH:26][N:27]=1>C1(C)C(C)=CC=CC=1>[S:24]1[CH:25]=[CH:26][N:27]=[C:23]1[NH:22][C:12]([C:11]1[C:2]([OH:1])=[N:3][C:4]2[C:9]([C:10]=1[OH:17])=[CH:8][CH:7]=[CH:6][C:5]=2[C:18]([F:21])([F:20])[F:19])=[O:13]
Reactant: Nc1nccs1
Reactant: CCOC(=O)c1c(O)nc2c(C(F)(F)F)cccc2c1O
Solvent: Cc1ccccc1C
Product: O=C(Nc1nccs1)c1c(O)nc2c(C(F)(F)F)cccc2c1O
Yield: 78.1 %

Procedure:
A mixture of 6.02 g of the product of Step C, 200 ml of xylene, 2 g of 2-amino-thiazole and 20 g of siliporite NK20 was refluxed for 2 hours and the resulting product was crystallized from acetic acid to obtain 5.54 g of N-(2-thiazolyl)-2,4-dihydroxy-8-trifluoromethyl-quinoline-3-carboxamide in the form of colorless crystals melting at 260° C.
Reaction SMILES: Br[C:2]1[N:7]=[C:6]2[N:8]([CH2:12][C:13]([CH3:16])([CH3:15])[CH3:14])[C:9]([NH2:11])=[N:10][C:5]2=[CH:4][CH:3]=1.CCN(CC)CC.[C:24]([C:26]1[CH:31]=[CH:30][C:29]([F:32])=[CH:28][C:27]=1[F:33])#[CH:25]>C1(C)C=CC=CC=1>[F:33][C:27]1[CH:28]=[C:29]([F:32])[CH:30]=[CH:31][C:26]=1[C:24]#[C:25][C:2]1[N:7]=[C:6]2[N:8]([CH2:12][C:13]([CH3:16])([CH3:15])[CH3:14])[C:9]([NH2:11])=[N:10][C:5]2=[CH:4][CH:3]=1
Reactant: CC(C)(C)Cn1c(N)nc2ccc(Br)nc21
Reactant: C#Cc1ccc(F)cc1F
Solvent: CCN(CC)CC
Solvent: Cc1ccccc1
Product: CC(C)(C)Cn1c(N)nc2ccc(C#Cc3ccc(F)cc3F)nc21
Yield: 40.1 %

Procedure:
Combine 5-bromo-3-(2,2-dimethyl-propyl)-3H-imidazo[4,5-b]pyridin-2-ylamine (30.00 g, 105.94 mmol), Et3N (60 mL), and Pd(OAc)2[P(Ph)3]2 (3.97 g, 5.30 mmol) in toluene (150 mL) and heat the resulting mixture to ˜65° C. under nitrogen. Add 1-ethynyl-2,4-difluoro-benzene (21.95 g, 158.92 mmol) in toluene (30 mL) dropwise to the above mixture, and then heat the resulting reaction mixture at 80° C. for 3 h. Cool the reaction to 25° C. and quench with saturated aqueous NH4Cl (300 mL). Stir the resulting reaction mixture at room temperature for 20 minutes, then filter, washing the solid with H2O and drying under vacuum filtration for 30 minutes. Slurry the solid in MTBE (200 mL), then filter and rinse with MTBE (50 mL). Dry the recovered solid under vacuum filtration to provide 14.47 g of the title compound as a light-yellow solid.
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:14]=[CH:13][C:12]([CH2:15][CH2:16][CH:17]=[CH:18][C:19](=[O:21])[CH3:20])=[CH:11][CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Br[CH2:23][C:24]([O:26][CH2:27][CH3:28])=[O:25]>[Zn]>[OH:21][C:19]([CH3:20])([CH:18]=[CH:17][CH2:16][CH2:15][C:12]1[CH:13]=[CH:14][C:9]([O:8][CH2:1][C:2]2[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=2)=[CH:10][CH:11]=1)[CH2:23][C:24]([O:26][CH2:27][CH3:28])=[O:25]
Reactant: CC(=O)C=CCCc1ccc(OCc2ccccc2)cc1
Reactant: CCOC(=O)CBr
Agent: [Zn]
Product: CCOC(=O)CC(C)(O)C=CCCc1ccc(OCc2ccccc2)cc1

Procedure:
Using 25.83 g of 6-(p-benzyloxyphenyl)-3-hexen-2-one, 11.3 ml of ethyl bromoacetate and 6.63 g of zinc, the reaction and the purification of the product were carried out according to the method described in Example I (a) affording 29.6 g of ethyl 3-hydroxy-3-methyl-7-(p-benzyloxyphenyl)-4-heptenoate.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[CH:4][C:5]([F:18])=[C:6]([C@:8]2([CH3:17])[C:13]([F:15])([F:14])[CH2:12][O:11][C:10]([NH2:16])=[N:9]2)[CH:7]=1.[N+:19]([C:22]1[O:26][C:25]([C:27](O)=[O:28])=[CH:24][CH:23]=1)([O-:21])=[O:20]>>[NH2:16][C:10]1[O:11][CH2:12][C:13]([F:14])([F:15])[C@:8]([C:6]2[CH:7]=[C:2]([NH:1][C:27]([C:25]3[O:26][C:22]([N+:19]([O-:21])=[O:20])=[CH:23][CH:24]=3)=[O:28])[CH:3]=[CH:4][C:5]=2[F:18])([CH3:17])[N:9]=1
Reactant: O=C(O)c1ccc([N+](=O)[O-])o1
Reactant: C[C@]1(c2cc(N)ccc2F)N=C(N)OCC1(F)F
Product: C[C@]1(c2cc(NC(=O)c3ccc([N+](=O)[O-])o3)ccc2F)N=C(N)OCC1(F)F

Procedure:
The condensation of (R)-4-(5-amino-2-fluoro-phenyl)-5,5-difluoro-4-methyl-5,6-dihydro-4H-[1,3]oxazin-2-ylamine (intermediate XI-1) and 5-nitro-furan-2-carboxylic acid (CAS645-12-5) following procedure I yielded the title compound after purification by preparative HPLC. MS (ISP): m/z=399.3 [M+H]+.
Reaction SMILES: [CH3:1][O:2][CH:3]1[CH2:8][CH2:7][CH:6]([CH:9]2[CH2:13][CH2:12][NH:11][C:10]2=[O:14])[CH2:5][CH2:4]1.[H-].[Na+].[Br:17][C:18]1[CH:19]=[C:20]([Cl:27])[C:21]([CH2:25]Br)=[C:22]([Cl:24])[CH:23]=1>CN(C=O)C>[Br:17][C:18]1[CH:19]=[C:20]([Cl:27])[C:21]([CH2:25][N:11]2[CH2:12][CH2:13][CH:9]([CH:6]3[CH2:5][CH2:4][CH:3]([O:2][CH3:1])[CH2:8][CH2:7]3)[C:10]2=[O:14])=[C:22]([Cl:24])[CH:23]=1
Reactant: Clc1cc(Br)cc(Cl)c1CBr
Reactant: COC1CCC(C2CCNC2=O)CC1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: COC1CCC(C2CCN(Cc3c(Cl)cc(Br)cc3Cl)C2=O)CC1
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 28.7 %

Procedure:
Treat a solution of 3-(4-methoxycyclohexyl)-pyrrolidin-2-one (0.0.71 g, 3.6 mmol) in DMF (20 mL) with a sodium hydride (0.0.29 mL, 7.2 mmol) and stir at room temperature for 10 minutes under N2. Treat the reaction with 5-Bromo-2-bromomethyl-1,3-dichloro-benzene (1.36 g, 4.3 mmol). Stir the mixture for 14 hours. Quench the reaction with water and extract with ethyl acetate. Dry the organic layer (Na2SO4), remove the solvent in vacuo to afford crude product, and purify with 25% ethyl acetate in hexanes to afford 0.45 g of the title compound.
Reaction SMILES: C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.CC(OC(/N=N/C(OC(C)C)=O)=O)C.[Cl:34][C:35]1[CH:55]=[C:54]([Cl:56])[CH:53]=[CH:52][C:36]=1[C:37]([NH:39][CH2:40][C:41]1([CH2:48][CH:49]2[CH2:51][CH2:50]2)[CH2:46][CH2:45][CH:44]([OH:47])[CH2:43][CH2:42]1)=[O:38].[C:57](O)(=[S:59])[CH3:58].C1(P(=O)(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>C1COCC1>[CH:49]1([CH2:48][C:41]2([CH2:40][NH:39][C:37](=[O:38])[C:36]3[CH:52]=[CH:53][C:54]([Cl:56])=[CH:55][C:35]=3[Cl:34])[CH2:42][CH2:43][CH:44]([O:47][C:57](=[S:59])[CH3:58])[CH2:45][CH2:46]2)[CH2:51][CH2:50]1
Reactant: CC(O)=S
Reactant: O=C(NCC1(CC2CC2)CCC(O)CC1)c1ccc(Cl)cc1Cl
Agent: CC(C)OC(=O)/N=N/C(=O)OC(C)C
Agent: O=P(c1ccccc1)(c1ccccc1)c1ccccc1
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: CC(=S)OC1CCC(CNC(=O)c2ccc(Cl)cc2Cl)(CC2CC2)CC1
Temperature: 0 °C
Reaction time: 1.5 h
Yield: 63.2 %

Procedure:
To a stirred solution of triphenylphosphine (0.44 g; 1.68 mmol) in THF (20 ml) at 0° C. was added diisopropylazodicarboxylate (0.34 g; 1.68 mmol) and the solution stirred at 0° C. for 90 minutes. To a stirred solution of 2,4-dichloro-N-{[1-(cyclopropylmethyl)-4-hydroxycyclohexyl]methyl}benzamide (0.30 g; 0.84 mmol; less polar alcohol isomer) in THF (10 ml) was added thioacetic acid (0.12 ml; 1.68 mmol). The resulting solution was added dropwise to the triphenylphosphine solution at 0° C. On complete addition, the solution was stirred at 0° C. for 1 hour then allowed to warm to ambient temperature and stirred for 18 hours. The reaction mixture was partitioned between EtOAc (200 ml) and water (100 ml). The organic phase was washed with brine (100 ml), dried over anhydrous sodium sulfate, filtered and evaporated to give a yellow oily solid. The crude product was chromatographed on silica eluted with 10-30% EtOAc in isohexane to give the product contaminated with triphenylphosphine oxide. The contaminated product was chromatographed on silica eluted with 1% EtOAc in dichloromethane to give the desired product as an oil (220 mg). 1H NMR δ (ppm) (CDCl3): 7.66 (1H, d, J=8.4 Hz), 7.43 (1H, d, J=2.1 Hz), 7.34 (1H, dd, J=2.1, 8.4 Hz), 6.26 (1H, s), 3.58 (2H, d, J=6.0 Hz), 3.45-3.52 (1H, m), 2.30 (3H, s), 1.83-1.88 (2H, m), 1.65-1.74 (4H, m), 1.44-1.52 (2H, m), 1.26 (2H, d, J=7.0 Hz), 0.64-0.71 (1H, m), 0.47-0.52 (2H, m), 0.00-0.06 (2H, m).
Reaction SMILES: [NH2:1][C:2]1[C:7]([CH3:8])=[CH:6][C:5]([N:9]2[CH:13]=[N:12][N:11]=[CH:10]2)=[CH:4][C:3]=1I.C1C[O:18][CH2:17]C1>[Pd].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.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>[NH2:1][C:2]1[C:7]([CH3:8])=[CH:6][C:5]([N:9]2[CH:13]=[N:12][N:11]=[CH:10]2)=[CH:4][C:3]=1[CH:17]=[O:18]
Reactant: C1CCOC1
Reactant: Cc1cc(-n2cnnc2)cc(I)c1N
Agent: [Pd]
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Product: Cc1cc(-n2cnnc2)cc(C=O)c1N
Reaction time: 0.5 h

Procedure:
A stirred mixture of 4-(4-amino-3-iodo-5-methylphenyl)-1,2,4-triazole (3.0 g) and tetrakis (triphenylphosphine) palladium (0) (1.0 g) in THF (300 cm3) was deoxygenated with a stream of nitrogen for 0.5 hours. The mixture was then placed under carbon monoxide (ca 2 atmospheres pressure), warmed to 50°, and a solution of tri-n-butyltin hydride (3.2 g) in THF (200 cm3) was added dropwise over 4 hours. After a further 0.5 hours, the mixture was poured onto an aqueous solution of potassium fluoride (10 g) in water (200 cm3) and the mixture was extracted with dichloromethane (5×200 cm3). The combined and dried (MgSO4) extracts were evaporated in vacuo and the residue was chromatographed on silica (Merck "MK 60.9385" [Trade Mark]), eluting with dichloromethane:methanol, 9:1. Combination and evaporation of the appropriate fractions gave a solid which was recrystallised from ethyl acetate-methanol to afford the title compound, m.p. 250°-252° (1.87 g), characterised spectroscopically to be identical to the product of Preparation 30.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:9](Cl)=[O:10])[CH:5]=[N:6][C:7]=1[Cl:8].O[NH:13][C:14](=[NH:19])[C:15]([CH3:18])([CH3:17])[CH3:16]>C1(C)C=CC=CC=1>[C:15]([C:14]1[N:19]=[C:9]([C:4]2[CH:5]=[N:6][C:7]([Cl:8])=[C:2]([Cl:1])[CH:3]=2)[O:10][N:13]=1)([CH3:18])([CH3:17])[CH3:16]
Reactant: CC(C)(C)C(=N)NO
Reactant: O=C(Cl)c1cnc(Cl)c(Cl)c1
Solvent: Cc1ccccc1
Product: CC(C)(C)c1noc(-c2cnc(Cl)c(Cl)c2)n1
Temperature: 25 °C
Reaction time: 2 h
Yield: 55.5 %

Procedure:
A mixture of 5,6-dichloro-pyridine-3-carbonyl chloride (1.8 g, 8.6 mmol) and N-hydroxy-2,2-dimethylpropanimidamide (1.0 g, 8.6 mmol) in toluene (40 mL) was stirred at room temperature for two hours and then heated under reflux for four hours. The mixture was cooled to room temperature and filtered through celite, the solids being washed with toluene (20 mL). Evaporation of the combined filtrates under reduced pressure gave the desired product (1.3 g, 56%) as a clear oil which crystallised on standing to a white solid, MP 98-101° C.
Reaction SMILES: N1CCC[C@H]1C1C=C(C=O)C=NC=1.[C:14]([O:18][C:19]([N:21](C)[C@@H:22](C)C(N[C@@H](C1CCCCC1)C(O)=O)=O)=[O:20])([CH3:17])([CH3:16])[CH3:15].O.[Cl-].COC1N=C(OC)N=C([N+]2(C)CCOCC2)N=1>C1COCC1.CCOC(C)=O>[C:14]([O:18][C:19](=[O:20])[NH:21][CH3:22])([CH3:17])([CH3:16])[CH3:15]
Reactant: C[C@@H](C(=O)N[C@H](C(=O)O)C1CCCCC1)N(C)C(=O)OC(C)(C)C
Agent: COc1nc(OC)nc([N+]2(C)CCOCC2)n1
Agent: O=Cc1cncc([C@@H]2CCCN2)c1
Agent: [Cl-]
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Solvent: O
Product: CNC(=O)OC(C)(C)C
Temperature: 20 °C
Reaction time: 2 h
Yield: 363 %

Procedure:
To a solution of 4-fluoro-phenyl)-((S)-5-pyrrolidin-2-yl-pyridin-3-yl)-methanone (2.57 g, 9.5 mmole) and (S)-[(S)-2-(tert-butoxycarbonyl-methyl-amino)-propionylamino]-cyclohexyl-acetic acid (5) (3.58 g, 10.5 mmole) in 75 mL of THF at 0° C., is added 4-(4,6-dimethoxy-[1,3,5]triazin-2-yl)-4-methyl-morpholinium chloride hydrate (2.97 g, 10.7 mmole) in one portion. After stirring at 20° C. for 2 hours, the reaction mixture is diluted with 100 mL of EtOAc, and washed with 3×20 mL of water. After concentration, the crude product is purified by flash column chromatography (CH2Cl2 95%, MeOH 5%) to give (S)-1-((S)-1-cyclohexyl-2-{(S)-2-[5-(4-fluoro-benzoyl)-pyridin-3-yl]pyrrolidin-1-yl}-2-oxo-ethylcarbamoyl)-ethyl]-methyl-carbamic acid tert-butyl ester (6) (5.0 g, yield 88%) as pale yellow solid.
Reaction SMILES: [NH2:1][C:2]1[C:10]([Br:11])=[CH:9][CH:8]=[CH:7][C:3]=1[C:4]([OH:6])=O.[C:12]1([N:18]=[C:19]=[S:20])[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1>CC(O)(C)C>[Br:11][C:10]1[CH:9]=[CH:8][CH:7]=[C:3]2[C:2]=1[NH:1][C:19](=[S:20])[N:18]([C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1)[C:4]2=[O:6]
Reactant: Nc1c(Br)cccc1C(=O)O
Reactant: S=C=Nc1ccccc1
Solvent: CC(C)(C)O
Product: O=c1c2cccc(Br)c2[nH]c(=S)n1-c1ccccc1
Temperature: 100 °C
Yield: 97.2 %

Procedure:
TEA (1.93 mL, 13.89 mmol), 2-amino-3-bromo-benzoic acid (Aldrich, 2.00 g, 9.26 mmol), phenyl isothiocyanate (Aldrich; 1.66 mL, 13.89 mmol) were combined in 30 mL t-BuOH, flask sealed, and heated to 100° C. overnight. The heterogeneous reaction was cooled to 40° C. and filtered, rinsing 3× Et2O, and the solid was collected and dried in vacuo to give 8-bromo-3-phenyl-2-thioxo-2,3-dihydroquinazolin-4(1H)-one (3.0 g, 9.00 mmol, 97% yield) as an off-white solid. 1H NMR (400 MHz, DMSO-d6) δ ppm 10.76 (1H, br. s.), 8.02 (1H, dd, J=7.8, 1.4 Hz), 7.94 (1H, dd, J=7.9, 1.3 Hz), 7.34-7.51 (3H, m), 7.14-7.26 (3H, m). m/z (ESI, +ve) 332.9/334.9 (M+H)+.
Reaction SMILES: [NH2:1][C@@H:2]1[CH2:6][CH2:5][N:4]([C:7]2[CH:12]=[CH:11][C:10]([N:13]3[CH2:22][CH2:21][C:20]4[C:15](=[CH:16][CH:17]=[C:18]([O:23][CH2:24][C@@H:25]5[CH2:29][CH2:28][CH2:27][O:26]5)[CH:19]=4)[C:14]3=[O:30])=[CH:9][C:8]=2[F:31])[CH2:3]1.Br[CH2:33][CH2:34][CH2:35][O:36][CH3:37]>>[F:31][C:8]1[CH:9]=[C:10]([N:13]2[CH2:22][CH2:21][C:20]3[C:15](=[CH:16][CH:17]=[C:18]([O:23][CH2:24][C@@H:25]4[CH2:29][CH2:28][CH2:27][O:26]4)[CH:19]=3)[C:14]2=[O:30])[CH:11]=[CH:12][C:7]=1[N:4]1[CH2:5][CH2:6][C@@H:2]([NH:1][CH2:33][CH2:34][CH2:35][O:36][CH3:37])[CH2:3]1
Reactant: N[C@@H]1CCN(c2ccc(N3CCc4cc(OC[C@@H]5CCCO5)ccc4C3=O)cc2F)C1
Reactant: COCCCBr
Product: COCCCN[C@@H]1CCN(c2ccc(N3CCc4cc(OC[C@@H]5CCCO5)ccc4C3=O)cc2F)C1

Procedure:
2-[4-((R)-3-Amino-pyrrolidin-1-yl)-3-fluoro-phenyl]-6-[(S)-1-(tetrahydro-furan-2-yl)methoxy]-3,4-dihydro-2H-isoquinolin-1-one was reacted with 1-Bromo-3-methoxypropane by method X. The product with the molecular weight of 497.62 (C28H36FN3O4) was obtained in this way; MS (ESI): 498 (M+H+).
Reaction SMILES: [OH:1][C:2]1[C:7]([C:8]([OH:10])=O)=[CH:6][N:5]=[C:4]([N:11]2[CH:15]=[CH:14][CH:13]=[N:12]2)[N:3]=1.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(CC)CC.[CH3:47][P:48]([C:53]1[CH:58]=[CH:57][C:56]([CH:59]([NH2:66])[C:60]2[CH:65]=[CH:64][CH:63]=[CH:62][CH:61]=2)=[CH:55][CH:54]=1)(=[O:52])[O:49][CH2:50][CH3:51]>CC#N>[OH:1][C:2]1[C:7]([C:8]([NH:66][CH:59]([C:60]2[CH:61]=[CH:62][CH:63]=[CH:64][CH:65]=2)[C:56]2[CH:55]=[CH:54][C:53]([P:48]([CH3:47])(=[O:52])[O:49][CH2:50][CH3:51])=[CH:58][CH:57]=2)=[O:10])=[CH:6][N:5]=[C:4]([N:11]2[CH:15]=[CH:14][CH:13]=[N:12]2)[N:3]=1
Reactant: CCOP(C)(=O)c1ccc(C(N)c2ccccc2)cc1
Reactant: O=C(O)c1cnc(-n2cccn2)nc1O
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(CC)CC
Solvent: CC#N
Product: CCOP(C)(=O)c1ccc(C(NC(=O)c2cnc(-n3cccn3)nc2O)c2ccccc2)cc1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a solution of 4-hydroxy-2-(1H-pyrazol-1-yl)pyrimidine-5-carboxylic acid, 8-b, (206 mg, 1 mmol) in MeCN (20 ml) were added HATU (395 mg, 1.04 mmol), Et3N (105 mg, 1.04 mmol) and ethyl methyl(4-(amino(phenyl)methyl)phenyl)phosphinate, 2-d, (289 mg, 1 mmol). The resulting mixture was stirred at room temperature for 2 hours. Then it was filtered before diluted with saturated NH4Cl solution. The mixture was extracted with ethyl acetate. The organic layer was dried over sodium sulfate and concentrated under vacuum. The residue was purified on silica gel chromatography to provide the product, 8-3, (150 mg, 31%). 1H NMR (CD3OD, 300 MHz,): δ 8.65 (s, 1H), 8.57 (m, 1H), 7.91 (s, 1H), 7.76 (m, 2H), 7.52 (m, 2H), 7.34 (m, 5H), 6.64 (s, 1H), 6.36 (s, 1H), 3.85 (m, 2H), 1.67 (d, 3H), 1.25 (m, 3H).
Reaction SMILES: [C:1]([C:5]1[CH:6]=[C:7]2[C:12](=[C:13]([F:15])[CH:14]=1)[C:11](=[O:16])[N:10]([C:17]1[CH:24]=[C:23]([F:25])[CH:22]=[C:21]([C:26]3[CH:31]=[C:30]([NH:32][C:33]4[CH:38]=[CH:37][C:36]([N:39]5[CH2:44][C@@H:43]([CH3:45])[N:42]([CH:46]6[CH2:49][O:48][CH2:47]6)[CH2:41][C@@H:40]5[CH3:50])=[CH:35][N:34]=4)[C:29](=[O:51])[N:28]([CH3:52])[CH:27]=3)[C:18]=1[CH:19]=[O:20])[N:9]=[CH:8]2)([CH3:4])([CH3:3])[CH3:2].[BH4-].[Na+]>CO>[C:1]([C:5]1[CH:6]=[C:7]2[C:12](=[C:13]([F:15])[CH:14]=1)[C:11](=[O:16])[N:10]([C:17]1[CH:24]=[C:23]([F:25])[CH:22]=[C:21]([C:26]3[CH:31]=[C:30]([NH:32][C:33]4[CH:38]=[CH:37][C:36]([N:39]5[CH2:44][C@@H:43]([CH3:45])[N:42]([CH:46]6[CH2:49][O:48][CH2:47]6)[CH2:41][C@@H:40]5[CH3:50])=[CH:35][N:34]=4)[C:29](=[O:51])[N:28]([CH3:52])[CH:27]=3)[C:18]=1[CH2:19][OH:20])[N:9]=[CH:8]2)([CH3:3])([CH3:4])[CH3:2]
Reactant: C[C@@H]1CN(c2ccc(Nc3cc(-c4cc(F)cc(-n5ncc6cc(C(C)(C)C)cc(F)c6c5=O)c4C=O)cn(C)c3=O)nc2)[C@@H](C)CN1C1COC1
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Product: C[C@@H]1CN(c2ccc(Nc3cc(-c4cc(F)cc(-n5ncc6cc(C(C)(C)C)cc(F)c6c5=O)c4CO)cn(C)c3=O)nc2)[C@@H](C)CN1C1COC1
Reaction time: 1 h
Yield: 22.2 %

Procedure:
At 0° C., to a solution of 2-(6-tert-butyl-8-fluoro-1-oxophthalazin-2(1H)-yl)-6-(5-(5-((2S,5R)-2,5-dimethyl-4-(oxetan-3-yl)piperazin-1-yl)pyridin-2-ylamino)-1-methyl-6-oxo-1,6-dihydropyridin-3-yl)-4-fluorobenzaldehyde 108a (54 mg, 0.076 mmol) in methanol (5 mL) was added sodium borohydride (9.0 mg, 0.23 mmol). The mixture was stirred for 60 minutes. It was then quenched with water (1.0 mL) and concentrated under reduced pressure. The residue was purified by reverse-phase prep-HPLC to afford 108 (12 mg, 22%). MS: [M+H]+ 712.3. 1H NMR (500 MHz, CDCl3) δ 8.63 (d, J=2.5 Hz, 1H), 8.31 (d, J=2.0 Hz, 1H), 8.05 (d, J=2.5 Hz, 1H), 7.87 (s, 1H), 7.58-7.55 (m, 2H), 7.44 (d, J=2.0 Hz, 1H), 7.36 (s, 1H), 7.30 (d, J=2.0 Hz, 1H), 7.12 (dd, J=2.5, 8.5 Hz, 1H), 6.82 (d, J=8.5 Hz, 1H), 4.76-4.73 (m, 2H), 4.68-4.61 (m, 2H), 4.38-4.36 (m, 2H), 3.74-3.72 (m, 2H), 3.72 (s, 3H), 3.22-3.20 (m, 1H), 2.94-2.92 (m, 1H), 2.74-2.72 (m, 2H), 2.50-2.48 (m, 1H), 1.98-1.96 (m, 1H), 1.45 (s, 9H), 0.93-0.91 (m, 6H).
Reaction SMILES: [I:1]I.[NH2:3][C:4]1[CH:13]=[C:12]([Cl:14])[CH:11]=[CH:10][C:5]=1[C:6]([O:8][CH3:9])=[O:7]>CCO.S([O-])([O-])(=O)=O.[Ag+2]>[NH2:3][C:4]1[CH:13]=[C:12]([Cl:14])[C:11]([I:1])=[CH:10][C:5]=1[C:6]([O:8][CH3:9])=[O:7]
Reactant: COC(=O)c1ccc(Cl)cc1N
Reactant: II
Agent: [Ag+2]
Agent: O=S(=O)([O-])[O-]
Solvent: CCO
Product: COC(=O)c1cc(I)c(Cl)cc1N
Temperature: 25 °C
Reaction time: 0.75 h
Yield: 101.1 %

Procedure:
To a mixture of iodine (68 g, 0.27 mol) and silver sulfate (84 g, 0.27 mol) in absolute EtOH (2.5 L) was added methyl 2-amino-4-chlorobenzoate (50 g, 0.27 mol). The reaction mixture was allowed to stir at rt for 45 min. The reaction mixture was then filtered through a pad of Celite® and the filtrate was concentrated. The residue was dissolved in EtOAc (2 L) and washed with saturated aqueous NaHCO3 (3×400 mL), water (3×400 mL), and brine. The organic solution was dried over Na2SO4, filtered, and concentrated to give methyl 2-amino-4-chloro-5-iodobenzoate (85 g, 99%).