Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][O:4][CH2:3][CH2:2]1.[Cl:7][C:8]1[C:31]([F:32])=[CH:30][CH:29]=[C:28]([F:33])[C:9]=1[CH2:10][N:11]1[CH2:16][CH2:15][NH:14][C:13]2[N:17]=[CH:18][C:19]([C:21]3[CH:26]=[CH:25][N:24]=[C:23](Cl)[CH:22]=3)=[CH:20][C:12]1=2>>[Cl:7][C:8]1[C:31]([F:32])=[CH:30][CH:29]=[C:28]([F:33])[C:9]=1[CH2:10][N:11]1[CH2:16][CH2:15][NH:14][C:13]2[N:17]=[CH:18][C:19]([C:21]3[CH:22]=[CH:23][N:24]=[C:25]([N:1]4[CH2:6][CH2:5][O:4][CH2:3][CH2:2]4)[CH:26]=3)=[CH:20][C:12]1=2
Reactant: C1COCCN1
Reactant: Fc1ccc(F)c(CN2CCNc3ncc(-c4ccnc(Cl)c4)cc32)c1Cl
Product: Fc1ccc(F)c(CN2CCNc3ncc(-c4ccnc(N5CCOCC5)c4)cc32)c1Cl
Yield: 21 %

Procedure:
Morpholine (2 mL) was added to 1-(2-chloro-3,6-difluorobenzyl)-7-(2-chloropyridin-4-yl)-1,2,3,4-tetrahydropyrido[2,3-b]pyrazine (61 mg), and the mixture was heated in a microwave oven for two (2) hours at 180° C. The mixture was then concentrated, and the residue was purified through silica gel chromatography followed by preparative reversed-phase HPLC. The trifluoroacetic acid salt was neutralized with saturated sodium bicarbonate, and the free base extracted into methylene chloride, washed with brine and dried with magnesium sulfate. The solution was concentrated to give the title compound as a yellow solid (21% yield). M.p.=157° C., LCMS: m/z=458.07 (M+H+), 1H-NMR (CDCl3, 400 MHz) δ 3.38 (2H, t, J=4.7 Hz), 3.56 (4H, t, J=4.8 Hz), 3.62 (2H, t, J=4.5 Hz), 3.86 (4H, t, J=4.8 Hz), 4.58 (2H, s), 6.65 (1H, s), 6.76 (1H, d, J=5.1 Hz), 7.06 (2H, m), 7.16 (1H, m), 7.59 (2H, m), 8.22 (1H, d, J=5.1 Hz).
Reaction SMILES: ClC(Cl)(OC(=O)[O:6][C:7]([Cl:10])(Cl)Cl)Cl.[CH3:13][C@H:14]1[CH2:23][NH:22][C:21]2[C:16](=[CH:17][CH:18]=[C:19]([C:24]3[CH:25]=[N:26][N:27]([CH:29]4[CH2:32][O:31][CH2:30]4)[CH:28]=3)[CH:20]=2)[N:15]1[C:33](=[O:35])[CH3:34].C(N(CC)C(C)C)(C)C>ClCCCl>[C:33]([N:15]1[C:16]2[C:21](=[CH:20][C:19]([C:24]3[CH:25]=[N:26][N:27]([CH:29]4[CH2:32][O:31][CH2:30]4)[CH:28]=3)=[CH:18][CH:17]=2)[N:22]([C:7]([Cl:10])=[O:6])[CH2:23][C@@H:14]1[CH3:13])(=[O:35])[CH3:34]
Reactant: CC(=O)N1c2ccc(-c3cnn(C4COC4)c3)cc2NC[C@@H]1C
Reactant: O=C(OC(Cl)(Cl)Cl)OC(Cl)(Cl)Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCCl
Product: CC(=O)N1c2ccc(-c3cnn(C4COC4)c3)cc2N(C(=O)Cl)C[C@@H]1C
Temperature: 25 °C
Reaction time: 1 h
Yield: 66.7 %

Procedure:
Triphosgene (0.048 g, 0.16 mmol) was added slowly to a solution of (S)-1-(2-methyl-6-(1-(oxetan-3-yl)-1H-pyrazol-4-yl)-3,4-dihydroquinoxaline-1(2H)-yl)ethanone (0.050 g, 0.16 mmol) and N,N-diisopropylethylamine (0.413 g, 3.20 mmol) in 1,2-dichloroethane (20 mL) at room temperature. The resulting solution was stirred for 1 hour at room temperature and then concentrated under vacuum. The crude product was purified via preparative thin layer chromatography (eluting with 1:1 petroleum ether:ethyl acetate) to afford (S)-4-acetyl-3-methyl-7-(1-(oxetan-3-yl)-1H-pyrazol-4-yl)-3,4-dihydroquinoxaline-1(2H)-carbonyl chloride (0.040 g, 67%) as a yellow solid. 1H-NMR (300 MHz, CDCl3, ppm): δ 7.92-7.80 (m, 3H), 7.41-7.38 (m, 1H), 7.26-7.23 (m, 1H), 5.55-5.45 (m, 1H), 5.13-5.08 (m, 5H), 4.58-4.53 (m, 1H), 3.33-3.20 (m, 1H), 2.23 (s, 3H), 1.10 (d, J=6.3 Hz, 3H). MS (ESI, pos. ion) m/z 375, 377 [M+H]+.
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[C@:9]1([C@@H:12](O)[CH3:13])[CH2:11][O:10]1.[F:15][C:16]([F:33])([O:20][C:21]1[CH:26]=[CH:25][C:24]([N:27]2[CH:31]=[CH:30][NH:29][C:28]2=[O:32])=[CH:23][CH:22]=1)[CH:17]([F:19])[F:18]>>[F:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[C@:9]1([O:10][CH2:11]1)[C@H:12]([N:29]1[CH:30]=[CH:31][N:27]([C:24]2[CH:23]=[CH:22][C:21]([O:20][C:16]([F:33])([F:15])[CH:17]([F:19])[F:18])=[CH:26][CH:25]=2)[C:28]1=[O:32])[CH3:13]
Reactant: C[C@H](O)[C@@]1(c2ccc(F)cc2F)CO1
Reactant: O=c1[nH]ccn1-c1ccc(OC(F)(F)C(F)F)cc1
Product: C[C@@H](n1ccn(-c2ccc(OC(F)(F)C(F)F)cc2)c1=O)[C@@]1(c2ccc(F)cc2F)CO1
Yield: 18.9 %

Procedure:
In the same manner as in Reference Example 5, starting from 1.01 g of (1S)-1-[(2R)-(2,4-difluorophenyl)-2-oxiranyl]ethanol and 1.15 g of 1-[4-(1,1,2,2tetrafluoroethoxy)phenyl]-2(1H,3H)-imidazolone, 0.36 g of 1-[(1R,2S)-2-(2,4-difluorophenyl)-2,3-epoxy-1-methylpropyl]-3-[4-(1,1,2,2-tetrafluoroethoxy)phenyl]-2(1H,3H)-imidazolone was obtained as colorless needles.
Reaction SMILES: [CH3:1][C:2]1[N:3]([C:16]2[CH:21]=[CH:20][NH:19][C:18](=[O:22])[CH:17]=2)[CH:4]=[C:5]([C:7]#[C:8][C:9]2[CH:10]=[C:11]([CH3:15])[CH:12]=[CH:13][CH:14]=2)[N:6]=1.I[CH2:24][CH2:25][OH:26]>>[OH:26][CH2:25][CH2:24][N:19]1[CH:20]=[CH:21][C:16]([N:3]2[CH:4]=[C:5]([C:7]#[C:8][C:9]3[CH:10]=[C:11]([CH3:15])[CH:12]=[CH:13][CH:14]=3)[N:6]=[C:2]2[CH3:1])=[CH:17][C:18]1=[O:22]
Reactant: Cc1cccc(C#Cc2cn(-c3cc[nH]c(=O)c3)c(C)n2)c1
Reactant: OCCI
Product: Cc1cccc(C#Cc2cn(-c3ccn(CCO)c(=O)c3)c(C)n2)c1

Procedure:
The title compound, light yellow solid, MS: m/e=334.2 (M+H+), was prepared in accordance with the general method of example 3 from 4-(2-Methyl-4-m-tolylethynyl-imidazol-1-yl)-1H-pyridin-2-one and 2-iodoethanol.
Reaction SMILES: C([O:3][C:4]([C:6]1[CH:7]=[C:8]2[N:24]=[C:23]([NH:25][C:26]3[C:31]([Cl:32])=[CH:30][CH:29]=[C:28]([CH2:33][NH:34][C:35](=[O:40])[C:36]([CH3:39])([CH3:38])[CH3:37])[C:27]=3[Cl:41])[N:22]([CH3:42])[C:9]2=[N:10][C:11]=1[N:12]1[CH2:17][CH2:16][CH:15]([C:18]([F:21])([F:20])[F:19])[CH2:14][CH2:13]1)=[O:5])C.CCO.OS([O-])(=O)=O.[K+]>O>[Cl:41][C:27]1[C:28]([CH2:33][NH:34][C:35](=[O:40])[C:36]([CH3:37])([CH3:38])[CH3:39])=[CH:29][CH:30]=[C:31]([Cl:32])[C:26]=1[NH:25][C:23]1[N:22]([CH3:42])[C:9]2=[N:10][C:11]([N:12]3[CH2:13][CH2:14][CH:15]([C:18]([F:19])([F:20])[F:21])[CH2:16][CH2:17]3)=[C:6]([C:4]([OH:5])=[O:3])[CH:7]=[C:8]2[N:24]=1
Reactant: CCOC(=O)c1cc2nc(Nc3c(Cl)ccc(CNC(=O)C(C)(C)C)c3Cl)n(C)c2nc1N1CCC(C(F)(F)F)CC1
Agent: O=S(=O)([O-])O
Agent: [K+]
Solvent: CCO
Solvent: O
Product: Cn1c(Nc2c(Cl)ccc(CNC(=O)C(C)(C)C)c2Cl)nc2cc(C(=O)O)c(N3CCC(C(F)(F)F)CC3)nc21
Temperature: 55 °C
Reaction time: 8 h

Procedure:
A mixture of 2-{2,6-dichloro-3-[(2,2-dimethyl-propionylamino)-methyl]-phenylamino}-5-[4-trifluoromethyl-piperidinyl]-3-methyl-3H-imidazo[4,5-b]pyridine-6-carboxylic acid ethyl ester (3.85 g, 6.1 mmol) 2 N NaOH (12 mL, 24 mmol) and 60 mL EtOH is stirred for 4.5 h at 55° C. and overnight at rt. Then the mixture is poured into 150 mL water, the mixture is acidified to pH ˜5.5 with aq. KHSO4 and the mixture is concentrated. The resulting precipitate is collected by filtration and dried. Yield: 1.44 g. HPLC Rt=1.47 min (method D). MS m/z: 599 [M+H]+.
Reaction SMILES: C(Cl)(=O)C.[NH2:5][CH2:6][C:7]1[CH:35]=[CH:34][C:10]([CH2:11][NH:12][C:13]([C:15]2[CH:20]=[CH:19][C:18]([NH:21][C:22]([N:24]3[CH2:32][C:31]4[C:26](=[CH:27][CH:28]=[C:29]([F:33])[CH:30]=4)[CH2:25]3)=[O:23])=[CH:17][CH:16]=2)=[O:14])=[CH:9][CH:8]=1.NC1C=C2C(=CC=1)CN(C(N[C:49]1[CH:54]=[CH:53][C:52]([C:55](=[O:60])NCCC)=[CH:51][CH:50]=1)=O)C2>>[C:55]([NH:5][CH2:6][C:7]1[CH:8]=[CH:9][C:10]([CH2:11][NH:12][C:13]([C:15]2[CH:16]=[CH:17][C:18]([NH:21][C:22]([N:24]3[CH2:32][C:31]4[C:26](=[CH:27][CH:28]=[C:29]([F:33])[CH:30]=4)[CH2:25]3)=[O:23])=[CH:19][CH:20]=2)=[O:14])=[CH:34][CH:35]=1)(=[O:60])[C:52]1[CH:53]=[CH:54][CH:49]=[CH:50][CH:51]=1
Reactant: NCc1ccc(CNC(=O)c2ccc(NC(=O)N3Cc4ccc(F)cc4C3)cc2)cc1
Reactant: CCCNC(=O)c1ccc(NC(=O)N2Cc3ccc(N)cc3C2)cc1
Solvent: CC(=O)Cl
Product: O=C(NCc1ccc(CNC(=O)c2ccc(NC(=O)N3Cc4ccc(F)cc4C3)cc2)cc1)c1ccccc1

Procedure:
The title compound was prepared as described in Example 278, substituting benzoyl chloride for acetyl chloride and N-(4-{[4-(aminomethyl)benzyl]carbamoyl}phenyl)-5-fluoro-1,3-dihydro-2H-isoindole-2-carboxamide for 5-amino-N-(4-(propylcarbamoyl)phenyl)isoindoline-2-carboxamide. 1H NMR (300 MHz, DMSO-d6) δ ppm 9.01 (t, J=6.0 Hz, 1H), 8.83 (t, J=5.9 Hz, 1H), 8.60 (s, 1H), 7.85-7.91 (m, 2H), 7.78-7.83 (m, 2H), 7.63-7.68 (m, 2H), 7.36-7.56 (m, 4H), 7.27 (s, 4H), 7.21-7.26 (m, 1H), 7.10-7.19 (m, 1H), 4.72-4.81 (m, 4H), 4.40-4.48 (m, 4H); MS (ESI(+)) m/e 523 (M+H)+.
Reaction SMILES: CO[C:3]([C@@H:5]1[CH2:10][CH2:9][CH2:8][CH2:7][C@@H:6]1[C:11]([OH:13])=[O:12])=O.C(N(CC)CC)C.ClC(OCC)=O>C1COCC1>[C:11]1(=[O:12])[C@H:6]2[C@H:5]([CH2:10][CH2:9][CH2:8][CH2:7]2)[CH2:3][O:13]1
Reactant: COC(=O)[C@@H]1CCCC[C@@H]1C(=O)O
Agent: CCOC(=O)Cl
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: O=C1OC[C@H]2CCCC[C@@H]12
Reaction time: 0.5 h
Yield: 68 %

Procedure:
Into a 25 mL jacketed vessel cooled to below 0° C. was placed a solution of (1S,2R)-2-(methoxycarbonyl) cyclohexane carboxylic acid (3, 880 mg, 4.72 mmol) and triethylamine 659 μL, 4.72 mmol) in THF (6.6 mL). A solution of ethyl chloroformate (512 μL, 4.72 mmol) in 1.2 mL of THF was added slowly over a few minutes and the resulting mixture was stirred for 30 minutes. The precipitated triethylamine hydrochloride salt was removed by filtration and the filtrate was added drop-wise to a suspension of sodium borohydride in 4.6 mL of water at 12° C. After the addition was complete, the reaction mixture was stirred at 20° C. for a further 3.5 hours. The reaction mixture was then cooled to below 10° C., acidified to pH 4 with 2M HCl solution, and extracted with 2×15 mL of dichloromethane. The combined organic extracts were dried over magnesium sulfate and solvent was removed under reduced pressure, to yield 450 mg of a colorless oil. The material was purified by short path distillation to yield 170 mg of colorless oil with e.e.=98% and [α]D20=−39.3° (c 1, methanol).
Reaction SMILES: [NH:1]1[CH2:5][CH2:4][CH2:3][CH2:2]1.[C:6]([N:8]=[C:9](OCC)[CH2:10][C:11]#[N:12])#[N:7]>O1CCCC1>[C:6]([N:8]=[C:9]([N:1]1[CH2:5][CH2:4][CH2:3][CH2:2]1)[CH2:10][C:11]#[N:12])#[N:7]
Reactant: CCOC(CC#N)=NC#N
Reactant: C1CCNC1
Solvent: C1CCOC1
Product: N#CCC(=NC#N)N1CCCC1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
Pyrrolidine (2.07 g, 0.0292 m) is added to 4.00 g (0.0292 m) of an ice-cooled solution of ethyl N,2-dicyanoacetimidate in 80 ml of tetrahydrofuran and stirred for two hours at room temperature. The crude product is isolated and chromatographed in the same manner as that of Example 2. The tlc-pure crystalline product (4.80 g) is triturated with diethyl ether to give 4.00 g (84%), mp 45° C. Nmr and ir are consistent.
Reaction SMILES: [C:1]1(=[O:11])[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[C:3](=[O:10])[CH2:2]1.[H][H].[BH4-].[Na+]>[Pd]>[OH:11][CH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[C:3](=[O:10])[CH2:2]1
Reactant: [H][H]
Reactant: O=C1CC(=O)c2ccccc21
Agent: [Pd]
Agent: [BH4-]
Agent: [Na+]
Product: O=C1CC(O)c2ccccc21
Yield: 95 %

Procedure:
A mixture of 73.25 g. (0.5 mole) of 1,3-indandione, 10.0 g. of 10% Pd on charcoal and 800 ml. of 2B-ethanol was added on the 1 liter flask of a Brown Hydrogenator, and hydrogen equivalent to 125 ml. of 1M sodium borohydride solution was added at room temperature and atmospheric pressure (0.5 mole H2). The solution was filtered through a bed of Celite Filter Aid, and the bed washed with ethanol. The ethanol solution was concentrated, and from the concentrate, a small amount of white solid separated, 1,3-indanediol, 1,6 g., m.p. 182°-187°. This by-product was filtered off and discarded. Evaporation of the filtrate gave 70.2 g. of nearly colorless oil (yield > 95%) which can be used directly in the aldehyde condensation. The IR spectrum of the product showed typical hydroxyl and carbonyl absorption.
Reaction SMILES: [C:1]([C:3]1[CH:4]=[CH:5][C:6]([O:13][CH3:14])=[C:7]([CH:12]=1)[C:8]([O:10][CH3:11])=[O:9])#[N:2].[N:15]([Sn](C)(C)C)=[N+:16]=[N-:17]>C1(C)C=CC=CC=1>[CH3:14][O:13][C:6]1[CH:5]=[CH:4][C:3]([C:1]2[NH:17][N:16]=[N:15][N:2]=2)=[CH:12][C:7]=1[C:8]([O:10][CH3:11])=[O:9]
Reactant: C[Sn](C)(C)N=[N+]=[N-]
Reactant: COC(=O)c1cc(C#N)ccc1OC
Solvent: Cc1ccccc1
Product: COC(=O)c1cc(-c2nnn[nH]2)ccc1OC
Temperature: 25 °C

Procedure:
A stirred solution of methyl 5-cyano-2-methoxybenzoate (0.87 g, 4.5 mmol) in toluene (4 mL) was treated with azidotrimethyltin (1.85 g, 9.0 mmol) and heated at reflux overnight. After cooling to room temperature, the solvents were evaporated. The crude product was dissolved in ethyl acetate, washed with brine (2×), dried over sodium sulfate, and concentrated. Column chromatography on silica gel (5% methanol/methylene chloride) afforded 0.78 g (75%). LC/MS (HPLC method 3): tR=1.66 min, 235.05 (MH)+.
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([S:8][CH3:9])[CH:5]=[CH:4][C:3]=1[NH:10][C:11]1[N:15]2[CH:16]=[N:17][CH:18]=[CH:19][C:14]2=[CH:13][C:12]=1[C:20]([OH:22])=O.[CH:23]([O:25][CH2:26][CH2:27][O:28][NH2:29])=[CH2:24].C1C=CC2N(O)N=NC=2C=1.CCN=C=NCCCN(C)C.Cl.CCN(C(C)C)C(C)C>CN(C=O)C>[CH:23]([O:25][CH2:26][CH2:27][O:28][NH:29][C:20]([C:12]1[CH:13]=[C:14]2[CH:19]=[CH:18][N:17]=[CH:16][N:15]2[C:11]=1[NH:10][C:3]1[CH:4]=[CH:5][C:6]([S:8][CH3:9])=[CH:7][C:2]=1[F:1])=[O:22])=[CH2:24]
Reactant: C=COCCON
Reactant: CSc1ccc(Nc2c(C(=O)O)cc3ccncn23)c(F)c1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: C=COCCONC(=O)c1cc2ccncn2c1Nc1ccc(SC)cc1F
Temperature: 25 °C
Reaction time: 16 h
Yield: 54.8 %

Procedure:
7-(2-Fluoro-4-methylsulfanyl-phenylamino)-pyrrolo[1,2-c]pyrimidine-6-carboxylic acid (200 mg, 0.63 mmol), O-(2-vinyloxy-ethyl)-hydroxylamine (106 mg, 0.69 mmol), HOBt (94 mg, 0.69 mmol), EDCI hydrochloride (132 mg, 0.69 mmol) and DIPEA (118 μL, 0.69 mmol) were dissolved in DMF (5 mL). The reaction was stirred at room temperature for 16 hours then concentrated in vacuo. The resultant residue was dissolved in ethyl acetate (10 mL), washed with aqueous saturated sodium bicarbonate solution (10 mL) and the aqueous fraction extracted twice with ethyl acetate (2×10 mL). The combined organic fractions were washed with brine, dried (MgSO4) and concentrated in vacuo. The resultant residue was subjected to flash chromatography (SiO2, gradient 0-100% ethylacetate in cyclohexane) to yield the title compound as a brown solid (139 mg, 55%). LCMS (Method B): RT=3.35 min, M+H+=403.
Reaction SMILES: C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].[C:15]([O:19][C:20]([NH:22][CH2:23][CH:24]1[CH2:28][CH2:27][NH:26][CH2:25]1)=[O:21])([CH3:18])([CH3:17])[CH3:16].[Cl:29][C:30]1[C:37]([Cl:38])=[CH:36][CH:35]=[CH:34][C:31]=1[CH:32]=O>ClC(Cl)C>[C:15]([O:19][C:20]([NH:22][CH2:23][CH:24]1[CH2:28][CH2:27][N:26]([CH2:32][C:31]2[CH:34]=[CH:35][CH:36]=[C:37]([Cl:38])[C:30]=2[Cl:29])[CH2:25]1)=[O:21])([CH3:18])([CH3:16])[CH3:17]
Reactant: O=Cc1cccc(Cl)c1Cl
Reactant: CC(C)(C)OC(=O)NCC1CCNC1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: CC(Cl)Cl
Product: CC(C)(C)OC(=O)NCC1CCN(Cc2cccc(Cl)c2Cl)C1
Reaction time: 8 h
Yield: 80.7 %

Procedure:
Sodium triacetoxyborohydride (3.2 g, 15 mmol, 1.5 equiv.) was added in one portion to a stirred solution of 3-(RS)-(N-tert-butoxycarbonylaminomethyl)pyrrolidine (2.0 g, 10 mmol) and 2,3-dichlorobenzaldehyde (1.9 g, 11 mmol, 1.1 equiv.) in dichloroethane (60 mL) at room temperature. The suspension was stirred overnight, then concentrated in vacuo. The residue was diluted with ether and quenched with 1 M hydrochloric acid. The aqueous phase was basified with 4 M sodium hydroxide to pH 12, then extracted with ethyl acetate. The organic extracts were combined and washed with brine, then dried over sodium sulfate and concentrated. Flash chromatography of the residue afforded 3-(RS)-(N-tert-butoxycarbonylaminomethyl)-1-(2,3-dichlorobenzyl)-pyrrolidine as a colorless oil (2.9 g). The oil was taken up into methylene chloride (30 mL) and treated with neat trifluoroacetic acid (5 mL). After 1 h, the volatile components were removed on a vacuum pump, then concentrated further under high vacuum to give 3-(RS)-aminomethyl-1-(2,3-dichlorobenzyl)pyrrolidine which was used directly without further purification.
Reaction SMILES: Cl.Cl.[NH:3]([C:5]1[C:14]2[C:9](=[CH:10][CH:11]=[CH:12][CH:13]=2)[N:8]=[C:7]([CH3:15])[N:6]=1)[NH2:4].C(N(CC)CC)C.[CH3:23][C:24]1[CH:29]=[C:28]([C:30]([CH3:32])=O)[CH:27]=[CH:26][CH:25]=1>C(O)C>[CH3:15][C:7]1[N:6]=[C:5]([NH:3][N:4]=[C:30]([C:28]2[CH:29]=[C:24]([CH3:23])[CH:25]=[CH:26][CH:27]=2)[CH3:32])[C:14]2[C:9](=[CH:10][CH:11]=[CH:12][CH:13]=2)[N:8]=1
Reactant: Cc1nc(NN)c2ccccc2n1
Reactant: CC(=O)c1cccc(C)c1
Agent: Cl
Solvent: CCO
Solvent: CCN(CC)CC
Product: CC(=NNc1nc(C)nc2ccccc12)c1cccc(C)c1

Procedure:
The title compound was prepared from 4-hydrazino-2-methylquinazoline dihydrochloride (250 mg, 1.01 mmol), triethylamine (0.35 mL, 2.02 mmol) and 3-methylacetophenone (0.35 mL, 2.63 mmol) in ethanol (5 mL) by a procedure similar to Example 4, step 4 yielding 11 mg (4%) of a yellow solid. HPLC Purity: 95%.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([CH2:9][C:10]([OH:12])=[O:11])[CH:5]=[C:6]([Cl:8])[CH:7]=1.Cl.[CH3:14]O>>[CH3:14][O:11][C:10](=[O:12])[CH2:9][C:4]1[CH:5]=[C:6]([Cl:8])[CH:7]=[C:2]([Br:1])[CH:3]=1
Reactant: O=C(O)Cc1cc(Cl)cc(Br)c1
Reactant: CO
Agent: Cl
Product: COC(=O)Cc1cc(Cl)cc(Br)c1
Temperature: 90 °C
Reaction time: 2 h

Procedure:
To a solution of (3-bromo-5-chloro-phenyl)-acetic acid (0.400 g, 1.60 mmol) in MeOH (15 mL) was added 4N aqueous HCl (2 mL), and the reaction was stirred at 90° C. for 2 hours. The mixture was concentrated and purified by silica gel chromatography (0-5% EtOAc in hexanes) to give the title compound.
Reaction SMILES: O.[NH2:2][NH2:3].[CH3:4][C:5]1[C:6]([C:25](OC)=[O:26])=[C:7]([NH:10][C:11](=[O:24])[CH2:12][N:13]2[C:22]3[C:17](=[CH:18][CH:19]=[CH:20][CH:21]=3)[CH2:16][CH2:15][C:14]2=[O:23])[S:8][CH:9]=1>C(O)C.[Cl-].[Na+].O>[NH:2]([C:25]([C:6]1[C:5]([CH3:4])=[CH:9][S:8][C:7]=1[NH:10][C:11](=[O:24])[CH2:12][N:13]1[C:22]2[C:17](=[CH:18][CH:19]=[CH:20][CH:21]=2)[CH2:16][CH2:15][C:14]1=[O:23])=[O:26])[NH2:3]
Reactant: NN
Reactant: COC(=O)c1c(C)csc1NC(=O)CN1C(=O)CCc2ccccc21
Agent: [Cl-]
Agent: [Na+]
Solvent: CCO
Solvent: O
Product: Cc1csc(NC(=O)CN2C(=O)CCc3ccccc32)c1C(=O)NN
Temperature: 50 °C
Reaction time: 24 h
Yield: 78.7 %

Procedure:
Hydrazine monohydrate (0.059 mL, 1.23 mmol) was added to a solution of methyl 4-methyl-2-(2-(2-oxo-3,4-dihydroquinolin-1(2H)-yl)acetamido)thiophene-3-carboxylate (221 mg, 0.616 mmol) in ethanol (2 mL) and the resulting solution was stirred at 50° C. for 24 h. The mixture was diluted with brine and extracted with ethyl acetate. The organic phase was separated, dried (Na2SO4), filtered, concentrated under vacuum to give N-(3-(hydrazinecarbonyl)-4-methylthiophen-2-yl)-2-(2-oxo-3,4-dihydroquinolin-1(2H)-yl)acetamide (174 mg, 0.485 mmol, 79%). Retention time (min)=1.435, method [1], MS (ESI) 359.1 (M+H).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]2[C:8](=[C:9]([C:11]([NH2:13])=[O:12])[CH:10]=1)[NH:7][CH:6]=[CH:5]2.O=[C:15]1[CH2:20][CH2:19][N:18]([C:21]([O:23][C:24]([CH3:27])([CH3:26])[CH3:25])=[O:22])[CH2:17][CH2:16]1.C[O-].[Na+]>CO>[NH2:13][C:11]([C:9]1[CH:10]=[C:2]([Br:1])[CH:3]=[C:4]2[C:8]=1[NH:7][CH:6]=[C:5]2[C:15]1[CH2:20][CH2:19][N:18]([C:21]([O:23][C:24]([CH3:27])([CH3:26])[CH3:25])=[O:22])[CH2:17][CH:16]=1)=[O:12]
Reactant: NC(=O)c1cc(Br)cc2cc[nH]c12
Reactant: CC(C)(C)OC(=O)N1CCC(=O)CC1
Agent: C[O-]
Agent: [Na+]
Solvent: CO
Product: CC(C)(C)OC(=O)N1CC=C(c2c[nH]c3c(C(N)=O)cc(Br)cc23)CC1

Procedure:
To a solution of 5-bromo-1H-indole-7-carboxamide (10 g, 41.84 mmol) in methanol (5 mL), 1,1-dimethylethyl 4-oxo-1-piperidinecarboxylate (684 mg, 3.42 mmol) and sodium methoxide (0.5 M in THF, 13.7 mL, 6.84 mmol) were added. The reaction mixture was stirred at reflux temperature for 16 hours. All solvent was evaporated under reduced pressure. The residue was partitioned between ethyl acetate (100 mL) and water (100 mL). The combined organic phase was dried over MgSO4 and concentrated under reduced pressure, and purified by flash column chromatography (ethyl acetate/hexanes, 1/1) to give the desired product (7.4 g, 43
Reaction SMILES: Cl[Si:2]([C:5]([CH3:8])([CH3:7])[CH3:6])([CH3:4])[CH3:3].[OH:9][CH:10]1[CH2:15][CH2:14][CH:13]([C:16]([O:18][CH2:19][CH3:20])=[O:17])[CH2:12][CH2:11]1.N1C=CN=C1.C(O)(=O)CC(CC(O)=O)(C(O)=O)O>CN(C)C=O>[CH3:6][C:5]([Si:2]([CH3:4])([CH3:3])[O:9][C@H:10]1[CH2:11][CH2:12][C@H:13]([C:16]([O:18][CH2:19][CH3:20])=[O:17])[CH2:14][CH2:15]1)([CH3:8])[CH3:7]
Reactant: CCOC(=O)C1CCC(O)CC1
Reactant: CC(C)(C)[Si](C)(C)Cl
Agent: O=C(O)CC(O)(CC(=O)O)C(=O)O
Agent: c1c[nH]cn1
Solvent: CN(C)C=O
Product: CCOC(=O)[C@H]1CC[C@H](O[Si](C)(C)C(C)(C)C)CC1
Temperature: 40 °C

Procedure:
Chloro(1,1-dimethylethyl)dimethylsilane (115 g; 0.76 mol) was added in portions over 1 hour to a solution of commercially available ethyl 4-hydroxycyclohexanecarboxylate (118 g; 0.68 mol), imidazole (103 g; 1.52 mol) and dimethylformamide (400 mL) stirred under an atmosphere of argon. A small exotherm was observed resulting in the reaction mixture temperature increasing to ˜40° C. The mixture was stirred at room temperature overnight then poured into 10% citric acid solution (2 L) and extracted with diethyl ether (2×800 mL). The ether extracts were washed with water, brine and then dried (Na2SO4) and the solvent was removed to give the title compound as an oil (198.4 g)
Reaction SMILES: [CH2:1]([NH:9][C:10]([C@@H:12]1[CH2:17][CH2:16][CH2:15][NH:14][NH:13]1)=[O:11])[CH2:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.CCN(CC)CC.[CH2:25]([O:32][C:33](Cl)=[O:34])[C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1>C(Cl)Cl>[CH2:25]([O:32][C:33]([N:14]1[CH2:15][CH2:16][CH2:17][C@@H:12]([C:10](=[O:11])[NH:9][CH2:1][CH2:2][C:3]2[CH:4]=[CH:5][CH:6]=[CH:7][CH:8]=2)[NH:13]1)=[O:34])[C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1
Reactant: O=C(NCCc1ccccc1)[C@@H]1CCCNN1
Reactant: O=C(Cl)OCc1ccccc1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: O=C(NCCc1ccccc1)[C@@H]1CCCN(C(=O)OCc2ccccc2)N1
Temperature: -5 °C
Reaction time: 1.5 h
Yield: 99.3 %

Procedure:
To a solution of (S)-hexahydro pyridazine-3-carboxylic acid phenethyl-amide (376 mg, 1.59 mmol) and Et3N (0.66 mL) in CH2Cl2 (10 mL) at 0° C., is added benzylchloroformate (270 mg, 1.59 mmol) dropwise. After stirring at −5° C. for 1.5 hours, the reaction mixture is diluted with CH2Cl2 (50 mL) and washed with 10 mL of water. The organic layer is dried over Na2SO4 and concentrated to give (S)-3-phenethylcarbamoyl-tetrahydro-pyridazine-1-carboxylic acid benzyl ester (580 mg) as pale gum without further purification for next step reaction. (NMR and MS data confirmed, U-3133-59).
Reaction SMILES: ClC(Cl)(O[C:5](=[O:11])[O:6][C:7](Cl)(Cl)Cl)Cl.[C:13]([O:17][C@H:18]([CH3:45])[C@H:19]([NH:22][C:23]1[CH:28]=[C:27]([F:29])[N:26]=[C:25]([NH:30][C@H:31]([C:33]2[CH:34]=[N:35][N:36]([C:38]3[CH:43]=[CH:42][C:41]([F:44])=[CH:40][CH:39]=3)[CH:37]=2)[CH3:32])[N:24]=1)CO)([CH3:16])([CH3:15])[CH3:14].N1C(C)=CC=CC=1C>C(Cl)Cl.[Cl-].[Na+]>[C:13]([O:17][C@@H:18]([C@H:19]1[CH2:7][O:6][C:5](=[O:11])[N:22]1[C:23]1[CH:28]=[C:27]([F:29])[N:26]=[C:25]([NH:30][C@H:31]([C:33]2[CH:34]=[N:35][N:36]([C:38]3[CH:43]=[CH:42][C:41]([F:44])=[CH:40][CH:39]=3)[CH:37]=2)[CH3:32])[N:24]=1)[CH3:45])([CH3:15])([CH3:16])[CH3:14]
Reactant: O=C(OC(Cl)(Cl)Cl)OC(Cl)(Cl)Cl
Reactant: C[C@H](Nc1nc(F)cc(N[C@H](CO)[C@@H](C)OC(C)(C)C)n1)c1cnn(-c2ccc(F)cc2)c1
Agent: [Cl-]
Agent: [Na+]
Solvent: ClCCl
Solvent: Cc1cccc(C)n1
Product: C[C@H](Nc1nc(F)cc(N2C(=O)OC[C@@H]2[C@@H](C)OC(C)(C)C)n1)c1cnn(-c2ccc(F)cc2)c1
Temperature: 25 °C

Procedure:
Triphosgene (18 mg, 0.062 mmol, 0.5 equiv) was added to a solution of (2R,3R)-3-(tert-butoxy)-2-((6-fluoro-2-(((S)-1-(1-(4-fluorophenyl)-1H-pyrazol-4-yl)ethyl)amino)pyrimidin-4-yl)amino)butan-1-ol (57 mg, 0.12 mmol) in DCM (1.2 mL) at −78° C., followed by the dropwise addition of 2,6-lutidine (0.058 mL, 0.49 mmol, 4 equiv). The solution was allowed to warm to room temperature and was then heated at 35° C. for 30 min. The reaction was then cooled to room temperature and diluted with DCM (30 mL) and saturated aqueous sodium chloride (30 mL). The layers were separated and the organic layer was dried over Na2SO4, filtered and concentrated to give crude (R)-4-((R)-1-(tert-butoxy)ethyl)-3-(6-fluoro-2-(((S)-1-(1-(4-fluorophenyl)-1H-pyrazol-4-yl)ethyl)amino)pyrimidin-4-yl)oxazolidin-2-one, which was used without further purification. MS m/z 487.4 (M+H)+; Rt-1.12 min.