Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:8]=[CH:7][C:5]([NH2:6])=[CH:4][C:3]=1[I:9].[CH3:10][C:11]1[C:15]([C:16](O)=[O:17])=[C:14]([CH3:19])[O:13][N:12]=1.C(Cl)CCl>>[CH3:10][C:11]1[C:15]([C:16]([NH:6][C:5]2[CH:7]=[CH:8][C:2]([Cl:1])=[C:3]([I:9])[CH:4]=2)=[O:17])=[C:14]([CH3:19])[O:13][N:12]=1
Reactant: Nc1ccc(Cl)c(I)c1
Reactant: Cc1noc(C)c1C(=O)O
Solvent: ClCCCl
Product: Cc1noc(C)c1C(=O)Nc1ccc(Cl)c(I)c1

Procedure:
4-Chloro-3-iodoaniline (1.01 g, 4 mmol) was used in procedure E with 3,5-dimethyl-4-isoxazolecarboxylic acid (0.565 g, 4 mmol), EDC (1.32 g, 6.8 mmol), TEA (0.5 mL), DMAP-(50 mg, 0.4 mmol) at 23° C. for overnight. The crude reaction was purified by silica gel chromatography (0-15% ethyl acetate/CH2Cl2) to yield 3,5-dimethyl-N-(4-chloro-3-iodophenyl)isoxazole-4-carboxamide as a white solid.
Reaction SMILES: C([O:8][C:9]1[CH:14]=[C:13]([O:15]CC2C=CC=CC=2)[C:12]([CH:23]([CH3:25])[CH3:24])=[CH:11][C:10]=1[C:26]1[N:27]([C:32]2[CH:33]=[C:34]3[C:38](=[CH:39][CH:40]=2)[CH2:37][C:36]2([O:44][CH2:43][CH2:42][O:41]2)[CH2:35]3)[C:28]([OH:31])=[N:29][N:30]=1)C1C=CC=CC=1>C1COCC1.CO.[Pd]>[CH2:37]1[C:38]2[C:34](=[CH:33][C:32]([N:27]3[C:28]([OH:31])=[N:29][N:30]=[C:26]3[C:10]3[CH:11]=[C:12]([CH:23]([CH3:25])[CH3:24])[C:13]([OH:15])=[CH:14][C:9]=3[OH:8])=[CH:40][CH:39]=2)[CH2:35][C:36]21[O:41][CH2:42][CH2:43][O:44]2
Reactant: CC(C)c1cc(-c2nnc(O)n2-c2ccc3c(c2)CC2(C3)OCCO2)c(OCc2ccccc2)cc1OCc1ccccc1
Agent: [Pd]
Solvent: CO
Solvent: C1CCOC1
Product: CC(C)c1cc(-c2nnc(O)n2-c2ccc3c(c2)CC2(C3)OCCO2)c(O)cc1O
Yield: 97.2 %

Procedure:
5-(2,4-Bis-benzyloxy-5-isopropyl-phenyl)-4-(1′,3′-dihydro-spiro[[1,3]dioxolane-2,2′-inden]-5′-yl)-4H-[1,2,4]triazol-3-ol (550 mg, 0.93 mmol) was subsequently hydrodebensylated using Pd/C (10%, dry, 100 mg) and H2 in THF/MeOH (1/1, mL) at 1 atm at r.t. for 2 h. The reaction mixture was filtered through a pad of celite and the mother liquid was concentrated. It was again filtered through a pad of silica gel and the filtrate was concentrated to give the title compound as a white solid (370 mg, 97%).
Reaction SMILES: [O-][CH2:2]C.[Na+].[CH3:5][O:6][C:7]1[N:12]=[CH:11][C:10]([CH2:13][C:14]2[C:15](=[O:21])[NH:16][C:17](=[S:20])[NH:18][CH:19]=2)=[CH:9][N:8]=1.CI>CCO>[CH3:5][O:6][C:7]1[N:8]=[CH:9][C:10]([CH2:13][C:14]2[C:15](=[O:21])[N:16]=[C:17]([S:20][CH3:2])[NH:18][CH:19]=2)=[CH:11][N:12]=1
Reactant: COc1ncc(Cc2c[nH]c(=S)[nH]c2=O)cn1
Reactant: CC[O-]
Agent: [Na+]
Solvent: CI
Solvent: CCO
Product: COc1ncc(Cc2c[nH]c(SC)nc2=O)cn1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 83.7 %

Procedure:
Into a stirred solution of sodium ethoxide (1.358 mmol, 2 eq) in EtOH (3 ml) was added 5-(2-methoxy-pyrimidin-5-ylmethyl)-2-thioxo-2,3-dihydro-1H-pyrimidin-4-one (0.679 mmol, 1 eq) at rt. After 30 min, the reaction mixture was treated with methyl iodide (1.358 mmol, 2 eq) and was stirred at rt overnight. Solvent was evaporated and a crude product was purified on Biotage SP1 Snap Si 10; 15 ml/min in the gradient of EtOAc in Cyclohexane: 0-10% in 30 CV. The appropriate fractions were combined and evaporated in vacuo to give the required product 5-(2-methoxy-pyrimidin-5-ylmethyl)-2-methylsulfanyl-1H-pyrimidin-4-one (0.568 mmol, yield=83%, purity=46%). [M+H]+=265.25 1H NMR (300 MHz, DMSO-d6) δ/ppm 2.39 (s, 1H), 3.82-3.87 (m, 3H), 7.75 (s, 1H), 8.47 (s, 2H)
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([O:9][CH2:10][C@H:11]2[CH2:15][CH2:14][CH2:13][N:12]2[C:16]([O:18][C:19]([CH3:22])([CH3:21])[CH3:20])=[O:17])[CH:5]=[N:6][C:7]=1[Cl:8].[S:23]1[CH:27]=[CH:26][CH:25]=[C:24]1B(O)O.C([O-])([O-])=O.[Na+].[Na+]>C1(C)C=CC=CC=1>[S:23]1[CH:27]=[CH:26][CH:25]=[C:24]1[C:2]1[CH:3]=[C:4]([O:9][CH2:10][CH:11]2[CH2:15][CH2:14][CH2:13][N:12]2[C:16]([O:18][C:19]([CH3:22])([CH3:21])[CH3:20])=[O:17])[CH:5]=[N:6][C:7]=1[Cl:8]
Reactant: OB(O)c1cccs1
Reactant: CC(C)(C)OC(=O)N1CCC[C@@H]1COc1cnc(Cl)c(Br)c1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: Cc1ccccc1
Product: CC(C)(C)OC(=O)N1CCCC1COc1cnc(Cl)c(-c2cccs2)c1
Yield: 18.6 %

Procedure:
A mixture of 5-bromo-6-chloro-3-(1-BOC-2(R)-pyrrolidinylmethoxy)pyridine from Example 69a (310 mg, 0.87 mmol), 2-thienylboronic acid (167 mg, 1.3 mmol), 2M Na2CO3 (3 mL) and Pd(0) (32 mg) were mixed together in toluene (6 mL), and the mixture was heated at reflux for 4 hours. The mixture was cooled and extracted with chloroform. The CHCl3 was removed under reduced pressure, and the residue was chromatographed on a silica gel column, eluting with hexane/ethyl acetate 1:1 to afford the title compound (64 mg, 20% yield). MS (DCI/NH3) m/z 287 (M+H)+. 1 H NMR (CDCl3, 300 MHz) δ: 1.47 (s, 9H), 1.84-2.11 (m, 3H), 3.31-3.48 (m, 2H), 3.82-4.30 (m, 3H), 7.12 (dd, J=4.5, 6, 1H), 7.34-7.42 (m, 3H), 7.46-7.57 (m, 1H), 8.23 (d, J=3, 1H).
Reaction SMILES: ClC1C=C(C=CC=1)C(OO)=[O:6].[CH2:12]([C:15]1[N:16]([CH2:28][CH2:29][CH2:30][O:31][N:32]2[C:40](=[O:41])[C:39]3[C:34](=[CH:35][CH:36]=[CH:37][CH:38]=3)[C:33]2=[O:42])[C:17]2[C:26]3[CH:25]=[CH:24][CH:23]=[CH:22][C:21]=3[N:20]=[CH:19][C:18]=2[N:27]=1)[CH2:13][CH3:14]>C(Cl)(Cl)Cl>[O-:6][N+:20]1[C:21]2[CH:22]=[CH:23][CH:24]=[CH:25][C:26]=2[C:17]2[N:16]([CH2:28][CH2:29][CH2:30][O:31][N:32]3[C:40](=[O:41])[C:39]4[C:34](=[CH:35][CH:36]=[CH:37][CH:38]=4)[C:33]3=[O:42])[C:15]([CH2:12][CH2:13][CH3:14])=[N:27][C:18]=2[CH:19]=1
Reactant: O=C(OO)c1cccc(Cl)c1
Reactant: CCCc1nc2cnc3ccccc3c2n1CCCON1C(=O)c2ccccc2C1=O
Solvent: ClC(Cl)Cl
Product: CCCc1nc2c[n+]([O-])c3ccccc3c2n1CCCON1C(=O)c2ccccc2C1=O
Temperature: 25 °C
Reaction time: 7 h
Yield: 99 %

Procedure:
3-Chloroperoxybenzoic acid (14.9 g, 66.4 mmol)(mCPBA, available as an approximately 77% pure mixture) was added to a solution of 2-[3-(2-propyl-1H-imidazo[4,5-c]quinolin-1-yl)propoxy]-1H-isoindole-1,3(2H)-dione (25.0 g, 60.3 mmol) in chloroform (200 mL), and the reaction was stirred for seven hours at room temperature. An analysis by liquid chromatography/mass spectrometry (LC/MS) indicated that the reaction was incomplete, and additional mCPBA (4.96 g, 22.1 mmol) was added. The reaction was allowed to stir at room temperature overnight. The solution was then washed with brine (2×100 mL) and saturated aqueous sodium bicarbonate (2×100 mL), dried over magnesium sulfate, filtered, and concentrated under reduced pressure to provide a fluffy, light-brown solid. The solid was dried under high vacuum for one hour to provide 25.7 g of 2-[3-(5-oxido-2-propyl-1H-imidazo[4,5-c]quinolin-1-yl)propoxy]-1H-isoindole-1,3(2H)-dione as a white solid.
Reaction SMILES: [CH3:1][N:2]1[CH2:7][CH2:6][N:5]([C:8]2[N:13]=[C:12]([N:14]3[CH2:19][CH2:18][CH:17]([CH3:20])[CH2:16][CH2:15]3)[C:11]([N+:21]([O-])=O)=[CH:10][CH:9]=2)[CH2:4][C:3]1=[O:24].[C:25]([C:27]1[O:31][C:30]([C:32](Cl)=[O:33])=[CH:29][CH:28]=1)#[N:26].C(C1OC(C(O)=O)=CC=1)#N>C(Cl)Cl>[CH3:20][CH:17]1[CH2:18][CH2:19][N:14]([C:12]2[C:11]([NH:21][C:32]([C:30]3[O:31][C:27]([C:25]#[N:26])=[CH:28][CH:29]=3)=[O:33])=[CH:10][CH:9]=[C:8]([N:5]3[CH2:6][CH2:7][N:2]([CH3:1])[C:3](=[O:24])[CH2:4]3)[N:13]=2)[CH2:15][CH2:16]1
Reactant: N#Cc1ccc(C(=O)Cl)o1
Reactant: CC1CCN(c2nc(N3CCN(C)C(=O)C3)ccc2[N+](=O)[O-])CC1
Agent: N#Cc1ccc(C(=O)O)o1
Solvent: ClCCl
Product: CC1CCN(c2nc(N3CCN(C)C(=O)C3)ccc2NC(=O)c2ccc(C#N)o2)CC1
Yield: 51 %

Procedure:
1-Methyl-4-(4-methyl-3′-nitro-3,4,5,6-tetrahydro-2H-[1,2′]bipyridinyl-6′-yl)-piperazin-2-one (as prepared in previous step) (166 mg, 0.50 mmol) was converted to the corresponding amine according to the procedure in Example 55, step (c) and coupled with 5-cyano-furan-2-carbonyl chloride as prepared in Example 4, step (c) (obtained from 137 mg, 1.00 mmol of 5-cyano-furan-2-carboxylic acid as prepared in Example 1) in CH2Cl2 (2 mL) at 0° C. The product was isolated by flash chromatography on silica (20% EtOAc/hexane-10% MeOH/EtOAc) to obtain the title compound (108 mg, 51%). 1H-NMR (CDCl3; 400 MHz): δ 8.73 (br s, 1H), 8.44 (d, 1H, J=8.7 Hz), 7.24 (d, 1H, J=3.7 Hz), 7.22 (d, 1H, J=3.7 Hz), 6.32 (d, 1H, J=8.7 Hz), 4.16 (m, 2H), 3.84 (m, 2H), 3.46 (m, 2H), 3.20 (m, 2H), 3.04 (s, 3H), 2.84 (m, 2H), 1.8 (m, 2H), 1.4 (m, 1H), 1.32 (m, 2H), 1.04 (d, 3H, J=6.3 Hz). LC-MS (ESI, m/z): Calcd. for C22H26N6O3, 423.2 (M+H), found 423.1
Reaction SMILES: [C:1]([C:9]1[CH:14]=[CH:13][N+:12]([O-])=[CH:11][CH:10]=1)(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.P(Cl)(Cl)([Cl:18])=O.[OH-].[Na+]>O>[C:1]([C:9]1[CH:14]=[CH:13][N:12]=[C:11]([Cl:18])[CH:10]=1)(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=C(c1ccccc1)c1cc[n+]([O-])cc1
Reactant: O=P(Cl)(Cl)Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: O=C(c1ccccc1)c1ccnc(Cl)c1

Procedure:
A mixture of 2.5 g 4-benzoylpyridine N-oxide m.p. 127°-30° C. (obtained according to T. KATO et. al., Yakugaku Zasshi 86, 1022-26, 1966), and 6 ml phosphorus oxychloride is refluxed for 2 hrs. After cooling, the reaction mixture is very slowly added to ice: water, basified (10N NaOH) and extracted with methylene chloride. The organic layer is washed with water, dried and solvent removed in a rotary evaporator. Yield: 2.4 g of title product, identical with that described in Ex. 4.
Reaction SMILES: [CH3:1][N:2]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[C:4]([C@@H:11]([CH2:22][CH:23]=[O:24])[CH2:12][O:13][C:14](=[O:21])[C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)=[CH:3]1.CC1C=CC(S(O)(=O)=O)=CC=1.[CH2:36](O)[CH2:37][OH:38]>C(Cl)Cl>[O:24]1[CH2:36][CH2:37][O:38][CH:23]1[CH2:22][C@H:11]([C:4]1[C:5]2[C:10](=[CH:9][CH:8]=[CH:7][CH:6]=2)[N:2]([CH3:1])[CH:3]=1)[CH2:12][O:13][C:14](=[O:21])[C:15]1[CH:16]=[CH:17][CH:18]=[CH:19][CH:20]=1
Reactant: Cn1cc([C@@H](CC=O)COC(=O)c2ccccc2)c2ccccc21
Reactant: OCCO
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: ClCCl
Product: Cn1cc([C@H](COC(=O)c2ccccc2)CC2OCCO2)c2ccccc21
Temperature: 25 °C
Reaction time: 8 h

Procedure:
(R)-Benzoic acid 2-(1-methyl-1H-indol-3-yl)-4-oxo-butyl ester (1.65 g, 5.10 mmol) was dissolved in CH2Cl2 (50 mL). This solution was treated with p-TSA (20 mg) and ethylene glycol (1.4 mL, 26 mmol). The reaction was stirred at room temperature overnight, at which time the organics were removed in vacuo. The solution was diluted with H2O (10 mL) and extracted with Et2O (3×20 mL). The collected organics were washed with brine, dried over Na2SO4 and concentrated in vacuo to provide (R)-benzoic acid 3-[1,3]dioxolan-2-yl-2-(1-methyl-1H-indol-3-yl)-propyl ester. The unpurified product was dissolved in MeOH/THF (18 mL/18 mL) and allowed to stir at room temperature for 10 min. To this was added a 4% NaOH/MeOH (18 mL) solution. The reaction was allowed to stir at room temperature for 1 h. The solution was diluted with H2O (10 mL) and extracted with Et2O (3×20 mL). The collected organics were washed with brine, dried over Na2SO4 and concentrated in vacuo to provide (R)-3-[1,3]dioxolan-2-yl-2-(1-methyl-1H-indol-3-yl)-propan-1-ol (600 mg, 2.30 mmol) after silica gel chromatography (50:50 Et2O/hexanes). 50% Et2O/hexanes). (R)-3-[1,3]Dioxolan-2-yl-2-(1-methyl-1H-indol-3-yl)-propan-1-ol (69.5 mg, 0.267 mmol) was dissolved in CH2Cl2 (8 mL) and Et3N (56 μl, 0.40 mmol). The reaction was cooled to 0° C. and treated with methanesulfonyl chloride (31 μl, 0.40 mmol). The reaction stirred for 1.5 h at this temperature then was allowed to warm to room temperature and stirred for an additional 10 min. The solution was diluted with H2O (5 mL) and extracted with Et2O (3×10 mL). The collected organics were washed with brine, dried over Na2SO4 and concentrated in vacuo to provide (R)-methanesulfonic acid 3-[1,3]dioxolan-2-yl-2-(1-methyl-1H-indol-3-yl)-propyl ester. Deoxygenation was performed following the method of Holder and Matturro (1977) J. Org. Chem. 42:2166.
Reaction SMILES: [CH3:1][NH:2][NH:3][C:4]1[CH2:5][N:6]=[C:7]([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=2[Cl:22])[C:8]2[CH:13]=[C:12]([CH2:14][CH3:15])[S:11][C:9]=2[N:10]=1.[C:23](Cl)(=[O:27])[O:24][CH2:25][CH3:26]>C(Cl)(Cl)Cl>[CH2:25]([O:24][C:23]([N:2]([CH3:1])[NH:3][C:4]1[CH2:5][N:6]=[C:7]([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=2[Cl:22])[C:8]2[CH:13]=[C:12]([CH2:14][CH3:15])[S:11][C:9]=2[N:10]=1)=[O:27])[CH3:26]
Reactant: CCc1cc2c(s1)N=C(NNC)CN=C2c1ccccc1Cl
Reactant: CCOC(=O)Cl
Solvent: ClC(Cl)Cl
Product: CCOC(=O)N(C)NC1=Nc2sc(CC)cc2C(c2ccccc2Cl)=NC1
Reaction time: 8 h

Procedure:
5 g of 2-(2-methylhydrazino)-5-o-chlorophenyl-7-ethyl-3H-thieno-[2,3-e][1,4]diazepine is dissolved in 30 ml of chloroform and a solution of 1.8 g of ethyl chlorocarbonate in 10 ml of chloroform is added dropwise with stirring, and the resulting mixture is stirred at room temperature for 2 hours. Then the reaction mixture is washed successively with water, an aqueous sodium hydrogen carbonate solution and water, and dried over anhydrous magnesium sulfate, and the chloroform is removed under reduced pressure. The residue is dissolved in ligroin, and the solution is allowed to stand overnight in a refrigerator to give 2-(2-ethoxycarbonyl-2-methylhydrazino)-5-o-chlorophenyl-7-ethyl-3H-thieno[2,3-e][1,4]diazepine appearing as pale yellow crystals, melting at 172°-174° C.
Reaction SMILES: [Cl:1][C:2]1[C:3]([CH3:30])=[N:4][O:5][C:6]=1[NH:7][S:8]([C:11]1[CH:15]=[CH:14][S:13][C:12]=1[C:16]([NH:18][C:19]1[C:24]([CH3:25])=[CH:23][C:22]([CH3:26])=[C:21]([CH2:27][OH:28])[C:20]=1[CH3:29])=[O:17])(=[O:10])=[O:9].Cl[C:32]1C(C)=N[O:35][C:36]=1NS(C1C=CSC=1C(NC1C(C)=CC(C)=C(C(OC)=O)C=1C)=O)(=O)=O>>[Cl:1][C:2]1[C:3]([CH3:30])=[N:4][O:5][C:6]=1[NH:7][S:8]([C:11]1[CH:15]=[CH:14][S:13][C:12]=1[C:16]([NH:18][C:19]1[C:24]([CH3:25])=[CH:23][C:22]([CH3:26])=[C:21]([CH2:27][O:28][C:36](=[O:35])[CH3:32])[C:20]=1[CH3:29])=[O:17])(=[O:10])=[O:9]
Reactant: Cc1cc(C)c(NC(=O)c2sccc2S(=O)(=O)Nc2onc(C)c2Cl)c(C)c1CO
Reactant: COC(=O)c1c(C)cc(C)c(NC(=O)c2sccc2S(=O)(=O)Nc2onc(C)c2Cl)c1C
Product: CC(=O)OCc1c(C)cc(C)c(NC(=O)c2sccc2S(=O)(=O)Nc2onc(C)c2Cl)c1C

Procedure:
N-(4-chloro-3-methyl-5-isoxazolyl)-2-(3-hydroxymethyl-2,4,6-trimethylphenylaminocarbonyl)thiophene-3-sulfonamide; and N-(4-chloro-3-methyl-5-isoxazolyl)-2-(3-methoxycarbonyl-2,4,6-trimethylphenylaminocarbonyl)thiophene-3-sulfonamide.
Reaction SMILES: Cl[CH2:2][C:3]([NH:5][C:6]1[CH:14]=[CH:13][C:12]([Cl:15])=[C:11]2[C:7]=1[C:8](=[O:33])[N:9]([C@@H:16]([C:22]1[CH:27]=[CH:26][C:25]([O:28][CH3:29])=[C:24]([O:30][CH2:31][CH3:32])[CH:23]=1)[CH2:17][S:18]([CH3:21])(=[O:20])=[O:19])[CH2:10]2)=[O:4].[NH:34]1[CH2:39][CH2:38][O:37][CH2:36][CH2:35]1.Cl>CC#N.CCOCC>[Cl:15][C:12]1[CH:13]=[CH:14][C:6]([NH:5][C:3](=[O:4])[CH2:2][N:34]2[CH2:39][CH2:38][O:37][CH2:36][CH2:35]2)=[C:7]2[C:11]=1[CH2:10][N:9]([C@@H:16]([C:22]1[CH:27]=[CH:26][C:25]([O:28][CH3:29])=[C:24]([O:30][CH2:31][CH3:32])[CH:23]=1)[CH2:17][S:18]([CH3:21])(=[O:20])=[O:19])[C:8]2=[O:33]
Reactant: C1COCCN1
Reactant: CCOc1cc([C@@H](CS(C)(=O)=O)N2Cc3c(Cl)ccc(NC(=O)CCl)c3C2=O)ccc1OC
Agent: Cl
Solvent: CCOCC
Solvent: CC#N
Product: CCOc1cc([C@@H](CS(C)(=O)=O)N2Cc3c(Cl)ccc(NC(=O)CN4CCOCC4)c3C2=O)ccc1OC
Temperature: 70 °C

Procedure:
To a solution of (1S)-2-chloro-N-{7-chloro-2-[1-(3-ethoxy-4-methoxy-phenyl)-2-methanesulfonyl-ethyl]-3-oxo-2,3-dihydro-1H-isoindol-4-yl}-acetamide (250 mg, 0.48 mmol) in CH3CN (10 ml) was added morpholine (0.17 ml, 1.94 mmol). The mixture was heated at 70° C. for 2 hrs. The reaction mixture was concentrated on rota-vap and extracted with water (50 ml) and EtOAc (50 ml). The organic layer was washed with water (50 ml), brine (25 ml), dried over Na2SO4 and concentrated. The resulted oil was purified by chromatography to give an oil which was stirred with HCl in ether (3 ml) to give (1S)—N-{7-chloro-2-[1-(3-ethoxy-4-methoxy-phenyl)-2-methanesulfonyl-ethyl]-3-oxo-2,3-dihydro-1H-isoindol-4-yl}-2-morpholin-4-yl-acetamide; hydrochloride as a white solid (200 mg, 68% yield): mp, 198-200° C.; 1H NMR (CDCl3 with D2O added) δ 1.46 (t, J=7.0 Hz, 3H, OCH2CH3), 2.68 (broad, 4H, CH2NCH2 on morpholino ring), 2.99 (s, 3H, SCH3), 3.24 (broad, 2H, CH2NCO), 3.72 (dd, J=5, 15 Hz, 1H, CHHSO2), 3.87-3.92 (m, 7H, OCH3+CH2OCH2 on morpholine ring), 4.05-4.23 (m, 4H, CHHSO2+CNHH+OCH2CH3), 4.40 (d, J=15 Hz, 1H, CHHN), 5.71-5.77 (m, 1H, NCH), 6.86-6.97 (m, 3H, Ar), 7.40 (d, J=8 Hz, 1H, Ar), 8.52 (d, J=8 Hz, 1H, Ar); 13C NMR (CDCl3) δ 14.75, 41.71, 47.09, 51.22, 51.59, 55.09, 56.02, 63.81, 64.10, 64.81, 105.68, 111.67, 112.28, 119.32, 120.0, 120.27, 124.03, 128.81, 133.20, 134.72, 139.41, 149.09, 150.01, 168.55. Anal Calcd for C26H33Cl2N3O7S+0.53H2O: C, 51.02; H, 5.61; N, 6.87. Found: C, 50.70; H, 5.38; N, 6.76, 0.98% H2O.
Reaction SMILES: [Br:1][C:2]1[C:7](F)=[CH:6][N:5]=[C:4]([C:9]2[CH2:13][CH2:12][C@:11]3([CH2:17][CH2:16][N:15]([CH3:18])[C:14]3=[O:19])[N:10]=2)[CH:3]=1.[CH3:20][O-:21].[Na+].CO>C1COCC1>[Br:1][C:2]1[C:7]([O:21][CH3:20])=[CH:6][N:5]=[C:4]([C:9]2[CH2:13][CH2:12][C@:11]3([CH2:17][CH2:16][N:15]([CH3:18])[C:14]3=[O:19])[N:10]=2)[CH:3]=1
Reactant: CN1CC[C@]2(CCC(c3cc(Br)c(F)cn3)=N2)C1=O
Reactant: C[O-]
Agent: [Na+]
Solvent: CO
Solvent: C1CCOC1
Product: COc1cnc(C2=N[C@]3(CC2)CCN(C)C3=O)cc1Br
Reaction time: 0.17 h

Procedure:
To a solution of (5R)-2-(4-bromo-5-fluoro-2-pyridyl)-7-methyl-1,7-diazaspiro[4.4]non-1-en-6-one (which may be prepared as described in Description 35) (50 mg, 0.1500 mmol) in THF (2 mL) was added 30% wt. sodium methoxide in methanol (27.6 mg, 0.1500 mmol). The solution was stirred for 10 mins. A further 2 portions of 30% wt. sodium methoxide in methanol (27.6 mg, 0.1500 mmol) were added and the mixture stirred at room temperature for a further 10 mins. A further portion of 30% wt. sodium methoxide in methanol (27.6 mg, 0.1500 mmol) was added and the mixture stirred for 10 mins. The mixture was concentrated and the residues partitioned between water and DCM. The layers were separated with a hydrophobic frit and the organic filtrate evaporated to give (5R)-2-(4-bromo-5-methoxy-2-pyridyl)-7-methyl-1,7-diazaspiro[4.4]non-1-en-6-one (D56) as a cream solid (47 mg);
Reaction SMILES: [CH3:1][CH:2]([CH3:15])[CH2:3][C:4]([C:6]1[CH:14]=[CH:13][C:9]([C:10]([OH:12])=O)=[CH:8][CH:7]=1)=[O:5].F[P-](F)(F)(F)(F)F.N1(OC(N(C)C)=[N+](C)C)C2N=CC=CC=2N=N1.Cl.[NH2:41][CH2:42][CH2:43][C:44]([O:46][CH3:47])=[O:45].C(N(CC)CC)C>CN(C)C=O>[CH3:15][CH:2]([CH3:1])[CH2:3][C:4]([C:6]1[CH:7]=[CH:8][C:9]([C:10]([NH:41][CH2:42][CH2:43][C:44]([O:46][CH3:47])=[O:45])=[O:12])=[CH:13][CH:14]=1)=[O:5]
Reactant: COC(=O)CCN
Reactant: CC(C)CC(=O)c1ccc(C(=O)O)cc1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: COC(=O)CCNC(=O)c1ccc(C(=O)CC(C)C)cc1
Temperature: 25 °C
Reaction time: 0.67 h
Yield: 74.6 %

Procedure:
To a solution of 4-(3-methylbutanoyl)benzoic acid (9.5 g, 46 mmol) in N,N-dimethylformamide (80 mL) was added O-(7-Azabenzotriazol-1-yl)-N,N,N′,N′-tetramethyluronium hexafluorophosphate (26.3 g, 69.1 mmol) at 0° C. The mixture was stirred for 40 minutes. Methyl 3-aminopropanoate hydrochloride (7.72 g, 55.3 mmol) and triethylamine (23.3 g, 230 mmol) were added and the reaction was allowed to warm to room temperature and stir for 16 hours. The reaction mixture was extracted with ethyl acetate (3×). The combined organics were washed with brine, dried over sodium sulfate, filtered, and concentrated. Purification by column chromatography gave methyl 3-(4-(3-methylbutanoyl)benzamido)propanoate (10 g, 77%) as a pale yellow solid. 1H NMR (400 MHz, CDCl3, δ): 7.98 (d, J=8.0 Hz, 2H), 7.83 (d, J=8.4 Hz, 2H), 6.91 (s, 1H), 3.72-3.76 (m, 5H), 2.84 (d, J=6.0 Hz, 2H), 2.66-2.69 (t, J=6.0 Hz, 2H), 2.23-2.33 (m, 1H), 0.99 (d, J=6.4 Hz, 6H).
Reaction SMILES: [CH2:1]([O:8][C:9]1[C:18](=[O:19])[N:17]2[C:12]([C:13]([CH3:21])([CH3:20])[O:14][CH2:15][CH2:16]2)=[N:11][C:10]=1[C:22](O)=[O:23])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[NH2:25][CH2:26][C:27]1[CH:32]=[CH:31][C:30]([F:33])=[CH:29][C:28]=1[N:34]1[C@H:38]([CH2:39][O:40][Si:41]([C:44]([CH3:47])([CH3:46])[CH3:45])([CH3:43])[CH3:42])[CH2:37][CH2:36][C:35]1=[O:48]>>[Si:41]([O:40][CH2:39][C@H:38]1[CH2:37][CH2:36][C:35](=[O:48])[N:34]1[C:28]1[CH:29]=[C:30]([F:33])[CH:31]=[CH:32][C:27]=1[CH2:26][NH:25][C:22]([C:10]1[N:11]=[C:12]2[N:17]([C:18](=[O:19])[C:9]=1[O:8][CH2:1][C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1)[CH2:16][CH2:15][O:14][C:13]2([CH3:20])[CH3:21])=[O:23])([C:44]([CH3:47])([CH3:46])[CH3:45])([CH3:43])[CH3:42]
Reactant: CC(C)(C)[Si](C)(C)OC[C@@H]1CCC(=O)N1c1cc(F)ccc1CN
Reactant: CC1(C)OCCn2c1nc(C(=O)O)c(OCc1ccccc1)c2=O
Product: CC1(C)OCCn2c1nc(C(=O)NCc1ccc(F)cc1N1C(=O)CC[C@@H]1CO[Si](C)(C)C(C)(C)C)c(OCc1ccccc1)c2=O

Procedure:
The title compound can be prepared from intermediate 27, 3-(benzyloxy)-9,9-dimethyl-4-oxo-4,6,7,9-tetrahydropyrimido-[2,1-c][1,4]oxazine-2-carboxylic acid and (S)-1-(2-(aminomethyl)-5-fluorophenyl)-5-((tert-butyldimethylsilyloxy)methyl)pyrrolidin-2-one, derived from reduction of intermediate 122, (R)-2-(2-((tert-butyldimethylsilyloxy)methyl)-5-oxopyrrolidin-1-yl)-4-fluorobenzonitrile 1HNMR 400 MHz (DMSO) δ ppm: 8.82 (1H, broad s), 7.47 (2H, m), 7.35 (4H, m), 7.00 (1H, broad s), 5.09 (2H, s), 4.60-4.10 (3H, m), 4.02 (3H, m), 3.88 (2H, m), 3.53 (2H, broad s), 2.42-2.35 (2H, m), 1.94 (1H, m), 1.56 (3H, s), 1.55 (3H, s), 0.82 (9H, broad s), −0.01 (6H, s). LCMS (M+H)+ m/z 665.
Reaction SMILES: [CH2:1]([C:3]1[N:7]([CH3:8])[N:6]=[C:5]([C:9]([O:11]CC)=O)[CH:4]=1)[CH3:2].[OH-].[NH4+:15]>>[CH2:1]([C:3]1[N:7]([CH3:8])[N:6]=[C:5]([C:9]([NH2:15])=[O:11])[CH:4]=1)[CH3:2]
Reactant: CCOC(=O)c1cc(CC)n(C)n1
Reactant: [NH4+]
Agent: [OH-]
Product: CCc1cc(C(N)=O)nn1C
Temperature: 25 °C
Reaction time: 18 h

Procedure:
A mixture of ethyl 5-ethyl-1-methyl-1H-pyrazole-3-carboxylate (5.03 g, 27.6 mmol) and ammonium hydroxide (28 mL of 30%) was stirred for 18 hours at ambient temperature. A precipitate formed, was isolated by filtration, and washed with cold hexanes to provide 2.60 g of 5-ethyl-1-methyl-1H-pyrazole-3-carboxamide as a white solid, mp 170-172° C.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:25]=[CH:26][C:27]=1[O:28][CH2:29][O:30][CH3:31])/[CH:6]=[CH:7]/[C:8]1[NH:16][C:15]2[C:14](=[O:17])[N:13]([CH2:18][CH2:19][CH3:20])[C:12](=[O:21])[N:11]([CH2:22][CH2:23][CH3:24])[C:10]=2[N:9]=1.[C:32](=O)([O-])[O-].[K+].[K+].CI.O>CN(C)C=O>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:25]=[CH:26][C:27]=1[O:28][CH2:29][O:30][CH3:31])/[CH:6]=[CH:7]/[C:8]1[N:16]([CH3:32])[C:15]2[C:14](=[O:17])[N:13]([CH2:18][CH2:19][CH3:20])[C:12](=[O:21])[N:11]([CH2:22][CH2:23][CH3:24])[C:10]=2[N:9]=1
Reactant: CCCn1c(=O)c2[nH]c(/C=C/c3ccc(OCOC)c(OC)c3)nc2n(CCC)c1=O
Reactant: O=C([O-])[O-]
Agent: [K+]
Solvent: CI
Solvent: O
Solvent: CN(C)C=O
Product: CCCn1c(=O)c2c(nc(/C=C/c3ccc(OCOC)c(OC)c3)n2C)n(CCC)c1=O
Temperature: 50 °C
Reaction time: 1 h
Yield: 78.8 %

Procedure:
Compound c (4.5 g, 10.5 mmol) obtained in Reference Example 3 was dissolved in 90 ml of dimethylformamide, and potassium carbonate (3.63 g, 26.26 mmol) and methyl iodide (1.31 ml, 21.04 mmol) were added thereto, followed by stirring at 50° C. for 1 hour. After cooling, water was added to the reaction mixture, and the resulting precipitate was collected by filtration. The obtained crude product was recrystallized from hexane/ethyl acetate to give 3.66 g (79% yield) of Compound d as pale yellow crystals.