Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][C:2]1[CH:11]=[CH:10][C:9]2[N:8]=[CH:7][C:6]3[NH:12][C:13](=[O:26])[N:14]([C:15]4[CH:20]=[CH:19][C:18]([C:21]([CH3:25])([CH3:24])[C:22]#[N:23])=[CH:17][CH:16]=4)[C:5]=3[C:4]=2[CH:3]=1.C(N(CC)CC)C.[CH3:34][C:35]1[CH:36]=[C:37]([S:41](Cl)(=[O:43])=[O:42])[CH:38]=[CH:39][CH:40]=1.O>ClCCl>[CH3:25][C:21]([C:18]1[CH:17]=[CH:16][C:15]([N:14]2[C:5]3[C:4]4[CH:3]=[C:2]([CH3:1])[CH:11]=[CH:10][C:9]=4[N:8]=[CH:7][C:6]=3[N:12]([S:41]([C:37]3[CH:36]=[C:35]([CH3:34])[CH:40]=[CH:39][CH:38]=3)(=[O:43])=[O:42])[C:13]2=[O:26])=[CH:20][CH:19]=1)([CH3:24])[C:22]#[N:23]
Reactant: Cc1cccc(S(=O)(=O)Cl)c1
Reactant: Cc1ccc2ncc3[nH]c(=O)n(-c4ccc(C(C)(C)C#N)cc4)c3c2c1
Solvent: ClCCl
Solvent: CCN(CC)CC
Solvent: O
Product: Cc1cccc(S(=O)(=O)n2c(=O)n(-c3ccc(C(C)(C)C#N)cc3)c3c4cc(C)ccc4ncc32)c1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
To a solution of 2-(4-(8-methyl-2-oxo-2,3-dihydro-1H-imidazo[4,5-c]quinolin-1-yl)phenyl)-2-methylpropanenitrile (Intermediate 3, 100 mg, 0.29 mmol) and triethylamine (60 mg, 0.58 mmol) in dichloromethane (6 ml) was added m-methylbenzene-1-sulfonyl chloride (83.5 mg, 0.44 mmol) at 0° C. The reaction was stirred at RT for 3 hours. The reaction mixture was poured into cold water and organic layer was separated. The aqueous layer was extracted with dichloromethane. The combined organic layer was washed with brine dried over sodium sulfate and evaporated to dryness. The crude product was purified by column chromatography (silica gel, 2% acetone in chloroform) to obtain the title compound. Yield: 25 mg (17%); 1H NMR (CDCl3, 300 MHz): δ 9.551 (s, 1H), 8.046-8.095 (d, 3H, J=8.4 Hz), 7.762-7.791 (d, 2H, J=8.7 Hz), 7.354-7.575 (m, 5H), 6.670 (s, 1H), 2.436 (s, 3H), 2.212 (s, 3H), 1.855 (s, 6H); MS: m/z 497 (M+).
Reaction SMILES: Cl[C:2]1[CH:7]=[N:6][CH:5]=[C:4]([CH3:8])[N:3]=1.[CH3:9][N:10]1[CH2:15][CH2:14][NH:13][CH2:12][CH2:11]1>CCO>[CH3:8][C:4]1[CH:5]=[N:6][CH:7]=[C:2]([N:13]2[CH2:14][CH2:15][N:10]([CH3:9])[CH2:11][CH2:12]2)[N:3]=1
Reactant: Cc1cncc(Cl)n1
Reactant: CN1CCNCC1
Solvent: CCO
Product: Cc1cncc(N2CCN(C)CC2)n1
Yield: 45.3 %

Procedure:
A 250 mL round bottom flask was charged with 2-chloro-6-methylpyrazine (4.0 g, 0.031 mol), 1-methylpiperazine (12.4 g, 0.125 mol) and EtOH (100 mL). The resulting mixture was heated at reflux overnight. Work-up: the solvent was evaporated. The residue was mixed with saturated aqueous NaHCO3 (100 mL) and then extracted with CH2Cl2 (100 mL×3). The combined organic layers were dried over anhydrous Na2SO4 and concentrated in vacuo. The residue was further purified by flash column chromatography on silica gel with 4% MeOH in CH2Cl2, to afford 2.7 g (45%) of the product as a white solid. MS m/z: 193 (M+H+).
Reaction SMILES: C[CH:2]([CH:6]1[C:10]2=[C:11]([S:20][C:21]3[CH:26]=[CH:25][C:24]([Cl:27])=[CH:23][CH:22]=3)[C:12]3[C:13](Br)=[CH:14][C:15]([F:18])=[CH:16][C:17]=3[N:9]2[CH2:8][CH2:7]1)[C:3]([O-:5])=[O:4].[N:28]1[C:37]2[C:32](=[CH:33][CH:34]=[CH:35][C:36]=2B(O)O)[CH:31]=[CH:30][CH:29]=1>>[Cl:27][C:24]1[CH:25]=[CH:26][C:21]([S:20][C:11]2[C:12]3[C:13]([C:36]4[CH:35]=[CH:34][CH:33]=[C:32]5[C:37]=4[N:28]=[CH:29][CH:30]=[CH:31]5)=[CH:14][C:15]([F:18])=[CH:16][C:17]=3[N:9]3[CH2:8][CH2:7][CH:6]([CH2:2][C:3]([OH:5])=[O:4])[C:10]=23)=[CH:22][CH:23]=1
Reactant: CC(C(=O)[O-])C1CCn2c1c(Sc1ccc(Cl)cc1)c1c(Br)cc(F)cc12
Reactant: OB(O)c1cccc2cccnc12
Product: O=C(O)CC1CCn2c1c(Sc1ccc(Cl)cc1)c1c(-c3cccc4cccnc34)cc(F)cc12

Procedure:
Starting from (+/−)-methyl[8-bromo-9-[(4-chlorophenyl)sulfanyl]-6-fluoro-2,3-dihydro-1H-pyrrolo[1,2-a]indol-1-yl]acetate (Example 7, Step 9) and quinolin-8-ylboronic acid, the title compound was synthesized following the procedures described in Example 108.
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[C:9]2[C:5]([C:6](=[O:19])[NH:7][N:8]2[CH2:11][C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=2[Cl:18])=[CH:4][C:3]=1[N+:20]([O-])=O.Cl.Cl[Sn]Cl.C(=O)(O)[O-].[Na+]>>[NH2:20][C:3]1[CH:4]=[C:5]2[C:9](=[CH:10][C:2]=1[Cl:1])[N:8]([CH2:11][C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=1[Cl:18])[NH:7][C:6]2=[O:19]
Reactant: O=c1[nH]n(Cc2ccccc2Cl)c2cc(Cl)c([N+](=O)[O-])cc12
Agent: Cl
Agent: Cl[Sn]Cl
Agent: O=C([O-])O
Product: Nc1cc2c(=O)[nH]n(Cc3ccccc3Cl)c2cc1Cl
Temperature: 85 °C
Yield: 73.9 %

Procedure:
To 6-chloro-1-(2-chloro-benzyl)-5-nitro-1,2-dihydro-indazol-3-one (0.49 g) was added HCl (37% aq.) solution (4 mL) followed by SnCl2.dihydrate (2.6 g). The mixture was heated to 85° C. for one hour. The reaction was then neutralized with sodium bicarbonate solution, filtered, and the filtrate extracted with EtOAc. The combined organic phases were washed with brine, dried over sodium sulfate, filtered and reduced in vacuo. Flash column chromatography of the residue over silica gel eluting with methylene chloride/methanol afforded the desired 5-amino-6-chloro-1-(2-chloro-benzyl)-1,2-dihydro-indazol-3-one (0.33 g) as a yellow solid. MS (ESI+): 308.3 [M+H]+).
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:15])[CH:5](O)[C:6]1[CH:11]=[CH:10][C:9]([S:12][CH3:13])=[CH:8][CH:7]=1)[CH3:2].O=S(Cl)[Cl:18]>C(Cl)Cl.[NH4+].[Cl-]>[CH2:1]([O:3][C:4](=[O:15])[CH:5]([Cl:18])[C:6]1[CH:11]=[CH:10][C:9]([S:12][CH3:13])=[CH:8][CH:7]=1)[CH3:2]
Reactant: O=S(Cl)Cl
Reactant: CCOC(=O)C(O)c1ccc(SC)cc1
Agent: [Cl-]
Agent: [NH4+]
Solvent: ClCCl
Product: CCOC(=O)C(Cl)c1ccc(SC)cc1
Temperature: 25 °C
Reaction time: 12 h

Procedure:
To a solution of the hydroxy-(4-methylsulfanyl-phenyl)-acetic acid ethyl ester of Step 2 (1.0 eq) in CH2Cl2 (0.2M) was added SOCl2 (5 eq). The resulting mixture was stirred at room temperature for 12 h, poured in saturated aqueous NH4Cl and extracted with Et2O (2×). The combined organic extracts were washed with brine, dried over MgSO4, filtered and concentrated. Flash chromatography (Hex:EtOAc; 9.5:0.5) afforded the desired compound as a yellow solid.
Reaction SMILES: [NH2:1][C:2]1[CH:11]=[CH:10][CH:9]=[C:8]2[C:3]=1[C:4](=[O:21])[N:5]([CH:13]1[CH2:18][CH2:17][C:16](=[O:19])[NH:15][C:14]1=[O:20])[C:6]([CH3:12])=[N:7]2.CC1N(C2CC[C:36](=[O:39])NC2=O)C(=O)C2C(=CC=CC=2[N+]([O-])=O)N=1>C(O)=O>[O:20]=[C:14]1[CH:13]([N:5]2[C:4](=[O:21])[C:3]3[C:8](=[CH:9][CH:10]=[CH:11][C:2]=3[NH:1][CH:36]=[O:39])[N:7]=[C:6]2[CH3:12])[CH2:18][CH2:17][C:16](=[O:19])[NH:15]1
Reactant: Cc1nc2cccc(N)c2c(=O)n1C1CCC(=O)NC1=O
Reactant: Cc1nc2cccc([N+](=O)[O-])c2c(=O)n1C1CCC(=O)NC1=O
Solvent: O=CO
Product: Cc1nc2cccc(NC=O)c2c(=O)n1C1CCC(=O)NC1=O

Procedure:
In another embodiment, provided herein is a method for preparing 3-(5-amino-2-methyl-4-oxoquinazolin-3(4H)-yl)piperidine-2,6-dione, or an enantiomer or a mixture of enantiomers thereof; or a pharmaceutically acceptable salt, solvate, hydrate, or polymorph thereof; comprising the steps of (a) reducing 3-(2-methyl-5-nitro-4-oxoquinazolin-3(4H)-yl)piperidine-2,6-dione in a solvent in the presence of formic acid to form N-(3-(2,6-dioxopiperidin-3-yl)-2-methyl-4-oxo-3,4-dihydroquinazolin-5-yl)formamide; and (b) hydrolyzing N-(3-(2,6-dioxopiperidin-3-yl)-2-methyl-4-oxo-3,4-dihydroquinazolin-5-yl)formamide in a solvent to form 3-(5-amino-2-methyl-4-oxoquinazolin-3(4H)-yl)piperidine-2,6-dione, or an enantiomer or a mixture of enantiomers thereof; or a pharmaceutically acceptable salt, solvate, hydrate, or polymorph thereof; wherein steps (a) and (b) are each as described herein elsewhere.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([S:8]([NH:11][C:12]2[C:13]([OH:21])=[C:14]([CH:18]=[CH:19][CH:20]=2)[C:15]([OH:17])=[O:16])(=[O:10])=[O:9])[S:5][C:6]=1[Cl:7].CC1(C)C(C)(C)OB([C:30]2[CH:35]=[CH:34][CH:33]=[CH:32][C:31]=2[OH:36])O1>>[Cl:7][C:6]1[S:5][C:4]([S:8]([NH:11][C:12]2[C:13]([OH:21])=[C:14]([CH:18]=[CH:19][CH:20]=2)[C:15]([OH:17])=[O:16])(=[O:10])=[O:9])=[CH:3][C:2]=1[C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][C:31]=1[OH:36]
Reactant: CC1(C)OB(c2ccccc2O)OC1(C)C
Reactant: O=C(O)c1cccc(NS(=O)(=O)c2cc(Br)c(Cl)s2)c1O
Product: O=C(O)c1cccc(NS(=O)(=O)c2cc(-c3ccccc3O)c(Cl)s2)c1O
Yield: 24 %

Procedure:
The product was prepared from 3-{[(4-bromo-5-chlorothiophen-2-yl)sulfonyl]amino}-2-hydroxybenzoic acid (Intermediate 22) (20.6 mg, 0.050 mmol) and 2-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenol (11 μl, 0.055 mmol) according to the General Procedure 12, described in Example 135. The title compound was obtained in 24% yield (5.3 mg). 1H NMR (500 MHz, MeOH-d4) δ ppm 6.85 (ddd, J=7.60, 7.32, 1.15 Hz, 1 H) 6.87 (ddd, J=8.21, 1.15, 0.45 Hz, 1 H) 6.88 (t, J=7.95 Hz, 1 H) 7.15 (ddd, J=7.60, 1.71, 0.45 Hz, 1 H) 7.20 (ddd, J=8.21, 7.32, 1.71 Hz, 1 H) 7.39 (s, 1 H) 7.65 (dd, J=7.95, 1.65 Hz, 1 H) 7.71 (dd, J=7.95, 1.65 Hz, 1 H). MS (ESI+) m/z 426 [M+H]+.
Reaction SMILES: C(NC(C)C)(C)C.[Li]CCCC.[C:13]([O:16][C:17]([CH3:20])([CH3:19])[CH3:18])(=[O:15])[CH3:14].[OH:21][C:22]1[C:23]([C:32](Cl)=[O:33])=[CH:24][C:25]2[C:30]([CH:31]=1)=[CH:29][CH:28]=[CH:27][CH:26]=2>>[OH:21][C:22]1[C:23]([C:32](=[O:33])[CH2:14][C:13]([O:16][C:17]([CH3:20])([CH3:19])[CH3:18])=[O:15])=[CH:24][C:25]2[C:30]([CH:31]=1)=[CH:29][CH:28]=[CH:27][CH:26]=2
Reactant: O=C(Cl)c1cc2ccccc2cc1O
Reactant: CC(=O)OC(C)(C)C
Agent: [Li]CCCC
Solvent: CC(C)NC(C)C
Product: CC(C)(C)OC(=O)CC(=O)c1cc2ccccc2cc1O

Procedure:
Prepared according to above procedure using diisopropylamine (2.0 mL, 15 mmol), nBuLi (11.4 mL, 1.2 M), tert-butyl acetate (3.4 mL, 12 mmol), 3-hydroxynaphthalene-2-carbonyl chloride (3.9 mmol, prepared from 730 mg of 3-hydroxy-2-naphthoic acid and SOCl2, 0.9 mL, heated to 40° C. in 9 mL toluene for 4 h) yielding 666 mg (57%) as yellow needles. mp=80-84° C.; IR (film) 2981.9; 2919.0; 1732.1; 1642.5; 1261.4; 1147.6 cm−1; 1H NMR (500 MHz, CDCl3) δ 11.17 (s, 1H); 8.29 (s, 1H); 7.78 (d, J=8.0 Hz, 1H); 7.65 (d, J=8.2 Hz, 1H); 7.50 (t, J=7.0, 1H); 7.33-7.27 (m, 2H); 4.05 (s, 2H); 1.42 (s, 9H); 13C NMR (125 MHz, CDCl3) δ 199.3, 166.2, 157.2, 138.5, 133.7, 130.2, 129.6, 127.1, 126.5, 124.5, 120.9, 112.7, 82.9, 47.8, 28.1; LRMS (electrospray): Mass calculated for C17H18O4, [M]+, 286.12. Found [M]+, 285.8.
Reaction SMILES: C(O)(C(F)(F)F)=O.[Br:8][C:9]1[C:10]([O:22][C:23]2[C:30]([CH3:31])=[CH:29][C:26]([C:27]#[N:28])=[CH:25][C:24]=2[CH3:32])=[N:11][C:12]([NH:15][CH:16]2[CH2:21][CH2:20][NH:19][CH2:18][CH2:17]2)=[N:13][CH:14]=1.Br[CH:34]([C:36]1[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=1)[CH3:35]>CC#N>[Br:8][C:9]1[C:10]([O:22][C:23]2[C:30]([CH3:31])=[CH:29][C:26]([C:27]#[N:28])=[CH:25][C:24]=2[CH3:32])=[N:11][C:12]([NH:15][CH:16]2[CH2:17][CH2:18][N:19]([CH:34]([C:36]3[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=3)[CH3:35])[CH2:20][CH2:21]2)=[N:13][CH:14]=1
Reactant: CC(Br)c1ccccc1
Reactant: Cc1cc(C#N)cc(C)c1Oc1nc(NC2CCNCC2)ncc1Br
Solvent: CC#N
Solvent: O=C(O)C(F)(F)F
Product: Cc1cc(C#N)cc(C)c1Oc1nc(NC2CCN(C(C)c3ccccc3)CC2)ncc1Br
Temperature: 25 °C
Reaction time: 6 h

Procedure:
To a solution of the TFA salt of 56 (1 mmol) in MeCN was added TEA (1.5 mmol) and (1-bromo-ethyl)-benzene (1 mmol) and the resulting mixture was stirred at RT for 6 h. After the reaction was complete, the solvent was removed and the residue was purified by preparative HPLC on a 30×100 mm C18 ODB column eluting with MeCN/H2O to afford 0.120 g (24.6%) of I-61.
Reaction SMILES: [C:1]1([N:7]2[C:11]([C:12]3[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=3)=[CH:10][CH:9]=[C:8]2[C:18]2[CH:19]=[C:20]3[C:25](=[CH:26][CH:27]=2)[CH:24]=[C:23]([O:28][CH2:29][C:30]#[N:31])[CH:22]=[CH:21]3)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[Cl-].[NH4+].[N-:34]=[N+:35]=[N-:36].[Na+]>CN(C=O)C>[C:1]1([N:7]2[C:11]([C:12]3[CH:13]=[CH:14][CH:15]=[CH:16][CH:17]=3)=[CH:10][CH:9]=[C:8]2[C:18]2[CH:19]=[C:20]3[C:25](=[CH:26][CH:27]=2)[CH:24]=[C:23]([O:28][CH2:29][C:30]2[NH:36][N:35]=[N:34][N:31]=2)[CH:22]=[CH:21]3)[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: N#CCOc1ccc2cc(-c3ccc(-c4ccccc4)n3-c3ccccc3)ccc2c1
Reactant: [N-]=[N+]=[N-]
Agent: [Cl-]
Agent: [NH4+]
Agent: [Na+]
Solvent: CN(C)C=O
Product: c1ccc(-c2ccc(-c3ccc4cc(OCc5nnn[nH]5)ccc4c3)n2-c2ccccc2)cc1
Yield: 78.6 %

Procedure:
In a similar manner as described in step 2 of Example 3, the title compound was prepared from {[6-(1,5-diphenyl-1H-pyrrol-2-yl)-2-naphthyl]oxy}acetonitrile (0.180 g, 0.373 mmol), prepared in the previous step, ammonium chloride (0.060 g, 1.12 mmol) and sodium azide (0.073 g, 1.12 mmol) in DMF (10 mL). The precipitated solids were isolated by vacuum filtration to give 5-({[6-(1,5-diphenyl-1H-pyrrol-2-yl)-2-naphthyl]oxy}methyl)-1H-tetraazole as an off-white solid (0.130 g, 98%), mp 269–270° C. (dec). Elemental Analysis for C28H21N5O Calc'd: C, 75.83; H, 4.77; N, 15.79. Found: C, 75.83; H, 4.69; N, 15.50.
Reaction SMILES: FC1C=C2C(=CC=1)NC=C2C1CCC(=O)CC1.C1O[C:21]2([CH2:26][CH2:25][CH:24]([C:27]3[C:35]4[C:30](=[CH:31][CH:32]=[C:33]([C:36]#[N:37])[CH:34]=4)[NH:29][CH:28]=3)[CH2:23][CH2:22]2)[O:20]C1>>[C:36]([C:33]1[CH:34]=[C:35]2[C:30](=[CH:31][CH:32]=1)[NH:29][CH:28]=[C:27]2[CH:24]1[CH2:25][CH2:26][C:21](=[O:20])[CH2:22][CH2:23]1)#[N:37]
Reactant: N#Cc1ccc2[nH]cc(C3CCC4(CC3)OCCO4)c2c1
Agent: O=C1CCC(c2c[nH]c3ccc(F)cc23)CC1
Product: N#Cc1ccc2[nH]cc(C3CCC(=O)CC3)c2c1

Procedure:
This compound was prepared in the manner as described above for (3a) by replacing 4-(5-fluoro-1H-3-indolyl)-cyclohexanone ethylene ketal with 4-(5-cyano-1H-3-indolyl)-cyclohexanone ethylene ketal (6 g) in 81% (4.0 g) of product as a white solid: mp 162.5-164° C.
Reaction SMILES: [CH:1]([OH:14])([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.O.C1(C)C=CC(S(O)(=O)=O)=CC=1.O[CH:28]1[CH2:33][CH2:32][NH:31][CH2:30][CH2:29]1>C1(C)C=CC=CC=1>[CH:1]([O:14][CH:28]1[CH2:33][CH2:32][NH:31][CH2:30][CH2:29]1)([C:8]1[CH:9]=[CH:10][CH:11]=[CH:12][CH:13]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: OC1CCNCC1
Reactant: OC(c1ccccc1)c1ccccc1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: O
Solvent: Cc1ccccc1
Product: c1ccc(C(OC2CCNCC2)c2ccccc2)cc1
Temperature: 25 °C
Yield: 50.6 %

Procedure:
Molecular sieves, benzhydrol (1.1 g, 5.5 mmol), and p-toluenesulfonic acid monohydrate (1.0 g, 5.5 mmol) were added to a suspension of 4-hydroxypiperidine (505 mg, 5 mmol) in toluene, and the mixture was refluxed for 3 hours while removing water using a Dean-Stark condenser. After the completion of the reaction was confirmed by HPLC, the reaction mixture was allowed to cool down to a room temperature. From the reaction mixture, the insoluble matter was removed, and then the solvent was distilled off. The resulting residue was dissolved in ethyl acetate and washed with a 2-N sodium hydroxide solution 3 times. The organic layer was dried over magnesium sulfate, and then the solvent was distilled off. Thus the title compound (676 mg, 50.6%) was obtained as an oily substance.
Reaction SMILES: [F:1][C:2]1[CH:28]=[CH:27][C:5]([O:6][C:7]2[CH:22]=[C:21]([C:23]([F:26])([F:25])[F:24])[CH:20]=[CH:19][C:8]=2[C:9]([NH:11][C:12]2[CH:17]=[CH:16][NH:15][C:14](=[O:18])[CH:13]=2)=[O:10])=[C:4]([CH3:29])[CH:3]=1.C(OCC)(=O)C.N12CCN(CC1)CC2.[Cl:44][C:45](OCCl)=O>O.CN(C=O)C>[Cl:44][CH2:45][N:15]1[CH:16]=[CH:17][C:12]([NH:11][C:9](=[O:10])[C:8]2[CH:19]=[CH:20][C:21]([C:23]([F:26])([F:24])[F:25])=[CH:22][C:7]=2[O:6][C:5]2[CH:27]=[CH:28][C:2]([F:1])=[CH:3][C:4]=2[CH3:29])=[CH:13][C:14]1=[O:18]
Reactant: Cc1cc(F)ccc1Oc1cc(C(F)(F)F)ccc1C(=O)Nc1cc[nH]c(=O)c1
Reactant: O=C(Cl)OCCl
Agent: C1CN2CCN1CC2
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Solvent: O
Product: Cc1cc(F)ccc1Oc1cc(C(F)(F)F)ccc1C(=O)Nc1ccn(CCl)c(=O)c1
Reaction time: 0.5 h
Yield: 86.7 %

Procedure:
To a 50 liter jacketed glass reactor fitted with an N2 inlet and a mechanical stirrer, and with a jacket temperature set at 20° C., was added 2-(4-fluoro-2-methylphenoxy)-N-(2-oxo-1,2-dihydropyridin-4-yl)-4-(trifluoromethyl)benzamide (9a, 2482.0 g, 6.11 moles, 1.0 eq) under nitrogen. Ethyl acetate (25 liters) was added with stirring at 100 rpm followed by 1,4-diazabicyclo [2.2.2] octane (DABCO) (342.6 g, 3.05 moles, 0.5 eq) and DMF (1.25 liters, Sigma-Aldrich). Chloromethyl chloroformate (815 ml, 9.16 moles, 1.5 eq) was then added over 30 minutes. When the addition of chloromethyl chloroformate was complete, the jacket temperature was ramped up to 60° C. over 30 minutes. The resulting yellow-slurry was stirred for 3 hours at about 60° C., at which time the reaction was judged to be complete by HPLC analysis. The jacket temperature was ramped down to 15° C. over 20 minutes before quenching the reaction by slow addition of water (500 ml) over 10 minutes. Additional water was added, and the mixture stirred at 115 rpm for 15 minutes. Stirring was stopped, the aqueous layer was discarded, and the organic layer washed with water (5 liters), followed by a saturated solution of NaHCO3 (137 g) in water (620 ml). The organic layer was seeded with 5 g of N-(1-(chloromethyl)-2-oxo-1,2-dihydropyridin-4-yl)-2-(4-fluoro-2-methylphenoxy)-4-(trifluoromethyl)benzamide (7), and the resulting slurry was partially concentrated (removed 18.5 liters of organics) in the rotovap (40° C., vacuum). The resulting suspension was stored at room temperature under nitrogen atmosphere overnight, during which time additional material crystallized out of solution. The remaining solvent was chased with heptanes adding more heptanes as needed to maintain the volume at 10 liters. The thick suspension was stirred on the rotovap at room temperature for 45 minutes, and then the solids were collected by filtration. The off-white solid was washed with heptanes (2.5 liters), then dried in vacuo (40° C., full house vacuum) to give 2409 g (87%) of N-(1-(chloromethyl)-2-oxo-1,2-dihydropyridin-4-yl)-2-(4-fluoro-2-methylphenoxy)-4-(trifluoromethyl)benzamide as an off-white crystalline solid.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][C@H:9]2[C:18]3[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=3)[N:12]([C:19]([C:21]3[CH:31]=[CH:30][C:24]4[N:25]([CH3:29])[CH2:26][CH2:27][O:28][C:23]=4[CH:22]=3)=[O:20])[C@@H:11]([CH3:32])[CH2:10]2)=[CH:4][CH:3]=1.C(N(C(C)C)CC)(C)C.[C:42](Cl)(=[O:44])[CH3:43]>C(Cl)Cl>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]([C@H:9]2[C:18]3[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=3)[N:12]([C:19]([C:21]3[CH:31]=[CH:30][C:24]4[N:25]([CH3:29])[CH2:26][CH2:27][O:28][C:23]=4[CH:22]=3)=[O:20])[C@@H:11]([CH3:32])[CH2:10]2)[C:42](=[O:44])[CH3:43])=[CH:4][CH:3]=1
Reactant: C[C@H]1C[C@@H](Nc2ccc(Cl)cc2)c2ccccc2N1C(=O)c1ccc2c(c1)OCCN2C
Reactant: CC(=O)Cl
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: CC(=O)N(c1ccc(Cl)cc1)[C@@H]1C[C@H](C)N(C(=O)c2ccc3c(c2)OCCN3C)c2ccccc21
Temperature: 25 °C
Reaction time: 4 h

Procedure:
To a solution of (2S,4R)-[4-(4-Chloro-phenylamino)-2-methyl-3,4-dihydro-2H-quinolin-1-yl]-(4-methyl-3,4-dihydro-2H-benzo[1,4]oxazin-7-yl)-methanone (540 mg, 1.25 mmol) in methylene chloride (5 mL) was added diisopropylethylamine (0.240 mL, 1.37 mmol) followed by acetyl chloride (2 mL). The mixture was stirred at room temperature 4 hours. The mixture was concentrated under reduced pressure, dissolved in ethyl acetate, washed with sat. aq. NaHCO3, brine and dried over magnesium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by silica gel chromatography (25/75 hexanes/ethyl acetate gradient) to afford the final product.
Reaction SMILES: [CH2:1]([O:5][CH2:6][CH2:7][O:8][C:9]1[CH:14]=[CH:13][C:12]([C:15]2[CH:16]=[CH:17][C:18]3[N:24]([C:25](=[O:30])[C:26]([F:29])([F:28])[F:27])[CH2:23][CH2:22][C:21]([C:31](O)=[O:32])=[CH:20][C:19]=3[CH:34]=2)=[CH:11][CH:10]=1)[CH2:2][CH2:3][CH3:4].[NH2:35][C:36]1[CH:41]=[CH:40][C:39]([CH:42]([C:44]2[CH:49]=[CH:48][CH:47]=[CH:46][N:45]=2)[OH:43])=[C:38]([O:50][CH3:51])[CH:37]=1.ON1C2C=CC=CC=2N=N1.Cl.C(N=C=NCCCN(C)C)C>CN(C)C=O.CN(C)C1C=CN=CC=1.O.C(N(CC)CC)C>[CH2:1]([O:5][CH2:6][CH2:7][O:8][C:9]1[CH:14]=[CH:13][C:12]([C:15]2[CH:16]=[CH:17][C:18]3[N:24]([C:25](=[O:30])[C:26]([F:28])([F:29])[F:27])[CH2:23][CH2:22][C:21]([C:31]([NH:35][C:36]4[CH:41]=[CH:40][C:39]([CH:42]([OH:43])[C:44]5[CH:49]=[CH:48][CH:47]=[CH:46][N:45]=5)=[C:38]([O:50][CH3:51])[CH:37]=4)=[O:32])=[CH:20][C:19]=3[CH:34]=2)=[CH:11][CH:10]=1)[CH2:2][CH2:3][CH3:4]
Reactant: CCCCOCCOc1ccc(-c2ccc3c(c2)C=C(C(=O)O)CCN3C(=O)C(F)(F)F)cc1
Reactant: COc1cc(N)ccc1C(O)c1ccccn1
Agent: CCN=C=NCCCN(C)C
Agent: CN(C)c1ccncc1
Agent: Cl
Solvent: CN(C)C=O
Solvent: O
Solvent: CCN(CC)CC
Product: CCCCOCCOc1ccc(-c2ccc3c(c2)C=C(C(=O)Nc2ccc(C(O)c4ccccn4)c(OC)c2)CCN3C(=O)C(F)(F)F)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 77.5 %

Procedure:
7-[4-(2-butoxyethoxy) phenyl]-1-trifluoroacetyl-2,3-dihydro-1H-1-benzazepine-4-carboxylic acid (0.5 g), (4-amino-2-methoxyphenyl)(pyridin-2-yl)methanol (0.26 g) and 1-hydroxybenzotriazole (0.18 g) were dissolved in N,N-dimethylformamide (5 ml), and to the solution were added 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (0.4 g), triethylamine (0.44 ml), 4-dimethylaminopyridine (catalytic amout) under ice-cooling at room temperature, and the mixture was stirred overnight. The mixture was poured into water, and the mixture was extracted with ethyl acetate. The organic layer was washed with water and saturated brine, and dried over anhydrous magnesium sulfate, and then, the solvent was distilled off. The residue was purified by silica gel column chromatography (elution solvent: ethyl acetate/hexane), to give 7-[4-(2-butoxyethoxy) phenyl]-N-[4-[hydroxy(pyridin-2-yl)methyl]-3-methoxyphenyl]-1-trifluoroacetyl-2,3-dihydro-1H-1-benzazepine-4-carboxamide (0.56 g) as colorless crystals.
Reaction SMILES: [Cl:1][C:2]1[CH:18]=[C:17]([Cl:19])[CH:16]=[CH:15][C:3]=1[CH2:4][NH:5][C:6]([N:8]1[CH2:14][CH:13]2[CH:10]([CH2:11][NH:12]2)[CH2:9]1)=[O:7].Br[C:21]1[N:26]=[CH:25][CH:24]=[CH:23][N:22]=1.C(N(CC)CC)C.C1C=CC(P(C2C(C3C(P(C4C=CC=CC=4)C4C=CC=CC=4)=CC=C4C=3C=CC=C4)=C3C(C=CC=C3)=CC=2)C2C=CC=CC=2)=CC=1.CC([O-])(C)C.[K+]>C1(C)C=CC=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd]>[Cl:1][C:2]1[CH:18]=[C:17]([Cl:19])[CH:16]=[CH:15][C:3]=1[CH2:4][NH:5][C:6]([N:8]1[CH2:14][CH:13]2[CH:10]([CH2:11][N:12]2[C:21]2[N:26]=[CH:25][CH:24]=[CH:23][N:22]=2)[CH2:9]1)=[O:7]
Reactant: Brc1ncccn1
Reactant: O=C(NCc1ccc(Cl)cc1Cl)N1CC2CNC2C1
Agent: [Pd]
Agent: CC(C)(C)[O-]
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Solvent: CCN(CC)CC
Solvent: Cc1ccccc1
Product: O=C(NCc1ccc(Cl)cc1Cl)N1CC2CN(c3ncccn3)C2C1
Temperature: 110 °C
Yield: 25.5 %

Procedure:
To a solution of rac-3,6-diaza-bicyclo[3.2.0]heptane-3-carboxylic acid 2,4-dichloro-benzylamide (150 mg, 270 μmol) in toluene (6 mL) were added 2-bromopyrimidine (43 mg, 270 μmol) and triethylamine (27 mg, 270 μmol). After addition of tris(dibenzylideneacetone)dipalladium(0) (5 mg, 5 μmol), BINAP (10 mg, 16 μmol) and potassium tert-butylate (30 mg, 270 μmol) the reaction mixture was heated under an argon atmosphere to 110° C. for 20 h. It was filtered and concentrated in vacuo. Purification by chromatography (SiO2; dichloromethane:methanol 1:0 to 9:1) afforded the title compound (26 mg, 25%) as a white solid. MS (EI) m/e: 378.3 (M+H)+.
Reaction SMILES: [CH3:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([OH:8])=[O:7])=[C:4]([CH2:11][CH2:12][C:13]2[CH:18]=[CH:17][CH:16]=[C:15]([CH:19]=[CH:20][CH3:21])[CH:14]=2)[CH:3]=1>C(OCC)(=O)C.[Pd]>[CH3:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([OH:8])=[O:7])=[C:4]([CH2:11][CH2:12][C:13]2[CH:18]=[CH:17][CH:16]=[C:15]([CH2:19][CH2:20][CH3:21])[CH:14]=2)[CH:3]=1
Reactant: CC=Cc1cccc(CCc2cc(C)ccc2C(=O)O)c1
Agent: [Pd]
Solvent: CCOC(C)=O
Product: CCCc1cccc(CCc2cc(C)ccc2C(=O)O)c1

Procedure:
The subtitle compound was prepared from the product of step (iv) (15.4 g) by the method of example 21 step (iii). The crude reaction product was contaminated with 4-methyl-2-[2-[3-[1-propenyl]phenyl]ethyl]benzoic acid. The crude reaction product was dissolved in ethyl acetate (100 ml) and the solution was hydrogenated over 10% palladium on carbon (1 g) at 3 atmospheres pressure for 2 hours. The catalyst was removed by filtration and the filtrate was evaporated. Yield 12.8 g.