Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C:2]1[C:10]([CH3:11])=[CH:9][C:8]([Br:12])=[CH:7][C:3]=1[C:4]([OH:6])=[O:5].[C:13](=O)([O-])[O-].[Cs+].[Cs+].IC>CN(C=O)C>[NH2:1][C:2]1[C:10]([CH3:11])=[CH:9][C:8]([Br:12])=[CH:7][C:3]=1[C:4]([O:6][CH3:13])=[O:5]
Reactant: Cc1cc(Br)cc(C(=O)O)c1N
Reactant: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Solvent: CI
Product: COC(=O)c1cc(Br)cc(C)c1N
Temperature: 25 °C
Reaction time: 8 h
Yield: 100.8 %

Procedure:
To a solution of 2-amino-5-bromo-3-methylbenzoic acid (3.0 g, 13 mmol) from Step A above in DMF was added cesium carbonate (6.4 g, 20 mmol) followed by iodomethane (0.8 ml, 13 mmol). The reaction was stirred at ambient temperature overnight. The mixture was washed with water and extracted with dichloromethane. The organic extract was dried (Na2SO4) and concentrated in vacuo to afford methyl 2-amino-5-bromo-3-methylbenzoate (3.2 g, 100%) as a grey solid: 1H NMR (500 MHz, CDCl3) δ 7.89 (d, J=2.4 Hz, 1H), 7.28 (d, J=2.1 Hz, 1H), 5.84 (brs, 2H), 3.87 (s, 3H), 2.15 (s, 3H); MS (ESI+) m/z 245 (M+H).
Reaction SMILES: [CH3:1][C:2]1([CH3:47])[C@@H:5]([C:6]([N:8]2[CH2:13][CH2:12][CH2:11][CH2:10][CH2:9]2)=[O:7])[CH2:4][C@H:3]1[NH:14][C:15]([C@:17]12[CH2:43][CH2:42][C@@H:41]([C:44]([CH3:46])=[CH2:45])[C@@H:18]1[C@@H:19]1[C@@:32]([CH3:35])([CH2:33][CH2:34]2)[C@@:31]2([CH3:36])[C@@H:22]([C@:23]3([CH3:40])[C@@H:28]([CH2:29][CH2:30]2)[C:27]([CH3:38])([CH3:37])[C@@H:26]([OH:39])[CH2:25][CH2:24]3)[CH2:21][CH2:20]1)=[O:16].[CH3:48][C:49]1([CH3:56])[CH2:54][C:53](=[O:55])[O:52][C:50]1=[O:51]>CN(C1C=CN=CC=1)C.N1C=CC=CC=1.CCOC(C)=O>[CH3:1][C:2]1([CH3:47])[C@@H:5]([C:6]([N:8]2[CH2:9][CH2:10][CH2:11][CH2:12][CH2:13]2)=[O:7])[CH2:4][C@H:3]1[NH:14][C:15]([C@:17]12[CH2:43][CH2:42][C@@H:41]([C:44]([CH3:46])=[CH2:45])[C@@H:18]1[C@@H:19]1[C@@:32]([CH3:35])([CH2:33][CH2:34]2)[C@@:31]2([CH3:36])[C@@H:22]([C@:23]3([CH3:40])[C@@H:28]([CH2:29][CH2:30]2)[C:27]([CH3:37])([CH3:38])[C@@H:26]([O:39][C:53](=[O:55])[CH2:54][C:49]([CH3:56])([CH3:48])[C:50]([OH:52])=[O:51])[CH2:25][CH2:24]3)[CH2:21][CH2:20]1)=[O:16]
Reactant: C=C(C)[C@@H]1CC[C@]2(C(=O)N[C@@H]3C[C@H](C(=O)N4CCCCC4)C3(C)C)CC[C@]3(C)[C@H](CC[C@@H]4[C@@]5(C)CC[C@H](O)C(C)(C)[C@@H]5CC[C@]43C)[C@@H]12
Reactant: CC1(C)CC(=O)OC1=O
Agent: CN(C)c1ccncc1
Solvent: c1ccncc1
Solvent: CCOC(C)=O
Product: C=C(C)[C@@H]1CC[C@]2(C(=O)N[C@@H]3C[C@H](C(=O)N4CCCCC4)C3(C)C)CC[C@]3(C)[C@H](CC[C@@H]4[C@@]5(C)CC[C@H](OC(=O)CC(C)(C)C(=O)O)C(C)(C)[C@@H]5CC[C@]43C)[C@@H]12
Yield: 39.6 %

Procedure:
To a stirred solution of (1R,3aS,5aR,5bR,7aR,9S,11aR,11bR,13aR,13bR)-N-((1R,3S)-2,2-dimethyl-3-(piperidine-1-carbonyl)cyclobutyl)-9-hydroxy-5a,5b,8,8,11a-pentamethyl-1-(prop-1-en-2-yl)icosahydro-1H-cyclopenta[a]chrysene-3a-carboxamide (Example 47, 0.190 g, 0.293 mmol) 2,2-Dimethylsuccinic anhydride (0.375 g, 2.932 mmol) and DMAP (0.071 g, 0.586 mmol) in pyridine (10 ml) were added at room temperature and refluxed for about 24 hours. After completion of the reaction (monitored by TLC), the reaction mixture was diluted with EtOAc, washed with aqueous 1N HCl, then water and brine, and dried over Na2SO4 then the solvent was evaporated and purified by silica gel column (100-200 mesh, elution 20% EtOAc in hexane) to afford the title compound as an off white solid. Wt: 0.090 g; Yield: 39.6%; 1H NMR (300 MHz, CDCl3): δ 5.96 (d, 111, J=8.1 Hz), 4.72 (s, 1H), 4.58 (s, 1H), 4.52-4.44 (m, 1H), 4.16-4.07 (m, 1H), 3.79-3.58 (m, 1H), 3.50-3.31 (m, 3H), 3.18-3.07 (m, 1H), 2.91-2.87 (m, 1H), 2.71-2.56 (m, 2H), 2.56-2.37 (m, 2H), 2.30-2.19 (m, 1H), 2.01-1.81 (m, 3H), 1.80-1.10 (m, 35H), 0.95, 0.93, 0.88, 0.87 (s, 21H); Mass: [M+1]+ 777 (30%), [M+Na]+ 799 (100%); IR (KBr, cm−1): 3400, 2947, 2868, 1733, 1622, 1456, 1390, 1369, 1320, 1252, 1231, 1192, 1150, 1021, 978, 881; HPLC: 97.37%; M.R: 168.5° C.-176.9° C.
Reaction SMILES: [C:1]1(=O)[CH2:12][CH2:11][CH2:10][CH2:9][CH2:8][CH2:7][CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[NH:14]1[CH2:19][CH2:18][O:17][CH2:16][CH2:15]1.C1(C)C=CC=CC=1>C1(C)C=CC(S(O)(=O)=O)=CC=1.O>[O:17]1[CH2:18][CH2:19][N:14]([C:1]2[CH2:12][CH2:11][CH2:10][CH2:9][CH2:8][CH2:7][CH2:6][CH2:5][CH2:4][CH2:3][CH:2]=2)[CH2:15][CH2:16]1
Reactant: O=C1CCCCCCCCCCC1
Reactant: C1COCCN1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: O
Solvent: Cc1ccccc1
Product: C1=C(N2CCOCC2)CCCCCCCCCC1
Yield: 59.8 %

Procedure:
A two liter three-necked flask was charged with 366 grams (2.0 moles) cyclododecanone, 348 grams (4.0 moles) morpholine, 600 ml toluene and 3.0 grams (0.0158 moles) para-toluene sulfonic acid catalyst. A magnetic stir bar was added along with a few carbon boiling chips. A Dean-Stark water trap and condenser were then attached and the mixture brought to reflux with stirring. After 46 hours reflux, 75 ml. of aqueous phase had been collected. The mixture was then cooled and the excess toluene and morpholine removed at reduced pressure (25-50 mm Hg). The residue was then distilled under vacuum (0.6 mm Hg) to yield 300.5 grams of a viscous clear oil, 1-morpholino-1-cyclododecene, b.p. 135°-150° C., 60% yield.
Reaction SMILES: Cl[CH2:2]/[CH:3]=[CH:4]/[B:5]1[O:9][C:8]([CH3:11])([CH3:10])[C:7]([CH3:13])([CH3:12])[O:6]1.[NH:14]1[CH2:19][CH2:18][CH2:17][CH:16]([NH:20][C:21](=[O:27])[O:22][C:23]([CH3:26])([CH3:25])[CH3:24])[CH2:15]1>>[CH3:12][C:7]1([CH3:13])[C:8]([CH3:11])([CH3:10])[O:9][B:5](/[CH:4]=[CH:3]/[CH2:2][N:14]2[CH2:19][CH2:18][CH2:17][CH:16]([NH:20][C:21](=[O:27])[O:22][C:23]([CH3:25])([CH3:24])[CH3:26])[CH2:15]2)[O:6]1
Reactant: CC1(C)OB(/C=C/CCl)OC1(C)C
Reactant: CC(C)(C)OC(=O)NC1CCCNC1
Product: CC(C)(C)OC(=O)NC1CCCN(C/C=C/B2OC(C)(C)C(C)(C)O2)C1
Yield: 34.9 %

Procedure:
Following the procedure outlined for Example 488, (E)-2-(3-chloroprop-1-enyl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (500 mg, 2.5 mmol) was reacted with tert-butyl piperidin-3-ylcarbamate (740 mg, 3.7 mmol) to afford the desired product (320 mg, 24%) as a yellow oil: ESI MS m/z 367 [C19H35BN2O4+H]+.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[CH:16]=[CH:15][CH:14]=[C:13]2[C:9]=1[CH2:10][C:11](=[O:17])[NH:12]2.[CH2:18]([N:20]([CH2:34][CH3:35])[CH2:21][CH2:22][NH:23][C:24]([C:26]1[CH:30]=[C:29]([CH3:31])[NH:28][C:27]=1[CH:32]=O)=[O:25])[CH3:19]>C(O)C.N1CCCCC1>[CH2:34]([N:20]([CH2:18][CH3:19])[CH2:21][CH2:22][NH:23][C:24]([C:26]1[CH:30]=[C:29]([CH3:31])[NH:28][C:27]=1[CH:32]=[C:10]1[C:9]2[C:13](=[CH:14][CH:15]=[CH:16][C:8]=2[C:3]2[CH:4]=[CH:5][CH:6]=[CH:7][C:2]=2[F:1])[NH:12][C:11]1=[O:17])=[O:25])[CH3:35]
Reactant: CCN(CC)CCNC(=O)c1cc(C)[nH]c1C=O
Reactant: O=C1Cc2c(cccc2-c2ccccc2F)N1
Solvent: CCO
Solvent: C1CCNCC1
Product: CCN(CC)CCNC(=O)c1cc(C)[nH]c1C=C1C(=O)Nc2cccc(-c3ccccc3F)c21
Temperature: 25 °C
Reaction time: 72 h
Yield: 49.9 %

Procedure:
To a solution of 4-(2-fluoro-phenyl)-1,3-dihydro-indol-2-one (56.8 mg, 0.25 mmol) and 2-formyl-5-methyl-1H-pyrrole-3-carboxylic acid (2-diethylamino-ethyl)-amide (65.3 mg, 0.26 mmol) in ethanol (2 mL) was added piperidine (3 drops). The reaction mixture was stirred at room temperature for three days. A yellow solid product was precipitated out, filtered, washed by ethanol for three times, and dried under high vacuum to provide pure product 2-[4-(2-fluoro-phenyl)-2-oxo-1,2-dihydro-indol-3-ylidenemethyl]-5-methyl-1H-pyrrole-3-carboxylic acid (2-diethylamino-ethyl)amide as a yellow solid (57.5 mg, 50%).
Reaction SMILES: [CH:1]1([N:6]([C@H:20]2[CH2:25][CH2:24][C@H:23]([CH2:26][CH3:27])[CH2:22][CH2:21]2)[C:7](=[O:19])[NH:8][C:9]2[S:10][C:11]([S:14]CC(O)=O)=[CH:12][N:13]=2)[CH2:5][CH2:4][CH2:3][CH2:2]1.C1(N[C@H]2CC[C@H](CC)CC2)CCCC1.C([O:44][C:45](=[O:55])[CH2:46][CH2:47]SC1SC(N)=NC=1)C>>[CH:1]1([N:6]([C@H:20]2[CH2:25][CH2:24][C@H:23]([CH2:26][CH3:27])[CH2:22][CH2:21]2)[C:7](=[O:19])[NH:8][C:9]2[S:10][C:11]([S:14][CH2:47][CH2:46][C:45]([OH:55])=[O:44])=[CH:12][N:13]=2)[CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: CCOC(=O)CCSc1cnc(N)s1
Reactant: CC[C@H]1CC[C@H](N(C(=O)Nc2ncc(SCC(=O)O)s2)C2CCCC2)CC1
Agent: CC[C@H]1CC[C@H](NC2CCCC2)CC1
Product: CC[C@H]1CC[C@H](N(C(=O)Nc2ncc(SCCC(=O)O)s2)C2CCCC2)CC1

Procedure:
Prepared in a similar manner to {2-[3-cyclopentyl-3-(trans-4-ethyl-cyclohexyl)-ureido]-thiazol-5-ylsulfanyl}-acetic acid via cyclopentyl-(trans-4-ethyl-cyclohexyl)-amine and 3-(2-amino-thiazol-5-ylsulfanyl)-propionic acid ethyl ester to give the title compound.
Reaction SMILES: [Cl:1][C:2]1[N:3]=[C:4]2[C:10](=[CH:11][N:12]=1)[N:9]([CH3:13])[C:8](=[O:14])[CH2:7][CH2:6][N:5]2[CH2:15][C:16]1C(C)=NOC=1C.Cl.ClCC[N:27]1[CH2:32][CH2:31][CH2:30][CH2:29][CH2:28]1.[H-].[Na+]>>[Cl:1][C:2]1[N:3]=[C:4]2[C:10]([N:9]([CH3:13])[C:8](=[O:14])[CH2:7][CH2:6][N:5]2[CH2:15][CH2:16][N:27]2[CH2:32][CH2:31][CH2:30][CH2:29][CH2:28]2)=[CH:11][N:12]=1
Reactant: ClCCN1CCCCC1
Reactant: Cc1noc(C)c1CN1CCC(=O)N(C)c2cnc(Cl)nc21
Agent: Cl
Agent: [H-]
Agent: [Na+]
Product: CN1C(=O)CCN(CCN2CCCCC2)c2nc(Cl)ncc21

Procedure:
The title compound was prepared by an analogous method to the preparation of Intermediate 156, on a 0.3 mmol scale, utilising 2-chloroethylpiperidine hydrochloride (Aldrich; 55 mg, 0.36 mmol) and Sodium Hydride (60% mineral oil dispersion; 36 mg, 0.75 mmol), as a solid (90 mg, 93%).
Reaction SMILES: [Br:1][C:2]1[CH:8]=[CH:7][C:5]([NH2:6])=[CH:4][C:3]=1[CH3:9].[CH3:10][C:11]1([CH3:17])[CH2:16][CH2:15]O[C:12]1=[O:13]>>[Br:1][C:2]1[CH:8]=[CH:7][C:5]([N:6]2[CH2:15][CH2:16][C:11]([CH3:17])([CH3:10])[C:12]2=[O:13])=[CH:4][C:3]=1[CH3:9]
Reactant: Cc1cc(N)ccc1Br
Reactant: CC1(C)CCOC1=O
Product: Cc1cc(N2CCC(C)(C)C2=O)ccc1Br

Procedure:
The title compound was prepared from 4-bromo-3-methylaniline and α,α-dimethyl-γ-butyrolactone following a similar procedure to Description 20, as a pink solid (53%).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:14]=[CH:15][C:16]=1[Cl:17])[O:5][C:6]1[CH:13]=[CH:12][C:9]([CH:10]=O)=[CH:8][CH:7]=1.[CH3:18][CH:19]([CH3:35])[C:20]([NH:22][C:23]1[CH:28]=[CH:27][CH:26]=[C:25]([CH:29]2[CH2:34][CH2:33][NH:32][CH2:31][CH2:30]2)[CH:24]=1)=[O:21]>>[Cl:1][C:2]1[CH:3]=[C:4]([CH:14]=[CH:15][C:16]=1[Cl:17])[O:5][C:6]1[CH:13]=[CH:12][C:9]([CH2:10][N:32]2[CH2:33][CH2:34][CH:29]([C:25]3[CH:24]=[C:23]([NH:22][C:20](=[O:21])[CH:19]([CH3:18])[CH3:35])[CH:28]=[CH:27][CH:26]=3)[CH2:30][CH2:31]2)=[CH:8][CH:7]=1
Reactant: CC(C)C(=O)Nc1cccc(C2CCNCC2)c1
Reactant: O=Cc1ccc(Oc2ccc(Cl)c(Cl)c2)cc1
Product: CC(C)C(=O)Nc1cccc(C2CCN(Cc3ccc(Oc4ccc(Cl)c(Cl)c4)cc3)CC2)c1

Procedure:
Prepared by Procedure F and Scheme R using 4-(3,4-dichlorophenoxy)benzaldehyde and 2-methyl-N-[3-(4-piperidinyl)phenyl]propanamide: ESMS m/e: 497.1 (M+H)+.
Reaction SMILES: C(O[CH:4](OCC)[CH2:5][NH:6][C:7]([NH:9][C:10]1[CH:15]=[CH:14][C:13]([F:16])=[CH:12][C:11]=1[F:17])=[O:8])C>CO.O.Cl>[F:17][C:11]1[CH:12]=[C:13]([F:16])[CH:14]=[CH:15][C:10]=1[N:9]1[CH:4]=[CH:5][NH:6][C:7]1=[O:8]
Reactant: CCOC(CNC(=O)Nc1ccc(F)cc1F)OCC
Agent: Cl
Solvent: O
Solvent: CO
Product: O=c1[nH]ccn1-c1ccc(F)cc1F
Temperature: 25 °C
Reaction time: 72 h
Yield: 89.4 %

Procedure:
This urea (37.5 g) was dissolved in a mixture of 560 ml of methanol and 280 ml of water, and 300 ml of 0.48M hydrochloric acid was added thereto and the resulting mixture was stirred for three days at room temperature. The reaction solution was concentrated under reduced pressure. The crystals thus separated out were washed with a mixture of water and methanol (5:1) to give 22.8 g of 1-(2,4-difluorophenyl)-2(1H,3H)-imidazolone as a colorless powder.
Reaction SMILES: [CH2:1]([C@@H:8]1[CH2:12][O:11][C:10](=[O:13])[N:9]1[C:14](=[O:19])[CH2:15][CH2:16][CH:17]=[CH2:18])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[Li+].C[Si]([N-][Si](C)(C)C)(C)C.Br[CH2:31][C:32]1[C:37]([Cl:38])=[CH:36][C:35]([O:39][CH2:40][C:41]2[CH:46]=[CH:45][CH:44]=[CH:43][CH:42]=2)=[CH:34][C:33]=1[Cl:47]>C1COCC1>[CH2:1]([C@@H:8]1[CH2:12][O:11][C:10](=[O:13])[N:9]1[C:14](=[O:19])[C@H:15]([CH2:31][C:32]1[C:33]([Cl:47])=[CH:34][C:35]([O:39][CH2:40][C:41]2[CH:42]=[CH:43][CH:44]=[CH:45][CH:46]=2)=[CH:36][C:37]=1[Cl:38])[CH2:16][CH:17]=[CH2:18])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: Clc1cc(OCc2ccccc2)cc(Cl)c1CBr
Reactant: C=CCCC(=O)N1C(=O)OC[C@H]1Cc1ccccc1
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Li+]
Solvent: C1CCOC1
Product: C=CC[C@@H](Cc1c(Cl)cc(OCc2ccccc2)cc1Cl)C(=O)N1C(=O)OC[C@H]1Cc1ccccc1
Temperature: -75 °C
Yield: 86 %

Procedure:
Stir a mixture of (R)-4-benzyl-3-pent-4-enoyl-oxazolidin-2-one (345 g, 1.33 mol) and THF (1.8 L) in a 12 L 3-neck round bottom flask, with internal temperature probe/nitrogen inlet and addition funnel, under a nitrogen atmosphere and cool to −75° C. Transfer 1 M LiHMDS (1.6 L) to the addition funnel and add at a rate such that the internal temperature does not reach above −60° C. After the addition is complete, allow the reaction to stir at −25° C. for 30 min then cool to about −60° C. At this point add solid 2-bromomethyl-1,3-dichloro-5-benzyloxy-benzene portionwise over 5 min. After the addition is complete, transfer the reaction vessel to a −10° C. acetone bath and maintain the internal reaction temperature below 10° C. for 1 hr. Cool the mixture to 0° C. then quench with 2 L aqueous 1N hydrochloric acid. Transfer the mixture to a 22 L separatory funnel and dilute with 2.5 L water and 2 L ether. Separate the layers and extract the aqueous layer with ether. Dry the combined organic phase over anhydrous magnesium sulfate, filter and concentrate to 800 g of a thick oil. Purify by silica gel chromatography using hexanes:ethyl acetate to obtain 597 g, (86%) of a colorless oil.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][C:4]([CH2:7][NH:8][CH2:9][CH2:10][CH2:11][OH:12])=[CH:3][CH:2]=1.[Li].C([Li])CCC.CCCCCC.[Cl:25][C:26]1[CH:43]=[CH:42][C:29]2[O:30][C:31]3[CH:41]=[CH:40][CH:39]=[CH:38][C:32]=3[CH2:33][N:34]([C:35](Cl)=[O:36])[C:28]=2[CH:27]=1>C1COCC1>[N:1]1[CH:6]=[CH:5][C:4]([CH2:7][NH:8][CH2:9][CH2:10][CH2:11][O:12][C:35]([N:34]2[CH2:33][C:32]3[CH:38]=[CH:39][CH:40]=[CH:41][C:31]=3[O:30][C:29]3[CH:42]=[CH:43][C:26]([Cl:25])=[CH:27][C:28]2=3)=[O:36])=[CH:3][CH:2]=1
Reactant: OCCCNCc1ccncc1
Reactant: O=C(Cl)N1Cc2ccccc2Oc2ccc(Cl)cc21
Agent: [Li]
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: CCCCCC
Product: O=C(OCCCNCc1ccncc1)N1Cc2ccccc2Oc2ccc(Cl)cc21
Yield: 40.9 %

Procedure:
By the procedure described in Example 11, 3-(4-pyridylmethylamino)-1-propanol (1.0 g, 3.4 mmol) in 30 mL of THF was converted to its lithium salt with 1.6M n-butyllithium in hexane (2.1 mL, 3.4 mmol) and reacted with the product of Example 2 (1.0 g, 3.4 mmol) to yield 590 mg of the title product.
Reaction SMILES: Cl[C:2]([C:8]1[CH:13]=[CH:12][C:11]([O:14][CH3:15])=[CH:10][CH:9]=1)([CH3:7])[C:3]([F:6])([F:5])[F:4].[CH3:16][Al](C)C>Cl>[CH3:15][O:14][C:11]1[CH:12]=[CH:13][C:8]([C:2]([CH3:16])([CH3:7])[C:3]([F:6])([F:5])[F:4])=[CH:9][CH:10]=1
Reactant: C[Al](C)C
Reactant: COc1ccc(C(C)(Cl)C(F)(F)F)cc1
Agent: Cl
Product: COc1ccc(C(C)(C)C(F)(F)F)cc1
Temperature: 95 °C
Reaction time: 1 h

Procedure:
A solution of 1-(2-chloro-1,1,1-trifluoropropan-2-yl)-4-methoxybenzene (18.0 g, 75 mmol) in 400 ml of hexanes was treated with trimethylaluminum (151 ml, 302 mmol) (2.0 M in heptane) at rt and the resulting mixture was heated at 95° C. overnight. The reaction mixture was cooled in an ice-water bath, conc. HCl was added to the reaction mixture dropwise. Fumes were generated. After about 10 ml of conc. HCl was added, more rapid addition of acid was possible due to the near complete quenching of the unreacted AlMe3. After addition of 100 ml of conc. HCl, 250 ml of H2O was added and the mixture was stirred vigorously for 1 h. The layers were separated. The org layer was dried (Na2SO4) and concentrated to give the title compound as an oil, which solidified upon drying on the vac line.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([Cl:8])[C:3]=1[C:9]1[CH:18]=[CH:17][C:16]2[C:11](=[CH:12][CH:13]=[C:14]([CH2:19][CH:20]([OH:25])[C:21]([O:23][CH3:24])=[O:22])[CH:15]=2)[N:10]=1.Br[CH2:27][C:28]1[C:33]([Cl:34])=[CH:32][CH:31]=[CH:30][C:29]=1[Cl:35].[H-].[Na+].C([O-])(O)=O.[Na+]>CN(C=O)C>[Cl:34][C:33]1[CH:32]=[CH:31][CH:30]=[C:29]([Cl:35])[C:28]=1[CH2:27][O:25][CH:20]([CH2:19][C:14]1[CH:15]=[C:16]2[C:11](=[CH:12][CH:13]=1)[N:10]=[C:9]([C:3]1[C:4]([Cl:8])=[CH:5][CH:6]=[CH:7][C:2]=1[Cl:1])[CH:18]=[CH:17]2)[C:21]([O:23][CH3:24])=[O:22]
Reactant: COC(=O)C(O)Cc1ccc2nc(-c3c(Cl)cccc3Cl)ccc2c1
Reactant: Clc1cccc(Cl)c1CBr
Agent: O=C([O-])O
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: COC(=O)C(Cc1ccc2nc(-c3c(Cl)cccc3Cl)ccc2c1)OCc1c(Cl)cccc1Cl
Temperature: 25 °C
Yield: 70 %

Procedure:
To a solution of methyl 3-[2-(2,6-dichlorophenyl)-6-quinolinyl]-2-hydroxypropanoate 55 (0.159 g) and α-bromo-2,6-dichlorotoluene (1.05 g) in DMF (3.5 ml) is added 17 mg of NaH (60% dispersion in mineral oil) and Ag2O (0.102 g). The solution is stirred for 1 night at room temperature. A saturated solution of NaHCO3 is added. The aqueous phase is extracted with AcOEt (3×10 ml). The organic phases are washed with water (2×10 ml), with brine and dried over MgSO4. After concentration, the residue is purified twice over silica gel using AcOEt/petroleum ether 10/90 then 15/85 as eluent to give methyl 2-[(2,6-dichlorobenzyl)oxy]-3-[2-(2,6-dichlorophenyl)-6-quinolinyl]propanoate 56.
Reaction SMILES: [OH:1][C:2]([C:4]1[CH:9]=[CH:8][C:7]([CH2:10][CH2:11][C:12]([CH3:14])=[O:13])=[CH:6][CH:5]=1)=[O:3].Cl.[CH3:16]O>>[CH3:16][O:3][C:2]([C:4]1[CH:9]=[CH:8][C:7]([CH2:10][CH2:11][C:12]([CH3:14])=[O:13])=[CH:6][CH:5]=1)=[O:1]
Reactant: CC(=O)CCc1ccc(C(=O)O)cc1
Reactant: CO
Agent: Cl
Product: COC(=O)c1ccc(CCC(C)=O)cc1

Procedure:
Methyl 2-(4-hydroxycarbonylphenyl)ethyl ketone was esterified by reaction with methyl alcohol and hydrochloric acid to provide methyl 2-(4-methoxycarbonylphenyl)ethyl ketone. The ketone was condensed with optically active S-α-methylbenzylamine, and the imine which was formed was reduced to provide N-(α-methylbenzyl)-1-methyl-3-(4-methoxycarbonylphenyl)propylamine. The amine was converted to the hydrochloride salt, and fractional crystallization of the salt thus formed afforded optically active S-N-(α-methylbenzyl)-1-methyl-3-(4-methoxycarbonylphenyl)propylaminium chloride. M.P. 198°-205° C. [α]D -81.2° (MeOH).
Reaction SMILES: [CH3:1][Sn:2]([CH3:15])([CH3:14])[C:3]1[CH:12]=[N:11][C:10]2[NH:9][C:8](=[O:13])[CH2:7][O:6][C:5]=2[CH:4]=1.[Li]N([Si](C)(C)C)[Si](C)(C)[CH3:19].S(O)(O)(=O)=O.COS(OC)(=O)=O>C1COCC1>[CH3:19][N:9]1[C:8](=[O:13])[CH2:7][O:6][C:5]2[CH:4]=[C:3]([Sn:2]([CH3:15])([CH3:14])[CH3:1])[CH:12]=[N:11][C:10]1=2
Reactant: [Li]N([Si](C)(C)C)[Si](C)(C)C
Reactant: C[Sn](C)(C)c1cnc2c(c1)OCC(=O)N2
Agent: O=S(=O)(O)O
Solvent: COS(=O)(=O)OC
Solvent: C1CCOC1
Product: CN1C(=O)COc2cc([Sn](C)(C)C)cnc21
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a suspension of 680 mg of 7-trimethylstannyl-2H-pyrido[3,2-b]-1,4-oxazin-3(4H)-one (0.0022 mole) in 10 ml of THF is added 2.4 ml of LiN(TMS)2 (0.0024 mole) in THF. The homogenous solution is maintained under nitrogen at room temperature for 20 min , 300 mg (0.0024 mole) of dimethylsulfate sulfate is added and the reaction mixture allowed to stir overnight. The reaction mixture is then quenched with 10 ml of sat. ammonium chloride and extracted with 3×50 ml ethyl acetate. The ethyl acetate is then washed with 3×10 ml sat. ammonium chloride, dried over sodium sulfate and concentrated to obtain off white product whish is used directly in the next step.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][N:6]=[C:5]2[CH3:11].[H-].[Na+].[CH3:14][Si:15]([CH3:22])([CH3:21])[CH2:16][CH2:17][O:18][CH2:19]Cl.C(OCC)(=O)C>CN(C=O)C>[Br:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[N:7]([CH2:19][O:18][CH2:17][CH2:16][Si:15]([CH3:22])([CH3:21])[CH3:14])[N:6]=[C:5]2[CH3:11]
Reactant: C[Si](C)(C)CCOCCl
Reactant: Cc1n[nH]c2ccc(Br)cc12
Agent: [H-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: Cc1nn(COCC[Si](C)(C)C)c2ccc(Br)cc12
Temperature: 25 °C
Reaction time: 1 h
Yield: 91.2 %

Procedure:
To a solution of 5-bromo-3-methylindazole 104 (2 g, 9.48 mmol) in anhydrous DMF (20 mL), cooled in ice bath, was added-sodium hydride (60% w/w, 0.57 g, 14.25 mmol) and (2-trimethylsilylethoxy)methyl chloride (2.5 mL, 14.16 mmol) in a dropwise manner. The reaction mixture was allowed to warm to room temperature and was stirred for 1 hour. Ethyl acetate (200 mL) was added. The organic layer was washed with saturated ammonium chloride solution, water and brine. The organic layer was dried over sodium sulfate. The organic solvent was evaporated under reduced pressure. The crude product was purified by flash column chromatography to yield the desired 5-bromo-3-methyl-N-(2-trimethylsilanylethoxymethyl)indazole 116 (2.95 g, 8.65 mmol) as a mixture of the 1H- and 2H-indazole regioisomers.
Reaction SMILES: [NH:1]1[CH2:7][CH2:6][CH2:5][NH:4][CH2:3][CH2:2]1.Cl[C:9]1[C:14]([NH:15][CH:16]([CH3:18])[CH3:17])=[N:13][CH:12]=[CH:11][N:10]=1>>[CH3:17][CH:16]([NH:15][C:14]1[C:9]([N:1]2[CH:7]=[CH:6][CH:5]=[N:4][CH:3]=[CH:2]2)=[N:10][CH:11]=[CH:12][N:13]=1)[CH3:18]
Reactant: CC(C)Nc1nccnc1Cl
Reactant: C1CNCCNC1
Product: CC(C)Nc1nccnc1N1C=CC=NC=C1

Procedure:
Following the general procedure of PREPARATION 24 and making non-critical variations but starting with homopiperazine (2.46 g) and 2-chloro-3-(1-methylethyl)aminopyrazine (PREPARATION 23), the title compound is obtained, NMR (300 MHz, CDCl3) 7.56, 7.34, 4.75, 4.04, 3.28-3.18, 3.00-2.94, 1.79, and 1.15 δ.
Reaction SMILES: [CH3:1][N:2]1[CH2:6][C@@H:5]2[NH:7][CH2:8][CH2:9][C@@H:4]2[CH2:3]1.[Cl:10][C:11]1[C:12]([C:30]2[CH:31]=[N:32][N:33]3[CH:38]=[CH:37][CH:36]=[CH:35][C:34]=23)=[N:13][C:14]([NH:17][C:18]2[CH:23]=[C:22]([N+:24]([O-:26])=[O:25])[C:21](F)=[CH:20][C:19]=2[O:28][CH3:29])=[N:15][CH:16]=1.CCN(C(C)C)C(C)C>FC(F)(F)CO>[CH3:1][N:2]1[CH2:6][C@@H:5]2[N:7]([C:21]3[C:22]([N+:24]([O-:26])=[O:25])=[CH:23][C:18]([NH:17][C:14]4[N:13]=[C:12]([C:30]5[CH:31]=[N:32][N:33]6[CH:38]=[CH:37][CH:36]=[CH:35][C:34]=56)[C:11]([Cl:10])=[CH:16][N:15]=4)=[C:19]([O:28][CH3:29])[CH:20]=3)[CH2:8][CH2:9][C@@H:4]2[CH2:3]1
Reactant: CN1C[C@H]2CCN[C@H]2C1
Reactant: COc1cc(F)c([N+](=O)[O-])cc1Nc1ncc(Cl)c(-c2cnn3ccccc23)n1
Solvent: CCN(C(C)C)C(C)C
Solvent: OCC(F)(F)F
Product: COc1cc(N2CC[C@@H]3CN(C)C[C@@H]32)c([N+](=O)[O-])cc1Nc1ncc(Cl)c(-c2cnn3ccccc23)n1
Temperature: 140 °C
Yield: 49.6 %

Procedure:
(3aR,6aR)-5-Methyl-2,3,3a,4,6,6a-hexahydro-1H-pyrrolo[3,2-c]pyrrole (Intermediate 37, 91 mg, 0.72 mmol) was added to a mixture of 5-chloro-N-(4-fluoro-2-methoxy-5-nitrophenyl)-4-pyrazolo[1,5-a]pyridin-3-ylpyrimidin-2-amine (Intermediate 20, 250 mg, 0.60 mmol) and DIPEA (0.334 mL, 1.93 mmol) in 2,2,2-trifluoroethanol (3 mL) and the mixture was heated at 140° C. in a microwave for 0.5 h. The mixture was then absorbed onto silica. Purification by FCC, eluting with 2% 7N methnaolic ammonia in CH2Cl2 gave material that was concentrated in vacuo and dissolved in CH3OH. The resulting solution was absorbed onto an SCX column and the column was washed with CH3OH then eluted with 7N methanolic ammonia. Appropriate fractions were concentrated in vacuo to give the title compound (155 mg, 49%) as a orange/red gummy solid; 1H NMR: (CDCl3) 1.89 (1H, dd), 2.04-2.19 (1H, m), 2.24 (3H, s), 2.30-2.39 (1H, m), 2.40-2.57 (2H, m), 2.68 (1H, t), 2.98-3.11 (1H, m), 3.23 (1H, t), 3.51-3.63 (1H, m), 3.97 (3H, s), 4.36-4.48 (1H, m), 6.46 (1H, s), 6.90-7.02 (1H, m), 7.31-7.43 (2H, m), 8.38 (1H, s), 8.48 (1H, dd), 8.53-8.57 (1H, m), 8.82 (1H, s), 8.93 (1H, s); m/z: ES+ MH+ 521.45.