Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C([N:3]([C:31](=O)[C:32]1[CH:37]=[CH:36][C:35](O)=[CH:34]C=1)[C:4]1[CH:9]=[C:8]([O:10][CH3:11])[C:7]([O:12][CH3:13])=[CH:6][C:5]=1[C@@H:14]1[CH2:23][CH2:22][C:21]2[CH:20]=[C:19]([O:24]C(=O)C(C)(C)C)[CH:18]=[CH:17][C:16]=2[CH2:15]1)C.[C:40]([N:44]([CH3:49])[C:45](=O)[CH2:46]Cl)([CH3:43])([CH3:42])[CH3:41]>>[C:40]([N:44]([CH3:49])[CH2:45][CH2:46][O:10][C:8]1[CH:7]=[CH:6][C:36]([CH2:37][CH2:32][CH2:31][NH:3][C:4]2[CH:9]=[C:8]([O:10][CH3:11])[C:7]([O:12][CH3:13])=[CH:6][C:5]=2[C@@H:14]2[CH2:23][CH2:22][C:21]3[CH:20]=[C:19]([OH:24])[CH:18]=[CH:17][C:16]=3[CH2:15]2)=[CH:35][CH:34]=1)([CH3:43])([CH3:42])[CH3:41]
Reactant: CCN(C(=O)c1ccc(O)cc1)c1cc(OC)c(OC)cc1[C@@H]1CCc2cc(OC(=O)C(C)(C)C)ccc2C1
Reactant: CN(C(=O)CCl)C(C)(C)C
Product: COc1cc(NCCCc2ccc(OCCN(C)C(C)(C)C)cc2)c([C@@H]2CCc3cc(O)ccc3C2)cc1OC
Yield: 104.5 %

Procedure:
Synthesized from pivalic acid (R)-6-{2-[ethyl(4-hydroxybenzoyl)amino]-4,5-dimethoxyphenyl}-5,6,7,8-tetrahydronaphthalen-2-yl ester (16 mg) and N-tert-butyl-2-chloro-N-methylacetamide (8.9 mg) according to an analogous synthetic method to Example 404 and purified by LC-MS, the title compound (8.6 mg) was obtained.
Reaction SMILES: [C:1](N)(C)(C)C.[OH:6][C:7]1[CH:8]=[C:9]([CH2:13][C@H:14]([O:18][CH:19]([CH3:21])[CH3:20])[C:15]([OH:17])=[O:16])[CH:10]=[CH:11][CH:12]=1.S(=O)(=O)(O)O.C(OC)(C)(C)C>CO>[OH:6][C:7]1[CH:8]=[C:9]([CH2:13][C@H:14]([O:18][CH:19]([CH3:21])[CH3:20])[C:15]([O:17][CH3:1])=[O:16])[CH:10]=[CH:11][CH:12]=1
Reactant: CC(C)O[C@@H](Cc1cccc(O)c1)C(=O)O
Reactant: CC(C)(C)N
Agent: O=S(=O)(O)O
Solvent: CO
Solvent: COC(C)(C)C
Product: COC(=O)[C@H](Cc1cccc(O)c1)OC(C)C
Temperature: 10 °C
Reaction time: 3 h
Yield: 99.2 %

Procedure:
(2S)-3-(3-Hydroxyphenyl)-2-isopropoxypropionic acid tert-butylamine salt (8.2 kg, 28 mol) was dissolved in methanol (41 L), and then the reaction mixture was cooled to 10° C. Concentrated sulfuric acid (1.9 L, 36 mol) was added to the reaction mixture at 10 to 20° C. over a period of 5 minutes. The reaction mixture was stirred at 60° C. for 3 hours, followed by adding tert-butylmethyl ether (164 L) and a 10% sodium chloride solution (41 L) to separate an organic layer. Then, the organic layer was washed sequentially with the 10% sodium chloride solution (41 L), a 7% sodium bicarbonate aqueous solution (16 L), and water (41 L), followed by vacuum concentration to obtain 6.62 kg of the title compound (yield: 100%). The 1H-NMR data thereof coincided with that of the compound of Example 1-(5).
Reaction SMILES: [CH3:1][O:2][C:3]1[N:8]=[C:7]([CH3:9])[N:6]=[C:5]([NH2:10])[CH:4]=1.Br[CH2:12][C:13](=O)[C:14]([C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1)=[O:15]>O1CCCC1.CCOCC>[CH3:1][O:2][C:3]1[N:8]=[C:7]([CH3:9])[N:6]2[CH:12]=[C:13]([C:14]([C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=3)=[O:15])[N:10]=[C:5]2[CH:4]=1
Reactant: O=C(CBr)C(=O)c1ccccc1
Reactant: COc1cc(N)nc(C)n1
Solvent: CCOCC
Solvent: C1CCOC1
Product: COc1cc2nc(C(=O)c3ccccc3)cn2c(C)n1
Reaction time: 8 h
Yield: 66.9 %

Procedure:
A stirred solution of 2.1 g of 6-methoxy-2-methyl-4-pyrimidinamine in dry tetrahydrofuran was treated with a solution of 5.4 g of 3-bromo-1-phenyl-1,2-propanedione in 5 ml of dry ether. After stirring overnight, the mixture was chilled and the precipitated salt filtered off. A suspension of the salt in dry ethanol was refluxed for 1.5 hours, chilled, and filtered. The solid was shaken with a mixture of chloroform and aqueous sodium bicarbonate and the organic layer was evaporated to dryness under reduced pressure. The residue was chromatographed in ethyl acetate on silica to obtain 2.7 g of (7-methoxy-5-methyl-imidazo[1,2-c]pyrimidin-2-yl)-phenylmethanone as a yellow crystalline solid melting at 165°-7° C.
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4]([S:8][C:9]2[CH:14]=[CH:13][C:12]([S:15]([N:18]([CH2:30][CH2:31][N:32]3[CH2:37][CH2:36][O:35][CH2:34][CH2:33]3)[C@@H:19]([C:23]([O:25]C(C)(C)C)=[O:24])[CH:20]([CH3:22])[CH3:21])(=[O:17])=[O:16])=[CH:11][CH:10]=2)[CH:5]=[CH:6][CH:7]=1.[ClH:38]>O>[ClH:38].[CH3:1][C:2]1[CH:3]=[C:4]([S:8][C:9]2[CH:10]=[CH:11][C:12]([S:15]([N:18]([CH2:30][CH2:31][N:32]3[CH2:37][CH2:36][O:35][CH2:34][CH2:33]3)[C@@H:19]([C:23]([OH:25])=[O:24])[CH:20]([CH3:22])[CH3:21])(=[O:17])=[O:16])=[CH:13][CH:14]=2)[CH:5]=[CH:6][CH:7]=1
Reactant: Cc1cccc(Sc2ccc(S(=O)(=O)N(CCN3CCOCC3)[C@@H](C(=O)OC(C)(C)C)C(C)C)cc2)c1
Agent: Cl
Solvent: O
Product: Cc1cccc(Sc2ccc(S(=O)(=O)N(CCN3CCOCC3)[C@@H](C(=O)O)C(C)C)cc2)c1

Procedure:
A solution of N-[[4-[(3-methylphenyl)thio]phenyl]sulfonyl]-N-[2-(4-morpholinyl)ethyl]-D-valine, 1,1-dimethylethyl ester, from Example 1d (5.21 g, 9.08 mmol) in 12 M HCl (30 mL) and H2O (30 mL) was stirred at room temperature for 30 minutes and then heated to reflux for 25 minutes. Concentration in vacuo afforded N-[[4-[(3-methylphenyl)thio]phenyl]sulfonyl]-N-[2-(4-morpholinyl)ethyl]-D-valine, monohydrochloride, as a white solid (5.30 g). MS MH+ calc'd for C24H33N2O5S2 : 494, found: 494. HRMS calc'd for C24H33N2O5S2 : 493.1831; found: 493.1833.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][OH:9])=[CH:4][C:3]=1[I:10].C(O[CH:14]=[C:15]([C:21]([O:23][CH2:24][CH3:25])=[O:22])[C:16]([O:18][CH2:19][CH3:20])=[O:17])C>C(Cl)Cl.CO>[OH:9][CH2:8][C:5]1[CH:6]=[CH:7][C:2]([NH:1][CH:14]=[C:15]([C:16]([O:18][CH2:19][CH3:20])=[O:17])[C:21]([O:23][CH2:24][CH3:25])=[O:22])=[C:3]([I:10])[CH:4]=1
Reactant: Nc1ccc(CO)cc1I
Reactant: CCOC=C(C(=O)OCC)C(=O)OCC
Solvent: CO
Solvent: ClCCl
Product: CCOC(=O)C(=CNc1ccc(CO)cc1I)C(=O)OCC
Temperature: 25 °C

Procedure:
A solution of (4-amino-3-iodophenyl)methanol (5.97 g) and diethyl ethoxymethylenemalonate (5.34 mL) is heated at 100° C. for 30 min. The reaction is cooled to room temperature. The resulting solid is dissolved in a mixture of CH2Cl2 and MeOH, adsorbed onto silica and chromatographed (Biotage flash 40M, eluant CH2Cl2, then 0.5% MeOH/CH2Cl2). Product containing fractions are combined and condensed to afford diethyl 2-{[4-(hydroxymethyl)-2-iodoanilino]methylene}malonate as a white solid, m.p. 152-154° C.
Reaction SMILES: Cl.[NH2:2][CH2:3][CH:4]([C:13]1[CH:18]=[CH:17][CH:16]=[C:15]([O:19][CH3:20])[CH:14]=1)[CH2:5][CH2:6][CH2:7][C:8]([O:10][CH2:11][CH3:12])=[O:9].[CH:21](OCC)=[O:22]>CCOCC>[CH:21]([NH:2][CH2:3][CH:4]([C:13]1[CH:18]=[CH:17][CH:16]=[C:15]([O:19][CH3:20])[CH:14]=1)[CH2:5][CH2:6][CH2:7][C:8]([O:10][CH2:11][CH3:12])=[O:9])=[O:22]
Reactant: CCOC(=O)CCCC(CN)c1cccc(OC)c1
Reactant: CCOC=O
Agent: Cl
Solvent: CCOCC
Product: CCOC(=O)CCCC(CNC=O)c1cccc(OC)c1

Procedure:
The amine obtained in Step B, in the form of a base (6.4 g; 27 mmol), is dissolved in 60 ml of ethyl formate. The reaction mixture is heated at reflux for 6 hours with stirring and then evaporated under reduced pressure. The residue obtained is taken up in ether. The organic phase is then washed in succession with acidic water (1N HCl), water, and a 10% hydrogen carbonate solution, subsequently dried over magnesium sulphate, filtered and evaporated under reduced pressure to yield the title product in the form of a yellow oil.
Reaction SMILES: [CH2:1]1COCC1.C(Cl)(=O)C(Cl)=O.[Cl:12][C:13]1[CH:18]=[CH:17][C:16]([C:19](=[O:22])[CH2:20][CH3:21])=[C:15]([NH:23][C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)[CH:14]=1>CN(C=O)C.O>[Cl:12][C:13]1[CH:14]=[C:15]2[C:16]([C:19](=[O:22])[C:20]([CH3:1])=[CH:21][N:23]2[C:24]2[CH:25]=[CH:26][CH:27]=[CH:28][CH:29]=2)=[CH:17][CH:18]=1
Reactant: CCC(=O)c1ccc(Cl)cc1Nc1ccccc1
Reactant: C1CCOC1
Agent: O=C(Cl)C(=O)Cl
Solvent: O
Solvent: CN(C)C=O
Product: Cc1cn(-c2ccccc2)c2cc(Cl)ccc2c1=O
Temperature: 115 °C
Reaction time: 1.5 h
Yield: 81.6 %

Procedure:
To a mixture of THF (60 mL) and DMF (7.5 mL) at 0° C. under nitrogen was added oxalyl chloride (6.5 mL, 76.8 mmol) during which time a white precipitate formed. The temperature was slowly raised to room temp. and stirred for 1.5 hr. THF was distilled off from the reaction mixture under reduced pressure and under nitrogen. The gummy residue was further diluted with DMF (100 mL). A solution of 1-(4-chloro-2-phenylamino-phenyl)-propan-1-one (5.0 g, 19.30 mmol) in DMF (50 mL) was added to the reaction mixture at room temperature. The reaction was heated at 115° C. for 2 hr. The reaction mixture was brought down to room temperature, then diluted with water (750 mL), and the mixture was extracted with ethyl acetate (2×750 mL). The combined organic layers were washed with brine (500 mL), dried, and concentrated under reduced pressure to yield 7-chloro-3-methyl-1-phenyl-1H-quinolin-4-one (4.25 g, 81.6%) as an off-white solid. 1H NMR (DMSO-d6) δ ppm 8.24 (d, J=8.8 Hz, 1H) 8.01 (s, 1H) 7.52-7.80 (m, 5H) 7.40 (dd, J=8.8, 1.8 Hz, 1H) 6.87 (d, J=1.8 Hz, 1H) 2.01 (s, 3H). MS calcd. for C16H12ClNO [(M+H)+] 270.0, obsd. 269.8.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6](F)[CH:5]=[CH:4][C:3]=1[S:9]([C@H:12]1[CH2:16][N:15]([C:17]2[N:21]([CH:22]3[CH2:27][CH2:26][O:25][CH2:24][CH2:23]3)[N:20]=[C:19]([CH3:28])[CH:18]=2)[C@H:14]([C:29]([NH:31][C:32]2([C:35]#[N:36])[CH2:34][CH2:33]2)=[O:30])[CH2:13]1)(=[O:11])=[O:10].Cl.[F:38][C:39]1([F:43])[CH2:42][NH:41][CH2:40]1>C(#N)C>[Cl:1][C:2]1[CH:7]=[C:6]([N:41]2[CH2:42][C:39]([F:43])([F:38])[CH2:40]2)[CH:5]=[CH:4][C:3]=1[S:9]([C@H:12]1[CH2:16][N:15]([C:17]2[N:21]([CH:22]3[CH2:23][CH2:24][O:25][CH2:26][CH2:27]3)[N:20]=[C:19]([CH3:28])[CH:18]=2)[C@H:14]([C:29]([NH:31][C:32]2([C:35]#[N:36])[CH2:34][CH2:33]2)=[O:30])[CH2:13]1)(=[O:10])=[O:11]
Reactant: Cc1cc(N2C[C@H](S(=O)(=O)c3ccc(F)cc3Cl)C[C@H]2C(=O)NC2(C#N)CC2)n(C2CCOCC2)n1
Reactant: FC1(F)CNC1
Agent: Cl
Solvent: CC#N
Product: Cc1cc(N2C[C@H](S(=O)(=O)c3ccc(N4CC(F)(F)C4)cc3Cl)C[C@H]2C(=O)NC2(C#N)CC2)n(C2CCOCC2)n1

Procedure:
In analogy to the procedure described in example 389, (2S,4R)-4-(2-chloro-4-fluorophenylsulfonyl)-N-(1-cyanocyclopropyl)-1-(3-methyl-1-(tetrahydro-2H-pyran-4-yl)-1H-pyrazol-5-yl)pyrrolidine-2-carboxamide was reacted with 3,3-difluoroazetidine hydrochloride (CAS Reg. No. 288315-03-7) in acetonitrile at 90° C. for 48 h to give the title compound as off-white foam. MS (ESI): m/z=609.2 [M+H]+.
Reaction SMILES: [C:1]1([CH:11]=[CH:12][CH2:13]Cl)[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][CH:2]=1.[NH2:15][C:16]1[S:17][C:18]2[CH2:19][CH2:20][NH:21][CH2:22][CH2:23][C:24]=2[N:25]=1.C(Cl)(Cl)Cl.CO>C(Cl)(Cl)Cl>[NH2:15][C:16]1[S:17][C:18]2[CH2:19][CH2:20][N:21]([CH2:13][CH:12]=[CH:11][C:1]3[C:10]4[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=4)[CH:4]=[CH:3][CH:2]=3)[CH2:22][CH2:23][C:24]=2[N:25]=1
Reactant: Nc1nc2c(s1)CCNCC2
Reactant: ClCC=Cc1cccc2ccccc12
Solvent: ClC(Cl)Cl
Solvent: CO
Product: Nc1nc2c(s1)CCN(CC=Cc1cccc3ccccc13)CC2
Yield: 31 %

Procedure:
Prepared from 3-(1-naphthyl)allyl chloride and 2 equivalents of 2-amino-4,5,7,8-tetrahydro-6 H-thiazolo[5,4-d]azepine in chloroform for 3 days at 20° C. Yield: 31% of theory, Melting point: 178°-180° C. (chloroform/methanol =100:1).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5]([OH:20])=[C:6]([CH:19]=1)[CH2:7][N:8]([C:11]1[N:16]=[N:15][C:14]([C:17]#[N:18])=[CH:13][CH:12]=1)[CH2:9][CH3:10].[F:21][C:22]([F:28])([F:27])[CH:23]([OH:26])[CH2:24]Br>>[Br:1][C:2]1[CH:3]=[CH:4][C:5]([O:20][CH2:24][CH:23]([OH:26])[C:22]([F:28])([F:27])[F:21])=[C:6]([CH:19]=1)[CH2:7][N:8]([C:11]1[N:16]=[N:15][C:14]([C:17]#[N:18])=[CH:13][CH:12]=1)[CH2:9][CH3:10]
Reactant: OC(CBr)C(F)(F)F
Reactant: CCN(Cc1cc(Br)ccc1O)c1ccc(C#N)nn1
Product: CCN(Cc1cc(Br)ccc1OCC(O)C(F)(F)F)c1ccc(C#N)nn1

Procedure:
The title compound was prepared by reacting 6-[N-(5-bromo-2-hydroxybenzyl)-N-ethylamino]-3-cyanopyridazine with 1,1,1-trifluoro-3-bromo-propan-2-ol using a method similar to that of reference example 4.
Reaction SMILES: [F:1][C:2]1[CH:22]=[C:21]([F:23])[CH:20]=[CH:19][C:3]=1[C:4]([NH:6][C:7]1[C:8]([CH3:18])=[N:9][NH:10][C:11]=1[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1)=O.Cl[Sn](Cl)(Cl)Cl>O>[F:1][C:2]1[CH:22]=[C:21]([F:23])[CH:20]=[CH:19][C:3]=1[C:4]1[C:13]2[CH:14]=[CH:15][CH:16]=[CH:17][C:12]=2[C:11]2[NH:10][N:9]=[C:8]([CH3:18])[C:7]=2[N:6]=1
Reactant: Cc1n[nH]c(-c2ccccc2)c1NC(=O)c1ccc(F)cc1F
Agent: Cl[Sn](Cl)(Cl)Cl
Solvent: O
Product: Cc1n[nH]c2c1nc(-c1ccc(F)cc1F)c1ccccc12

Procedure:
The preparation took place in analogy to example 33 (B) using 233 mg of 2,4-difluoro-N-(3-methyl-5-phenyl-1H-pyrazol-4-yl)-benzamide, except the reaction mixture was heated for 4 h after addition of SnCl4, and addition of water gave a tan precipitate. This material was triturated with hot methanol to give a solid that was further triturated with dichloromethane and methanol to give the title compound as a white solid.
Reaction SMILES: [Br-].[CH2:2]([P+](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[CH2:3][C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1.[CH3:29][CH:30]1[CH:35]=[C:34]([CH3:36])[CH2:33][CH2:32][CH:31]1[CH:37]=O>>[CH3:29][CH:30]1[CH:35]=[C:34]([CH3:36])[CH2:33][CH2:32][CH:31]1[CH:37]=[CH:2][CH2:3][C:4]1[CH:5]=[CH:6][CH:7]=[CH:8][CH:9]=1
Reactant: CC1=CC(C)C(C=O)CC1
Reactant: c1ccc(CC[P+](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: [Br-]
Product: CC1=CC(C)C(C=CCc2ccccc2)CC1
Yield: 61.4 %

Procedure:
Starting from phenethyltriphenylphosphonium bromide (3.67 g, 8.20 mmol, 1.0 equiv.), n-Buli (1.6 M in hexanes, 5.1 mL, 8.20 mmol, 1.0 equiv.) and 2,4-dimethylcyclohex-3-enecarbaldehyde (1.70 g, 12.3 mmol, 1.5 equiv.), 1.14 g (61%) of the title compound as a colorless oil was obtained after purification by flash chromatography on SiO2 (cyclohexane).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:10]([C:29]([F:32])([F:31])[F:30])/[CH:11]=[CH:12]/[C:13]2[CH:14]=[C:15]3[C:19](=[CH:20][CH:21]=2)[N:18](C(OC(C)(C)C)=O)[CH:17]=[CH:16]3)[CH:5]=[C:6]([Cl:9])[C:7]=1[F:8].C(O)(C(F)(F)F)=O>C(Cl)Cl>[Cl:9][C:6]1[CH:5]=[C:4]([CH:10]([C:29]([F:30])([F:32])[F:31])/[CH:11]=[CH:12]/[C:13]2[CH:14]=[C:15]3[C:19](=[CH:20][CH:21]=2)[NH:18][CH:17]=[CH:16]3)[CH:3]=[C:2]([Cl:1])[C:7]=1[F:8]
Reactant: CC(C)(C)OC(=O)n1ccc2cc(/C=C/C(c3cc(Cl)c(F)c(Cl)c3)C(F)(F)F)ccc21
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: Fc1c(Cl)cc(C(/C=C/c2ccc3[nH]ccc3c2)C(F)(F)F)cc1Cl
Temperature: 25 °C
Reaction time: 2 h
Yield: 128.8 %

Procedure:
To a stirred solution of (E)-tert-butyl 5-(3-(3,5-dichloro-4-fluorophenyl)-4,4,4-trifluorobut-1-enyl)-1H-indole-1-carboxylate (0.2 g, 0.40 mmol) in CH2Cl2 (10.0 mL) was added TFA (70 mg, 0.61 mmol) and the reaction was stirred at ambient temperature for 2 h. The reaction mixture was diluted with CH2Cl2 and washed with saturated NaHCO3 solution, water and brine solution. The separated CH2Cl2 layer was dried over anhydrous Na2SO4 and concentrated under reduced pressure to afford the title compound as a light brown solid (0.2 g, 97%): mp 132.9-138.8° C.; 1H NMR (400 MHz, CDCl3) δ 11.19 (br, 1H), 8.20 (d, J=8.0 Hz, 1H), 7.60 (m, 2H), 7.39 (m, 3H), 6.69 (d, J=16.0 Hz, 1H), 6.55 (d, J=10.5 Hz, 1H), 6.36 (dd, J=16.0, 8.0 Hz, 1H), 4.82 (m, 1H); ESIMS m/z 387.98 ([M+H]+).
Reaction SMILES: [OH:1][CH2:2][C:3]1[CH:8]=C(C)[N:6]=[C:5]([C:10]#N)[CH:4]=1.CO.C[CH2:15][O:16][C:17]([CH3:19])=[O:18].C([O-])(O)=O.[Na+]>OS(O)(=O)=O.O>[OH:1][CH2:2][C:3]1[CH:4]=[C:5]([CH3:10])[N:6]=[C:19]([C:17]([O:16][CH3:15])=[O:18])[CH:8]=1
Reactant: Cc1cc(CO)cc(C#N)n1
Reactant: CCOC(C)=O
Agent: O=C([O-])O
Agent: O=S(=O)(O)O
Agent: [Na+]
Solvent: CO
Solvent: O
Product: COC(=O)c1cc(CO)cc(C)n1
Temperature: 135 °C
Reaction time: 12 h

Procedure:
A mixture of 440 mg of the 4-(hydroxymethyl)-6-methylpicolinonitrile in 3 mL of concentrated H2SO4 and 1.8 mL of H2O was stirred at 135° C. for 12 h. The temperature was decreased to 95° C., 6 mL of MeOH was added, and the solution was stirred at 95° C. for 1 h. The solution was added to ice with H2O and EtOAc. Solid NaHCO3 and sat. NaHCO3 solution were added to a pH=8. The aqueous layer was extracted with EtOAc (2×). The combined extracts washed with brine (40 mL), dried over Na2SO4, filtered and concentrated to give 393 mg of methyl 4-(hydroxymethyl)-6-methylpicolinate which was used without further purification.
Reaction SMILES: S(OOS([O-])(=O)=O)([O-])(=O)=[O:2].[K+].[K+].[Br:13][C:14]1[CH:15]=[CH:16][C:17]2[O:27][C:20]3([CH2:26][CH2:25][CH2:24][CH2:23][CH2:22][CH2:21]3)[CH2:19][C:18]=2[CH:28]=1>C(#N)C.O>[Br:13][C:14]1[CH:15]=[CH:16][C:17]2[O:27][C:20]3([CH2:26][CH2:25][CH2:24][CH2:23][CH2:22][CH2:21]3)[C:19](=[O:2])[C:18]=2[CH:28]=1
Reactant: Brc1ccc2c(c1)CC1(CCCCCC1)O2
Reactant: O=S(=O)([O-])OOS(=O)(=O)[O-]
Agent: [K+]
Solvent: O
Solvent: CC#N
Product: O=C1c2cc(Br)ccc2OC12CCCCCC2
Temperature: 25 °C
Reaction time: 1.5 h

Procedure:
To a stirred mixture of 17.57 g of potassium persulfate, 5.19 g of cupric sulfate and 100 ml of distilled water was added a solution of 9.13 g of 5-bromo-spiro[benzofuran-2(3H),1'-cycloheptane] in 100 ml of acetonitrile. The mixture was stirred and heated to reflux; after 1.5 hours, GC showed only 6% unreacted starting material. Another 3.51 g of potassium persulfate was added and the mixture was refluxed for another hour and thereafter cooled to room temperature. The mixture was diluted with water (1.0 liter) and extracted with ether (1×500 ml, 2×250 ml). The combined ether extracts were washed with water (250 ml) and saturated sodium chloride solution (250 ml), dried overnight over anhydrous sodium sulfate, filtered and concentrated in vacuo to a gum weighing 7.63 g. This material was taken up in 100 ml of hexane and gravity-filtered to remove insoluble material, and the flask, filter paper and insoluble material were rinsed with another 100 ml of hexane. The hexane filtrate was concentrated in vacuo to an oil weighing 5.84 g. Vacuum distillation of this material afforded 2.76 g of viscous distillate, b.p. 135°-140° C. @ 0.15 mm.
Reaction SMILES: C([O:4][C@@:5]1([CH2:40][CH3:41])[C:37]2[CH:36]=[C:35]3[N:11]([CH2:12][C:13]4[C:14]3=[N:15][C:16]3[C:17]5[C:18]=4[N:19]([CH2:30][CH2:31][CH2:32][CH2:33][CH3:34])[C:20]([C:26]([F:29])([F:28])[F:27])=[N:21][C:22]=5[CH:23]=[CH:24][CH:25]=3)[C:10](=[O:38])[C:9]=2[CH2:8][O:7][C:6]1=[O:39])(=O)C.NN.Cl>CO>[CH2:40]([C@:5]1([OH:4])[C:37]2[CH:36]=[C:35]3[N:11]([CH2:12][C:13]4[C:14]3=[N:15][C:16]3[C:17]5[C:18]=4[N:19]([CH2:30][CH2:31][CH2:32][CH2:33][CH3:34])[C:20]([C:26]([F:29])([F:28])[F:27])=[N:21][C:22]=5[CH:23]=[CH:24][CH:25]=3)[C:10](=[O:38])[C:9]=2[CH2:8][O:7][C:6]1=[O:39])[CH3:41]
Reactant: CCCCCN1C(C(F)(F)F)=Nc2cccc3nc4c(c1c23)Cn1c-4cc2c(c1=O)COC(=O)[C@@]2(CC)OC(C)=O
Agent: Cl
Agent: NN
Solvent: CO
Product: CCCCCN1C(C(F)(F)F)=Nc2cccc3nc4c(c1c23)Cn1c-4cc2c(c1=O)COC(=O)[C@]2(O)CC
Temperature: 25 °C
Reaction time: 2 h
Yield: 78.1 %

Procedure:
To a cold (0° C.) stirred solution of (9S)-9-acetoxy-9-ethyl-1-pentyl-2-trifluoromethyl-1H,12H-pyrano[3″,4″:6′,7′]indolizino[1′,2′:6,5]pyrido[4,3,2-de]quinazoline-10,13(9H,15H)-dione (105 mg, 0.18 mmol) in MeOH (15 ml) was added anhydrous hydrazine (0.29 ml, 9.00 mmol). After being stirred at room temperature for 2 hr., the mixture was acidified with 10% HCl solution in MeOH at 0° C. and stirred at room temperature for 2 h. The mixture was filtered and washed with CH2Cl2. After the combined filtrate and washings were concentrated under reduced pressure, the residue was suspended in CH2Cl2 (30 ml). The mixture was filtered and washed with CH2Cl2. The combined filtrate and washings were concentrated under reduced pressure. The residue was purified by column chromatography on silica gel (dichloromethane/methanol=40/1-20/1) to give pure product (74.0 mg, 76%).
Reaction SMILES: [CH2:1]([NH:3][C:4](=[O:23])[C@H:5]([CH3:22])[NH:6][C:7](=[O:21])[C@H:8]([CH3:20])[NH:9]C(OCC1C=CC=CC=1)=O)[CH3:2].[BrH:24].CCOCC>C(O)(=O)C>[BrH:24].[CH2:1]([NH:3][C:4](=[O:23])[C@H:5]([CH3:22])[NH:6][C:7](=[O:21])[C@H:8]([CH3:20])[NH2:9])[CH3:2]
Reactant: CCNC(=O)[C@H](C)NC(=O)[C@H](C)NC(=O)OCc1ccccc1
Agent: Br
Solvent: CCOCC
Solvent: CC(=O)O
Product: CCNC(=O)[C@H](C)NC(=O)[C@H](C)N

Procedure:
7.5 g (0.023 mol) of N-benzyloxycarbonyl-L-alanyl-L-alanine ethylamide were stirred for 1 hour in 50 ml of 4-N hydrobromic acid in acetic acid. To the solution were added 300 ml of dry ether and, after stirring for a few minutes, the oil was allowed to settle and the ether decanted from the oil and discarded. The oil was then dissolved in methanol, the desired L-alanyl-L-alanine ethylamide hydrobromide crystallising out on the addition of ethyl acetate. The yield was 6.0 g (83%) and the melting point was 229°-231° C.; [α]D20 =-28.0° (c=1% in water).
Reaction SMILES: [C:1]([C:5]1[C:6]([S:13][C:14]#[N:15])=[CH:7][C:8]([CH3:12])=[C:9]([OH:11])[CH:10]=1)([CH3:4])([CH3:3])[CH3:2].C(=O)([O-])[O-].[Cs+].[Cs+].[CH3:22][N:23]([CH3:28])[S:24](Cl)(=[O:26])=[O:25]>C(#N)C>[C:1]([C:5]1[C:6]([S:13][C:14]#[N:15])=[CH:7][C:8]([CH3:12])=[C:9]([O:11][S:24](=[O:26])(=[O:25])[N:23]([CH3:28])[CH3:22])[CH:10]=1)([CH3:4])([CH3:2])[CH3:3]
Reactant: CN(C)S(=O)(=O)Cl
Reactant: Cc1cc(SC#N)c(C(C)(C)C)cc1O
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CC#N
Product: Cc1cc(SC#N)c(C(C)(C)C)cc1OS(=O)(=O)N(C)C

Procedure:
To a round bottom flask equipped with a condenser and magnetic stirrer were added 5-tert-butyl-2-methyl-4-thiocyanato-phenol prepared in Example GGG (1.5 g, 6.8 mmol), cesium carbonate (2.44 g, 7.49 mmol), and acetonitrile (30 mL). This slurry was brought to reflux for 15 minutes. Dimethyl sulfamoyl chloride (0.80 mL, 7.49 mmol) was added to the slurry via syringe. The reaction was quenched with brine and extracted with EtOAc; the organic layer was dried (MgSO4) and concentrated. The residue was submitted to column chromatography (7:3 hexane:EtOAc) to give the title compound. 1H NMR (CDCl3) δ 1.46 (s, 9 H), 2.22 (s, 3 H), 3.03 (s, 6 H), 7.30 (s, 1 H), 7.47 (s, 1 H).
Reaction SMILES: O[C:2]1[C:7]([C:8]([O:10][CH2:11][CH3:12])=[O:9])=[CH:6][N:5]=[C:4]([C:13]2[CH:18]=[CH:17][C:16]([C:19]([F:22])([F:21])[F:20])=[CH:15][CH:14]=2)[N:3]=1.O=P(Cl)(Cl)[Cl:25]>>[Cl:25][C:2]1[C:7]([C:8]([O:10][CH2:11][CH3:12])=[O:9])=[CH:6][N:5]=[C:4]([C:13]2[CH:18]=[CH:17][C:16]([C:19]([F:22])([F:21])[F:20])=[CH:15][CH:14]=2)[N:3]=1
Reactant: O=P(Cl)(Cl)Cl
Reactant: CCOC(=O)c1cnc(-c2ccc(C(F)(F)F)cc2)nc1O
Product: CCOC(=O)c1cnc(-c2ccc(C(F)(F)F)cc2)nc1Cl
Yield: 97 %

Procedure:
The title compound was prepared by (a) of diethyl ethoxymethylenemalonate (6.3 g, 29 mmol) with 4-trifluoromethylphenylbenzamidine (5.5 g, 29 mmol) to afford 50% of ethyl 4-hydroxy-2-(4'-trifluoromethylphenyl)pyrimidine-5-carboxylate in analogy to Example 15, (b) reaction of ethyl 4-hydroxy-2-(4'-trifluoromethylphenyl)pyrimidine-5-carboxylate (3 g, 9.6 mmol) with POCl3 (49 g, 322 mmol) to afford 97% of ethyl 4-chloro-2-(4'-trifluoromethylphenyl)pyrimidine-5-carboxylate in analogy to Example 7, (c) reaction of ethyl 4-chloro-2-(4'-trifluoromethylphenyl)pyrimidine-5-carboxylate (2 g, 6 mmol) with hydrazine (0.6 g, 18 mmol) to afford 60% of ethyl 4-hydrazino-2-(4'trifluoromethylphenyl)pyrimidine-5-carboxylate in analogy to Example 18, (d) reaction of ethyl 4-hydrazino-2-(4'-trifluoromethylphenyl)pyrimidine-5-carboxylate (1 g, 3 mmol) with citraconic anhydride (1 g, 9 mmol) to afford 40% (0.5 g) of the title compound (m.p. 148-150° C.) in analogy to Example 21.
Reaction SMILES: [CH3:1][NH:2][C:3]1[CH:4]=[C:5]([OH:12])[CH:6]=[CH:7][C:8]=1[N+:9]([O-])=O.[CH3:13]O>C(O)=O.[Fe]>[CH3:1][N:2]1[C:3]2[CH:4]=[C:5]([OH:12])[CH:6]=[CH:7][C:8]=2[N:9]=[CH:13]1
Reactant: CO
Reactant: CNc1cc(O)ccc1[N+](=O)[O-]
Agent: [Fe]
Solvent: O=CO
Product: Cn1cnc2ccc(O)cc21
Temperature: 100 °C

Procedure:
Fe Powder (4.33 g, 77.4 mmol) was added to a solution of 3-(methylamino)-4-nitrophenol (1.3 g, 7.74 mmol) in HCOOH (30 mL) and the mixture heated to 100° C. for 16 h. After cooling to room temperature, MeOH (250 mL) was added to mixture and filtered over a pad of Celite. The filtrate was collected, concentrated and the residue purified by column chromatography to give the crude desired product (1.2 g) and was used directly in the next step. LCMS (m/z): 149.06 (M+1).
Reaction SMILES: [NH2:1][C:2]1[C:7]([NH2:8])=[CH:6][C:5]([Br:9])=[CH:4][N:3]=1.Cl[CH2:11][CH:12]=O.O>CC(O)C>[Br:9][C:5]1[CH:6]=[C:7]([NH2:8])[C:2]2[N:3]([CH:11]=[CH:12][N:1]=2)[CH:4]=1
Reactant: Nc1cc(Br)cnc1N
Reactant: O=CCCl
Solvent: O
Solvent: CC(C)O
Product: Nc1cc(Br)cn2ccnc12
Yield: 93.6 %

Procedure:
2,3-diamino-5-bromopyridine (10.0 g, 45.86 mmol) was dissolved in 80 ml of IPA and then 50% wt chloroacetaldehyde/H2O (6.51 ml, 50.45 mmol) was added. The resulting mixture was heated at reflux for 24 hrs. The mixture was cooled down and then filtered. The cake was dried to afford 9.10 g of product.