Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5]2[N:6]3[CH:24]=[C:23]([CH3:25])[C:22](=[O:26])[C:8]4[CH:9]=[C:10]([O:15][CH2:16][C:17]([O:19]CC)=[O:18])[CH:11]=[C:12]([C:13]=2[CH:14]=1)[C:7]3=4.C(O)C>C(Cl)Cl>[Br:1][C:2]1[CH:3]=[CH:4][C:5]2[N:6]3[CH:24]=[C:23]([CH3:25])[C:22](=[O:26])[C:8]4[CH:9]=[C:10]([O:15][CH2:16][C:17]([OH:19])=[O:18])[CH:11]=[C:12]([C:13]=2[CH:14]=1)[C:7]3=4
Reactant: CCOC(=O)COc1cc2c(=O)c(C)cn3c4ccc(Br)cc4c(c1)c23
Solvent: CCO
Solvent: ClCCl
Product: Cc1cn2c3ccc(Br)cc3c3cc(OCC(=O)O)cc(c1=O)c32
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 91.2 %

Procedure:
10-bromo-2-ethoxycarbonylmethyloxy-5-methyl-4H-pyrido[3,2,1-jk]carbazole-4-one (200 mg) obtained in Example 52 was suspended in a mixed solution of ethanol (10 ml) and methylene chloride (10 ml), and 1N aqueous solution of sodium-hydroxide (1 ml) was added to the suspension. The mixture was stirred at room temperature for 90 minutes, and the solvent was evaporated under reduced pressure. To the residue was added water and 1N hydrochloric acid to pH 1, and the crystals precipitated were recovered by filtration to obtain the title compound (170 mg, 91%).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([Cl:8])[C:5]([O:9][CH2:10][C:11]#[CH:12])=[CH:4][C:3]=1[N:13]1[C:17](=[O:18])[NH:16][C:15]([CH2:19][CH2:20][CH:21]2[O:23][CH2:22]2)=[N:14]1.C(=O)([O-])[O-].[K+].[K+]>C(#N)C>[Cl:1][C:2]1[CH:7]=[C:6]([Cl:8])[C:5]([O:9][CH2:10][C:11]#[CH:12])=[CH:4][C:3]=1[N:13]1[C:17](=[O:18])[N:16]2[CH2:22][CH:21]([OH:23])[CH2:20][CH2:19][C:15]2=[N:14]1
Reactant: C#CCOc1cc(-n2nc(CCC3CO3)[nH]c2=O)c(Cl)cc1Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: C#CCOc1cc(-n2nc3n(c2=O)CC(O)CC3)c(Cl)cc1Cl
Temperature: 25 °C
Yield: 36.8 %

Procedure:
A mixture of 500 mg (1.41 mmol) of 2-[2,4-dichloro-5-(2-propynyloxy)-phenyl]-2,4-dihydro-5-(3,4-epoxybutyl)-3H-1,2,4-triazol-3-one and 563 mg (4.08 mmol) of potassium carbonate in 20 mL of acetonitrile was warmed at reflux for 2h. The mixture was cooled to room temperature and filtered. The filtrate was evaporated in vacuo. The crude product was purified by flash chromatography over silica gel, eluting with a 95:5 v:v mixture of dichloromethane and methanol to give 184 mg of the title product of Step 4 as a pale yellow foam, 1H NMR (CDCl3, 400 MHz) δ 7.5 (s,1H), 7.15 (s,1H), 4.8 (s,2H), 4.45 (broad t,1H), 3.8 (m,2H), 3.0 (m,1H), 2.8 (m,1H), 2.6 (s,1H), 2.2 (s,1H), 2.15 (m,1H), 1.95 (m,1H).
Reaction SMILES: [NH2:1][CH:2]([CH3:18])[C:3]([O:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH3:17])=[O:4].C(=O)(O)[O-].[Na+].[CH2:24]([CH2:26]N)[OH:25]>Cl.CN(C)C(C)C(OCCCCCCCCCCCC)=O>[OH:25][CH2:24][CH2:26][NH:1][CH:2]([CH3:18])[C:3]([O:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH3:17])=[O:4]
Reactant: NCCO
Reactant: CCCCCCCCCCCCOC(=O)C(C)N
Agent: CCCCCCCCCCCCOC(=O)C(C)N(C)C
Agent: Cl
Agent: O=C([O-])O
Product: CCCCCCCCCCCCOC(=O)C(C)NCCO
Temperature: 25 °C
Reaction time: 12 h
Yield: 95 %

Procedure:
To a stirred solution of 3 (1 g, 3.2 mmol) in acetonitrile/water (5:5 mL) was added sodium bicarbonate (0.262 g 3.2 mmol) and followed by ethanol amine (0.5 mL, 0.5 vol) at 25-30° C. The reaction mixture was stirred for 12 h at RT; the reaction was monitored by TLC. The solid obtained in the reaction mixture was filtered under vacuum, the solvent concentrated, diluted with ethyl acetate/water and stirred for 15 minutes at 25-30° C. The aqueous and organic layers were separated, and the aqueous layer was extracted with ethyl acetate (2×10 mL). The combined organic layers were washed with brine solution. The organic layer was dried over Na2SO4 and concentrated under vacuum to afford crude 64 (0.9 g, yield: 95%) as a liquid
Reaction SMILES: [C:1]([C:4]1([O:9]/[N:10]=[C:11](/[C:16]2[O:17][CH:18]=[CH:19][CH:20]=2)\[C:12]([O:14][CH3:15])=[O:13])[CH2:8][CH2:7][CH2:6][CH2:5]1)([OH:3])=O.[CH3:21][O:22][NH2:23].C(Br)(Br)Br>CS(C)=O>[CH3:21][O:22][NH:23][C:1]([C:4]1([O:9][N:10]=[C:11]([C:16]2[O:17][CH:18]=[CH:19][CH:20]=2)[C:12]([O:14][CH3:15])=[O:13])[CH2:8][CH2:7][CH2:6][CH2:5]1)=[O:3]
Reactant: COC(=O)/C(=N\OC1(C(=O)O)CCCC1)c1ccco1
Reactant: CON
Solvent: BrC(Br)Br
Solvent: CS(C)=O
Product: CONC(=O)C1(ON=C(C(=O)OC)c2ccco2)CCCC1
Yield: 75 %

Procedure:
This compound was prepared from methyl Z-2-(carboxycyclopent-1-yloxyimino)-2-(fur-2-yl)acetate and methoxyamine as described in Preparation 7(c) νmax (CHBr3) 3400, 3350 (--NH--), 1740 (--CO2R), 1686 cm-1 (--CONH--), τ(DMSO d6), 6.4 (--OMe), --0.88 (--CONHO), 7.7-8.7 (cylopentyl), 2.1, 3.1, 3.3 (furyl), 6.1 (--CO2Me). Yield 75%
Reaction SMILES: [C:1]([C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:12]=1[O:13][C:14]1[CH:19]=[CH:18][C:17]([C:20](=[O:30])[NH:21][CH2:22][CH2:23][C:24]3[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=3)=[CH:16][CH:15]=1)[O:9][CH2:8][CH2:7][CH:6]2[C:31]([O:33]C)=[O:32])#[N:2].[OH-].[Na+].O.CO>C1COCC1.C(OCC)(=O)C.Cl>[C:1]([C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:12]=1[O:13][C:14]1[CH:15]=[CH:16][C:17]([C:20](=[O:30])[NH:21][CH2:22][CH2:23][C:24]3[CH:25]=[CH:26][CH:27]=[CH:28][CH:29]=3)=[CH:18][CH:19]=1)[O:9][CH2:8][CH2:7][CH:6]2[C:31]([OH:33])=[O:32])#[N:2]
Reactant: COC(=O)C1CCOc2cc(Oc3ccc(C(=O)NCCc4ccccc4)cc3)c(C#N)cc21
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: N#Cc1cc2c(cc1Oc1ccc(C(=O)NCCc3ccccc3)cc1)OCCC2C(=O)O
Reaction time: 3 h
Yield: 76.8 %

Procedure:
Methyl 6-cyano-7-(4-(phenethylcarbamoyl)phenoxy)chroman-4-carboxylate (16.1 mg, 0.0353 mmol) was diluted with THF (500 μL) followed by the addition of NaOH (0.0705 mL, 0.353 mmol) and water (100 μL) and methanol (100 μL). After stirring for 3 hours, the reaction was diluted with ethyl acetate and 2N HCl. The layers were separated and the organic layer was dried over MgSO4, filtered and concentrated to yield the title compound (12.0 mg, 76.9% yield). 1H NMR (400 MHz, CD3OD) δ □7.85 (d, 2H), 7.66 (s, 1H), 7.20-7.30 (m, 5H), 7.15 (d, 2H), 6.40 (s, 1H), 4.20-4.35 (m, 2H), 3.85 (bt, 1H), 3.58 (t, 2H), 2.92 (t, 2H), 2.3-2.4 (m, 1H), 2.1-2.2 (m, 1H).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:30])[CH2:4][C@H:5]1[C:9]2[CH:10]=[CH:11][C:12]([O:14][C@H:15]3[C:23]4[C:18](=[C:19]([CH:28]=C)[C:20]([C:24]([F:27])([F:26])[F:25])=[CH:21][CH:22]=4)[CH2:17][CH2:16]3)=[CH:13][C:8]=2[O:7][CH2:6]1.[O:31]1CCCC1>O=[Os](=O)(=O)=O.O>[CH3:1][O:2][C:3](=[O:30])[CH2:4][C@H:5]1[C:9]2[CH:10]=[CH:11][C:12]([O:14][C@H:15]3[C:23]4[C:18](=[C:19]([CH:28]=[O:31])[C:20]([C:24]([F:26])([F:27])[F:25])=[CH:21][CH:22]=4)[CH2:17][CH2:16]3)=[CH:13][C:8]=2[O:7][CH2:6]1
Reactant: C=Cc1c(C(F)(F)F)ccc2c1CC[C@H]2Oc1ccc2c(c1)OC[C@H]2CC(=O)OC
Reactant: C1CCOC1
Agent: O=[Os](=O)(=O)=O
Solvent: O
Product: COC(=O)C[C@@H]1COc2cc(O[C@@H]3CCc4c3ccc(C(F)(F)F)c4C=O)ccc21
Temperature: 50 °C
Reaction time: 8 h

Procedure:
NaIO4 (1.80 g) and OsO4 (4% in water, 50 μL) are added to a mixture of {(S)-6-[(R)-5-trifluoromethyl-4-vinyl-indan-1-yloxy]-2,3-dihydro-benzofuran-3-yl}-acetic acid methyl ester (1.25 g), tetrahydrofuran (16 mL), and water (4 mL) at room temperature. The mixture is stirred at 50° C. overnight. After cooling to room temperature, water is added and the mixture is extracted with ethyl acetate. The combined extract is washed with brine, dried (Na2SO4), and concentrated. The residue is chromatographed on silica gel (cyclohexane/ethyl acetate) to give the title compound. LC (method 2): tR=1.19 min; Mass spectrum (ESI+): m/z=421 [M+H]+.
Reaction SMILES: C[O:2][C:3](=[O:31])[CH2:4][O:5][C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][C:7]=1[N:12]([C:14](=[O:30])[C:15]1[CH:20]=[CH:19][C:18]([Cl:21])=[C:17]([C:22]2[CH:23]=[N:24][C:25]([Cl:29])=[CH:26][C:27]=2[CH3:28])[CH:16]=1)[CH3:13].[Li+].[OH-]>C1COCC1>[Cl:21][C:18]1[CH:19]=[CH:20][C:15]([C:14]([N:12]([CH3:13])[C:7]2[CH:8]=[CH:9][CH:10]=[CH:11][C:6]=2[O:5][CH2:4][C:3]([OH:31])=[O:2])=[O:30])=[CH:16][C:17]=1[C:22]1[CH:23]=[N:24][C:25]([Cl:29])=[CH:26][C:27]=1[CH3:28]
Reactant: COC(=O)COc1ccccc1N(C)C(=O)c1ccc(Cl)c(-c2cnc(Cl)cc2C)c1
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Product: Cc1cc(Cl)ncc1-c1cc(C(=O)N(C)c2ccccc2OCC(=O)O)ccc1Cl
Temperature: 25 °C

Procedure:
(2-{[4-Chloro-3-(6-chloro-4-methyl-pyridin-3-yl)-benzoyl]-methyl-amino}-phenoxy)-acetic acid methyl ester (10 mg, 0.02 mmol) was dissolved in THF (300 μL) and 1M LiOH (100 μL) was added. The mixture was stirred at room temperature until LCMS indicated that starting material was completely consumed. The mixture was diluted with EtOAc and acidified with 1 N HCl. The organic layer was concentrated, dissolved in MeOH and purified by prep LCMS to yield (2-{[4-chloro-3-(6-chloro-4-methyl-pyridin-3-yl)-benzoyl]-methyl-amino}-phenoxy)-acetic acid 4-1. MS [M+H]+: 445.0; tR=6.75 min, (method 2)
Reaction SMILES: Cl.Cl.[NH2:3][C:4]1[C:19]([Cl:20])=[CH:18][C:7]([C:8]([NH:10][CH2:11][CH:12]2[CH2:17][CH2:16][NH:15][CH2:14][CH2:13]2)=[O:9])=[C:6]([O:21][CH3:22])[CH:5]=1.Br[CH2:24][CH2:25][CH2:26][CH2:27][C:28]([C:30]1[C:38]2[C:33](=[CH:34][CH:35]=[CH:36][CH:37]=2)[N:32]([CH3:39])[CH:31]=1)=[O:29]>>[NH2:3][C:4]1[C:19]([Cl:20])=[CH:18][C:7]([C:8]([NH:10][CH2:11][CH:12]2[CH2:13][CH2:14][N:15]([CH2:24][CH2:25][CH2:26][CH2:27][C:28]([C:30]3[C:38]4[C:33](=[CH:34][CH:35]=[CH:36][CH:37]=4)[N:32]([CH3:39])[CH:31]=3)=[O:29])[CH2:16][CH2:17]2)=[O:9])=[C:6]([O:21][CH3:22])[CH:5]=1
Reactant: COc1cc(N)c(Cl)cc1C(=O)NCC1CCNCC1
Reactant: Cn1cc(C(=O)CCCCBr)c2ccccc21
Agent: Cl
Product: COc1cc(N)c(Cl)cc1C(=O)NCC1CCN(CCCCC(=O)c2cn(C)c3ccccc23)CC1

Procedure:
4-Amino-5-chloro-2-methoxy-N-(piperidin-4-ylmethyl)benzamide dihydrochloride as starting compound and 5-bromo-1-(1-methyl-1 H-indol-3-yl)-1-pentanone were reacted and treated in the same manner as in Example 172 to give 4-amino-5-chloro-2-methoxy-N-((1-(5-(1 -methyl-1 H-indol-3-yl)-5-oxopentyl)piperidin-4-yl)methyl)benzamide.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([CH3:8])=[CH:4][C:3]=1[NH:9][C:10]1[N:15]2[N:16]=[CH:17][C:18]([S:19]([NH2:22])(=[O:21])=[O:20])=[C:14]2[N:13]=[CH:12][C:11]=1[C:23]([N:25]1[CH2:30][CH2:29][CH:28]([C:31]2[CH:36]=[CH:35][C:34]([F:37])=[CH:33][CH:32]=2)[CH2:27][CH2:26]1)=[O:24].[CH:38]1([N:41]=[C:42]=[O:43])[CH2:40][CH2:39]1>>[F:1][C:2]1[CH:7]=[CH:6][C:5]([CH3:8])=[CH:4][C:3]=1[NH:9][C:10]1[N:15]2[N:16]=[CH:17][C:18]([S:19]([NH:22][C:42](=[O:43])[NH:41][CH:38]3[CH2:40][CH2:39]3)(=[O:21])=[O:20])=[C:14]2[N:13]=[CH:12][C:11]=1[C:23]([N:25]1[CH2:30][CH2:29][CH:28]([C:31]2[CH:32]=[CH:33][C:34]([F:37])=[CH:35][CH:36]=2)[CH2:27][CH2:26]1)=[O:24]
Reactant: Cc1ccc(F)c(Nc2c(C(=O)N3CCC(c4ccc(F)cc4)CC3)cnc3c(S(N)(=O)=O)cnn23)c1
Reactant: O=C=NC1CC1
Product: Cc1ccc(F)c(Nc2c(C(=O)N3CCC(c4ccc(F)cc4)CC3)cnc3c(S(=O)(=O)NC(=O)NC4CC4)cnn23)c1
Yield: 45.8 %

Procedure:
Using 7-(2-fluoro-5-methylphenylamino)-6-[4-(4-fluorophenyl)piperidine-1-carbonyl]pyrazolo[1,5-a]pyrimidine-3-sulfonamide (0.10 g, 0.19 mmol) obtained in Example 31 step 5 and cyclopropylisocyanate (0.048 g, 0.57 mmol) instead of ethylisocyanate, and in the same manner as in Example 7, the title compound (0.053 g, 62%) was obtained.
Reaction SMILES: C(OC(=O)[NH:7][C:8]1[CH:13]=[C:12]([N:14]2[CH2:18][CH2:17][CH2:16][CH2:15]2)[C:11]([F:19])=[CH:10][C:9]=1[NH:20][C:21](=[O:44])[CH2:22][C:23](=O)[C:24]1[CH:29]=[CH:28][CH:27]=[C:26]([N:30]2[C:34]([CH2:35][O:36]C3CCCCO3)=[CH:33][N:32]=[N:31]2)[CH:25]=1)(C)(C)C.C(O)(C(F)(F)F)=O>C(Cl)Cl>[F:19][C:11]1[C:12]([N:14]2[CH2:18][CH2:17][CH2:16][CH2:15]2)=[CH:13][C:8]2[N:7]=[C:23]([C:24]3[CH:29]=[CH:28][CH:27]=[C:26]([N:30]4[C:34]([CH2:35][OH:36])=[CH:33][N:32]=[N:31]4)[CH:25]=3)[CH2:22][C:21](=[O:44])[NH:20][C:9]=2[CH:10]=1
Reactant: CC(C)(C)OC(=O)Nc1cc(N2CCCC2)c(F)cc1NC(=O)CC(=O)c1cccc(-n2nncc2COC2CCCCO2)c1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: O=C1CC(c2cccc(-n3nncc3CO)c2)=Nc2cc(N3CCCC3)c(F)cc2N1

Procedure:
The title compound was prepared from (RS)-[4-fluoro-2-(3-oxo-3-{3-[5-(tetrahydro-pyran-2-yloxymethyl)-[1,2,3]triazol-1-yl]-phenyl}-propionylamino)-5-pyrrolidin-1-yl-phenyl]-carbamic acid tert.-butyl ester (Example M49) by treatment with TFA in CH2Cl2 according to the general procedure N. Obtained as an orange solid (72 mg).
Reaction SMILES: [CH2:1]([C:4]([F:22])([F:21])[C:5]([F:20])([F:19])[C:6]([F:18])([F:17])[C:7]([F:16])([F:15])[C:8]([F:14])([F:13])[C:9]([F:12])([F:11])[F:10])[CH2:2][OH:3].[C:23](O)(=[O:26])[C:24]#[CH:25].C1(N=C=NC2CCCCC2)CCCCC1>C(Cl)Cl.CN(C)C1C=CN=CC=1>[C:23]([O:3][CH2:2][CH2:1][C:4]([F:21])([F:22])[C:5]([F:19])([F:20])[C:6]([F:17])([F:18])[C:7]([F:15])([F:16])[C:8]([F:13])([F:14])[C:9]([F:12])([F:11])[F:10])(=[O:26])[C:24]#[CH:25]
Reactant: OCCC(F)(F)C(F)(F)C(F)(F)C(F)(F)C(F)(F)C(F)(F)F
Reactant: C#CC(=O)O
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: CN(C)c1ccncc1
Solvent: ClCCl
Product: C#CC(=O)OCCC(F)(F)C(F)(F)C(F)(F)C(F)(F)C(F)(F)C(F)(F)F
Temperature: 0 °C
Yield: 72.1 %

Procedure:
1H,1H,2H,2H-perfluoro-1-octanol (10.1 g, 27.7 mmol) and propiolic acid (1.70 mL, 27.7 mmol) were dissolved in methylene chloride (15 mL), and the resulting solution cooled to 0° C. under nitrogen. To this was added a solution of dicyclohexylcarbodiimide (5.72 g, 27.7 mmol) and para-dimethylaminopyridine (0.034 g, 0.28 mmol) in methylene chloride (15 mL) over a 1 hour period, with stirring. The mixture was then allowed to warm to room temperature and a tan solid (dicyclohexylurea) precipitated. The reaction mixture was stirred overnight and then filtered to remove the dicyclohexylurea, and the filtrate was concentrated under vacuum to afford the crude product as a red oil. The crude product was chromatographed on a 15 cm×5 ccm silica gel column using 15% ethyl acetate in hexane to afford 8.31 g of (3,3,4,4,5,5,6,6,7,7,8,8,8-tridecafluorooctyl) propiolate as a yellow oil (72% yield).
Reaction SMILES: [NH:1]([C:8]1[N:13]=[C:12]2[N:14]([C:27]3[CH:32]=[CH:31][CH:30]=[C:29]([CH2:33][CH2:34][N:35]4C(=O)C5=CC=CC=C5C4=O)[CH:28]=3)[C:15](=[O:26])[N:16]([C:18]3[C:23]([CH3:24])=[CH:22][CH:21]=[CH:20][C:19]=3[Cl:25])[CH2:17][C:11]2=[CH:10][N:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.O.NN>C(O)C>[NH2:35][CH2:34][CH2:33][C:29]1[CH:28]=[C:27]([N:14]2[C:12]3=[N:13][C:8]([NH:1][C:2]4[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=4)=[N:9][CH:10]=[C:11]3[CH2:17][N:16]([C:18]3[C:23]([CH3:24])=[CH:22][CH:21]=[CH:20][C:19]=3[Cl:25])[C:15]2=[O:26])[CH:32]=[CH:31][CH:30]=1
Reactant: Cc1cccc(Cl)c1N1Cc2cnc(Nc3ccccc3)nc2N(c2cccc(CCN3C(=O)c4ccccc4C3=O)c2)C1=O
Agent: NN
Solvent: O
Solvent: CCO
Product: Cc1cccc(Cl)c1N1Cc2cnc(Nc3ccccc3)nc2N(c2cccc(CCN)c2)C1=O
Yield: 15.5 %

Procedure:
A solution of 250 mg (0.4 mmol) of 7-anilino-3-(2-chloro-6-methylphenyl)-3,4-dihydro-1-[3-(2-phthalimidoethyl)phenyl]pyrimido[4,5-d]pyrimidin-2(1H)-one in 10 ml of ethanol was treated with 0.5 ml of hydrazine hydrate. After 18 hours the mixture was evaporated and the product purified by column chromatography on silica gel using dichloromethane/methanol/acetic acid/water (240:24:3:2) for the elution. Product-containing fractions were combined, evaporated and the residue evaporated with toluene. The residue was then dissolved in 40 ml of dichloromethane, washed with 40 ml of saturated aqueous sodium bicarbonate solution, dried over magnesium sulfate, filtered and evaporated. Trituration of the residue with hexane followed by filtration afforded 30 mg (15%) of 1-[3-(2-aminoethyl)phenyl]-7-anilino-3-(2-chloro-6-methylphenyl)-3,4-dihydropyrimido[4,5-d]pyrimidin-2(1H)-one as a white solid of melting point 192° C.
Reaction SMILES: C(Cl)(=O)C(Cl)=O.CS(C)=O.[C:11]([O:15][C:16]([N:18]1[C@H:23]([CH2:24][OH:25])[C@@H:22]2[CH2:26][C@H:19]1[CH2:20][CH2:21]2)=[O:17])([CH3:14])([CH3:13])[CH3:12].CCN(C(C)C)C(C)C>C(Cl)Cl>[C:11]([O:15][C:16]([N:18]1[C@H:23]([CH:24]=[O:25])[C@@H:22]2[CH2:26][C@H:19]1[CH2:20][CH2:21]2)=[O:17])([CH3:14])([CH3:12])[CH3:13]
Reactant: CC(C)(C)OC(=O)N1[C@@H]2CC[C@@H](C2)[C@H]1CO
Agent: O=C(Cl)C(=O)Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Solvent: CS(C)=O
Product: CC(C)(C)OC(=O)N1[C@@H]2CC[C@@H](C2)[C@H]1C=O
Reaction time: 0.75 h

Procedure:
To a cold (−60° C.) solution of oxalyl chloride (60.8 mmol) in dry DCM (130 mL) is added dropwise DMSO (111 mmol) within 5 min. After 15 min a solution of (1R,3S,4S)-3-hydroxymethyl-2-aza-bicyclo[2.2.1]heptane-2-carboxylic acid tert-butyl ester (50.7 mmol) in dry DCM (40 mL) is added dropwise within 15 min. Stirring is continued for 45 min at −55° C., then DIPEA (253 mmol; dried over 3 A molecular sieve) is added during 5 min. The reaction mixture is allowed to reach rt and diluted with water (250 mL). The layers are separated and the organic layer is washed twice with aq. citric acid (5%, 200 mL each) and twice with brine. The combined organic layers are dried over MgSO4 and concentrated in vacuo to give the desired product which is used without further purification. 1H-NMR (CDCl3, 2 rotamers): δ=1.31-1.37 (m, 1H); 1.44 & 1.50 (2 s, 9H); 1.58-1.84 (m, 5H); 2.78 & 2.81 (2 bs, 1H); 3.60 & 3.74 (2 bs, 1H); 4.26 & 4.41 (2 bs, 1H); 9.55 & 9.60 (2 bs, 1H).
Reaction SMILES: [NH2:1][C:2]1[CH:10]=[CH:9][C:8]([F:11])=[CH:7][C:3]=1[C:4]([OH:6])=[O:5].CN(C)C=O.[Br:17]N1C(=O)CCC1=O>O>[NH2:1][C:2]1[C:10]([Br:17])=[CH:9][C:8]([F:11])=[CH:7][C:3]=1[C:4]([OH:6])=[O:5]
Reactant: Nc1ccc(F)cc1C(=O)O
Reactant: O=C1CCC(=O)N1Br
Solvent: O
Solvent: CN(C)C=O
Product: Nc1c(Br)cc(F)cc1C(=O)O
Temperature: 25 °C
Reaction time: 5 h
Yield: 36.5 %

Procedure:
To a mixture of 0.78 g of 2-amino-5-fluorobenzoic acid and 100 ml of N,N-dimethylformamide was added 1.1 g of N-bromosuccinimide at room temperature, and the mixture was stirred at room temperature for 5 hours. After water was added to the reaction mixture, a deposited precipitate was collected by filtration, and then washed with acetone to obtain 0.43 g of 2-amino-3-bromo-5-fluorobenzoic acid of the formula:
Reaction SMILES: [CH2:1]([C@H:8]1[CH2:12][O:11][C:10](=[O:13])[N:9]1[C:14](=[O:24])[CH2:15][C:16]1[CH:21]=[CH:20][C:19]([O:22][CH3:23])=[CH:18][CH:17]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(N(C(C)C)CC)(C)C.[C:34]1(=[O:40])[CH2:39][CH2:38][CH2:37][CH2:36][CH2:35]1>C(Cl)Cl.[Ti](Cl)(Cl)(Cl)Cl>[CH2:1]([C@H:8]1[CH2:12][O:11][C:10](=[O:13])[N:9]1[C:14](=[O:24])[C@@H:15]([C:34]1([OH:40])[CH2:39][CH2:38][CH2:37][CH2:36][CH2:35]1)[C:16]1[CH:17]=[CH:18][C:19]([O:22][CH3:23])=[CH:20][CH:21]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=C1CCCCC1
Reactant: COc1ccc(CC(=O)N2C(=O)OC[C@@H]2Cc2ccccc2)cc1
Agent: Cl[Ti](Cl)(Cl)Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: COc1ccc([C@@H](C(=O)N2C(=O)OC[C@@H]2Cc2ccccc2)C2(O)CCCCC2)cc1
Temperature: 0 °C
Reaction time: 1 h
Yield: 82.1 %

Procedure:
A solution of (4S)-4-benzyl-3-[2-(4-methoxyphenyl)acetyl]-1,3-oxazolidin-2-one (2.5 g, 7.68 mmol) in dry methylene chloride (50 mL) was cooled to −78° C. and treated with diisopropylethylamine (1.09 g, 8.45 mmol) followed by titanium tetrachloride (0.88 mL, 8.06 mmol). The resulting reaction was warmed to 0° C. where it was stirred for 1 h, during which time the reaction turned dark purple. The reaction was then re-cooled to −78° C. and was treated with another portion of titanium tetrachloride (0.88 mL, 8.06 mmol) followed by a solution of cyclohexanone (0.91 mL, 8.83 mmol) in methylene chloride (10 mL). After addition, the reaction was warmed to 0° C. where it was stirred for 2 h, after which time the reaction was carefully quenched with the addition of a saturated aqueous solution of sodium bicarbonate and the mixture was stirred at 0° C. for 30 minutes. The reaction was filtered to remove the titanium salt that had precipitated, and the layers of the filtrate were then separated. The aqueous layer was washed with methylene chloride (3×30 mL). The solid precipitate was then collected and stirred vigorously in a 2N aqueous solution of hydrochloric acid (50 mL) for 20 minutes, after which time, the remaining product was extracted from the aqueous layer with methylene chloride (3×60 mL), and the combined organic extracts (from the filtrate and the liberated salt) were dried over magnesium sulfate and concentrated in vacuo. The product was purified via Biotage™ Horizon chromatography (FLASH 40 M, silica, gradient from 10% ethyl acetate/hexane to 45% ethyl acetate/hexane) to yield 2.67 g (82%) (4S)-4-benzyl-3-[(2R)-2-(1-hydroxycyclohexyl)-2-(4-methoxyphenyl)acetyl]-1,3-oxazolidin-2-one as a colorless foam. MS (ESI) m/z 406; [α]D25=+109° (c=0.010 g/mL, EtOH).
Reaction SMILES: [C:1]([O:6][C@@H:7]1[C@@H:15]([CH2:16][CH2:17][OH:18])[C:14](=[O:19])[O:13][CH2:12][C@H:11]([NH:20][C:21]([O:23][C:24]([CH3:27])([CH3:26])[CH3:25])=[O:22])[C:10](=[O:28])[O:9][C@H:8]1[CH3:29])(=[O:5])[CH:2]([CH3:4])[CH3:3].N1C=CC=CC=1.[CH3:36][S:37](Cl)(=[O:39])=[O:38]>C(Cl)Cl>[C:1]([O:6][C@@H:7]1[C@@H:15]([CH2:16][CH2:17][O:18][S:37]([CH3:36])(=[O:39])=[O:38])[C:14](=[O:19])[O:13][CH2:12][C@H:11]([NH:20][C:21]([O:23][C:24]([CH3:26])([CH3:25])[CH3:27])=[O:22])[C:10](=[O:28])[O:9][C@H:8]1[CH3:29])(=[O:5])[CH:2]([CH3:4])[CH3:3]
Reactant: CC(C)C(=O)O[C@H]1[C@H](C)OC(=O)[C@@H](NC(=O)OC(C)(C)C)COC(=O)[C@@H]1CCO
Reactant: CS(=O)(=O)Cl
Solvent: ClCCl
Solvent: c1ccncc1
Product: CC(C)C(=O)O[C@H]1[C@H](C)OC(=O)[C@@H](NC(=O)OC(C)(C)C)COC(=O)[C@@H]1CCOS(C)(=O)=O
Temperature: 22 °C
Reaction time: 8 h
Yield: 84.3 %

Procedure:
To a solution of (3S,6S,7R,8R)-3-(tert-butoxycarbonylamino)-8-(2-hydroxyethyl)-6-methyl-4,9-dioxo-1,5-dioxonan-7-yl isobutyrate (660 mg, 1.58 mmol) in CH2Cl2 (15 mL) at 0° C. was added pyridine (750 mg, 9.48 mmol), followed by methanesulfonyl chloride (362 mg, 3.16 mmol). The resulting reaction mixture was warmed up to room temperature (about 22° C.) and stirred overnight. The reaction mixture was partitioned between sat'd aqueous NaHCO3 solution (30 mL) and EtOAc (40 mL) and the phases were separated. The aqueous phase was extracted with additional EtOAc (2×30 mL) and the combined EtOAc extracts were dried over Na2SO4, filtered, and concentrated to dryness. The crude residue was purified via column chromatography (SiO2, hexanes/EtOAc gradient) to afford the title compound (660 mg, 84%) as a white solid: 1H NMR (300 MHz, CDCl3) δ 5.24 (s, 2H), 5.06 (t, J=9.8 Hz, 1H), 4.95-4.77 (m, 2H), 4.32-4.19 (m, 1H), 4.13-4.05 (m, 1H), 3.62 (s, 1H), 2.98 (s, 3H), 2.78 (dd, J=14.9, 6.4 Hz, 1H), 2.62 (dt, J=13.9, 7.0 Hz, 1H), 2.25-2.08 (m, 1H), 1.83 (s, 1H), 1.47 (d, J=11.9 Hz, 9H), 1.28 (d, J=6.3 Hz, 3H), 1.21 (d, J=6.9 Hz, 6H); ESIMS m/z 496 ([M+H]+).
Reaction SMILES: CC(C[AlH]CC(C)C)C.CO[C:12](=O)[CH2:13][O:14][C:15]1[CH:20]=[CH:19][C:18]([CH3:21])=[CH:17][C:16]=1[Br:22].[NH2:24][CH2:25][CH2:26][NH:27][S:28]([C:31]1[C:32]2[CH:33]=[CH:34][N:35]=[CH:36][C:37]=2[CH:38]=[CH:39][CH:40]=1)(=[O:30])=[O:29]>>[Br:22][C:16]1[CH:17]=[C:18]([CH3:21])[CH:19]=[CH:20][C:15]=1[O:14][CH2:13][CH2:12][NH:24][CH2:25][CH2:26][NH:27][S:28]([C:31]1[C:32]2[CH:33]=[CH:34][N:35]=[CH:36][C:37]=2[CH:38]=[CH:39][CH:40]=1)(=[O:30])=[O:29]
Reactant: COC(=O)COc1ccc(C)cc1Br
Reactant: NCCNS(=O)(=O)c1cccc2cnccc12
Agent: CC(C)C[AlH]CC(C)C
Product: Cc1ccc(OCCNCCNS(=O)(=O)c2cccc3cnccc23)c(Br)c1

Procedure:
By following a similar procedure as described in Example 1, DIBAL-H reduction of (2-bromo-4-methyl-phenoxy)-acetic acid methyl ester, and subsequent reductive amination with isoquinoline-5-sulfonic acid (2-amino-ethyl)-amide gives the free amine of the title compound as a clear gum. ESIMS: m/z 464 [(M+H)+, 79Br], 466 [(M+H)+, 81Br].