Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Br:1][C:2]1[C:10]2[O:9][C:8]([C:11]([OH:13])=O)=[CH:7][C:6]=2[CH:5]=[CH:4][CH:3]=1.Cl.Cl.[NH2:16][C@H:17]1[CH:22]2[CH2:23][CH2:24][N:19]([CH2:20][CH2:21]2)[CH2:18]1.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.C(N(CC)C(C)C)(C)C>CN(C=O)C>[N:19]12[CH2:24][CH2:23][CH:22]([CH2:21][CH2:20]1)[C@H:17]([NH:16][C:11]([C:8]1[O:9][C:10]3[C:2]([Br:1])=[CH:3][CH:4]=[CH:5][C:6]=3[CH:7]=1)=[O:13])[CH2:18]2
Reactant: O=C(O)c1cc2cccc(Br)c2o1
Reactant: N[C@@H]1CN2CCC1CC2
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: O=C(N[C@@H]1CN2CCC1CC2)c1cc2cccc(Br)c2o1

Procedure:
4.0 g (16.59 mmol) of 7-bromobenzofuran-2-carboxylic acid (Example 29A), 3.3 g (16.59 mmol) of (S)-3-aminoquinuclidine dihydrochloride, 7.57 g (19.91 mmol) of HATU, 10.41 ml (59.74 mmol) of N,N-diisopropylethylamine and 21 ml of DMF are reacted by general method C. The solvent is removed under reduced pressure, and the crude product is taken up in 100 ml of ethyl acetate and washed 15 times with a total of 1.5 l of 1N sodium hydroxide solution. The organic phase is dried over magnesium sulphate and freed of solvent. 5.0 g (85% of theory) of the title compound are isolated.
Reaction SMILES: [CH2:1]([C:5]1[NH:6][C:7]([C:16]#[N:17])=[C:8]([C:10](=[O:15])[C:11]([CH3:14])([CH3:13])[CH3:12])[N:9]=1)[CH2:2][CH2:3][CH3:4].[C:18]([N:37]1[C:41]([C:42]2[CH:47]=[CH:46][CH:45]=[CH:44][C:43]=2[C:48]2[CH:55]=[CH:54][C:51]([CH2:52]Br)=[CH:50][CH:49]=2)=[N:40][N:39]=[N:38]1)([C:31]1[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=1)([C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1)[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1.CC(C)([O-])C.[K+]>>[CH2:1]([C:5]1[N:6]([CH2:52][C:51]2[CH:50]=[CH:49][C:48]([C:43]3[CH:44]=[CH:45][CH:46]=[CH:47][C:42]=3[C:41]3[N:37]([C:18]([C:31]4[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=4)([C:25]4[CH:26]=[CH:27][CH:28]=[CH:29][CH:30]=4)[C:19]4[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=4)[N:38]=[N:39][N:40]=3)=[CH:55][CH:54]=2)[C:7]([C:16]#[N:17])=[C:8]([C:10](=[O:15])[C:11]([CH3:12])([CH3:14])[CH3:13])[N:9]=1)[CH2:2][CH2:3][CH3:4]
Reactant: BrCc1ccc(-c2ccccc2-c2nnnn2C(c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Reactant: CCCCc1nc(C(=O)C(C)(C)C)c(C#N)[nH]1
Agent: CC(C)(C)[O-]
Agent: [K+]
Product: CCCCc1nc(C(=O)C(C)(C)C)c(C#N)n1Cc1ccc(-c2ccccc2-c2nnnn2C(c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Yield: 87.5 %

Procedure:
Following a procedure similar to that described in Example 74(a), but using 2.04 g of 2-butyl-4-pivaloylimidazole-5-carbonitrile (prepared as described in Preparation 40), 5.6 g of 4-[2-(trityltetrazol-5-yl)phenyl]benzyl bromide and 1.06 g of potassium t-butoxide, 5.43 g of the title compound were obtained as crystals, melting at 103°-105° C.
Reaction SMILES: Cl.[NH2:2][CH2:3][C:4]1[CH:12]=[CH:11][CH:10]=[C:9]2[C:5]=1[C:6](=[O:22])[N:7]([CH:14]1[CH2:19][CH2:18][C:17](=[O:20])[NH:16][C:15]1=[O:21])[C:8]2=[O:13].N12CCCN=C1CCCCC2.[F:34][CH:35]([F:46])[O:36][C:37]1[CH:45]=[CH:44][C:40]([C:41](O)=[O:42])=[CH:39][CH:38]=1.Cl.CN(C)CCCN=C=NCC>CC#N>[F:34][CH:35]([F:46])[O:36][C:37]1[CH:38]=[CH:39][C:40]([C:41]([NH:2][CH2:3][C:4]2[CH:12]=[CH:11][CH:10]=[C:9]3[C:5]=2[C:6](=[O:22])[N:7]([CH:14]2[CH2:19][CH2:18][C:17](=[O:20])[NH:16][C:15]2=[O:21])[C:8]3=[O:13])=[O:42])=[CH:44][CH:45]=1
Reactant: O=C(O)c1ccc(OC(F)F)cc1
Reactant: NCc1cccc2c1C(=O)N(C1CCC(=O)NC1=O)C2=O
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Solvent: CC#N
Solvent: C1CCC2=NCCCN2CC1
Product: O=C1CCC(N2C(=O)c3cccc(CNC(=O)c4ccc(OC(F)F)cc4)c3C2=O)C(=O)N1
Reaction time: 0.17 h
Yield: 62.6 %

Procedure:
To a stirred suspension of 4-aminomethyl-2-(2,6-dioxo-piperidin-3-yl)-isoindole-1,3-dione hydrochloride (0.70 g, 2.2 mmol) in CH3CN (60 ml), was added 1,8-diazabicyclo[5.4.0]undec-7-ene (0.82 g, 5.4 mmol). After stirring for 10 minutes, 1-hydroxybenzenetriazole (0.35 g, 2.6 mmol) and 4-difluoromethoxy benzoic acid (0.45 g, 2.4 mmol) were added followed by 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (0.62 g, 3.2 mmol). After stirring at room temperature overnight, the reaction mixture was concentrated in vacuo, and the residue was dissolved in CH2Cl2 (50 mL). The CH2Cl2 solution was washed with water (2×30 mL) and brine (30 mL) and dried over MgSO4. Solvent was removed in vacuo, and the resulting oil was purified by ISCO silica gel flash chromatography (eluent: 0% MeOH in CH2Cl2 to 5% MeOH in 10 min then stay at this ratio for 15 min) to afford 4-difluoromethoxy-N-[2-(2,6-dioxo-piperidin-3-yl)-1,3-dioxo-2,3-dihydro-1H-isoindol-4-ylmethyl]-benzamide as a yellow solid (0.63 g, 64%): mp, 155-157° C.; HPLC: Waters Symmetry C-18, 3.9×150 mm, 5 micro, 1 mL/min, 240 nm, 40/60 (CH3CN/H2O): tR=4.2 min. (97%); 1H NMR (DMSO-d6): δ 2.06-2.11 (m, 1H), 2.50-2.65 (m, 2H), 2.85-2.92 (m, 1H), 4.95 (d, J=5.8 Hz, 2H), 5.16-5.21 (dd, J=5, 12 Hz, 1H), 7.28-7.30 (m, 2H), 7.36 (t, J=73.5 Hz, 1H), 7.72-7.86 (m, 3H), 7.98-8.02 (m, 2H), 9.18 (t, J=5.8 Hz, 1H), 11.15 (s, 1H). 13C NMR (DMSO-d6) δ: 21.97, 30.92, 38.34, 48.86, 112.61, 116.03, 117.97, 119.45, 121.87, 127.13, 129.45, 130.55, 131.52, 133.05, 134.79, 139.22, 153.30, 165.60, 166.95, 167.52, 169.81, 172.74. Anal Calcd for C22H17F2N3O6: C, 57.77; H, 3.75; N, 9.19; F, 8.31. Found: C, 57.67; H, 3.59; N, 9.01; F, 8.22.
Reaction SMILES: [OH:1][C:2]1[C:10]([CH2:11][CH:12]=[CH2:13])=[C:9]([OH:14])[CH:8]=[CH:7][C:3]=1[C:4]([NH2:6])=[O:5].I[CH2:16][CH2:17][CH2:18][O:19][C:20]1[CH:33]=[CH:32][C:23]2[CH2:24][CH2:25][CH:26]([C:28]([O:30][CH3:31])=[O:29])[O:27][C:22]=2[C:21]=1[CH2:34][CH2:35][CH3:36].C(=O)([O-])[O-].[K+].[K+].CN(C=O)C>C(OCC)(=O)C>[NH2:6][C:4]([C:3]1[CH:7]=[CH:8][C:9]([O:14][CH2:16][CH2:17][CH2:18][O:19][C:20]2[CH:33]=[CH:32][C:23]3[CH2:24][CH2:25][CH:26]([C:28]([O:30][CH3:31])=[O:29])[O:27][C:22]=3[C:21]=2[CH2:34][CH2:35][CH3:36])=[C:10]([CH2:11][CH:12]=[CH2:13])[C:2]=1[OH:1])=[O:5]
Reactant: C=CCc1c(O)ccc(C(N)=O)c1O
Reactant: CCCc1c(OCCCI)ccc2c1OC(C(=O)OC)CC2
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: C=CCc1c(OCCCOc2ccc3c(c2CCC)OC(C(=O)OC)CC3)ccc(C(N)=O)c1O
Temperature: 25 °C
Reaction time: 12 h

Procedure:
The compound of Example 20 (550 mg, 2.89 mmol), the compound of Example 23 (1.21 g, 2.89 mmol), and potassium carbonate (800 mg, 5.78 mmol) were added to about 25 to 30 ml of DMF. The reaction mixture as stirred at room temperature for 12 hours. The reaction mixture was diluted with ethyl acetate and washed with water. The organic layer was dried over magnesium sulfate and concentrated under vacuum. The crude material was chromatographed on silica gel with 30% ethyl acetate/hexane as eluant. The fractions containing the product were collected and the solvent was removed under vacuum to give the product as a white solid.
Reaction SMILES: I[C:2]1[N:3]=[C:4]([CH3:16])[N:5]([C:8]2[N:13]=[CH:12][N:11]([CH3:14])[C:10](=[O:15])[CH:9]=2)[C:6]=1[CH3:7].[C:17]([C:19]1[CH:24]=[CH:23][CH:22]=[C:21]([CH3:25])[CH:20]=1)#[CH:18]>>[CH3:16][C:4]1[N:5]([C:8]2[N:13]=[CH:12][N:11]([CH3:14])[C:10](=[O:15])[CH:9]=2)[C:6]([CH3:7])=[C:2]([C:18]#[C:17][C:19]2[CH:20]=[C:21]([CH3:25])[CH:22]=[CH:23][CH:24]=2)[N:3]=1
Reactant: C#Cc1cccc(C)c1
Reactant: Cc1nc(I)c(C)n1-c1cc(=O)n(C)cn1
Product: Cc1cccc(C#Cc2nc(C)n(-c3cc(=O)n(C)cn3)c2C)c1

Procedure:
The title compound, yellow solid, MS: m/e=319.2 (M+H+), was prepared in accordance with the general method of example 1c from 6-(4-iodo-2,5-dimethyl-imidazol-1-yl)-3-methyl-3H-pyrimidin-4-one and 1-ethynyl-3-methyl-benzene.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([N:17]2[C:22](=[O:23])[NH:21][C:20](=[O:24])[CH2:19][N:18]2[CH3:25])[CH:5]=[C:6]([Cl:16])[C:7]=1[S:8][C:9]1[CH:14]=[CH:13][C:12]([CH3:15])=[CH:11][CH:10]=1.[H-].[Na+].[CH3:28]I>CN(C)C=O>[Cl:1][C:2]1[CH:3]=[C:4]([N:17]2[C:22](=[O:23])[N:21]([CH3:28])[C:20](=[O:24])[CH2:19][N:18]2[CH3:25])[CH:5]=[C:6]([Cl:16])[C:7]=1[S:8][C:9]1[CH:10]=[CH:11][C:12]([CH3:15])=[CH:13][CH:14]=1
Reactant: CI
Reactant: Cc1ccc(Sc2c(Cl)cc(N3C(=O)NC(=O)CN3C)cc2Cl)cc1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: Cc1ccc(Sc2c(Cl)cc(N3C(=O)N(C)C(=O)CN3C)cc2Cl)cc1
Temperature: 25 °C
Reaction time: 4 h

Procedure:
0.7 g of 2-[3,5-dichloro-4-(4-methylthiophenoxy)phenyl]-1-methylhexahydro-1,2,4-triazine-3,5-dione (Example 2) was dissolved in 5 ml of cold dimethylformamide. About 200 mg of a suspension (about 50%)of sodium hydride were added and, when evolution of gases was complete, 1 ml of methyl iodide was added dropwise, and the mixture was stirred at room temperature for 4 hours. After acidification with 2N HCl, extraction with methylene chloride and evaporation were carried out, and the remaining oil was triturated with petroleum ether, whereupon it crystallized; melting point 148° C. after recrystallization from isopropanol.
Reaction SMILES: C([O:3][C:4](=[O:26])[CH2:5][CH2:6][CH2:7][O:8][C:9]1[CH:14]=[C:13]([CH3:15])[CH:12]=[CH:11][C:10]=1[C:16]12[CH2:25][CH:20]3[CH2:21][CH:22]([CH2:24][CH:18]([CH2:19]3)[CH2:17]1)[CH2:23]2)C>C(O)C.[OH-].[Na+]>[C:16]12([C:10]3[CH:11]=[CH:12][C:13]([CH3:15])=[CH:14][C:9]=3[O:8][CH2:7][CH2:6][CH2:5][C:4]([OH:26])=[O:3])[CH2:23][CH:22]3[CH2:24][CH:18]([CH2:19][CH:20]([CH2:21]3)[CH2:25]1)[CH2:17]2
Reactant: CCOC(=O)CCCOc1cc(C)ccc1C12CC3CC(CC(C3)C1)C2
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: Cc1ccc(C23CC4CC(CC(C4)C2)C3)c(OCCCC(=O)O)c1
Reaction time: 60 h

Procedure:
A solution of 7.9 g of 4-[2-(1-adamantyl)-5-methylphenoxy]-butyric acid ethyl ester in 80 ml of ethanol and 80 ml of 1 N sodium hydroxide solution is left to stand for 60 hours at about 25° C. It is then evaporated to dryness in vacuo and the evaporation residue is partitioned between 100 ml of 2 N hydrochloric acid and twice 200 ml of ether. The organic phases are washed until neutral, treated with active charcoal, dried over sodium sulphate and evaporated in vacuo. Crystallising the evaporation residue twice from ether-petroleum ether gives 4-[2-(1-adamantyl)-5-methylphenoxy]-butyric acid of melting point 147°-150° C.
Reaction SMILES: CC(C)([O-])C.[K+].[CH3:7][C@H:8]1[CH2:13][C@@H:12]([OH:14])[CH2:11][CH2:10][NH:9]1.Cl[C:16]1[N:21]=[N:20][C:19]([C:22]2[CH:27]=[CH:26][C:25]([N:28]3[CH:32]=[CH:31][CH:30]=[N:29]3)=[CH:24][C:23]=2[OH:33])=[CH:18][CH:17]=1.FC(F)(F)C(O)=O>C1COCC1>[CH3:7][C@H:8]1[CH2:13][C@@H:12]([O:14][C:16]2[N:21]=[N:20][C:19]([C:22]3[CH:27]=[CH:26][C:25]([N:28]4[CH:32]=[CH:31][CH:30]=[N:29]4)=[CH:24][C:23]=3[OH:33])=[CH:18][CH:17]=2)[CH2:11][CH2:10][NH:9]1
Reactant: C[C@H]1C[C@@H](O)CCN1
Reactant: Oc1cc(-n2cccn2)ccc1-c1ccc(Cl)nn1
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: O=C(O)C(F)(F)F
Solvent: C1CCOC1
Product: C[C@H]1C[C@@H](Oc2ccc(-c3ccc(-n4cccn4)cc3O)nn2)CCN1
Temperature: 50 °C
Reaction time: 0.17 h

Procedure:
Potassium tert-butoxide (1.0 M in THF, 1.4 mL, 1.4 mmol) was added to cis-2-methylpiperidin-4-ol (0.10 g, 0.68 mmol) in THF (3 mL) and the mixture was stirred for 10 min at 50° C. 2-(6-Chloropyridazin-3-yl)-5-(1H-pyrazol-1-yl)phenol Intermediate 2-2 (0.08 g, 0.28 mmol) was added to the reaction at 0° C. and the mixture was stirred for 2 days at RT. Trifluoroacetic acid (0.3 mL) was added and the solvent was evaporated under reduced pressure. The crude material was purified via preparative HPLC (5 to 95% acetonitrile in water, 0.1% trifluoroacetic acid as modifier). Enantiomer 1 and Enantiomer 2 were isolated via preparative SFC. Two solids (10 mg (10%) and (15 mg (16%)) were afforded.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]=[C:9]=[O:10])=[CH:4][C:3]=1[S:11]([F:16])([F:15])([F:14])([F:13])[F:12].[NH2:17][C:18]1[CH:34]=[CH:33][C:21]([O:22][C:23]2[CH:28]=[CH:27][N:26]=[C:25]([C:29]([NH:31][CH3:32])=[O:30])[CH:24]=2)=[CH:20][CH:19]=1>C(Cl)Cl>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][C:9]([NH:17][C:18]2[CH:34]=[CH:33][C:21]([O:22][C:23]3[CH:28]=[CH:27][N:26]=[C:25]([C:29]([NH:31][CH3:32])=[O:30])[CH:24]=3)=[CH:20][CH:19]=2)=[O:10])=[CH:4][C:3]=1[S:11]([F:16])([F:12])([F:13])([F:14])[F:15]
Reactant: O=C=Nc1ccc(Br)c(S(F)(F)(F)(F)F)c1
Reactant: CNC(=O)c1cc(Oc2ccc(N)cc2)ccn1
Solvent: ClCCl
Product: CNC(=O)c1cc(Oc2ccc(NC(=O)Nc3ccc(Br)c(S(F)(F)(F)(F)F)c3)cc2)ccn1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 72 %

Procedure:
The crude 1-bromo-4-isocyanato-2-(pentafluoro-λ6-sulfanyl)benzene obtained above was dissolved in DCM (70 mL). 4-(4-aminophenoxy)-N-methylpicolinamide (1.54 g, 6.34 mmol, 0.8 eq) was added at room temperature under N2. The mixture was stirred at room temperature for about 30 min, a lot of solid precipitated. DCM (30 mL) was added and made the mixture stirred at room temperature for 18 hrs. The solid was filtrated, washed with DCM (50 mL), dried under high vacuum to afford 2.6 g (yield 72%) of the title compound as a white solid.
Reaction SMILES: Cl.[N:2]1[C:6]2[CH2:7][CH2:8][CH:9]([C:11](N3CCCC3)=[O:12])[CH2:10][C:5]=2[NH:4][CH:3]=1.ClC(Cl)C.[NH:22]1[C:30]2[C:25](=[CH:26][CH:27]=[CH:28][CH:29]=2)[CH:24]=[CH:23]1.P(Cl)(Cl)(Cl)=O>C(=O)([O-])[O-].[K+].[K+]>[NH:22]1[C:30]2[C:25](=[CH:26][CH:27]=[CH:28][CH:29]=2)[C:24]([C:11]([CH:9]2[CH2:8][CH2:7][C:6]3[N:2]=[CH:3][NH:4][C:5]=3[CH2:10]2)=[O:12])=[CH:23]1
Reactant: c1ccc2[nH]ccc2c1
Reactant: O=C(C1CCc2nc[nH]c2C1)N1CCCC1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(Cl)Cl
Solvent: O=P(Cl)(Cl)Cl
Product: O=C(c1c[nH]c2ccccc12)C1CCc2nc[nH]c2C1
Reaction time: 7 h
Yield: 43.9 %

Procedure:
4 g of N-[(4,5,6,7-tetrahydrobenzimidazol-5-yl)carbonyl]pyrrolidine hydrochloride obtained in Example 5 were added to 40 ml of dichloroethane, and 2.74 g of indole and 4.4 ml of phosphorus oxychloride were added thereto. The mixture was stirred at 80° to 85° C. for 7 hours and then at room temperature overnight. To the mixture was added 40 ml of a cold potassium carbonate aqueous solution, followed by extraction with chloroform. The extract was dried over anhydrous magnesium sulfate, and the solvent was removed by distillation under reduced pressure. The residue was subjected to column chromatography using chloroform/methanol as an eluent to obtain 1.82 g of 5-[(indol-3-yl)carbonyl]-4,5,6,7-tetrahydrobenzimidazole as a foam-like substance. In 1 ml of methanol were dissolved 0.16 g of the resulting product and 0.06 g of fumaric acid, and 5 ml of acetonitrile was added to the solution. The formed crystal was collected by filtration to obtain 0.13 g of 5-[(indol- 3-yl)carbonyl]-4,5,6,7-tetrahydrobenzimidazole fumarate.
Reaction SMILES: [CH2:1]([C:3]1[C:4]2[CH:5]=[C:6]([CH3:27])[C:7]([NH:15][C:16]3[CH:26]=[CH:25][C:19]([C:20]([O:22][CH2:23][CH3:24])=[O:21])=[CH:18][CH:17]=3)=[CH:8][C:9]=2[C:10]([CH3:14])([CH3:13])[CH2:11][CH:12]=1)[CH3:2].[CH:28](=O)[CH3:29]>>[CH2:28]([N:15]([C:7]1[C:6]([CH3:27])=[CH:5][C:4]2[C:3]([CH2:1][CH3:2])=[CH:12][CH2:11][C:10]([CH3:13])([CH3:14])[C:9]=2[CH:8]=1)[C:16]1[CH:17]=[CH:18][C:19]([C:20]([O:22][CH2:23][CH3:24])=[O:21])=[CH:25][CH:26]=1)[CH3:29]
Reactant: CC=O
Reactant: CCOC(=O)c1ccc(Nc2cc3c(cc2C)C(CC)=CCC3(C)C)cc1
Product: CCOC(=O)c1ccc(N(CC)c2cc3c(cc2C)C(CC)=CCC3(C)C)cc1
Yield: 63 %

Procedure:
Following General Procedure D, ethyl 4-(5-ethyl-3,8,8-tetramethyl-7,8-dihydronaphthalen-2-ylamino)benzoate (Compound 55, 0.37 g, 1.0 mmol) was reacted with acetaldehyde (0.56 mL, 10.0 mmol) to give 0.25 g (63%) of the title compound as a clear oil.
Reaction SMILES: C[O:2][C:3]([C@@H:5]1[O:9][C:8](=[O:10])[N:7]([C:11]2[CH:22]=[CH:21][C:14]3[N:15]([CH3:20])[C:16](=[O:19])[CH2:17][O:18][C:13]=3[CH:12]=2)[CH2:6]1)=O.[NH3:23]>CO.CCOCC>[CH3:20][N:15]1[C:14]2[CH:21]=[CH:22][C:11]([N:7]3[CH2:6][C@H:5]([C:3]([NH2:23])=[O:2])[O:9][C:8]3=[O:10])=[CH:12][C:13]=2[O:18][CH2:17][C:16]1=[O:19]
Reactant: COC(=O)[C@H]1CN(c2ccc3c(c2)OCC(=O)N3C)C(=O)O1
Reactant: N
Solvent: CCOCC
Solvent: CO
Product: CN1C(=O)COc2cc(N3C[C@H](C(N)=O)OC3=O)ccc21
Reaction time: 16 h
Yield: 81 %

Procedure:
To a stirred solution of (5R)-3-(3,4-dihydro-4-methyl-3-oxo-2H-1,4-benzoxazin-7-yl)-2-oxo-oxazolidine-5-carboxylic acid methyl ester (Step 2, 2.41 g, 7.87 mmol) in MeOH (25 mL) is added 2M NH3 in MeOH (25 mL, 50 mmol). The resulting clear solution becomes turbid after ˜10 min. This mixture is stirred for 16 h at which time the reaction is diluted with ether (20 mL) and the resulting white solid filtered off. This white solid is washed with several portion of ether (50 mL) and dried under high vacuum to give the title compound (1.87 g, 81%), 1H NMR (300 MHz, DMSO) δ 7.85 (br s, 1H), 7.60 (br s, 1H), 7.31-7.14 (m, 3H), 5.00 (dd, 1H), 4.65 (s, 2H), 4.21 (t, 1H), 3.97 (dd, 1H), 3.32 (s, 3H); MS for C14H13N3O5 m/z 292.5 (M+H)+.
Reaction SMILES: [Cl:1][C:2]1[CH:29]=[CH:28][C:5]([CH2:6][N:7]2[C:12](=[O:13])[CH:11]=[CH:10][C:9]([C:14]3[CH:19]=[CH:18][C:17]([NH:20][C:21](=[O:27])[O:22][C:23]([CH3:26])([CH3:25])[CH3:24])=[CH:16][CH:15]=3)=[CH:8]2)=[CH:4][CH:3]=1.[H-].[Na+].[CH3:32][N:33]([CH2:35][CH2:36]Cl)[CH3:34]>C1COCC1.C(Cl)Cl>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([CH2:6][N:7]2[C:12](=[O:13])[CH:11]=[CH:10][C:9]([C:14]3[CH:19]=[CH:18][C:17]([N:20]([CH2:36][CH2:35][N:33]([CH3:34])[CH3:32])[C:21](=[O:27])[O:22][C:23]([CH3:24])([CH3:25])[CH3:26])=[CH:16][CH:15]=3)=[CH:8]2)=[CH:28][CH:29]=1
Reactant: CN(C)CCCl
Reactant: CC(C)(C)OC(=O)Nc1ccc(-c2ccc(=O)n(Cc3ccc(Cl)cc3)c2)cc1
Agent: [H-]
Agent: [Na+]
Solvent: ClCCl
Solvent: C1CCOC1
Product: CN(C)CCN(C(=O)OC(C)(C)C)c1ccc(-c2ccc(=O)n(Cc3ccc(Cl)cc3)c2)cc1
Temperature: 0 °C
Reaction time: 0.17 h
Yield: 53.6 %

Procedure:
According to Scheme 19 Step 4: tert-Butyl 4-(1-(4-chlorobenzyl)-6-oxo-1,6-dihydropyridin-3-yl)phenylcarbamate (0.34 mmol 0.14 g) was dissolved in dry THF (4 mL) and the resulting solution was cooled at 0° C. Then, NaH (60% mineral oil; 1.02 mmol, 40.8 mg) was added, the mixture was stirred at 0° C. for 10 minutes, warmed at room temperature and stirred for 30 minutes. After, N,N-dimethylaminoethyl chloride (0.69 mmol) and KI (0.34 mmol, 57.0 mg) were added and the reaction mixture was heated at 90° C. for 16 hours. The resulting suspension was taken up in CH2Cl2, washed with water, washed with brine, filtered off and the filtrate washed with CH2Cl2. The organic solvent was separated, dried (Na2SO4) and the solvent was evaporated under reduced pressure. The residue was purified in a manifold (vac.) using a Sep-Pak silica cartridge (CH2Cl2/MeOH(NH3)sat. 95/5). The product fractions were collected and the solvent was evaporated to yield tert-butyl 4-(1-(4-chlorobenzyl)-6-oxo-1,6-dihydropyridin-3-yl)phenyl(2-(dimethylamino)ethyl)carbamate (87.9 mg)
Reaction SMILES: C(N(CC)C(C)C)(C)C.[NH2:10][C@H:11]1[C:19]2[C:14](=[CH:15][C:16]([Cl:20])=[CH:17][CH:18]=2)[CH2:13][C@H:12]1[OH:21].[C:22]1(=O)[O:27][C:25](=[O:26])[C:24]2=[CH:28][CH:29]=[CH:30][CH:31]=[C:23]12.C1(C)C=CC=CC=1>>[Cl:20][C:16]1[CH:15]=[C:14]2[C:19](=[CH:18][CH:17]=1)[C@@H:11]([N:10]1[C:25](=[O:26])[C:24]3[C:23](=[CH:31][CH:30]=[CH:29][CH:28]=3)[C:22]1=[O:27])[C@@H:12]([OH:21])[CH2:13]2
Reactant: O=C1OC(=O)c2ccccc21
Reactant: N[C@H]1c2ccc(Cl)cc2C[C@H]1O
Solvent: Cc1ccccc1
Solvent: CCN(C(C)C)C(C)C
Product: O=C1c2ccccc2C(=O)N1[C@@H]1c2ccc(Cl)cc2C[C@@H]1O
Temperature: 25 °C

Procedure:
In a 1 L round bottom flask, N,N-diisopropylethylamine (15.2 mL, 0.0871 mol) was added to a suspension of (1S,2R)-1-amino-5-chloroindan-2-ol (16.0 g, 0.0871 mol) and phthalic anhydride (14.2 g, 0.0958 mol) in toluene (473 mL, 4.44 mol), and the reaction mixture was heated at reflux for 18 hours. The reaction was cooled to room temperature, at which point a large amount of solid precipitated. The solid, which was the desired product, was filtered, rinsed with EtOAc and collected. The filtrate was cooled to 0° C., filtered and the solid was rinsed with EtOAc and combined with the first batch. The filtrate was transferred to a separatory funnel and diluted with H2O (200 mL). The layers were separated, and the aqueous layer was extracted EtOAc (3×200 mL). The combined organic layers were washed 1× brine (100 mL), dried over MgSO4, filtered, and concentrated in vacuo. The resulting off-white solid was suspended in EtOAc, the large chunks were broken up with sonication, and the suspension was cooled to 0° C. The solid was filtered and combined with the previous 2 batches. The filtrate was concentrated in vacuo, and the resultant white solid was suspended one final time in Et2O (100 mL), filtered and combined with the previous 3 batches. The total yield of all four batches of solid was 25.3 g (92%). LCMS: (FA) ES+ molecular ion 314, major ionization 167; 1H NMR (400 MHz, DMSO) δ 7.83 (s, 4H), 7.33 (s, 1H), 7.27 (d, J=8.2, 1H), 7.19 (dd, J=2.0, 8.1, 1H), 5.52 (d, J=7.4, 1H), 5.34 (d, J=5.2, 1H), 4.64 (dt, J=6.9, 12.7, 1H), 3.21 (dd, J=7.4, 16.1, 1H), 3.02 (dd, J=6.1, 16.1, 1H).
Reaction SMILES: [O:1]([C:9]1[CH:14]=[CH:13][C:12]([C:15]([C:20]2[CH:25]=[CH:24][C:23]([C:26]#[C:27][CH:28]([OH:33])[C:29]([CH3:32])([CH3:31])[CH3:30])=[C:22]([CH3:34])[CH:21]=2)([CH2:18][CH3:19])[CH2:16][CH3:17])=[CH:11][C:10]=1[CH3:35])[Si:2]([C:5]([CH3:8])([CH3:7])[CH3:6])([CH3:4])[CH3:3].[H][H]>[Pd].CO>[O:1]([C:9]1[CH:14]=[CH:13][C:12]([C:15]([C:20]2[CH:25]=[CH:24][C:23](/[CH:26]=[CH:27]\[CH:28]([OH:33])[C:29]([CH3:32])([CH3:31])[CH3:30])=[C:22]([CH3:34])[CH:21]=2)([CH2:16][CH3:17])[CH2:18][CH3:19])=[CH:11][C:10]=1[CH3:35])[Si:2]([C:5]([CH3:6])([CH3:7])[CH3:8])([CH3:3])[CH3:4]
Reactant: [H][H]
Reactant: CCC(CC)(c1ccc(C#CC(O)C(C)(C)C)c(C)c1)c1ccc(O[Si](C)(C)C(C)(C)C)c(C)c1
Agent: [Pd]
Solvent: CO
Product: CCC(CC)(c1ccc(/C=C\C(O)C(C)(C)C)c(C)c1)c1ccc(O[Si](C)(C)C(C)(C)C)c(C)c1
Reaction time: 3 h
Yield: 70.7 %

Procedure:
A solution of 1-(4-{1-[4-(tert-butyl-dimethylsiloxy)-3-methylphenyl]-1-ethylpropyl}-2-methylphenyl)-4,4-dimethylpent-1-yn-3-ol (0.4 g, 0.8 mmol) in anhyd MeOH (10 mL) was sparged with a stream of nitrogen (5 min) and then charged with 5% Pd/C (17 mg). Next an atmosphere of hydrogen (ambient pressure) was introduced into the reaction flask via a hydrogen-filled balloon with an inlet needle. After sparging briefly with hydrogen (5 min), the reaction mixture was stirred 3 h at ambient pressure. The reaction mixture was diluted with EtOAc (30 mL) and filtered through Celite. The filter agent was rinsed with EtOAc, and the combined filtrates were concentrated to yield (Z)-1-(4{-1-[4-(tert-butyl-dimethylsiloxy)-3-methylphenyl]-1-ethylpropyl}-2-methylphenyl)-4,4-dimethylpent-1-en-3-ol (0.28 g, 71%), which was used without purification in the next step.
Reaction SMILES: [Cl:1][C:2]1[C:7]([Cl:8])=[CH:6][CH:5]=[C:4]([Cl:9])[C:3]=1[C:10]1[C:20]([NH2:21])=[N:19][C:13]2[N:14]=[C:15]([NH2:18])[N:16]=[CH:17][C:12]=2[CH:11]=1.[C:22]([N:26]=[C:27]=[O:28])([CH3:25])([CH3:24])[CH3:23]>>[NH2:18][C:15]1[N:16]=[CH:17][C:12]2[CH:11]=[C:10]([C:3]3[C:4]([Cl:9])=[CH:5][CH:6]=[C:7]([Cl:8])[C:2]=3[Cl:1])[C:20]([NH:21][C:27]([NH:26][C:22]([CH3:25])([CH3:24])[CH3:23])=[O:28])=[N:19][C:13]=2[N:14]=1
Reactant: CC(C)(C)N=C=O
Reactant: Nc1ncc2cc(-c3c(Cl)ccc(Cl)c3Cl)c(N)nc2n1
Product: CC(C)(C)NC(=O)Nc1nc2nc(N)ncc2cc1-c1c(Cl)ccc(Cl)c1Cl

Procedure:
The procedure of Example 2 was followed to react 0.30 g of 6-(2,3,6-trichloro-phenyl)-pyrido[2,3-d]pyrimidine-2,7-diamine from Example 85 with tert-butyl isocyanate (0.108 mL). The product is purified by medium pressure chromatography (MPLC) using silica gel and eluting with 1:1 CHCl3 :EtOAc to afford the title compound; mp 329°-330° C., CIMS (1% ammonia in methane): m/z (relative intensity) 439 (MH+ -1, 3), 441 (MH+ +1, 3), 84 (100).