Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [H-].[Na+].[F:3][C:4]1[CH:5]=[C:6]2[C:10](=[CH:11][CH:12]=1)[NH:9][CH:8]=[C:7]2[CH:13]1[CH2:17][CH2:16][C:15](=[O:18])[CH2:14]1.I[CH3:20].O>CN(C)C=O>[F:3][C:4]1[CH:5]=[C:6]2[C:10](=[CH:11][CH:12]=1)[N:9]([CH3:20])[CH:8]=[C:7]2[CH:13]1[CH2:17][CH2:16][C:15](=[O:18])[CH2:14]1
Reactant: O=C1CCC(c2c[nH]c3ccc(F)cc23)C1
Reactant: CI
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: Cn1cc(C2CCC(=O)C2)c2cc(F)ccc21
Temperature: 25 °C
Yield: 75.2 %

Procedure:
A suspension of sodium hydride (60% dispersion in oil, 0.335 g, 8.2 mmol) in dimethylformamide (20 mL) was stirred at room temperature. A solution of 3-(5-fluoro-1H-indol-3-yl)-cyclopentanone (1.5 g, 6.9 mmol) in 10 mL of DMF was added dropwise over 10 min. The reaction mixture was stirred at room temperature for an additional 30 min, then iodomethane (3.1 g, 21.8 mmol) was added. After stirring at room temperature for 24 hours, the reaction mixture was poured into water (100 mL) and extracted with ethyl acetate (2×100 mL). The combined organic layers were washed with water (50 mL) and brine (50 mL), then were dried over anhydrous sodium sulfate, filtered, and concentrated to give 1.6 g of crude product. Flash chromatography on silica gel (50% ethyl acetate/hexane) afforded 1.2 g (81%) of the title compound as a thick oil which solidified on standing. An analytical sample was recrystallized from ethyl acetate/hexane: mp 104-105° C.; MS (ESI) m/z 232 [M+H]+.
Reaction SMILES: [CH3:1][S:2][C:3]1[N:8]=[C:7]([N:9]2[C:14]3=[N:15][C:16]([C:20]4[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=4)=[CH:17][C:18](=[O:19])[N:13]3[CH2:12][CH2:11][CH2:10]2)[CH:6]=[CH:5][N:4]=1.F[B-](F)(F)F.[O:31]=[N+:32]=[O:33]>ClCCl>[CH3:1][S:2][C:3]1[N:8]=[C:7]([N:9]2[C:14]3=[N:15][C:16]([C:20]4[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=4)=[C:17]([N+:32]([O-:33])=[O:31])[C:18](=[O:19])[N:13]3[CH2:12][CH2:11][CH2:10]2)[CH:6]=[CH:5][N:4]=1
Reactant: CSc1nccc(N2CCCn3c2nc(-c2ccccc2)cc3=O)n1
Reactant: O=[N+]=O
Agent: F[B-](F)(F)F
Solvent: ClCCl
Product: CSc1nccc(N2CCCn3c2nc(-c2ccccc2)c([N+](=O)[O-])c3=O)n1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a stirring solution of 9-(2-methylsulfanyl-pyrimidin-4-yl)-2-phenyl-6,7,8,9-tetrahydro-pyrimido[1,2-a]pyrimidin-4-one (500 mg, 1.42 mmol) in dichloromethane (10 mL) at 0° C. under nitrogen was added nitronium tetrafluoroborate in a 0.5M solution (7 mL, 3.55 mmol). External cooling removed and reaction warmed to room temperature while stirring for 1 h. Reaction washed with 5% sodium bicarbonate and saturated ammonium chloride. Organic concentrated under vacuum and orange solid isolated after purification on silica. M+1=397.
Reaction SMILES: F[C:2]1[CH:7]=[CH:6][C:5]([C:8](=[O:10])[CH3:9])=[CH:4][C:3]=1[N+:11]([O-:13])=[O:12].[NH:14]1[CH:18]=[CH:17][N:16]=[C:15]1[CH2:19][CH2:20][C:21]([O:23][CH2:24][CH3:25])=[O:22].C(=O)([O-])[O-].[K+].[K+].CN(C)C(=O)C>C(OCC)C>[C:8]([C:5]1[CH:6]=[CH:7][C:2]([N:14]2[CH:18]=[CH:17][N:16]=[C:15]2[CH2:19][CH2:20][C:21]([O:23][CH2:24][CH3:25])=[O:22])=[C:3]([N+:11]([O-:13])=[O:12])[CH:4]=1)(=[O:10])[CH3:9]
Reactant: CC(=O)c1ccc(F)c([N+](=O)[O-])c1
Reactant: CCOC(=O)CCc1ncc[nH]1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOCC
Solvent: CC(=O)N(C)C
Product: CCOC(=O)CCc1nccn1-c1ccc(C(C)=O)cc1[N+](=O)[O-]
Temperature: 100 °C
Yield: 69 %

Procedure:
A mixture of 4′-fluoro-3′-nitroacetophenone 2.04 g, ethyl 3-(1H-imidazol-2-yl)propanoate 1.87 g, potassium carbonate 3.07 g and N,N-dimethylacetamide 28 mL was heated at 100° C. for 16.5 hours. The reaction liquid was allowed to cool off and to which 60 mL of diethyl ether was added, followed by filtration. Adding 100 mL of water to the filtrate, the organic layer was separated. The aqueous layer was extracted with 100 mL of diethyl ether. The extract was combined with the organic layer, washed twice with 20 mL of water and once with 10 mL of saturated brine by the order stated, and dried over magnesium sulfate. Distilling the solvent off under reduced pressure, 2.54 g of the title compound was obtained.
Reaction SMILES: [Br:1][C:2]1[S:6][C:5]([CH:7]2[N:11]([C:12]3[CH:17]=[CH:16][C:15]([F:18])=[CH:14][C:13]=3[F:19])[N:10]=[C:9]([CH:20]([OH:25])[C:21]([F:24])([F:23])[F:22])[CH2:8]2)=[CH:4][CH:3]=1>ClCCl>[Br:1][C:2]1[S:6][C:5]([CH:7]2[N:11]([C:12]3[CH:17]=[CH:16][C:15]([F:18])=[CH:14][C:13]=3[F:19])[N:10]=[C:9]([C:20](=[O:25])[C:21]([F:24])([F:23])[F:22])[CH2:8]2)=[CH:4][CH:3]=1
Reactant: OC(C1=NN(c2ccc(F)cc2F)C(c2ccc(Br)s2)C1)C(F)(F)F
Solvent: ClCCl
Product: O=C(C1=NN(c2ccc(F)cc2F)C(c2ccc(Br)s2)C1)C(F)(F)F
Temperature: 25 °C
Reaction time: 1 h
Yield: 86.4 %

Procedure:
To a solution of 1-[5-(5-bromo-thiophen-2-yl)-1-(2,4-difluoro-phenyl)-4,5-dihydro-1H-pyrazol-3-yl]-2,2,2-trifluoro-ethanol (9.9 g, 22.4 mmol) prepared in Step 6 in dichloromethane (100.0 mL), was slowly added DMP (10.5 g, 24.7 mmol) at 0° C. The reaction mixture was stirred at room temperature for 1 hour, quenched with a saturated sodium thiosulfate solution, and then extracted with diethyl ether. The extract was washed with a saturated solution of sodium hydrogen carbonate, dried on anhydrous magnesium sulfate, and then concentrated under reduced pressure to give a yellow liquid residue. The resulting residue was purified by silica gel column chromatography (eluent: dichloromethane/n-hexane=2/5) to give 8.5 g of the titled compound as a yellow solid.
Reaction SMILES: [C:1]1([C:7]2[C:8]([C:17]3[CH:24]=[CH:23][C:20]([CH:21]=O)=[CH:19][CH:18]=3)=[N:9][C:10]3[C:15]([CH:16]=2)=[CH:14][CH:13]=[CH:12][N:11]=3)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[NH:25]1[CH2:30][CH2:29][CH:28]([N:31]2[C:35]3[CH:36]=[CH:37][CH:38]=[CH:39][C:34]=3[NH:33][C:32]2=[O:40])[CH2:27][CH2:26]1.CC(O)=O.[BH-](OC(C)=O)(OC(C)=O)OC(C)=O.[Na+]>CN(C=O)C>[C:1]1([C:7]2[C:8]([C:17]3[CH:18]=[CH:19][C:20]([CH2:21][N:25]4[CH2:26][CH2:27][CH:28]([N:31]5[C:35]6[CH:36]=[CH:37][CH:38]=[CH:39][C:34]=6[NH:33][C:32]5=[O:40])[CH2:29][CH2:30]4)=[CH:23][CH:24]=3)=[N:9][C:10]3[C:15]([CH:16]=2)=[CH:14][CH:13]=[CH:12][N:11]=3)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: O=c1[nH]c2ccccc2n1C1CCNCC1
Reactant: O=Cc1ccc(-c2nc3ncccc3cc2-c2ccccc2)cc1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: CC(=O)O
Solvent: CN(C)C=O
Product: O=c1[nH]c2ccccc2n1C1CCN(Cc2ccc(-c3nc4ncccc4cc3-c3ccccc3)cc2)CC1

Procedure:
To a solution of 4-(3-phenyl-1,8-naphthyridin-2-yl)benzaldehyde (9-3) (135 mg, 0.44 mmole) in dry DMF (2 mL) was added 1-piperidin-4-yl-1,3-dihydro-2H-benzimidazol-2-one (123 mg, 0.57 mmole) and HOAc (0.13 mL, 2.18 mmole) at RT. After 30 min NaBH(OAc)3 (120 mg, 0.57 mmole) was added. After 4 hr the mixture was concentrated. The residue was taken up in saturated NaHCO3 and extracted with EtOAc (3×). The combined organic layers were washed with brine, dried (MgSO4), filtered, and concentrated. Flash column (gradient, 0–10% MeOH/CH2Cl2) gave the title compound as a cream colored solid (9-4): 1H-NMR (500 MHz, CDCl3) δ 9.15 (dd, J=1.71, 2.44 Hz, 1 H), 8.56 (bs, 1 H), 8.24 (m, 1 H), 8.19 (s, 1 H), 7.53 (m, 2 H), 7.30 (m, 7 H), 7.06 (m, 3H), 4.36 (m, 1 H), 3.56 (s, 2 H), 3.01 (d, J=11.47 Hz, 2 H), 2.44 (m, 2 H), 2.17 (m, 2H), 1.79 (d, J=11.72 Hz, 2 H); HRMS, calc'd for C33H29N5O (M+1), 512.2445; found 512.2478.
Reaction SMILES: [F:1][C:2]1[C:7]([O:8][CH3:9])=[CH:6][CH:5]=[CH:4][C:3]=1[C:10]([CH3:14])([CH3:13])[C:11]#N.CC(C[AlH]CC(C)C)C.C(O)(=O)[C@@H]([C@H](C(O)=O)O)[OH:26]>C1(C)C=CC=CC=1>[F:1][C:2]1[C:7]([O:8][CH3:9])=[CH:6][CH:5]=[CH:4][C:3]=1[C:10]([CH3:14])([CH3:13])[CH:11]=[O:26]
Reactant: COc1cccc(C(C)(C)C#N)c1F
Reactant: O=C(O)[C@H](O)[C@@H](O)C(=O)O
Agent: CC(C)C[AlH]CC(C)C
Solvent: Cc1ccccc1
Product: COc1cccc(C(C)(C)C=O)c1F
Temperature: -65 °C

Procedure:
4.66 g (24.12 mmol) of 2-(2-fluoro-3-methoxyphenyl)-2-methylpropanenitrile is dissolved in 96 ml of toluene. At −65° C. to −60° C., 30 ml (36.18 mmol) of a 1.2 molar solution of DIBAH in toluene is added in drops. After three and one-half hours of stirring at −65° C., 276 ml of a 10% L(+)-tartaric acid solution is added in drops at this temperature. In this case, the temperature rises to 0° C. The cold bath is removed, and the batch is stirred vigorously at room temperature for one hour. The reaction mixture is extracted three times with 300 ml each of diethyl ether. The combined organic extracts are treated as usual (water, brine, drying). After the solvent is spun off, 4.78 g (slightly above 100%) of the desired compound remains.
Reaction SMILES: [C:1]([O:4][CH2:5][CH2:6][N:7]1[C:11]([N+:12]([O-:14])=[O:13])=[CH:10][N:9]=[CH:8]1)(=[O:3])[CH3:2].[CH2:15]=[O:16]>CS(C)=O>[C:1]([O:4][CH2:5][CH2:6][N:7]1[C:11]([N+:12]([O-:14])=[O:13])=[CH:10][N:9]=[C:8]1[CH2:15][OH:16])(=[O:3])[CH3:2]
Reactant: CC(=O)OCCn1cncc1[N+](=O)[O-]
Reactant: C=O
Solvent: CS(C)=O
Product: CC(=O)OCCn1c([N+](=O)[O-])cnc1CO

Procedure:
A mixture of 24.25 g. of 1-(2'-acetoxyethyl)-5-nitroimidazole prepared as in Example 4, 15 g. of paraformaldehyde and 150 ml. of dimethylsulfoxide is heated in a sealed tube overnight at 100°-150° C. The dimethylsulfoxide is removed completely at reduced pressure, and the residue is dissolved in water and extracted with chloroform. The chloroform extract is dried and concentrated. The residue is dissolved in ethyl acetate, and the solution is charged on a column of alumina. Elution with ethyl acetate and evaporation of the solvent yields 1-(2'-acetoxyethyl)-2-hydroxymethyl-5-nitroimidazole, m.p. 38°-145° C.
Reaction SMILES: Br[C:2]1[CH:11]=[CH:10][C:9]2[C:4](=[CH:5][CH:6]=[C:7]([O:12][CH:13]3[CH2:18][CH2:17][CH:16]([C:19]([CH3:22])([CH3:21])[CH3:20])[CH2:15][CH2:14]3)[CH:8]=2)[CH:3]=1.[F:23][C:24]([F:32])([F:31])[C:25](N(OC)C)=[O:26]>C1COCC1>[C:19]([CH:16]1[CH2:15][CH2:14][CH:13]([O:12][C:7]2[CH:8]=[C:9]3[C:4](=[CH:5][CH:6]=2)[CH:3]=[C:2]([C:25](=[O:26])[C:24]([F:32])([F:31])[F:23])[CH:11]=[CH:10]3)[CH2:18][CH2:17]1)([CH3:20])([CH3:21])[CH3:22]
Reactant: CC(C)(C)C1CCC(Oc2ccc3cc(Br)ccc3c2)CC1
Reactant: CON(C)C(=O)C(F)(F)F
Solvent: C1CCOC1
Product: CC(C)(C)C1CCC(Oc2ccc3cc(C(=O)C(F)(F)F)ccc3c2)CC1
Temperature: -78 °C
Reaction time: 0.25 h

Procedure:
To a solution of 2-Bromo-6-(4-tert-butyl-cyclohexyloxy)-naphthalene (2 g, 0.006 mol) in 15 mL dry THF stirring at −78° C., was added dropwise. The reaction was then stirred at −78° C. for 15 minutes, yellow color results. 2,2,2-Trifluoro-N-methoxy-N-methyl-acetamide (1.0 mL, 0.0083 mol) in 10 mL THF was then added dropwise while the reaction was stirred at −78° C. Once all of the starting material was added reaction the reaction was allowed to warm to room temperature while stirring for 2 hours. The Reaction was then quenched with water and extracted three times with EtOAc. Organics were dried over MgSO4, filtered, and concentrated to dryness under reduced pressure. Crude NMR shows about 80% purity (looks like des-bromostarting material). Material was purified via column chromatography using a gradient of hexanes for one column volume followed by 0-10% EtOAC/Hexanes on 25 g of SiO2 to give the title compound as a yellow solid. Material will be carried on without additional purification
Reaction SMILES: [Br:1][CH2:2][CH2:3][C:4]1[CH:13]=[CH:12][C:7]([O:8][CH2:9][CH2:10][OH:11])=[CH:6][CH:5]=1.[C:14](OC(=O)C)(=[O:16])[CH3:15].C(N(CC)CC)C>CN(C1C=CN=CC=1)C.C(Cl)Cl>[C:14]([O:11][CH2:10][CH2:9][O:8][C:7]1[CH:12]=[CH:13][C:4]([CH2:3][CH2:2][Br:1])=[CH:5][CH:6]=1)(=[O:16])[CH3:15]
Reactant: CC(=O)OC(C)=O
Reactant: OCCOc1ccc(CCBr)cc1
Agent: CN(C)c1ccncc1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CC(=O)OCCOc1ccc(CCBr)cc1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
A mixture of 2-[4-(2-bromoethyl)phenoxy]ethanol (900 mg), acetic anhydride (0.5 mL), triethylamine (1.0 mL) and DMAP (13 mg) in DCM (5 mL) was stirred at room temperature for 0.5 h. The reaction was quenched by pouring into aq. NaHCO3 and the organic layer was washed with 2M HCl, dried (MgSO4) and concentrated in vacuo to give the title compound (1.03 g). LCMS RT=3.32 min.
Reaction SMILES: Cl[CH2:2][CH2:3][CH2:4][CH2:5][O:6][C:7]1[CH:8]=[CH:9][C:10]2[NH:15][C:14](=[O:16])[O:13][C:12]([CH3:18])([CH3:17])[C:11]=2[CH:19]=1.[CH3:20][O:21][C:22]1[CH:23]=[C:24]([SH:30])[CH:25]=[CH:26][C:27]=1[O:28][CH3:29]>>[CH3:20][O:21][C:22]1[CH:23]=[C:24]([S:30][CH2:2][CH2:3][CH2:4][CH2:5][O:6][C:7]2[CH:8]=[CH:9][C:10]3[NH:15][C:14](=[O:16])[O:13][C:12]([CH3:18])([CH3:17])[C:11]=3[CH:19]=2)[CH:25]=[CH:26][C:27]=1[O:28][CH3:29]
Reactant: COc1ccc(S)cc1OC
Reactant: CC1(C)OC(=O)Nc2ccc(OCCCCCl)cc21
Product: COc1ccc(SCCCCOc2ccc3c(c2)C(C)(C)OC(=O)N3)cc1OC

Procedure:
Prepared analogously to Example 1 from 6-(4-chlorobutoxy)-4,4-dimethyl-4H-3,1-benzoxazin-2-one and 3,4-dimethoxy-thiophenol.
Reaction SMILES: Cl[C:2]1[CH:19]=[CH:18][C:5]([C:6]([NH:8][CH2:9][C:10]2[CH:15]=[CH:14][CH:13]=[C:12]([O:16][CH3:17])[CH:11]=2)=[O:7])=[CH:4][N:3]=1.[CH:20]1([NH:23][C:24](=[O:41])[C:25]2[CH:30]=[CH:29][C:28]([CH3:31])=[C:27](B3OC(C)(C)C(C)(C)O3)[CH:26]=2)[CH2:22][CH2:21]1>>[CH:20]1([NH:23][C:24]([C:25]2[CH:30]=[CH:29][C:28]([CH3:31])=[C:27]([C:2]3[CH:19]=[CH:18][C:5]([C:6]([NH:8][CH2:9][C:10]4[CH:15]=[CH:14][CH:13]=[C:12]([O:16][CH3:17])[CH:11]=4)=[O:7])=[CH:4][N:3]=3)[CH:26]=2)=[O:41])[CH2:21][CH2:22]1
Reactant: COc1cccc(CNC(=O)c2ccc(Cl)nc2)c1
Reactant: Cc1ccc(C(=O)NC2CC2)cc1B1OC(C)(C)C(C)(C)O1
Product: COc1cccc(CNC(=O)c2ccc(-c3cc(C(=O)NC4CC4)ccc3C)nc2)c1

Procedure:
6-[5-Cyclopropylcarbamoyl-2-methyl-phenyl]-N-(3-methoxybenzyl)-nicotinamide was prepared from 6-chloro-N-(3-methoxybenzyl)nicotinamide (intermediate 3) and N-cyclopropyl-4-methyl-3-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-benzamide (Intermediate 8) using General Method B. LCMS: retention time 2.94 min, MH+ 416. NMR: δH [2H6]-DMSO 9.29,(1H, t), 9.15,(1H, s), 8.48,(1H, d), 8.35,(1H, d), 7.89,(1H, s), 7.81,(1H, d), 7.72,(1H, d), 7.41,(1H, d), 7.26,(1H, t), 6.93,(2H, m), 6.84,(1H, s), 4.51,(2H, d), 3.75,(3H, s), 2.86,(1H, m), 2.38,(3H, s), 0.69,(2H, m), 0.57,(2H, m).
Reaction SMILES: [C:1]([C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=1[NH:15][S:16]([C:19]1[CH:27]=[CH:26][C:22]([C:23](O)=[O:24])=[CH:21][CH:20]=1)(=[O:18])=[O:17])(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Cl.[CH2:29]([O:31][C:32](=[O:35])[CH2:33][NH2:34])[CH3:30]>>[CH2:29]([O:31][C:32](=[O:35])[CH2:33][NH:34][C:23](=[O:24])[C:22]1[CH:21]=[CH:20][C:19]([S:16](=[O:17])(=[O:18])[NH:15][C:10]2[CH:11]=[CH:12][CH:13]=[CH:14][C:9]=2[C:1](=[O:8])[C:2]2[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=2)=[CH:27][CH:26]=1)[CH3:30]
Reactant: O=C(O)c1ccc(S(=O)(=O)Nc2ccccc2C(=O)c2ccccc2)cc1
Reactant: CCOC(=O)CN
Agent: Cl
Product: CCOC(=O)CNC(=O)c1ccc(S(=O)(=O)Nc2ccccc2C(=O)c2ccccc2)cc1

Procedure:
The title compound was prepared from 4-(2-benzoyl-phenylsulfamoyl)-benzoic acid and glycine ethyl ester hydrochloride (Aldrich) according to the method described in Example 1.1/d. MS (EI) 867.2 (MH+).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:11]=[C:10]([O:12][CH3:13])[CH:9]=[C:8]2[C:4]=1[C:5]1([C:26]3[C:17](=[CH:18][C:19]4[O:24][CH2:23][CH2:22][O:21][C:20]=4[CH:25]=3)[O:16][CH2:15]1)[C:6](=[O:14])[NH:7]2.N1C2C(=CC=CC=2)[C@@]2(C3C(=C[C:40]4[O:45][CH2:44][CH2:43][O:42][C:41]=4[CH:46]=3)OC2)C1=O>>[CH3:1][O:2][C:3]1[CH:11]=[C:10]([O:12][CH3:13])[CH:9]=[C:8]2[C:4]=1[C:5]1([C:26]3[C:17](=[CH:18][C:19]4[O:24][CH2:23][CH2:22][O:21][C:20]=4[CH:25]=3)[O:16][CH2:15]1)[C:6](=[O:14])[N:7]2[CH2:46][CH2:41][O:42][CH2:43][CH2:44][O:45][CH3:40]
Reactant: O=C1Nc2ccccc2[C@]12COc1cc3c(cc12)OCCO3
Reactant: COc1cc2c(c(OC)c1)C1(COc3cc4c(cc31)OCCO4)C(=O)N2
Product: COCCOCCN1C(=O)C2(COc3cc4c(cc32)OCCO4)c2c(OC)cc(OC)cc21

Procedure:
Following the procedure as described in EXAMPLE 9.70 and making non-critical variations using 4′,6′-dimethoxy-2,3-dihydrospiro[furo[2,3-g][1,4]benzodioxine-8,3′-indol]-2′(1′H)-one to replace (8S)-2,3-dihydrospiro[furo[2,3-g][1,4]benzodioxine-8,3′-indol]-2′(1′H)-one, 4′,6′-dimethoxy-1′-[2-(2-methoxyethoxy)ethyl]-2,3-dihydrospiro[furo[2,3-g][1,4]benzodioxine-8,3′-indol]-2′(1′H)-one was obtained (80%) as a colorless solid: mp 158-160° C.; 1H NMR (300 MHz, DMSO-d6) δ6.43 (s, 1H), 6.33 (d, J=4.2 Hz, 1H), 6.20 (s, 1H), 6.06 (d, J=4.2 Hz, 1H), 4.70-4.46 (m, 2H), 4.19-3.99 (m, 4H), 3.79-3.72 (m, 2H), 3.65-3.52 (m, 4H), 3.52-3.42 (m, 2H), 3.38-3.24 (m, 6H), 3.18-3.11 (m, 3H); 13C NMR (75 MHz, CDCl3) δ178.8, 162.0, 156.7, 155.6, 155.5, 144.7, 144.1, 137.6, 120.4, 110.9, 109.2, 98.8, 92.9, 89.2, 71.0, 70.4, 68.3, 64.4, 63.9, 59.0, 56.9, 55.6, 55.5, 40.3; MS (ES+) m/z 458.1 (M+1).
Reaction SMILES: [CH:1]1([NH2:4])[CH2:3][CH2:2]1.[Cl:5][CH2:6][CH2:7][N:8]=[C:9]=[O:10]>C1COCC1>[Cl:5][CH2:6][CH2:7][NH:8][C:9]([NH:4][CH:1]1[CH2:3][CH2:2]1)=[O:10]
Reactant: O=C=NCCCl
Reactant: NC1CC1
Solvent: C1CCOC1
Product: O=C(NCCCl)NC1CC1
Temperature: 25 °C
Reaction time: 2 h
Yield: 85 %

Procedure:
A solution of cyclopropanamine (0.541 g, 9.48 mmol) in THF (10 mL) was treated with chloroethylisocyanate (1.0 g, 9.48 mmol), stirred at RT for 2 h, then concentrated to dryness and treated with MeCN. The resulting solid was collected via filtration and dried to afford 1-(2-chloroethyl)-3-cyclopropylurea (1.31 g, 85%). 1H NMR (400 MHz, DMSO-d6): δ 6.28 (s, 1 H), 6.12 (br s, 1 H), 3.55 (t, J=6.4 Hz, 2 H), 3.30 (m, 2 H), 2.36 (m, 1 H), 0.55 (m, 2 H), 0.31 (m, 2 H); MS (ESI) m/z: 162.9 (M+H+).
Reaction SMILES: B.CSC.[CH2:5]([N:12]1[C:24]2[CH:23]=[CH:22][CH:21]=[C:20]([O:25][CH2:26][C:27]#[N:28])[C:19]=2[C:18]2[C:13]1=[CH:14][CH:15]=[C:16]([CH3:29])[CH:17]=2)[C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1>C1COCC1>[CH2:5]([N:12]1[C:24]2[CH:23]=[CH:22][CH:21]=[C:20]([O:25][CH2:26][CH2:27][NH2:28])[C:19]=2[C:18]2[C:13]1=[CH:14][CH:15]=[C:16]([CH3:29])[CH:17]=2)[C:6]1[CH:7]=[CH:8][CH:9]=[CH:10][CH:11]=1
Reactant: Cc1ccc2c(c1)c1c(OCC#N)cccc1n2Cc1ccccc1
Agent: B
Solvent: C1CCOC1
Solvent: CSC
Product: Cc1ccc2c(c1)c1c(OCCN)cccc1n2Cc1ccccc1
Temperature: 25 °C
Reaction time: 5.5 h
Yield: 65.7 %

Procedure:
Borane-methyl sulfide (1.2 mL, 0.013 mol) is added to a mixture of 2-[(9-benzyl-6-methyl-9H-carbazol-4-yl)oxy]acetonitrile (1.3337 g, 0.0041 mol) in dry THF (35 mL) and the mixture is allowed to stir at room temperature for 5.5 h. The excess borane then is cautiously quenched with methanol and the mixture is concentrated under reduced pressure. Methanol and dichloromethane are added to the residue and the solution is again concentrated under reduced pressure (repeated twice). The solids are then dissolved in methanol/dichloromethane with heating and 4N HCl (10 mL) is added. The mixture is stirred for 15 min while being warmed slightly. The solvent is then removed under reduced pressure and the residue is partitioned between dichloromethane and aq. sodium bicarbonate. The combined organic layers are dried over sodium sulfate and concentrated to dryness. The residue is chromatographed on silica gel (300 mL) using methanol/dichloromethane (2/98 and 6/94) to give 0.89 g (66%) of the title compound. The salt of 2-[(9-benzyl-6-methyl-9H-carbazol-4-yl)oxy]ethylamine (0.2310 g, 0.70 mmol) is formed with maleic acid in dichloromethane and recrystallized from methanol/dichloromethane/hexane to give 0.2051 g (66%) of the maleic acid salt; mp 187.5-188° C.; MS (ESI+) for C22H22N2O m/z 331.3 (M+H)+; IR (drift) 3027, 2984, 2926, 2887, 1601, 1579, 1497, 1483, 1465, 1364, 1344, 1267, 1150, 865, 747 cm−1; 1H NMR (CD3OD) δ2.52, 3.59, 4.52, 5.54, 6.23, 6.77, 7.09, 7.22, 7.33, 8.16, NH2 not seen. Anal. Calcd for C22H22N2O.C4H4O4: C, 69.94; H, 5.87; N, 6.27. Found: C, 69.93; H, 5.90; N, 6.29.
Reaction SMILES: Br[C:2]1[CH:7]=[N:6][CH:5]=[C:4]([C:8]2[CH:13]=[CH:12][C:11]([C:14]([F:17])([F:16])[F:15])=[CH:10][CH:9]=2)[N:3]=1.C(N(CC)C(C)C)(C)C.[CH3:27][O:28][CH2:29][CH2:30][NH:31][CH2:32][C:33]1[CH:45]=[CH:44][C:36]([O:37][CH2:38][C:39]([O:41][CH2:42][CH3:43])=[O:40])=[C:35]([CH3:46])[CH:34]=1>O>[CH3:27][O:28][CH2:29][CH2:30][N:31]([CH2:32][C:33]1[CH:45]=[CH:44][C:36]([O:37][CH2:38][C:39]([O:41][CH2:42][CH3:43])=[O:40])=[C:35]([CH3:46])[CH:34]=1)[C:2]1[CH:7]=[N:6][CH:5]=[C:4]([C:8]2[CH:13]=[CH:12][C:11]([C:14]([F:17])([F:16])[F:15])=[CH:10][CH:9]=2)[N:3]=1
Reactant: FC(F)(F)c1ccc(-c2cncc(Br)n2)cc1
Reactant: CCOC(=O)COc1ccc(CNCCOC)cc1C
Solvent: CCN(C(C)C)C(C)C
Solvent: O
Product: CCOC(=O)COc1ccc(CN(CCOC)c2cncc(-c3ccc(C(F)(F)F)cc3)n2)cc1C
Temperature: 100 °C
Yield: 19.3 %

Procedure:
A mixture of 2-bromo-6-[4-(trifluoromethyl)phenyl]pyrazine (0.5 g, 1.65 mmol), N,N-diisopropylethylamine (0.29 mL, 1.65 mmol) and ethyl (4-{[(2-methoxyethyl)amino]methyl}-2-methylphenoxy)acetate (0.7 g, 2.47 mmol) was heated at 100° C. in a sealed reactivial for 20 h. The reaction mixture was then allowed to come to room temperature, and the residue was diluted with water (40 mL) and extracted CH2Cl2 (2×40 mL). The organic extract was passed through a hydrophobic frit and concentrated in vacuo. Purification by Biotage™ chromatography (Silica, 90 g) eluting 1:19–1:4 EtOAc:cyclohexane afforded the title compound as a pale yellow oil (0.16 g).
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([C:8]([F:11])([F:10])[F:9])=[CH:4][C:3]=1[CH2:12][C:13]([O:15][CH3:16])=[O:14].F[B-](F)(F)F.[CH3:22][Si:23]([C:26]#[CH:27])([CH3:25])[CH3:24].CN(C=O)C>Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.[Cu]I.CCN(CC)CC>[F:9][C:8]([F:11])([F:10])[C:5]1[CH:6]=[CH:7][C:2]([C:27]#[C:26][Si:23]([CH3:25])([CH3:24])[CH3:22])=[C:3]([CH2:12][C:13]([O:15][CH3:16])=[O:14])[CH:4]=1
Reactant: C#C[Si](C)(C)C
Reactant: COC(=O)Cc1cc(C(F)(F)F)ccc1Br
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Cu]I
Agent: F[B-](F)(F)F
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: COC(=O)Cc1cc(C(F)(F)F)ccc1C#C[Si](C)(C)C
Temperature: 80 °C
Reaction time: 16 h

Procedure:
A suspension of methyl 2-(2-bromo-5-(trifluoromethyl)phenyl)acetate (A103) (1.00 g, 3.36 mmol), PdCl2(PPh3)2 (0.118 g, 0.168 mmol), t-Bu3PH.BF4 (0.049 g, 0.17 mmol), CuI (0.032 g, 0.17 mmol) and trimethylsilylacetylene (0.951 mL, 6.73 mmol) in anhydrous degassed DMF (10 mL) and Et3N (10 mL) was stirred at 80° C. for 16 hours. The resulting mixture was adsorbed onto silica gel and purified by column chromatography (Biotage Isolera, SiO2 cartridge, 0-10% EtOAc in petroleum benzine 40-60° C.) to give the title compound A104 as an orange liquid (0.863 g, 82%); 1H NMR (400 MHz, CDCl3) δ 7.57 (d, J=8.0 Hz, 1H), 7.53 (d, J=0.5 Hz, 1H), 7.50-7.44 (m, 1H), 3.87 (s, 2H), 3.7s (s, 3H), 0.24 (s, 9H). LCMS: rt 6.931 min; m/z 315.1 [M+H]+.
Reaction SMILES: [OH:1][C:2]([CH3:32])([CH3:31])[CH2:3][C@@:4]1([CH:28]([CH3:30])[CH3:29])[O:9][C:8](=[O:10])[N:7]([C@H:11]([C:13]2[CH:18]=[CH:17][C:16](B3OC(C)(C)C(C)(C)O3)=[CH:15][CH:14]=2)[CH3:12])[CH2:6][CH2:5]1.Br[C:34]1[CH:35]=[N:36][C:37]([C:40]([OH:42])=[O:41])=[N:38][CH:39]=1>>[OH:1][C:2]([CH3:31])([CH3:32])[CH2:3][C@@:4]1([CH:28]([CH3:30])[CH3:29])[O:9][C:8](=[O:10])[N:7]([C@H:11]([C:13]2[CH:18]=[CH:17][C:16]([C:34]3[CH:35]=[N:36][C:37]([C:40]([OH:42])=[O:41])=[N:38][CH:39]=3)=[CH:15][CH:14]=2)[CH3:12])[CH2:6][CH2:5]1
Reactant: CC(C)[C@@]1(CC(C)(C)O)CCN([C@@H](C)c2ccc(B3OC(C)(C)C(C)(C)O3)cc2)C(=O)O1
Reactant: O=C(O)c1ncc(Br)cn1
Product: CC(C)[C@@]1(CC(C)(C)O)CCN([C@@H](C)c2ccc(-c3cnc(C(=O)O)nc3)cc2)C(=O)O1

Procedure:
5-(4-((S)-1-((S)-6-(2-hydroxy-2-methylpropyl)-6-isopropyl-2-oxo-1,3-oxazinan-3-yl)ethyl)phenyl)pyrimidine-2-carboxylic acid was prepared from (S)-6-(2-hydroxy-2-methylpropyl)-6-isopropyl-3-((S)-1-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)ethyl)-1,3-oxazinan-2-one and 5-bromopyrimidine-2-carboxylic acid following a procedure analogous to that described in Example 1 Step 2.