Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]1[CH:10]=[C:9]([C:11]([F:14])([F:13])[F:12])[CH:8]=[CH:7][C:3]=1[C:4](Cl)=[O:5].[CH3:15][O:16][C:17]1[CH:22]=[C:21]([NH2:23])[CH:20]=[CH:19][N:18]=1.N1C=CC=CC=1.Cl>ClCCl>[F:1][C:2]1[CH:10]=[C:9]([C:11]([F:14])([F:13])[F:12])[CH:8]=[CH:7][C:3]=1[C:4]([NH:23][C:21]1[CH:20]=[CH:19][N:18]=[C:17]([O:16][CH3:15])[CH:22]=1)=[O:5]
Reactant: COc1cc(N)ccn1
Reactant: O=C(Cl)c1ccc(C(F)(F)F)cc1F
Agent: Cl
Solvent: c1ccncc1
Solvent: ClCCl
Product: COc1cc(NC(=O)c2ccc(C(F)(F)F)cc2F)ccn1
Temperature: 25 °C
Reaction time: 8 h
Yield: 74.1 %

Procedure:
A solution of 2-fluoro-4-(trifluoromethyl)benzoyl chloride (25.0 g, 110.3 mmol) in dichloromethane (125.0 mL) was added drop-wise to a mixture of 2-methoxypyridin-4-amine (13.7 g, 110.3 mmol), pyridine (26.8 mL, 330.9 mmol) and dichloromethane (500.0 mL) at 0° C. The mixture was allowed to warm to room temperature and was stirred at that temperature overnight. The mixture was poured into 1N HCl (200 mL) and dichloromethane (200 mL). The layers were separated and the organic layer was dried over sodium sulfate, filtered and concentrated under reduced pressure. The product was slurried in hexane, the hexane was decanted and the product was dried under reduced pressure to yield 2-fluoro-N-(2-methoxy-4-pyridyl)-4-(trifluoromethyl)benzamide (25.7 g, 74%) as a cream solid. ESI-MS m/z calc. 314.07, found 315.3 (M+1)+; Retention time: 1.49 minutes (3 minutes run). 1H NMR (400 MHz, DMSO-d6) δ 10.96 (s, 1H), 8.15-8.04 (m, 1H), 8.00-7.85 (m, 2H), 7.76 (d, J=8.1 Hz, 1H), 7.26-7.15 (m, 2H), 3.85 (s, 3H) ppm.
Reaction SMILES: C([O:3][C:4]([C:6]1[O:7][C:8]2[CH:15]=[CH:14][CH:13]=[C:12]([O:16][CH2:17][CH3:18])[C:9]=2[C:10]=1[CH3:11])=[O:5])C.[Li+].[OH-]>C1COCC1>[CH2:17]([O:16][C:12]1[C:9]2[C:10]([CH3:11])=[C:6]([C:4]([OH:5])=[O:3])[O:7][C:8]=2[CH:15]=[CH:14][CH:13]=1)[CH3:18]
Reactant: CCOC(=O)c1oc2cccc(OCC)c2c1C
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Product: CCOc1cccc2oc(C(=O)O)c(C)c12
Temperature: 25 °C
Reaction time: 8 h
Yield: 91.6 %

Procedure:
To a solution of 160 mg of 4-ethoxy-3-methyl-benzofuran-2-carboxylic acid ethyl ester dissolved in 1 mL of THF was added 3 mL of LiOH solution (3.6 g LiOH/50 mL MeOH/50 mL H2O). The mixture was stirred at room temperature overnight. The solvents were removed under vacuum and the residue was dissolved in 5 mL of water. The solution was acidified and the resulting suspension was filtered. The solid product was dried under vacuum to give 130 mg (92% yield) of 4-ethoxy-3-methyl-benzofuran-2-carboxylic acid was obtained as white solid.
Reaction SMILES: [C:1]([C:4]1[CH:9]=[CH:8][C:7]([O:10][CH2:11][CH2:12][CH2:13][O:14][C:15]2[CH:20]=[CH:19][C:18]([C@H:21]3[O:25][C:24](=[O:26])[CH2:23][C@H:22]3[CH3:27])=[CH:17][CH:16]=2)=[C:6]([CH2:28][CH2:29][CH3:30])[C:5]=1[OH:31])(=[O:3])[CH3:2].[OH-:32].[Na+:33].CO>C1COCC1>[C:1]([C:4]1[CH:9]=[CH:8][C:7]([O:10][CH2:11][CH2:12][CH2:13][O:14][C:15]2[CH:20]=[CH:19][C:18]([CH:21]([OH:25])[CH:22]([CH3:27])[CH2:23][C:24]([O-:26])=[O:32])=[CH:17][CH:16]=2)=[C:6]([CH2:28][CH2:29][CH3:30])[C:5]=1[OH:31])(=[O:3])[CH3:2].[Na+:33]
Reactant: [OH-]
Reactant: CCCc1c(OCCCOc2ccc([C@H]3OC(=O)C[C@H]3C)cc2)ccc(C(C)=O)c1O
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CO
Product: CCCc1c(OCCCOc2ccc(C(O)C(C)CC(=O)[O-])cc2)ccc(C(C)=O)c1O

Procedure:
The lactone from Example 13 (3.0 g, 7.0 mmol) was hydrolyzed with 1N NaOH (10.5 ml), methanol (1 ml) and THF (15 ml) at room temperature for 15 hours. The mixture was concentrated and the residue was Purified by chromatography on XAD-8 to provide the title compound as a foam.
Reaction SMILES: C[O:2][C:3]1[CH:4]=[C:5]([C:9]2[CH:17]=[C:16]3[C:12]([C:13]([C:18]4[NH:22][C:21]5[CH:23]=[CH:24][CH:25]=[CH:26][C:20]=5[N:19]=4)=[N:14][NH:15]3)=[CH:11][CH:10]=2)[CH:6]=[CH:7][CH:8]=1.COC1C=C(B(O)O)C=CC=1.COC1C=C(O)C=CC=1C1C=C2C(C(C3NC4C=CC=CC=4N=3)=NN2)=CC=1>>[NH:22]1[C:21]2[CH:23]=[CH:24][CH:25]=[CH:26][C:20]=2[N:19]=[C:18]1[C:13]1[C:12]2[C:16](=[CH:17][C:9]([C:5]3[CH:6]=[CH:7][CH:8]=[C:3]([OH:2])[CH:4]=3)=[CH:10][CH:11]=2)[NH:15][N:14]=1
Reactant: COc1cccc(-c2ccc3c(-c4nc5ccccc5[nH]4)n[nH]c3c2)c1
Agent: COc1cc(O)ccc1-c1ccc2c(-c3nc4ccccc4[nH]3)n[nH]c2c1
Agent: COc1cccc(B(O)O)c1
Product: Oc1cccc(-c2ccc3c(-c4nc5ccccc5[nH]4)n[nH]c3c2)c1

Procedure:
Example 24(o) was prepared in a similar manner to that described for Example 24(f), except that 6-(3-methoxy-phenyl)-3-1H-benzoimidazol-2-yl-1H-indazole, prepared in a similar manner to that described for example 24(a) except that 3-methoxy-phenylboronic acid was used instead of 5-methoxy-2-methyl-4-[2-(trimethylsilanyl)-ethoxymethoxy]-phenylboronic acid in step (viii), was used instead of 6-(2-methoxy-4-hydroxyphenyl)-3-1H-benzoimidazol-2-yl-1H-indazole. 1H NMR (300 MHz, DMSO-d6) δ 13.67 (s, 1H), 13.00 (s, 1H), 9.58 (s, 1H), 8.55 (d, 1H, J=8.4 Hz), 7.71–7.75 (m, 2H), 7.49–7.57 (m, 2H), 7.30 (t, 1H, J=7.8 Hz), 7.12–7.24 (m, 4H), 6.80 (dd, 1H, J=8.1, 1.5 Hz). MS (ES) [m+H]/z calc'd 327. found 327. [m−H]/z calc'd 325. found 325.
Reaction SMILES: [F:1][C:2]1[CH:3]=[CH:4][C:5]2[N:9]=[CH:8][N:7]([CH2:10][C:11]([OH:13])=O)[C:6]=2[C:14]=1[F:15].[NH2:16][CH:17]([C:19]1[CH:24]=[CH:23][C:22]([C:25]2([C:31]#[N:32])[CH2:30][CH2:29][S:28][CH2:27][CH2:26]2)=[CH:21][C:20]=1[CH3:33])[CH3:18].CCN(CC)CC.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F>>[C:31]([C:25]1([C:22]2[CH:23]=[CH:24][C:19]([CH:17]([NH:16][C:11](=[O:13])[CH2:10][N:7]3[C:6]4[C:14]([F:15])=[C:2]([F:1])[CH:3]=[CH:4][C:5]=4[N:9]=[CH:8]3)[CH3:18])=[C:20]([CH3:33])[CH:21]=2)[CH2:26][CH2:27][S:28][CH2:29][CH2:30]1)#[N:32]
Reactant: Cc1cc(C2(C#N)CCSCC2)ccc1C(C)N
Reactant: O=C(O)Cn1cnc2ccc(F)c(F)c21
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(CC)CC
Product: Cc1cc(C2(C#N)CCSCC2)ccc1C(C)NC(=O)Cn1cnc2ccc(F)c(F)c21

Procedure:
The amide is synthesized according to example 1 by mixing (6,7-difluoro-1H-benzimidazol-1-yl)acetic acid (96 mg, 0.45 mmol) prepared according to scheme 2, 4-[4-(1-aminoethyl)-3-methylphenyl]tetrahydro-2H-thiopyran-4-carbonitrile (129 mg, 0.50 mmol) prepared according to scheme 14, Et3N (0.69 μL, 0.50 mmol) and HATU (189 mg, 0.50 mmol) in MECN (3.0 mL). The compound is purified by silica gel column chromatography (10% MeOH in DCM) (121 mg, 59%). 1H NMR (400 MHz, DMSO-D6) δ ppm 1.35 (d, J=7.03 Hz, 3H), 2.05-2.16 (m, 2H), 2.26-2.35 (m, 5H), 2.72-2.81 (m, J=14.06 Hz, 2H), 2.88-2.99 (m, J=12.50, 12.50 Hz, 2H), 5.01-5.11 (m, 3H), 7.16-7.26 (m, 1H), 7.30 (s, 1H), 7.33-7.38 (m, 1H), 7.39-7.48 (m, 2 H), 8.18 (s, 1H), 8.84 (d, J=7.42 Hz, 1H). MS [M+H], calcd: 455.5. found: 455.3.
Reaction SMILES: Cl.[NH2:2][CH2:3][CH:4]1[O:18][C:7]2=[C:8]3[C:13](=[C:14]([CH3:16])[CH:15]=[C:6]2[CH:5]1[CH3:19])[NH:12][C:11](=[O:17])[CH:10]=[CH:9]3.[H][H]>O.[C].[Pd]>[NH2:2][CH2:3][CH:4]1[O:18][C:7]2=[C:8]3[C:13](=[C:14]([CH3:16])[CH:15]=[C:6]2[CH:5]1[CH3:19])[NH:12][C:11](=[O:17])[CH2:10][CH2:9]3
Reactant: Cc1cc2c(c3ccc(=O)[nH]c13)OC(CN)C2C
Reactant: [H][H]
Agent: [Pd]
Agent: Cl
Solvent: O
Product: Cc1cc2c(c3c1NC(=O)CC3)OC(CN)C2C
Yield: 82.4 %

Procedure:
The hydrochloric acid salt of (2RS,3SR)-2-aminomethyl-3,5-dimethyl-2,3,6,7-tetrahydrofuro-[2,3-f]quinoline-7-one obtained in Example 12 (575 mg, 2.05 mmol) in water (20 ml) was combined with 10% palladium-carbon (600 mg), then stirred in the presence of hydrogen gas at 80° C. for 4 hours. From the reaction mixture, palladium-carbon was filtered off. Water was distilled off under reduced pressure, and the residue was recrystallized from a solvent mixture of methanol--ether. As a result, 416 mg of a hydrochloric acid salt of (2 RS, 3 SR)-2-aminomethyl-3,5-dimethyl-2,3,6,7,8,9-hexahydrofuro-[2,3-f]quinoline-7-one was obtained as colorless crystals (71.8%). mp. >300° C.
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[C:9]2[C:5]([C:6]([C:11]([N:13]3[CH2:18][CH2:17][C:16]4([C:22]5[CH:23]=[CH:24][CH:25]=[CH:26][C:21]=5[CH2:20][O:19]4)[CH2:15][CH2:14]3)=[O:12])=[CH:7][NH:8]2)=[CH:4][CH:3]=1.[O:27]1[CH2:32][CH2:31][CH:30]([CH2:33]COS(C)(=O)=O)[CH2:29][CH2:28]1>>[Cl:1][C:2]1[CH:10]=[C:9]2[C:5]([C:6]([C:11]([N:13]3[CH2:18][CH2:17][C:16]4([C:22]5[CH:23]=[CH:24][CH:25]=[CH:26][C:21]=5[CH2:20][O:19]4)[CH2:15][CH2:14]3)=[O:12])=[CH:7][N:8]2[CH2:33][CH:30]2[CH2:31][CH2:32][O:27][CH2:28][CH2:29]2)=[CH:4][CH:3]=1
Reactant: CS(=O)(=O)OCCC1CCOCC1
Reactant: O=C(c1c[nH]c2cc(Cl)ccc12)N1CCC2(CC1)OCc1ccccc12
Product: O=C(c1cn(CC2CCOCC2)c2cc(Cl)ccc12)N1CCC2(CC1)OCc1ccccc12
Yield: 55 %

Procedure:
Following the general procedure III as described above, the alkylation of 1′-[(6-chloro-1H-indol-3-yl)carbonyl]-3H-spiro[2-benzofuran-1,4′-piperidine] (prepared according to example 69) with commercially available methanesulfonic acid 2-(tetrahydro-pyran-4-yl)-ethyl ester (described in US 2004220214) gave the title compound in 55% yield. ES-MS m/e (%): 465.2 (M+H+).
Reaction SMILES: [C:1]([C:3]1[CH:8]=[CH:7][C:6]([CH:9]2[CH2:14][CH2:13][N:12]([C:15]([O:17][C:18]([CH3:21])([CH3:20])[CH3:19])=[O:16])[CH2:11][CH:10]2[O:22][CH2:23][C:24]2[CH:33]=[CH:32][C:31]3[C:26](=[CH:27][CH:28]=[CH:29][CH:30]=3)[CH:25]=2)=[CH:5][CH:4]=1)#[N:2]>O1CCCC1>[NH2:2][CH2:1][C:3]1[CH:8]=[CH:7][C:6]([CH:9]2[CH2:14][CH2:13][N:12]([C:15]([O:17][C:18]([CH3:21])([CH3:19])[CH3:20])=[O:16])[CH2:11][CH:10]2[O:22][CH2:23][C:24]2[CH:33]=[CH:32][C:31]3[C:26](=[CH:27][CH:28]=[CH:29][CH:30]=3)[CH:25]=2)=[CH:5][CH:4]=1
Reactant: CC(C)(C)OC(=O)N1CCC(c2ccc(C#N)cc2)C(OCc2ccc3ccccc3c2)C1
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)N1CCC(c2ccc(CN)cc2)C(OCc2ccc3ccccc3c2)C1
Yield: 78.9 %

Procedure:
A solution of 133 mg (0.301 mmol) of tert-butyl (3RS,4RS)-4-(4-cyano-phenyl)-3-(naphthalen-2-ylmethoxy)-piperidine-1-carboxylate in 0.5 ml of tetrahydrofuran was treated with 1.5 ml (1.5 mmol) of a 1M borane-tetrahydrofuran complex solution in tetrahydrofuran and the mixture was heated to reflux under argon for 6 hours. The reaction mixture was partitioned between methylene chloride and water, the organic phase was dried over magnesium sulphate and finally the solvent was removed under reduced pressure. The crude product (163 mg) was purified by chromatography on silica gel with a 14:1:0.1 mixture of methylene chloride, methanol and a 25% ammonia solution as the eluent. There were obtained 106 mg (79% of theory) of tert-butyl (3RS,4RS)-4-(4-aminomethyl-phenyl)-3-(naphthalen-2-ylmethoxy)-piperidine-1-carboxylate as a colourless resin; MS: 447 (M+H)+.
Reaction SMILES: Cl[C:2]([C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)([C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1)[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.Cl.[CH3:22][O:23][C:24](=[O:29])[C@H:25]([CH2:27][OH:28])[NH2:26].C(N(CC)CC)C>ClCCl>[C:2]([NH:26][C@H:25]([C:24]([O:23][CH3:22])=[O:29])[CH2:27][OH:28])([C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)([C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1)[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1
Reactant: COC(=O)[C@@H](N)CO
Reactant: ClC(c1ccccc1)(c1ccccc1)c1ccccc1
Agent: Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: COC(=O)[C@H](CO)NC(c1ccccc1)(c1ccccc1)c1ccccc1
Temperature: 25 °C
Reaction time: 18 h
Yield: 90.3 %

Procedure:
Chlorotriphenylmethane (265 g, 950 mmol) dissolved in 750 mL of dichloromethane was added dropwise to a stirred solution of L-serine methyl ester hydrochloride (148 g, 950 mmol) and triethylamine (260 mL, 1900 mmol) in 1.5 L of CH2Cl2 at 0° C. The cloudy yellow solution was stirred for 18 hours at ambient temperature. The reaction mixture was filtered to remove solids and the filtrate was washed with water. The organic layer was dried over Na2SO4, filtered, and concentrated under reduced pressure to give a yellow oil. The oil was concentrated from acetonitrile and then stirred in hexanes until a precipitate formed. The resulting solid was filtered to afford 310 g of methyl N-trityl-L-serinate as an off white powder.
Reaction SMILES: OS(O)(=O)=O.[Cl:6][C:7]1[C:8]([O:16][CH3:17])=[CH:9][C:10]([O:14][CH3:15])=[C:11]([NH2:13])[CH:12]=1.N([O-])=O.[Na+].[N-:22]=[N+:23]=[N-].[Na+]>O>[N:13]([C:11]1[CH:12]=[C:7]([Cl:6])[C:8]([O:16][CH3:17])=[CH:9][C:10]=1[O:14][CH3:15])=[N+:22]=[N-:23]
Reactant: COc1cc(OC)c(Cl)cc1N
Reactant: [N-]=[N+]=[N-]
Agent: O=N[O-]
Agent: O=S(=O)(O)O
Agent: [Na+]
Solvent: O
Product: COc1cc(OC)c(N=[N+]=[N-])cc1Cl
Temperature: 0 °C

Procedure:
To a solution of concentrated H2SO4 (5 mL) in water (15 mL), 5-chloro-2,4-dimethoxy-phenylamine (3 g, 16 mmol) was added, resulting a deep purple suspension. More water (15 mL) was then added and the mixture was cooled and stirred vigorously at 0° C. in an ice-salt bath. A solution of sodium nitrite (1.2 g, 17.4 mmol) in water (5 mL) was added slowly and a brown solution was obtained. This solution was stirred at this temperature for an hour. After that, a solution of sodium azide (1.2 g, 18.5 mmol) in water (10 mL) was followed and the solution turned grey. This solution was then stirred for an hour. The grey precipitations (1.0 g, 30%) formed were collected, washed with water and dried. Yellow solids formed in the filtrate were also collected, washed and dried. The second crop (1.47 g, 43%) turned to light grey quickly.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]([OH:26])[CH2:9][CH2:10][CH2:11][C:12]([N:14]2[CH:18]([C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=3)[CH2:17][O:16][C:15]2=[O:25])=[O:13])=[CH:4][CH:3]=1.N1C=CN=C1.[Si:32](Cl)([C:35]([CH3:38])([CH3:37])[CH3:36])([CH3:34])[CH3:33]>CN(C=O)C>[Si:32]([O:26][CH:8]([C:5]1[CH:6]=[CH:7][C:2]([F:1])=[CH:3][CH:4]=1)[CH2:9][CH2:10][CH2:11][C:12]([N:14]1[CH:18]([C:19]2[CH:20]=[CH:21][CH:22]=[CH:23][CH:24]=2)[CH2:17][O:16][C:15]1=[O:25])=[O:13])([C:35]([CH3:38])([CH3:37])[CH3:36])([CH3:34])[CH3:33]
Reactant: CC(C)(C)[Si](C)(C)Cl
Reactant: O=C(CCCC(O)c1ccc(F)cc1)N1C(=O)OCC1c1ccccc1
Agent: c1c[nH]cn1
Solvent: CN(C)C=O
Product: CC(C)(C)[Si](C)(C)OC(CCCC(=O)N1C(=O)OCC1c1ccccc1)c1ccc(F)cc1
Temperature: 25 °C

Procedure:
30 g of 3-[5-(4-Fluorophenyl)-5-hydroxypentanoyl]-4-phenyloxazolidin-2-one are dissolved in 50 ml of DMF. 14.3 g of imidazole and 19 g of tert-butyldimethylsilyl chloride in 25 ml of DMF are added, and the mixture is then stirred at room temperature until the reaction has gone to completion (2-4 h). The reaction solution is concentrated, water is added and the mixture is extracted with ethyl acetate. The organic phase is dried over magnesium sulfate and concentrated, giving 10:
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH2:11][C@@H:10]([C:14]([OH:16])=O)[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].Cl.[CH3:18][NH:19][O:20][CH3:21].CCN=C=NCCCN(C)C.Cl.C(N(C(C)C)CC)(C)C>CCOC(C)=O>[CH3:21][O:20][N:19]([CH3:18])[C:14]([C@@H:10]1[CH2:11][CH2:12][CH2:13][N:8]([C:6]([O:5][C:1]([CH3:2])([CH3:3])[CH3:4])=[O:7])[CH2:9]1)=[O:16]
Reactant: CC(C)(C)OC(=O)N1CCC[C@@H](C(=O)O)C1
Reactant: CNOC
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: CCOC(C)=O
Product: CON(C)C(=O)[C@@H]1CCCN(C(=O)OC(C)(C)C)C1
Temperature: 25 °C
Reaction time: 8 h
Yield: 81.5 %

Procedure:
(R)-1-(tert-Butoxycarbonyl)piperidine-3-carboxylic acid (25 g, 0.11 mol, 1.0 equiv), N,O-dimethylhydroxylamine hydrochloride, (10.5 g, 0.14 mol, 1.25 equiv) and EDCI.HCl (26.3 g, 0.14 mol, 1.25 equiv) and diisopropylethylamine (48 mL, 0.28 mol, 2.5 equiv) were dissolved in solvent (400 mL) and stirred overnight at rt. The reaction mixture was diluted with EtOAc, washed with 5% aq HCl (2×150 mL), satd aq NaHCO3 (150 mL), brine (100 mL), and dried over Na2SO4. Concentration afforded (R)-tert-butyl 3-(methoxy(methyl)carbamoyl)piperidine-1-carboxylate (24.42 g, 82%) as a clear oil. The crude product was used for next step without further purification. MS ESI +ve m/z 295 (M+Na). 1H NMR (CDCl3) δ 4.19-4.00 (m, 2H), 3.77 (m, 3H), 3.12 (s, 3H), 2.79 (m, 2H), 2.64 (m, 1H), 1.89 (m, 1H), 1.71-1.52 (m, 2H), 1.51-1.33 (m, 10H).
Reaction SMILES: [OH:1][CH:2]1[CH2:6][CH2:5][N:4]([C:7]2[N:12]=[C:11](O)[CH:10]=[CH:9][N:8]=2)[CH2:3]1.O=P(Cl)(Cl)[Cl:16]>CN(C=O)C>[Cl:16][C:11]1[CH:10]=[CH:9][N:8]=[C:7]([N:4]2[CH2:5][CH2:6][CH:2]([OH:1])[CH2:3]2)[N:12]=1
Reactant: O=P(Cl)(Cl)Cl
Reactant: Oc1ccnc(N2CCC(O)C2)n1
Solvent: CN(C)C=O
Product: OC1CCN(c2nccc(Cl)n2)C1
Temperature: 50 °C
Reaction time: 2 h

Procedure:
To a solution of 2-(3-hydroxypyrrolidin-1-yl)pyrimidin-4-ol (4.0 g, 23 mol) in DMF (50 mL) was added POCl3 (4.2 g, 27 mmol). The reaction mixture was stirred at 50° C. for 2 hours. The reaction mixture was poured into 200 mL ice-water. The resulting solution was concentrated at 60° C. under vacuum. The residue was purified by acidic reverse phase HPLC (10-100% acetonitrile/water+0.05% TFA modifier) to afford the title compound.
Reaction SMILES: [C:1]([OH:16])(=[O:15])[CH:2]=[CH:3][CH:4]=[CH:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH3:14].[N+](C1C=CC(O)=CC=1)([O-])=O.C1(N=C=NC2CCCCC2)CCCCC1>CN(C)C=O>[C:1]([OH:16])(=[O:15])/[CH:2]=[CH:3]/[CH:4]=[CH:5]/[CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH3:14]
Reactant: CCCCCCCCCC=CC=CC(=O)O
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: O=[N+]([O-])c1ccc(O)cc1
Solvent: CN(C)C=O
Product: CCCCCCCCC/C=C/C=C/C(=O)O
Reaction time: 12 h

Procedure:
To a solution of trans-2-dodecenal (4.5 g) dissolved in methylene chloride (80 ml ) was added (carbomethoxymethylene)triphenylphosphorane (8.3 g), and the mixture was stirred for 2 hours. The reaction mixture was subjected to chromatography on a silica gel column with eluent systems of n-hexane-ethyl acetate (from 100:1 to 20:1) to give the methyl ester of trans,trans-2,4-tetradecadienoic acid (5.4 g). To a solution of potassium hydroxide (6.5 g) in a mixed solvent of ethanol-water (1:1) (100 ml) was added the methyl ester of trans,trans-2,4-tetradecadienoic acid (5.4 g), and the mixture was stirred at 60° C. for 40 minutes. The reaction mixture was cooled, and acidified to a weak acidic range of pH with citric acid and extracted with ethyl acetate. The ethyl acetate layer was dried over anhydrous sodium sulfate and concentrated to give trans,trans-2,4-tetradecadienoic acid (4.3 g). To the tetradecadienoic acid dissolved in N,N-dimethylformamide (DMF, 50 ml) was added para-nitrophenol (2.67 g) and N,N'-dicyclohexylcarbodiimide (3.9 g), and the mixture was stirred for 12 hours. After precipitates produced were removed by filtration and DMF was evaporated, the residue was subjected to chromatography on a silica gel column with eluent systems of n-hexane-ethyl acetate (from 200:1 to 50:1) to give the active ester of trans,trans-2,4-tetradecadienoic acid (5.1 g). To the active ester (500 mg) dissolved in DMF (30 ml) were added 6-(4'-N-glycyl-septaminyl-amino)purine hydrochloride (560 mg) and triethylamine (1.5 ml), and the mixture was stirred for 18 hours. The solvent was evaporated, and the residue was subjected to chromatography on a silica gel column with eluent systems of chloroform-methanol (from 7:1 to 5:1) to give SPT241 in the yield of 271 mg.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:17])[C:5]([F:16])([F:15])[C:6]1[CH:11]=[CH:10][C:9]([N+:12]([O-])=O)=[CH:8][CH:7]=1)[CH3:2].ClCCl.[F:21][C:22]([F:33])([F:32])[C:23]1[CH:24]=[C:25]([CH:29]=[CH:30][CH:31]=1)[C:26](Cl)=[O:27].CCN(C(C)C)C(C)C>CCOC(C)=O.[Pd].O>[CH2:1]([O:3][C:4](=[O:17])[C:5]([F:16])([F:15])[C:6]1[CH:11]=[CH:10][C:9]([NH:12][C:26](=[O:27])[C:25]2[CH:29]=[CH:30][CH:31]=[C:23]([C:22]([F:21])([F:32])[F:33])[CH:24]=2)=[CH:8][CH:7]=1)[CH3:2]
Reactant: CCOC(=O)C(F)(F)c1ccc([N+](=O)[O-])cc1
Reactant: O=C(Cl)c1cccc(C(F)(F)F)c1
Agent: [Pd]
Solvent: O
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: CCOC(=O)C(F)(F)c1ccc(NC(=O)c2cccc(C(F)(F)F)c2)cc1

Procedure:
Difluoro-(4-nitro-phenyl)-acetic acid ethyl ester (compound 32.1) is reacted according to Sato, K. et. al. Chem. Pharm. Bull. 1999, 47, 1013). Briefly, compound 32.1 and catalytic Pd/C in EtOAc are placed under an atmosphere of hydrogen for 3 hours. The reaction mixture is filtered, concentrated and taken on crude to the next reaction. The crude compound, dichloromethane, 3-(trifluoromethyl)benzoyl chloride and DIEA are stirred at room temperature for 10 minutes. Water is added after which the mixture partitioned between EtOAc and water. The organic layer is separated, washed with brine, dried, filtered and concentrated under reduced pressure. Purification by flash column chromatography on silica gel using a gradient of EtOAc/hexanes provides difluoro-[4-(3-trifluoromethyl-benzoylamino)-phenyl]-acetic acid ethyl ester (compound 32.2).
Reaction SMILES: [C:1]([C:5]1[CH:17]=[CH:16][C:15]2[C:14]3[C:9](=[CH:10][C:11]([C:18]([CH3:21])([CH3:20])[CH3:19])=[CH:12][CH:13]=3)[CH2:8][C:7]=2[CH:6]=1)([CH3:4])([CH3:3])[CH3:2].C([Li])CCC.[C:27]1([CH3:46])[CH:32]=[CH:31][C:30]([C:33]([C:39]2[CH:44]=[CH:43][C:42]([CH3:45])=[CH:41][CH:40]=2)=[C:34]2[CH:38]=[CH:37][CH:36]=[CH:35]2)=[CH:29][CH:28]=1.[Cl-].[NH4+]>O1CCCC1.O.C(OCC)C.CCCCCC>[C:1]([C:5]1[CH:17]=[CH:16][C:15]2[C:14]3[C:9](=[CH:10][C:11]([C:18]([CH3:21])([CH3:20])[CH3:19])=[CH:12][CH:13]=3)[CH2:8][C:7]=2[C:6]=1[C:33]([CH:34]1[CH:35]=[CH:36][CH:37]=[CH:38]1)([C:30]1[CH:29]=[CH:28][C:27]([CH3:46])=[CH:32][CH:31]=1)[C:39]1[CH:40]=[CH:41][C:42]([CH3:45])=[CH:43][CH:44]=1)([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)c1ccc2c(c1)Cc1cc(C(C)(C)C)ccc1-2
Reactant: Cc1ccc(C(=C2C=CC=C2)c2ccc(C)cc2)cc1
Agent: [Cl-]
Agent: [Li]CCCC
Agent: [NH4+]
Solvent: C1CCOC1
Solvent: CCOCC
Solvent: O
Product: Cc1ccc(C(c2ccc(C)cc2)(c2c(C(C)(C)C)ccc3c2Cc2cc(C(C)(C)C)ccc2-3)C2C=CC=C2)cc1
Temperature: 25 °C
Reaction time: 6.5 h
Yield: 67.5 %

Procedure:
A 300 ml two-necked flask equipped with a magnetic stirrer, a three-way cock and a dropping funnel, was purged thoroughly with nitrogen. 2,7-di-tert-butylfluorene 1.58 g (5.66 mmol) was placed in the flask, and dehydrated tetrahydrofuran 40 ml was further added. With cooling in an ice bath, 1.56 mol/L n-hexane solution of n-butyllithium, 3.8 ml (5.9 mmol), was dropwise added. The contents were stirred at room temperature in a nitrogen atmosphere for 6.5 hours to obtain a solution. With the flask cooled in a dry ice/methanol bath, a solution of 6,6-di-p-tolyl fulvene 1.76 g (6.82 mmol) in 20 ml of dehydrated tetrahydrofuran, was dropwise added to the flask over a period of 20 minutes by means of the dropping funnel. The liquid temperature was gradually raised to room temperature, and the contents were stirred in a nitrogen atmosphere at the temperature for 18 hours to obtain a solution. A saturated aqueous solution of ammonium chloride 100 ml and diethyl ether 100 ml were gradually added in this order. The resulting two-phase solution was poured into a 300 ml separation funnel, and the funnel was shaken several times so that the water phase was removed. The obtained organic phase was washed three times with water 100 ml and once with a saturated salt solution 100 ml, and dried over anhydrous magnesium sulfate. The solution was filtered to remove solids, and the solvent of the filtrate was distilled away. The resultant solid was washed with n-hexane to obtain 2.05 g of (2,7-di-tert-butylfluorenyl)cyclopentadienyl di-p-tolyl methane as a white solid (3.82 mmol, 67.5% yield). Identification of the (2,7-di-tert-butylfluorenyl)cyclopentadienyl di-p-tolyl methane was made by 1H NMR and the FD-mass spectrometric analysis, the results being given below:
Reaction SMILES: [CH3:1][C:2]1[N:3]=[CH:4][C:5]2[N:6](S(C3C=CC(C)=CC=3)(=O)=O)[C:7]3[CH:8]=[CH:9][CH:10]=[CH:11][C:12]=3[C:13]=2[N:14]=1.[Na].P([O-])(O)(O)=O.[Na+]>C(O)C>[CH3:1][C:2]1[N:3]=[CH:4][C:5]2[NH:6][C:7]3[CH:8]=[CH:9][CH:10]=[CH:11][C:12]=3[C:13]=2[N:14]=1
Reactant: Cc1ccc(S(=O)(=O)n2c3ccccc3c3nc(C)ncc32)cc1
Agent: O=P([O-])(O)O
Agent: [Na+]
Agent: [Na]
Solvent: CCO
Product: Cc1ncc2[nH]c3ccccc3c2n1

Procedure:
The residue (2-methyl-5-tosyl-5H-pyrimido-[5,4-b]indole) is taken up in 100 ml of ethanol and combined with a solution of 1.4 g of sodium in 90 ml of ethanol. The mixture is refluxed for 2 hours. Then the mixture is poured into an aqueous sodium dihydrogen phosphate solution. The aqueous phase is extracted by shaking with methylene chloride. The methylene chloride extracts are washed with saturated sodium chloride solution, dried, and evaporated. The residue is chromatographed with a mixture of 10 parts of methylene chloride and one part of methanol on silica gel, thus obtaining 0.13 g of 2-methyl-5H-pyrimido[5,4-b]indole, mp 240°-242° C.