Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: O[CH:2]1[C:11]2[C:6](=[C:7]([Cl:18])[CH:8]=[C:9]([C:13]([O:15][CH2:16][CH3:17])=[O:14])[C:10]=2[CH3:12])[S:5][CH2:4][CH2:3]1.C(N(CC)CC)C.CS([Cl:30])(=O)=O>C(Cl)Cl>[Cl:30][CH:2]1[C:11]2[C:6](=[C:7]([Cl:18])[CH:8]=[C:9]([C:13]([O:15][CH2:16][CH3:17])=[O:14])[C:10]=2[CH3:12])[S:5][CH2:4][CH2:3]1
Reactant: CS(=O)(=O)Cl
Reactant: CCOC(=O)c1cc(Cl)c2c(c1C)C(O)CCS2
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CCOC(=O)c1cc(Cl)c2c(c1C)C(Cl)CCS2
Temperature: 25 °C
Reaction time: 1 h
Yield: 116.1 %

Procedure:
1.0 Gram (3.5 mmol) of 4-hydroxy-5-methyl-6-ethoxycarbonyl-8-chlorothiochroman was dissolved in 5 ml of methylene chloride, and 0.72 ml (5.2 mmol) of triethylamine and 0.4 ml (5.2 mmol) of methanesulfonyl chloride were added with an ice bath cooling. The mixture was stirred at room temperature for 1 hour. After the completion of the reaction, an organic layer was washed with 2N hydrochloric acid and with a saturated sodium hydrogencarbonate aqueous solution and dried over anhydrous sodium sulfate, and the solvent was distilled off to give 1.24 g (yield 100%) of 4,8-dichloro-5-methyl-6-ethoxycarbonylthiochroman.
Reaction SMILES: [CH2:1]([CH2:4][C:5]12[CH2:11][CH:8]([CH:9]=[CH:10]1)[CH:7]1[C:12](O[C:15](=[O:16])[CH:6]21)=[O:13])[CH:2]=[CH2:3].[NH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][NH2:24]>>[CH2:1]([CH2:4][C:5]12[CH2:11][CH:8]([CH:9]=[CH:10]1)[CH:7]1[C:12](=[O:13])[N:17]([CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][N:24]3[C:12](=[O:13])[CH:7]4[CH:6]([C:5]5([CH2:4][CH2:1][CH:2]=[CH2:3])[CH2:11][CH:8]4[CH:9]=[CH:10]5)[C:15]3=[O:16])[C:15](=[O:16])[CH:6]21)[CH:2]=[CH2:3]
Reactant: NCCCCCCN
Reactant: C=CCCC12C=CC(C1)C1C(=O)OC(=O)C12
Product: C=CCCC12C=CC(C1)C1C(=O)N(CCCCCCN3C(=O)C4C5C=CC(CCC=C)(C5)C4C3=O)C(=O)C12
Temperature: 130 °C

Procedure:
300 g of allylmethylbicyclo[2.2.1]hept-5-ene-2,3-dicarboxylic anhydride are taken and heated to 130° C., and 79.9 g of melted hexamethylene diamine are added dropwise, with stirring. Water is removed by distillation, the temperature is raised to 180° C. and the pressure is reduced to 53 Pa. 180° C. and 53 Pa are maintained for 15 minutes. This gives 345 g (97% of theory) of a brown, viscous resin having a viscosity of 1.356 Pa.s at 80° C.
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]2[C:11](=[CH:12][CH:13]=1)[NH:10][C:9](=O)[NH:8][C:7]2=O)([O-:3])=[O:2].P(Cl)(Cl)([Cl:18])=O.C(N(C(C)C)C=O)(C)C.[C:30]([NH2:34])([CH3:33])([CH3:32])[CH3:31]>O>[C:30]([NH:34][C:7]1[C:6]2[C:11](=[CH:12][CH:13]=[C:4]([N+:1]([O-:3])=[O:2])[CH:5]=2)[N:10]=[C:9]([Cl:18])[N:8]=1)([CH3:33])([CH3:32])[CH3:31]
Reactant: O=c1[nH]c(=O)c2cc([N+](=O)[O-])ccc2[nH]1
Reactant: O=P(Cl)(Cl)Cl
Reactant: CC(C)(C)N
Agent: CC(C)N(C=O)C(C)C
Solvent: O
Product: CC(C)(C)Nc1nc(Cl)nc2ccc([N+](=O)[O-])cc12
Reaction time: 0.5 h
Yield: 64.2 %

Procedure:
To 250 mg (1.21 mmol) of 6-nitroquinazoline-2,4(1H,3H)-dione were added 5.00 ml (53.64 mmol) of phosphorus oxychloride and 0.18 ml (1.21 mmol) of diisopropylformamide, and the resulting mixture was subjected to heating under reflux for 24 hours. After phosphorus oxychloride was removed in vacuo, the mixture was dissolved in 5 ml of acetonitrile, followed by addition of 1.26 ml (12.10 mmol) of t-butylamine under ice cooling and stirring under ice cooling for 30 minutes. To the reaction solution was added water, followed by extraction with ethyl acetate, washing with brine and drying over anhydrous sodium sulfate. After the solvent was distilled off, the residue was purified by a silica gel column to give 218 mg (64.2%) of the title compound.
Reaction SMILES: [Cl:1][C:2]1[CH:26]=[CH:25][C:5]([CH2:6][N:7]2[C:15]3[C:10](=[CH:11][C:12](/[CH:16]=[C:17]4/[C:18](=[O:23])[NH:19][C:20](=[O:22])[S:21]/4)=[CH:13][CH:14]=3)[C:9]([CH3:24])=[N:8]2)=[C:4]([C:27]([F:30])([F:29])[F:28])[CH:3]=1.Cl.Cl[CH2:33][CH2:34][N:35]1[CH2:39][CH2:38][CH2:37][CH2:36]1>>[Cl:1][C:2]1[CH:26]=[CH:25][C:5]([CH2:6][N:7]2[C:15]3[C:10](=[CH:11][C:12](/[CH:16]=[C:17]4/[C:18](=[O:23])[N:19]([CH2:33][CH2:34][N:35]5[CH2:39][CH2:38][CH2:37][CH2:36]5)[C:20](=[O:22])[S:21]/4)=[CH:13][CH:14]=3)[C:9]([CH3:24])=[N:8]2)=[C:4]([C:27]([F:28])([F:30])[F:29])[CH:3]=1
Reactant: Cc1nn(Cc2ccc(Cl)cc2C(F)(F)F)c2ccc(/C=C3\SC(=O)NC3=O)cc12
Reactant: ClCCN1CCCC1
Agent: Cl
Product: Cc1nn(Cc2ccc(Cl)cc2C(F)(F)F)c2ccc(/C=C3\SC(=O)N(CCN4CCCC4)C3=O)cc12

Procedure:
(5Z)-5-({1-[4-Chloro-2-(trifluoromethyl)benzyl]-3-methyl-1H-indazol-5-yl}methylidene)-3-(2-pyrrolidin-1-ylethyl)-1,3-thiazolidine-2,4-dione was prepared from [(5Z)-5-({1-[4-Chloro-2-(trifluoromethyl)benzyl]-3-methyl-1H-indazol-5-yl}methylidene)-2,4-dioxo-1,3-thiazolidine (from Example 36) and 1-(2-chloroethyl)pyrrolidine hydrochloride following General Procedure H.
Reaction SMILES: [F:1][CH:2]([F:22])[O:3][C:4]1[CH:9]=[CH:8][C:7]([NH:10][C:11]2[C:20]3[C:15](=[CH:16][CH:17]=[CH:18][CH:19]=3)[N:14]=[C:13]([CH3:21])[N:12]=2)=[CH:6][CH:5]=1.[CH3:23]I>>[F:22][CH:2]([F:1])[O:3][C:4]1[CH:9]=[CH:8][C:7]([N:10]([C:11]2[C:20]3[C:15](=[CH:16][CH:17]=[CH:18][CH:19]=3)[N:14]=[C:13]([CH3:21])[N:12]=2)[CH3:23])=[CH:6][CH:5]=1
Reactant: CI
Reactant: Cc1nc(Nc2ccc(OC(F)F)cc2)c2ccccc2n1
Product: Cc1nc(N(C)c2ccc(OC(F)F)cc2)c2ccccc2n1

Procedure:
The title compound was prepared from (4-difluoromethoxy-phenyl)-(2-methyl-quinazolin-4-yl)-amine (710 mg, 2.36 mmol) and methyl iodide (1.03 ml, 16.52 mmol), by a procedure similar to Example 36 (40.8% yield). 1H NMR (CDCl3): 7.77 (dd, J=8.4 Hz, J=0.9 Hz, 1H), 7.59-7.53 (m, 1H), 7.17-7.10 (m, 4H), 7.06-6.99 (m, 2H), 6.78 (d, J=0.6 Hz, 0.25H), 6.54 (d, J=0.9 Hz, 0.5H), 6.29 (d, J=0.9 Hz, 0.25H), 3.62 (s, 3H), 2.75 (s, 3H).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:31]=[CH:32][C:33]=1[NH:34][C:35]([C:37]1([C:40](=[O:49])[NH:41][C:42]2[CH:47]=[CH:46][C:45]([F:48])=[CH:44][CH:43]=2)[CH2:39][CH2:38]1)=[O:36])[O:5][C:6]1[CH:11]=[CH:10][N:9]=[C:8]([N:12]([C:22]([O:24]C2C=CC=CC=2)=O)C(=O)OC2C=CC=CC=2)[CH:7]=1.[N:50]1([CH:55]2[CH2:60][CH2:59][NH:58][CH2:57][CH2:56]2)[CH2:54][CH2:53][CH2:52][CH2:51]1>CN(C)C=O>[F:48][C:45]1[CH:44]=[CH:43][C:42]([NH:41][C:40]([C:37]2([C:35]([NH:34][C:33]3[CH:32]=[CH:31][C:4]([O:5][C:6]4[CH:11]=[CH:10][N:9]=[C:8]([NH:12][C:22]([N:58]5[CH2:59][CH2:60][CH:55]([N:50]6[CH2:54][CH2:53][CH2:52][CH2:51]6)[CH2:56][CH2:57]5)=[O:24])[CH:7]=4)=[CH:3][C:2]=3[F:1])=[O:36])[CH2:38][CH2:39]2)=[O:49])=[CH:47][CH:46]=1
Reactant: C1CCN(C2CCNCC2)C1
Reactant: O=C(Oc1ccccc1)N(C(=O)Oc1ccccc1)c1cc(Oc2ccc(NC(=O)C3(C(=O)Nc4ccc(F)cc4)CC3)c(F)c2)ccn1
Solvent: CN(C)C=O
Product: O=C(Nc1cc(Oc2ccc(NC(=O)C3(C(=O)Nc4ccc(F)cc4)CC3)c(F)c2)ccn1)N1CCC(N2CCCC2)CC1
Temperature: 25 °C
Reaction time: 16 h
Yield: 81.1 %

Procedure:
To a solution of phenyl N-[4-(3-fluoro-4-{[1-(4-fluorophenylcarbamoyl)cyclopropanecarbonyl]amino}phenoxy)pyridin-2-yl]-N-phenoxycarbonylcarbamate (50.0 mg) in N,N-dimethylformamide (1.0 ml) was added 4-(pyrrolidin-1-yl)piperidine (46.3 mg), followed by stirring at room temperature for 16 hr. The reaction mixture was partitioned between ethyl acetate and a 1N aqueous solution of sodium hydroxide. The organic layer was washed with brine, and dried over anhydrous sodium sulfate. The solvent was removed, and the residue was purified by silica gel column chromatography (Fuji Silysia NH, heptane:ethyl acetate=1:2, ethyl acetate, then ethyl acetate:methanol=20:1). Fractions containing the target compound were concentrated. To the residue was added diethyl ether:hexane=1:3, and the precipitate was collected by filtration. This was washed with diethyl ether:hexane=1:3 and dried under aeration to provide the titled compound as white powder (36.9 mg, 81.4%).
Reaction SMILES: Cl.C([N:9]1[CH2:21][C@@H:20]2[C@H:11]([C:12](=[O:25])[N:13]3[CH2:24][CH2:23][CH2:22][C:15]4[CH:16]=[CH:17][CH:18]=[C:19]2[C:14]3=4)[CH2:10]1)C1C=CC=CC=1.[Cl:26]C(OC(Cl)C)=O.C(=O)([O-])[O-].[Na+].[Na+].Cl.CCOCC>C1(C)C=CC=CC=1.C(Cl)(Cl)Cl>[ClH:26].[CH:18]1[CH:17]=[CH:16][C:15]2[CH2:22][CH2:23][CH2:24][N:13]3[C:14]=2[C:19]=1[C@@H:20]1[CH2:21][NH:9][CH2:10][C@H:11]1[C:12]3=[O:25]
Reactant: CC(Cl)OC(=O)Cl
Reactant: O=C1[C@@H]2CN(Cc3ccccc3)C[C@H]2c2cccc3c2N1CCC3
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CCOCC
Solvent: ClC(Cl)Cl
Solvent: Cc1ccccc1
Product: O=C1[C@@H]2CNC[C@H]2c2cccc3c2N1CCC3
Temperature: 110 °C
Reaction time: 3 h
Yield: 50 %

Procedure:
To a solution of (±)-trans-10-benzyl-5,6,9,10,11,11a-hexahydro-4H-pyrido[3,2,1-ij]pyrrolo[3,4-c]quinolin-8(8aH)-one from EXAMPLE 1, Part E (1.2 g, 3.8 mmol) in 20 mL of toluene was added 1-chloroethyl chloroformate (0.81 mL, 7.53 mmol) and the resulting solution was stirred at 110° C. for 3 h. The reaction mixture was cooled and the toluene was removed under reduced pressure. The residue was taken up in 20 mL of methanol and was stirred at 65° C. for 1 h. The reaction was cooled and the methanol was removed under reduced pressure. A portion of the residue (50 mg, 0.19 mol) was partitioned between chloroform and saturated aqueous sodium carbonate. The organics were washed with brine, dried (K2CO3) and concentrated in vacuo. The residue was dissolved in ether and there was added 2M HCl in ether (0.095 mL, 0.19 mmol). The solvent was decanted and the remaining solid was triturated twice with ether and was dried in vacuo to afford 25 mg (50%) of the title compound of EXAMPLE 3 as an off white powder. LRMS (ES)+: 270.3 (M+H+CH3CN)+.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([P:8]([OH:11])(=[O:10])[OH:9])[CH:5]=[CH:6][CH:7]=1.Cl.N([O-])=O.[Na+].N[C:18]([NH2:20])=S.[NH2:21][C:22]1[CH:23]=[C:24](C=[CH:29][CH:30]=1)[C:25]([OH:27])=[O:26]>CO.O>[C:25]([C:24]1[CH:23]=[C:22]([NH2:21])[CH:30]=[CH:29][C:18]=1[N:20]=[N:1][C:2]1[CH:3]=[C:4]([P:8]([OH:11])(=[O:9])[OH:10])[CH:5]=[CH:6][CH:7]=1)([OH:27])=[O:26]
Reactant: NC(N)=S
Reactant: Nc1cccc(P(=O)(O)O)c1
Reactant: Nc1cccc(C(=O)O)c1
Agent: Cl
Agent: O=N[O-]
Agent: [Na+]
Solvent: CO
Solvent: O
Product: Nc1ccc(N=Nc2cccc(P(=O)(O)O)c2)c(C(=O)O)c1
Temperature: 0 °C

Procedure:
Into water (500 ml), m-aminobenzenephosphonic acid (87.0 g) was suspended with stirring. To the mixture, 35% hydrochloric acid (101.3 g) was added, and the mixture was cooled to 0° C. While the solution was maintained at a temperature below 5° C., 36% sodium nitrite (105.4 g) was added dropwise to the solution. The mixture was stirred for 50 minutes to diazotize m-aminobenzenephosphonic acid. Thiourea was then added to the resulting aqueous solution, and the unreacted nitrite was removed to give a diazotized compound containing solution. On the other hand, 3-aminobenzoic acid (58.6 g) was dispersed into methanol (800 ml) and heated to 55° C. to form a solution containing a coupling compound, which was then cooled to 0° C. The diazotized compound containing solution prepared above was added dropwise while the mixture was maintained at a temperature below 5° C. After stirring the mixture at 3°-5° C. for 18 hours, the resulting precipitates were collected by filtration, washed with water to give a monoazo compound, m-(2-carboxy-4-amino-phenylazo)benzenephosphonic acid in a yield of about 125.3 g.
Reaction SMILES: O[CH:2]=[C:3]1[C:11]2[C:6](=[CH:7][C:8]([C:12]([C:14]3[CH:15]=[C:16]([NH:20][C:21]([C:23]4[N:24]([CH3:29])[N:25]=[C:26]([CH3:28])[CH:27]=4)=[O:22])[CH:17]=[CH:18][CH:19]=3)=[O:13])=[CH:9][CH:10]=2)[NH:5][C:4]1=[O:30].C1COCC1.[NH2:36][C:37]1[CH:42]=[CH:41][C:40]([CH2:43][OH:44])=[CH:39][CH:38]=1>CCOC(C)=O>[OH:44][CH2:43][C:40]1[CH:41]=[CH:42][C:37]([NH:36][CH:2]=[C:3]2[C:11]3[C:6](=[CH:7][C:8]([C:12]([C:14]4[CH:15]=[C:16]([NH:20][C:21]([C:23]5[N:24]([CH3:29])[N:25]=[C:26]([CH3:28])[CH:27]=5)=[O:22])[CH:17]=[CH:18][CH:19]=4)=[O:13])=[CH:9][CH:10]=3)[NH:5][C:4]2=[O:30])=[CH:38][CH:39]=1
Reactant: Nc1ccc(CO)cc1
Reactant: Cc1cc(C(=O)Nc2cccc(C(=O)c3ccc4c(c3)NC(=O)C4=CO)c2)n(C)n1
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: Cc1cc(C(=O)Nc2cccc(C(=O)c3ccc4c(c3)NC(=O)C4=CNc3ccc(CO)cc3)c2)n(C)n1
Temperature: 65 °C
Reaction time: 24 h
Yield: 24 %

Procedure:
A small screw cap test tube was charged with 2,5-Dimethyl-2H-pyrazole-3-carboxylic acid [3-(3-hydroxymethylene-2-oxo-2,3-dihydro-1H-indole-6-carbonyl)-phenyl]-amide (as prepared in Example 60, 300 mg, 0.746 mmol) and THF (7.5 mL). To the resulting solution was added (4-amino-phenyl)-methanol (133 mg, 0.955 mmol), and the mixture was stirred for 24 h at 65° C. Subsequently, the reaction mixture was cooled to room temperature and the resulting suspension was filtered. The solids collected were washed with 0° C. iPrOH (5 mL) and set aside. The filtrate was concentrated in vacuo and the residue obtained was dissolved in EtOAc (5 mL). The resulting solution was triturated with Hexanes (˜50 mL) to yield a precipitate. This precipitate was then filtered and washed with 0° C. iPrOH (5 mL). The solids collected were combined with those previously set aside to afford the title compound in 24% yield (0.091 g, 0.179 mmol).
Reaction SMILES: [CH3:1][C:2]1[C:10]2[C:5](=[CH:6][CH:7]=[C:8]([CH:11]=O)[CH:9]=2)[NH:4][N:3]=1.[NH2:13]/[C:14](/[CH3:18])=[CH:15]\[C:16]#[N:17]>C(O)(=O)C>[CH3:18][C:14]1[NH:13][C:9]([CH3:8])=[C:10]([C:2]#[N:3])[CH:11]([C:8]2[CH:9]=[C:10]3[C:5](=[CH:6][CH:7]=2)[NH:4][N:3]=[C:2]3[CH3:1])[C:15]=1[C:16]#[N:17]
Reactant: C/C(N)=C/C#N
Reactant: Cc1n[nH]c2ccc(C=O)cc12
Solvent: CC(=O)O
Product: CC1=C(C#N)C(c2ccc3[nH]nc(C)c3c2)C(C#N)=C(C)N1
Temperature: 25 °C
Reaction time: 8 h
Yield: 115.3 %

Procedure:
A mixture of 17.0 g (106.13 mmol) 3-methyl-1H-indazole-5-carbaldehyde, from Synthetic Preparation 10, and 17.86 g (217.57 mmol) 3-aminocrotononitrile were dissolved in 340 mL acetic acid and refluxed for 3 hours. After stirring overnight at room temperature the mixture was cooled with an ice bath, filtered and washed with a small amount of acetic acid. The product was dried under vacuum at 60° C. to afford 1,4-dihydro-2,6-dimethyl-4-(3-methyl-1H-indazol-5-yl)-3,5-pyridinedicarbonitrile (17.7 g, 57.6%) (Cpd. No. 81, Table 2). 1H-NMR (DMSO-D6): δ=12.68 (s, 1H), 9.51 (s, 1H), 7.53 (s, 1H), 7.49 (d, 1H), 7.27 (d, 1H), 4.50 (s, 1H), 2.49 (s, 3H), 2.05 (s, 6H) ppm. MS (ES+): 290.42 (M++1, 100%).
Reaction SMILES: [O:1]=[C:2](Cl)OC(Cl)(Cl)Cl.[CH3:9][O:10][N:11]=[CH:12][C:13]1[CH:18]=[C:17]([NH2:19])[C:16]([F:20])=[CH:15][C:14]=1[Cl:21]>C1(C)C=CC=CC=1>[CH3:9][O:10][N:11]=[CH:12][C:13]1[CH:18]=[C:17]([N:19]=[C:2]=[O:1])[C:16]([F:20])=[CH:15][C:14]=1[Cl:21]
Reactant: CON=Cc1cc(N)c(F)cc1Cl
Reactant: O=C(Cl)OC(Cl)(Cl)Cl
Solvent: Cc1ccccc1
Product: CON=Cc1cc(N=C=O)c(F)cc1Cl
Temperature: 110 °C

Procedure:
411.3 g of diphosgene (2.08 mol) were added dropwise to a solution of 383 g (1.89 mol) of 5-amino-2-chloro-4-fluorobenzaldehyde (O-methyl)oxime in 2 l of toluene. The temperature was then slowly raised to 110° C. in the course of approximately 6 hours so that the evolution of gas proceeded in a controlled manner. The mixture was subsequently refluxed for a further 5 hours. The reaction mixture was then left to cool and finally concentrated. Yield: 432 g.
Reaction SMILES: [CH3:1][C@H:2]1[C@H:28]([CH3:29])[C@@H:27]2[C@@:5]([C:31]([OH:33])=[O:32])([CH2:6][CH2:7][C@@:8]3([CH3:30])[C@:13]4([CH3:26])[CH2:14][CH2:15][C@H:16]5[C:21]([CH3:23])([CH3:22])[C@@H:20]([OH:24])[CH2:19][CH2:18][C@:17]5([CH3:25])[C@H:12]4[CH2:11][CH:10]=[C:9]32)[CH2:4][CH2:3]1.C(N(CC)CC)C.[CH2:41](Cl)[C:42]1[CH:47]=[CH:46][CH:45]=[CH:44][CH:43]=1>CN(C)C=O>[CH3:1][C@H:2]1[C@H:28]([CH3:29])[C@@H:27]2[C@@:5]([C:31]([O:33][CH2:41][C:42]3[CH:47]=[CH:46][CH:45]=[CH:44][CH:43]=3)=[O:32])([CH2:6][CH2:7][C@@:8]3([CH3:30])[C@:13]4([CH3:26])[CH2:14][CH2:15][C@H:16]5[C:21]([CH3:23])([CH3:22])[C@@H:20]([OH:24])[CH2:19][CH2:18][C@:17]5([CH3:25])[C@H:12]4[CH2:11][CH:10]=[C:9]32)[CH2:4][CH2:3]1
Reactant: C[C@H]1[C@H](C)CC[C@]2(C(=O)O)CC[C@]3(C)C(=CC[C@@H]4[C@@]5(C)CC[C@H](O)C(C)(C)[C@@H]5CC[C@]43C)[C@H]12
Reactant: ClCc1ccccc1
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: C[C@H]1[C@H](C)CC[C@]2(C(=O)OCc3ccccc3)CC[C@]3(C)C(=CC[C@@H]4[C@@]5(C)CC[C@H](O)C(C)(C)[C@@H]5CC[C@]43C)[C@H]12
Temperature: 50 °C
Reaction time: 1 h

Procedure:
5 g of ursolic acid was dissolved in 300 ml of dimethylformamide, and 63 ml of triethylamine was added thereto. Then, 20 g of benzyl chloride was added thereto, and the whole was stirred at 50° C. for 1 hour and concentrated under reduced pressure, followed by purification by silica gel chromatography (elution solvent; chloroform:methanol=100:0 to 80:20), to thereby obtain benzyl ursolate.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[CH:4][C:3]=1[NH:9][C:10]1[N:14]([CH2:15][CH:16]([OH:19])[CH2:17][OH:18])[C:13]2[C:20]([N:24]([CH2:27][CH3:28])[CH2:25][CH3:26])=[CH:21][CH:22]=[CH:23][C:12]=2[N:11]=1.[C:29](Cl)(=[O:31])[CH3:30]>N1C=CC=CC=1>[C:29]([O:18][CH2:17][CH:16]([OH:19])[CH2:15][N:14]1[C:13]2[C:20]([N:24]([CH2:27][CH3:28])[CH2:25][CH3:26])=[CH:21][CH:22]=[CH:23][C:12]=2[N:11]=[C:10]1[NH:9][C:3]1[CH:4]=[CH:5][C:6]([Cl:8])=[CH:7][C:2]=1[Cl:1])(=[O:31])[CH3:30]
Reactant: CCN(CC)c1cccc2nc(Nc3ccc(Cl)cc3Cl)n(CC(O)CO)c12
Reactant: CC(=O)Cl
Solvent: c1ccncc1
Product: CCN(CC)c1cccc2nc(Nc3ccc(Cl)cc3Cl)n(CC(O)COC(C)=O)c12
Reaction time: 5 h
Yield: 64 %

Procedure:
To a solution of 3-[2-[(2,4-dichlorophenyl)amino]-7-(diethylamino)-1H-benzimidazol-1-yl]propane-1,2-diol (Reference Example 88; 46.2 mg, 0.109 mmol) in pyridine (0.5 mL) was added acetyl chloride (0.0155 mL, 0.218 mmol) at 0° C. After 5 hr, the mixture was quenched with aqueous sodium hydrogen carbonate, diluted with ethyl acetate, washed with water and brine, dried over anhydrous sodium sulfate, filtered, and concentrated in vacuo. The residue was purified by NH flash column chromatography on silica gel eluting with a 10-50% ethyl acetate/n-hexane gradient mixture to give the title compound as a colorless solid (32.5 mg, 0.0698 mmol, 64%).
Reaction SMILES: I[C:2]1[CH:11]=[CH:10][C:9]([CH3:12])=[CH:8][C:3]=1[C:4]([O:6][CH3:7])=[O:5].[C:13]1(B(O)O)[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1.C([O-])([O-])=O.[Na+].[Na+].CCOCC>C1(C)C=CC=CC=1.CCO.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[CH3:12][C:9]1[CH:8]=[C:3]([C:4]([O:6][CH3:7])=[O:5])[C:2]([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)=[CH:11][CH:10]=1
Reactant: OB(O)c1ccccc1
Reactant: COC(=O)c1cc(C)ccc1I
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: Cc1ccccc1
Solvent: CCO
Solvent: CCOCC
Product: COC(=O)c1cc(C)ccc1-c1ccccc1
Reaction time: 0.17 h

Procedure:
Pd(PPh3)4 (523 mg, 0.45 mmol) was added to a rt solution of methyl 2-iodo-5-methylbenzoate in toluene (23 mL). After the solution was stirred for 10 min, a solution of phenylboronic acid (1.24 g, 9.96 mmol) in EtOH (10 mL) was added, followed by 2M aq. Na2CO3 (21 mL). The mixture was vigorously stirred and heated to reflux for 24 h. The rxn mixture was allowed to reach rt, then Et2O was added and the org. layer was separated and concentrated in vacuo. Purification by FC (Biotage SP1: EtOAc/hept eluting with a gradient of 0-10% EtOAc) was performed to give methyl 4-methyl-[1,1′-biphenyl]-2-carboxylate as a colorless oil. LC-MS A: tR=0.94 min; [M+H]+=227.16.
Reaction SMILES: C[O:2][C:3](=[O:20])[CH:4]([CH3:19])[C:5]1[CH:17]=[CH:16][C:15]2[C:14]3[C:9](=[CH:10][C:11](N)=[CH:12][CH:13]=3)[CH2:8][C:7]=2[CH:6]=1.[OH2:21]>>[OH:21][C:12]1[CH:13]=[C:14]2[C:9]([C:8]3[CH:16]=[CH:17][C:5]([CH:4]([CH3:19])[C:3]([OH:2])=[O:20])=[CH:6][C:7]=3[CH2:15]2)=[CH:10][CH:11]=1
Reactant: O
Reactant: COC(=O)C(C)c1ccc2c(c1)Cc1cc(N)ccc1-2
Product: CC(C(=O)O)c1ccc2c(c1)Cc1cc(O)ccc1-2

Procedure:
The ester is dissolved in water (300 ml) containing concentrated HCL (11 ml) with the aid of heat. The solution is cooled to 3°, stirred and treated dropwise with a solution of sodium nitrite (2.84 g) in water (15 ml) over a 30 minute period. The resulting diazonium solution is then added dropwise over a 1 hour period to boiling water (800 ml) containing concentrated sulfuric acid (13 ml), and then stirred for 30 minutes and cooled. The precipitate is collected by filtration and heated in 10% aqueous potassium hydroxide containing charcoal for 1 hour, cooled and acidified with 4N HCl. The solid is collected by filtration to give 8.0 g, mp 205°-207° of the titled product. The analytical sample is prepared by sublimation, mp 218-219°.
Reaction SMILES: [CH3:1][C:2]1([CH3:14])[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[C:4]([CH3:12])([CH3:11])[CH:3]1[CH3:13].[CH3:15]C1(C)C2C(CCCC2)C(C)(C)C1C.Cl.[OH-:30].[Na+]>>[CH3:11][C:4]1([CH3:12])[C:5]2[CH2:6][CH2:7][CH2:8][CH:9]([CH:15]=[O:30])[C:10]=2[C:2]([CH3:14])([CH3:1])[CH:3]1[CH3:13]
Reactant: CC1C(C)(C)C2CCCCC2C1(C)C
Reactant: [OH-]
Reactant: CC1C(C)(C)c2ccccc2C1(C)C
Agent: Cl
Agent: [Na+]
Product: CC1C(C)(C)C2=C(C(C=O)CCC2)C1(C)C

Procedure:
prepared according to the disclosure of U.S. Pat. No. 4,902,840 issued on Feb. 20, 1990, the specification for which is incorporated herein by reference; 20% 1,1,2,3,3-pentamethylindane and 35% hexahydro-1,1,2,3,3-pentamethylindane is heated to 150° C. Hydrogen chloride gas evolves and is passed through a caustic soda scrubber. This solution is then washed with a 5% aqueous sodium hydroxide solution, dried over anhydrous magnesium sulfate and used without further purification in the next step, the carrying out of an oxo-reaction.
Reaction SMILES: [OH:1][C:2]1([CH2:15][CH:16]=O)[CH2:14][CH2:13][C:5]2([O:10][CH2:9][C:8]([CH3:12])([CH3:11])[CH2:7][O:6]2)[CH2:4][CH2:3]1.[Cl:18][C:19]1[CH:24]=[CH:23][C:22]([C@@H:25]([NH2:27])[CH3:26])=[CH:21][CH:20]=1>>[Cl:18][C:19]1[CH:24]=[CH:23][C:22]([C@@H:25]([NH:27][CH2:16][CH2:15][C:2]2([OH:1])[CH2:3][CH2:4][C:5]3([O:10][CH2:9][C:8]([CH3:12])([CH3:11])[CH2:7][O:6]3)[CH2:13][CH2:14]2)[CH3:26])=[CH:21][CH:20]=1
Reactant: C[C@H](N)c1ccc(Cl)cc1
Reactant: CC1(C)COC2(CCC(O)(CC=O)CC2)OC1
Product: C[C@H](NCCC1(O)CCC2(CC1)OCC(C)(C)CO2)c1ccc(Cl)cc1
Yield: 63 %

Procedure:
The title compound is prepared from (9-hydroxy-3,3-dimethyl-1,5-dioxa-spiro[5.5]undec-9-yl)-acetaldehyde and (S)-1-(4-chloro-phenyl)-ethylamine following a procedure analogous to that described in Step 3 of Intermediate 2. Yield: 63% of theory; LC (method 1): tR=1.55 min; Mass spectrum (ESI+): m/z=382/384 (Cl) [M+H]+.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]2[CH2:10][C@:9]3([CH:15]4[CH2:16][CH2:17][N:12]([CH2:13][CH2:14]4)[CH2:11]3)[O:8][C:5]2=[N:6][CH:7]=1.[F:18][C:19]1[O:20][C:21]2[CH:34]=[CH:33][CH:32]=[CH:31][C:22]=2[C:23]=1[Sn](CC)(CC)CC>>[F:18][C:19]1[O:20][C:21]2[CH:34]=[CH:33][CH:32]=[CH:31][C:22]=2[C:23]=1[C:2]1[CH:3]=[C:4]2[CH2:10][C@:9]3([CH:15]4[CH2:16][CH2:17][N:12]([CH2:13][CH2:14]4)[CH2:11]3)[O:8][C:5]2=[N:6][CH:7]=1
Reactant: Brc1cnc2c(c1)C[C@@]1(CN3CCC1CC3)O2
Reactant: CC[Sn](CC)(CC)c1c(F)oc2ccccc12
Product: Fc1oc2ccccc2c1-c1cnc2c(c1)C[C@@]1(CN3CCC1CC3)O2

Procedure:
Prepared by a method analogous to that described for the preparation of Example 4 from (2′R)-5′-bromospiro[1-azabicyclo[2.2.2]octane-3,2′(3′H)-furo[2,3-b]pyridine] and 2-fluoro-3-triethylstannylbenzofuran. The title compound was obtained as a colourless solid; m/e 351 (MH+).
Reaction SMILES: [Cl:1][C:2]1[N:3]=[C:4]([N:22]2[CH2:27][CH2:26][O:25][CH2:24][CH2:23]2)[C:5]2[S:10][C:9]([CH2:11][N:12]3[CH2:17][CH2:16][NH:15][C:14](=[O:18])[C@@H:13]3C(C)C)=[CH:8][C:6]=2[N:7]=1.[CH2:28]1[C@H:33]2[CH2:34]NCCN2C(=O)C[O:29]1>>[Cl:1][C:2]1[N:3]=[C:4]([N:22]2[CH2:23][CH2:24][O:25][CH2:26][CH2:27]2)[C:5]2[S:10][C:9]([CH2:11][N:12]3[CH2:17][CH2:16][N:15]4[C@@H:33]([CH2:28][O:29][CH2:13][C:14]4=[O:18])[CH2:34]3)=[CH:8][C:6]=2[N:7]=1
Reactant: CC(C)[C@H]1C(=O)NCCN1Cc1cc2nc(Cl)nc(N3CCOCC3)c2s1
Reactant: O=C1COC[C@H]2CNCCN12
Product: O=C1COC[C@H]2CN(Cc3cc4nc(Cl)nc(N5CCOCC5)c4s3)CCN12

Procedure:
Prepared according to the method used in the preparation of (S)-4-(2-chloro-4-morpholin-4-yl-thieno[3,2-d]pyrimidin-6-ylmethyl)-3-isopropyl-piperazin-2-one using (R)-hexahydro-pyrazino[2,1-c][1,4]oxazin-4-one in place of (S)-3-isopropyl-piperazin-2-one. The title compound was obtained as a tan solid (79 mg, 69%).