Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl.[N:2]1[C:11]2[C:6](=[CH:7][C:8]([C:12](Cl)=[O:13])=[CH:9][CH:10]=2)[CH:5]=[CH:4][CH:3]=1.[C:15]12([OH:25])[CH2:24][CH:19]3[CH2:20][CH:21]([CH2:23][CH:17]([CH2:18]3)[CH2:16]1)[CH2:22]2.O>N1C=CC=CC=1>[N:2]1[C:11]2[C:6](=[CH:7][C:8]([C:12]([O:25][C:15]34[CH2:22][CH:21]5[CH2:20][CH:19]([CH2:18][CH:17]([CH2:23]5)[CH2:16]3)[CH2:24]4)=[O:13])=[CH:9][CH:10]=2)[CH:5]=[CH:4][CH:3]=1
Reactant: O=C(Cl)c1ccc2ncccc2c1
Reactant: OC12CC3CC(CC(C3)C1)C2
Agent: Cl
Solvent: c1ccncc1
Solvent: O
Product: O=C(OC12CC3CC(CC(C3)C1)C2)c1ccc2ncccc2c1
Temperature: 70 °C
Reaction time: 16 h
Yield: 31.5 %

Procedure:
6-Quinolinecarbonyl chloride hydrochloride (0.76 g, 3.3 mmol) in pyridine (2 mL) was added to a solution of 1-adamantanol (0.60 g, 3.9 mmol) in pyridine (8 mL). The reaction was stirred at 70° C. for 16 h. To the stirring reaction mixture was added water (100 mL) which caused the product to precipitate. This precipitate was filtered and then washed with water (3×25 mL). The filter cake was dissolved in ethanol (20 mL) and water was then added to the cloud point (16 mL). The crystallizing solution was allowed to stand for 15 h. Filtering and drying under high vacuum for 7 h provided 0.32 g (26%) of (61) as light brown needle-like crystals:
Reaction SMILES: [CH2:1]([NH2:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:9]([NH:17][C:18]1[S:19][C:20]([C:24](O)=[O:25])=[C:21]([Cl:23])[N:22]=1)(=[O:16])[C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1>>[CH2:1]([NH:8][C:24]([C:20]1[S:19][C:18]([NH:17][C:9](=[O:16])[C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)=[N:22][C:21]=1[Cl:23])=[O:25])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: NCc1ccccc1
Reactant: O=C(Nc1nc(Cl)c(C(=O)O)s1)c1ccccc1
Product: O=C(Nc1nc(Cl)c(C(=O)NCc2ccccc2)s1)c1ccccc1
Yield: 20 %

Procedure:
Following the procedure as described in Example 3, making variations only as required to use benzylamine in place of α-ethylbenzylamine to react with 2-benzoylamino-4-chlorothiazole-5-carboxylic acid, the title compound was obtained as a white solid in 20% yield; m. p. 247-249° C.; 1H NMR (DMSO-d6, 300 MHz) δ 12.5 (s, 1H), 8.11-7.93 (m, 2H), 7.72 (t, J=5.7 Hz, 1H), 7.58-6.95 (m, 8H), 4.48 (d, J=5.7 Hz, 2H); 13C NMR (DMSO-d6, 75 MHz) δ 166.1, 160.0, 138.5, 134.2, 133.0, 131.4, 128.6, 128.5, 128.4, 127.5, 127.2, 119.6, 43.4; MS (ES+) m/z 372.3 (M+1).
Reaction SMILES: [CH2:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[CH2:3][CH:2]1[C:10]([OH:12])=O.C([N:20]1[CH:24]=CN=C1)(N1C=CN=C1)=O.C(N(CC)C(C)C)(C)C.Cl.[CH3:35][O:36]CN.S(=O)(=O)(O)O>CN(C=O)C>[CH3:35][O:36][N:20]([CH3:24])[C:10]([CH:2]1[CH2:3][C:4]2[C:9](=[CH:8][CH:7]=[CH:6][CH:5]=2)[CH2:1]1)=[O:12]
Reactant: O=C(O)C1Cc2ccccc2C1
Reactant: COCN
Reactant: O=C(n1ccnc1)n1ccnc1
Agent: Cl
Agent: O=S(=O)(O)O
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: CON(C)C(=O)C1Cc2ccccc2C1
Temperature: 25 °C
Reaction time: 18 h

Procedure:
A solution of indane 2-carboxylic acid (324 mg, 2 mmol) and carbonyldiimidazole (299 mg, 2.2 mmol) in DMF (5 mL) was stirred at room temperature for 30 min. N,N-diisopropylethylamine (0.522 mL, 3 mmol) was added followed by N-methoxymethyl amine hydrochloride (195 mg, 2 mmol). The reaction mixture was stirred at room temperature for 18 h, and then treated with 1N sulfuric acid (100 mL). The mixture was extracted with methylene chloride (3×50 mL), and the combined extracts were washed with water, dried over anhydrous sodium sulfate, and evaporated to give N-methoxy-N-methyl-indane-2-carboxamide as a light brownish oil which was used without further purification in the next step.
Reaction SMILES: [Br:1][C:2]1[C:3]([F:12])=[CH:4][C:5]([F:11])=[C:6]([C:8](=O)[CH3:9])[CH:7]=1.[CH3:13][C:14]([S@:17]([NH2:19])=[O:18])([CH3:16])[CH3:15].O>C1COCC1>[Br:1][C:2]1[C:3]([F:12])=[CH:4][C:5]([F:11])=[C:6]([C:8](=[N:19][S@@:17]([C:14]([CH3:16])([CH3:15])[CH3:13])=[O:18])[CH3:9])[CH:7]=1
Reactant: CC(=O)c1cc(Br)c(F)cc1F
Reactant: CC(C)(C)[S@](N)=O
Solvent: O
Solvent: C1CCOC1
Product: CC(=N[S@](=O)C(C)(C)C)c1cc(Br)c(F)cc1F
Temperature: 70 °C
Reaction time: 18 h
Yield: 81 %

Procedure:
To a solution of 1-(5-bromo-2,4-difluoro-phenyl)-ethanone (19 g, 64.7 mmoles, 1 equiv.) and (R)-2-methyl-propane-2-sulfinic acid amide (10.2 g, 84.1 mmoles, 0.76 equiv) in THF (0.3 M, 215 mL) is added Ti(OEt)4 (29.5 g, 129 mmoles, 2.0 equiv) in a single portion at ambient temperature. The reaction is heated to 70° C. and allowed to stir 18 h. The reaction is cooled to ambient temperature, and poured into water. The resulting suspension is filtered through a pad of diatomaceous earth and washed with ethyl acetate. The filtrate is collected and extracted with ethyl acetate. The organic layers are combined, dried over sodium sulfate, filtered, and concentrated under reduced pressure to give a residue. The residue is purified by silica gel chromatography, eluting with a linear gradient of hexane to hexane:ethyl acetate (3:1) over 20 minutes to give the title compound (81% yield): MS (m/z): 338, 340 (M+1).
Reaction SMILES: [C:1]([O:9][C:10]([CH3:49])([CH3:48])[C:11]([O:13][C:14]1[CH:15]=[C:16]([CH2:35][C@H:36]([NH:40]C(OC(C)(C)C)=O)[C:37]([OH:39])=[O:38])[CH:17]=[CH:18][C:19]=1[O:20][C:21](=[O:34])[C:22]([CH3:33])([O:24][C:25](=[O:32])[C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1)[CH3:23])=[O:12])(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:50]1([CH3:60])[CH:55]=[CH:54][C:53]([S:56]([OH:59])(=[O:58])=[O:57])=[CH:52][CH:51]=1>>[S:56]([C:53]1[CH:54]=[CH:55][C:50]([CH3:60])=[CH:51][CH:52]=1)([OH:59])(=[O:58])=[O:57].[NH2:40][C@@H:36]([CH2:35][C:16]1[CH:17]=[CH:18][C:19]([O:20][C:21](=[O:34])[C:22]([CH3:23])([O:24][C:25](=[O:32])[C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=2)[CH3:33])=[C:14]([O:13][C:11](=[O:12])[C:10]([O:9][C:1](=[O:8])[C:2]2[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=2)([CH3:49])[CH3:48])[CH:15]=1)[C:37]([OH:39])=[O:38]
Reactant: CC(C)(C)OC(=O)N[C@@H](Cc1ccc(OC(=O)C(C)(C)OC(=O)c2ccccc2)c(OC(=O)C(C)(C)OC(=O)c2ccccc2)c1)C(=O)O
Agent: Cc1ccc(S(=O)(=O)O)cc1
Product: CC(C)(OC(=O)c1ccccc1)C(=O)Oc1ccc(C[C@H](N)C(=O)O)cc1OC(=O)C(C)(C)OC(=O)c1ccccc1

Procedure:
Method 1 is a method in which after (2S)-3-(3,4-bis((2-(benzoyloxy)-2-methylpropanoyl)oxy)phenyl)-2-((tert-butoxycarbonyl)amino)propanoic acid is subjected to a deprotection reaction using p-toluenesulfonic acid, a solvate of (2S)-2-amino-3-(3,4-bis((2-(benzoyloxy)-2-methylpropanoyl)oxy)phenyl)propanoic acid tosylate is produced without performing an isolation operation, followed by drying by heating under reduced pressure, whereby a type A crystal is produced.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[C:6]([C:8](=O)[CH2:9][CH3:10])[CH:5]=[C:4]([CH3:12])[C:3]=1[OH:13].Cl.[CH3:15][O:16][C:17]1[CH:22]=[CH:21][C:20]([NH:23]N)=[CH:19][CH:18]=1.O>C(O)(C)C>[OH:13][C:3]1[C:2]([CH3:1])=[CH:7][C:6]([C:8]2[NH:23][C:20]3[C:21]([C:9]=2[CH3:10])=[CH:22][C:17]([O:16][CH3:15])=[CH:18][CH:19]=3)=[CH:5][C:4]=1[CH3:12]
Reactant: COc1ccc(NN)cc1
Reactant: CCC(=O)c1cc(C)c(O)c(C)c1
Agent: Cl
Solvent: O
Solvent: CC(C)O
Product: COc1ccc2[nH]c(-c3cc(C)c(O)c(C)c3)c(C)c2c1
Yield: 72 %

Procedure:
5.1 g of 2,6-dimethyl-4-propionylphenol and 5.0 g of 4-methoxyphenylhydrazine hydrochloride were dispersed in 30 ml of isopropanol, and the dispersion was refluxed for 20 hours in a nitrogen stream. Water was added to the reaction mixture, and the precipitated crystals were collected by filtration. The crystals were dissolved in ethyl acetate, and washed with a 5% aqueous sodium hydroxide solution, water, 2N hydrochloric acid and water. The organic layer was dried, and the solvent was evaporated. Recrystallization of the resulting crude crystals from ethanol-hexane gave 5.8 g of 2-(4-hydroxy-3,5-dimethylphenyl)-5-methoxy-3-methylindole.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:10]=[C:9]([O:11][CH3:12])[CH:8]=[CH:7][C:4]=1[CH:5]=[O:6].[I:13]Cl.Cl>CO>[I:13][C:8]1[C:9]([O:11][CH3:12])=[CH:10][C:3]([O:2][CH3:1])=[C:4]([CH:7]=1)[CH:5]=[O:6]
Reactant: COc1ccc(C=O)c(OC)c1
Reactant: ClI
Agent: Cl
Solvent: CO
Product: COc1cc(OC)c(C=O)cc1I
Temperature: 25 °C
Reaction time: 3 h
Yield: 87.1 %

Procedure:
To a solution of 2,4-dimethoxy-benzaldehyde (20.0 g, 120.4 mmol) in methanol (550 mL) was added a solution of iodine monochloride (23.25 g, 144.9 mmol) in methanol (60 mL) dropwise over 20 min. The solution was allowed to stir at ambient temperature for 3 hours and then poured into a solution of hydrochloric acid (0.5 M, 600 mL). The resulting precipitate was collected by filtration, washed with water, and dried in vacuo. The crude product was further recrystallized from a mixture of tetrahydrofuran and heptane (1:1, v/v) to give the title compound as a white solid (30.62 g, 87.5%), m.p. 170–172° C. 1H NMR (CDCl3) δ 10.19 (s, 1H), 8.22 (s, 1H), 6.39 (s, 1H), 3.97 (s, 3H), 3.95 (s, 3H).
Reaction SMILES: [CH2:1]([NH2:3])[CH3:2].[I:4][C:5]1[CH:13]=[CH:12][C:8]([C:9](Cl)=[O:10])=[CH:7][CH:6]=1.O>C1COCC1.ClCCl>[CH2:1]([NH:3][C:9](=[O:10])[C:8]1[CH:12]=[CH:13][C:5]([I:4])=[CH:6][CH:7]=1)[CH3:2]
Reactant: O=C(Cl)c1ccc(I)cc1
Reactant: CCN
Solvent: O
Solvent: ClCCl
Solvent: C1CCOC1
Product: CCNC(=O)c1ccc(I)cc1
Reaction time: 1 h

Procedure:
90 ml (45 mmol) of a 0.5N solution of ethylamine in THF were introduced into a round-bottomed flask and a solution of 4 g (15 mmol) of 4-iodobenzoyl chloride in 20 ml of dichloromethane was added dropwise. Stirring was carried out at room temperature for one hour and the reaction mixture was poured into water and extracted with ethyl ether. The organic phase was separated by settling, dried over magnesium sulfate and evaporated. The residue obtained was purified by chromatography on a silica column eluted with dichloromethane. After evaporating the solvents, 3.41 g (82%) of the expected amide was recovered.
Reaction SMILES: CO[CH:3](OC)[N:4]([CH3:6])[CH3:5].[NH:9]1[C:13]2[CH:14]=[CH:15][C:16]([C:18]([NH:20][NH2:21])=[O:19])=[CH:17][C:12]=2[N:11]=[CH:10]1.C1(C)C=CC=CC=1>CO>[CH3:6][N:4]([CH:3]=[N:21][NH:20][C:18]([C:16]1[CH:15]=[CH:14][C:13]2[NH:9][CH:10]=[N:11][C:12]=2[CH:17]=1)=[O:19])[CH3:5]
Reactant: NNC(=O)c1ccc2[nH]cnc2c1
Reactant: COC(OC)N(C)C
Solvent: Cc1ccccc1
Solvent: CO
Product: CN(C)C=NNC(=O)c1ccc2[nH]cnc2c1
Yield: 87 %

Procedure:
Dimethylformamide dimethyl acetal (19 g, 15.90 mmol) was added to a suspension of 1H-benzo[d]imidazole-5-carbohydrazide (3.50 g, 19.88 mmol) in 1:1 toluene; methanol (60 mL) and refluxed overnight. The volatiles were evaporated in vacuo to afford crude compound which was triturated with 6% methanol in chloroform (10 mL), precipitated solid was filtered and dried under reduced pressure to afford 3.20 g (69.56%%) 1H-benzimidazole-5-carboxylic acid dimethylaminomethylene-hydrazide as brown solid.
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=1[NH:15][C:16](/[CH:18]=[CH:19]/[C:20]1[CH:25]=[CH:24][C:23]([CH:26]([N:30]([C:40]([O:42][C:43]([CH3:46])([CH3:45])[CH3:44])=[O:41])[CH2:31][CH:32]([N:34]2[CH2:39][CH2:38][O:37][CH2:36][CH2:35]2)[CH3:33])[C:27](O)=[O:28])=[CH:22][CH:21]=1)=[O:17])=[O:7])([CH3:4])([CH3:3])[CH3:2].F[P-](F)(F)(F)(F)F.Br[P+](N1CCCC1)(N1CCCC1)N1CCCC1.C(N(C(C)C)CC)(C)C.[CH:80]([C:83]1[CH:89]=[CH:88][C:86]([NH2:87])=[CH:85][CH:84]=1)([CH3:82])[CH3:81]>ClCCl>[C:1]([O:5][C:6](=[O:7])[NH:8][C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=1[NH:15][C:16](=[O:17])/[CH:18]=[CH:19]/[C:20]1[CH:25]=[CH:24][C:23]([CH:26]([N:30]([C:40]([O:42][C:43]([CH3:46])([CH3:45])[CH3:44])=[O:41])[CH2:31][CH:32]([N:34]2[CH2:39][CH2:38][O:37][CH2:36][CH2:35]2)[CH3:33])[C:27](=[O:28])[NH:87][C:86]2[CH:88]=[CH:89][C:83]([CH:80]([CH3:82])[CH3:81])=[CH:84][CH:85]=2)=[CH:22][CH:21]=1)([CH3:3])([CH3:2])[CH3:4]
Reactant: CC(CN(C(=O)OC(C)(C)C)C(C(=O)O)c1ccc(/C=C/C(=O)Nc2ccccc2NC(=O)OC(C)(C)C)cc1)N1CCOCC1
Reactant: CC(C)c1ccc(N)cc1
Agent: Br[P+](N1CCCC1)(N1CCCC1)N1CCCC1
Agent: F[P-](F)(F)(F)(F)F
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: CC(C)c1ccc(NC(=O)C(c2ccc(/C=C/C(=O)Nc3ccccc3NC(=O)OC(C)(C)C)cc2)N(CC(C)N2CCOCC2)C(=O)OC(C)(C)C)cc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of (E)-{4-[2-(2-tert-Butoxycarbonylamino-phenylcarbamoyl)-vinyl]-phenyl}-[tert-butoxycarbonyl-(2-morpholin-4-yl-propyl)-amino]-acetic acid (306 mg, 0.480 mmol) and bromo-tris-pyrrolidino-phosphoniumhexafluorophosphate (447 mg, 0.960 mmol) in anhydrous dichloromethane (5 mL) was added diisopropylethylamine (0.167 mL, 0.960 mmol) followed by 4-isopropylaniline (0.131 mL, 0.960 mmol). After stirring at room temperature overnight, the reaction was diluted to 15 mL with dichloromethane, washed with water and brine, dried over Na2SO4, filtered, and concentrated in vacuo to afford crude product. This material was used without further purification. MS: calc'd 756 (MH+), exp 756 (MH+).
Reaction SMILES: [SH:1][C:2]1[C:10]([O:11][CH3:12])=[CH:9][CH:8]=[CH:7][C:3]=1[C:4]([OH:6])=[O:5].[C:13](OC(=O)C)(=[O:15])[CH3:14].Cl>C(O)(=O)C>[C:13]([S:1][C:2]1[C:10]([O:11][CH3:12])=[CH:9][CH:8]=[CH:7][C:3]=1[C:4]([OH:6])=[O:5])(=[O:15])[CH3:14]
Reactant: COc1cccc(C(=O)O)c1S
Reactant: CC(=O)OC(C)=O
Agent: Cl
Solvent: CC(=O)O
Product: COc1cccc(C(=O)O)c1SC(C)=O

Procedure:
A solution of 2-mercapto-3-methoxybenzoic acid (14.6 g, 79 mmol), acetic anhydride (9.7 g, 95 mmol) and glacial acetic acid (35 ml) was refluxed 15 minutes, then cooled and poured into dilute hydrochloric acid. The product was vacuum-filtered.
Reaction SMILES: [P:1]([O:5][CH2:6][CH2:7][N+:8]([CH3:11])([CH3:10])[CH3:9])([OH:4])([OH:3])=[O:2].C(O[N:20]([CH3:26])[CH2:21][C:22](=C=O)[OH:23])C1C=CC=CC=1.[H][H]>O1CCOCC1.O.[Pd]>[P:1]([O:5][CH2:6][CH2:7][N+:8]([CH3:11])([CH3:10])[CH3:9])([OH:3])([OH:4])=[O:2].[CH3:26][NH:20][CH2:21][CH2:22][OH:23]
Reactant: CN(CC(O)=C=O)OCc1ccccc1
Reactant: [H][H]
Agent: [Pd]
Agent: C[N+](C)(C)CCOP(=O)(O)O
Solvent: O
Solvent: C1COCCO1
Product: CNCCO

Procedure:
8 g of N-benzyloxy carbonyl-N-methyl-2-aminoethanol phosphocholine are dissolved in 60 ml of dioxane and 15 ml of water; the solution is mixed with 0.8 g of 10% palladium active carbon and the reaction mixture hydrogenated with hydrogen. After the H2 -absorption has terminated, the solution is filtered and the filtrate reduced in vacuo to dryness.
Reaction SMILES: [CH2:1]([O:3][C:4]1[CH:9]=[CH:8][CH:7]=[C:6]([OH:10])[C:5]=1[C:11](=[NH:13])[NH2:12])[CH3:2].[S:14](N1C=CN=C1)(N1C=CN=C1)(=[O:16])=[O:15]>O>[NH2:13][C:11]1[C:5]2[C:4]([O:3][CH2:1][CH3:2])=[CH:9][CH:8]=[CH:7][C:6]=2[O:10][S:14](=[O:16])(=[O:15])[N:12]=1
Reactant: CCOc1cccc(O)c1C(=N)N
Reactant: O=S(=O)(n1ccnc1)n1ccnc1
Solvent: O
Product: CCOc1cccc2c1C(N)=NS(=O)(=O)O2

Procedure:
0.25 g (1.39 mmol) of 2-ethoxy-6-hydroxybenzenecarboximidamide is stirred without solvent with 0.65 g (3.28 mmol) of 1,1′-sulphonyldiimidazole at 130° C. for 18 hours. Cooling is followed by stirring the mixture with water and removing with dichloromethane. The organic phase is dried over magnesium sulphate and concentrated under reduced pressure. This gives 0.2 g of a pale yellow, crystalline material.
Reaction SMILES: Cl[C:2]1[N:3]=[C:4]([N:23]2[CH2:28][CH2:27][O:26][CH2:25][CH2:24]2)[C:5]2[N:11]=[C:10]([CH2:12][N:13]3[CH2:18][CH2:17][CH:16]([C:19]([OH:22])([CH3:21])[CH3:20])[CH2:15][CH2:14]3)[CH:9]=[CH:8][C:6]=2[N:7]=1.[NH:29]1[C:33]2[CH:34]=[CH:35][CH:36]=[CH:37][C:32]=2[N:31]=[C:30]1[CH2:38][CH2:39][OH:40]>>[OH:40][CH2:39][CH2:38][C:30]1[N:29]([C:2]2[N:3]=[C:4]([N:23]3[CH2:24][CH2:25][O:26][CH2:27][CH2:28]3)[C:5]3[N:11]=[C:10]([CH2:12][N:13]4[CH2:14][CH2:15][CH:16]([C:19]([OH:22])([CH3:20])[CH3:21])[CH2:17][CH2:18]4)[CH:9]=[CH:8][C:6]=3[N:7]=2)[C:33]2[CH:34]=[CH:35][CH:36]=[CH:37][C:32]=2[N:31]=1
Reactant: OCCc1nc2ccccc2[nH]1
Reactant: CC(C)(O)C1CCN(Cc2ccc3nc(Cl)nc(N4CCOCC4)c3n2)CC1
Product: CC(C)(O)C1CCN(Cc2ccc3nc(-n4c(CCO)nc5ccccc54)nc(N4CCOCC4)c3n2)CC1

Procedure:
2-(1-((2-chloro-4-morpholinopyrido[3,2-d]pyrimidin-6-yl)methyl)piperidin-4-yl)propan-2-ol from Example 8 (0.15 g) was reacted with 2-(1H-benzo[d]imidazol-2-yl)ethanol via General Procedure D to produce 19 mg of 168 following reverse phase HPLC purification. MS (Q1) 532.3 (M)+
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([CH3:8])[C:3]=1[C:9]([N:11]1[CH2:16][CH2:15][C:14]([CH3:34])([N:17]2[CH2:22][CH2:21][CH:20]([NH:23][C:24]3[CH:25]=[CH:26][CH:27]=[C:28]4[C:32]=3[N:31]([CH3:33])[CH:30]=[CH:29]4)[CH2:19][CH2:18]2)[CH2:13][CH2:12]1)=[O:10].Cl[CH2:36][C:37]1[N:38]=[C:39]([CH3:42])[S:40][CH:41]=1.CC1C=CC=C(C)C=1C(N1CCC(C)(N2CCC(=O)CC2)CC1)=O.CN1C2C(=CC=CC=2N)C=C1>>[CH3:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([CH3:8])[C:3]=1[C:9]([N:11]1[CH2:12][CH2:13][C:14]([CH3:34])([N:17]2[CH2:22][CH2:21][CH:20]([N:23]([C:24]3[CH:25]=[CH:26][CH:27]=[C:28]4[C:32]=3[N:31]([CH3:33])[CH:30]=[CH:29]4)[CH2:36][C:37]3[N:38]=[C:39]([CH3:42])[S:40][CH:41]=3)[CH2:19][CH2:18]2)[CH2:15][CH2:16]1)=[O:10]
Reactant: Cc1cccc(C)c1C(=O)N1CCC(C)(N2CCC(Nc3cccc4ccn(C)c34)CC2)CC1
Reactant: Cc1nc(CCl)cs1
Agent: Cc1cccc(C)c1C(=O)N1CCC(C)(N2CCC(=O)CC2)CC1
Agent: Cn1ccc2cccc(N)c21
Product: Cc1nc(CN(c2cccc3ccn(C)c23)C2CCN(C3(C)CCN(C(=O)c4c(C)cccc4C)CC3)CC2)cs1

Procedure:
It is prepared from (2,6-dimethyl-phenyl)-[4′-methyl-4-(1-methyl-1H-indol-7-ylamino)-[1,4′]bipiperidinyl-1′-yl]-methanone and 4-chloromethyl-2-methyl-thiazole using a procedure as described for Example 52 of PCT/EP02/03871. MS/ESI 570 [M+H]+. (2,6-Dimethyl-phenyl)-[4′-methyl-4-(1-methyl-1H-indol-7-ylamino)-[1,4′]bipiperidinyl-1′-yl]-methanone used as starting material may be prepared from 1′-(2,6-dimethyl-benzoyl)-4′-methyl-[1,4′]bipiperidinyl-4-one and 1-methyl-1H-indol-7-ylamine using a procedure as described in Example 51e of PCT/EP02/03871. MS/ESI 459 [M+H]+. 1′-(2,6-Dimethyl-benzoyl)-4′-methyl-[1,4′]bipiperidinyl-4-one may be prepared using a procedure as described in Example 51a-d of PCT/EP02/03871. MS/ESI 329 [M+H]+.
Reaction SMILES: [Cl:1][C:2]1[C:8]([Cl:9])=[CH:7][CH:6]=[CH:5][C:3]=1N.[C:10](Cl)([CH3:12])=[O:11].[N:14]1C=CC=CC=1>>[Cl:1][C:2]1[C:8]([Cl:9])=[CH:7][CH:6]=[CH:5][C:3]=1[CH2:12][C:10]([NH2:14])=[O:11]
Reactant: Nc1cccc(Cl)c1Cl
Reactant: CC(=O)Cl
Reactant: c1ccncc1
Product: NC(=O)Cc1cccc(Cl)c1Cl
Temperature: 25 °C
Reaction time: 1 h

Procedure:
A solution of 2,3-dichloroaniline (5.00 g, 30.86 mmol) in pyridine (20 ml) was cooled to 0° C. and treated with AcCl (4.85 g, 62 mmol). The reaction mixture was stirred at r.t. for 1 h and then concentrated under reduced pressure. The residue was dissolved in ethyl acetate, washed with 1% aqueous hydrochloric acid, water and brine, and dried over MgSO4. The solution was concentrated and recrystallized from EtOAc/hexane to give (2,3-dichloro-phenyl)-acetamide (4.50 g, 22 mmol). HPLC Rt: 5.52 min. 1H-NMR (CDCl3): δ 8.35 (br. s, 1H), 7.7 (1H), 7.24 (1H), 7.23 (1H), 2.28 (s, 3H).
Reaction SMILES: [C:1]([CH2:7][C:8](=O)[CH2:9][CH:10]([CH3:12])[CH3:11])(=O)[CH2:2][CH:3]([CH3:5])[CH3:4].[H-].[Na+].C([O:18][C:19](=[O:22])[CH2:20]Br)C.[C:23]1([NH:29][NH2:30])[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1>C(O)(=O)C.C1C=CC=CC=1>[CH2:2]([C:1]1[C:7]([CH2:20][C:19]([OH:18])=[O:22])=[C:8]([CH2:9][CH:10]([CH3:12])[CH3:11])[N:29]([C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=2)[N:30]=1)[CH:3]([CH3:5])[CH3:4]
Reactant: CCOC(=O)CBr
Reactant: CC(C)CC(=O)CC(=O)CC(C)C
Reactant: NNc1ccccc1
Agent: [H-]
Agent: [Na+]
Solvent: c1ccccc1
Solvent: CC(=O)O
Product: CC(C)Cc1nn(-c2ccccc2)c(CC(C)C)c1CC(=O)O
Yield: 44 %

Procedure:
10 grams diisovalerylmethane (as described by Swamer and Hauser), were reacted with 1.3 gram of a 50% suspension of sodium hydride in paraffin oil and 10 grams bromoacetic acid-ethylester by a procedure analogous to that described in Example (2b). The benzene solution obtained in this procedure was evaporated and the residue of crude 3,3-diisovalerylpropionic acid-ethyl ester obtained thereby was mixed with 6.5 grams phenylhydrazine and 4 grams glacial acetic acid and the mixture was heated to the boiling temperature under reflux for 2 hours. The reaction mixture obtained thereby was then worked up in accordance with a procedure analogous to that described in Example (1a). The ester thus recovered was saponified and the free acid recovered by a procedure analogous to that described in Example (1b). 7.5 grams 3,5-diisobutyl-1-phenyl-pyrazol-4-acetic acid, melting at 125°-126° C., were obtained representing a yield of 44% on the diisovalerylmethane starting material.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:20])[CH:5]([NH:12][C:13]([O:15][C:16]([CH3:19])([CH3:18])[CH3:17])=[O:14])[C:6]1[N:7]=[C:8]([NH2:11])[S:9][CH:10]=1)[CH3:2].[Cl:21][CH2:22][C:23](Cl)=[O:24].O>CN(C)C(=O)C>[CH2:1]([O:3][C:4](=[O:20])[CH:5]([NH:12][C:13]([O:15][C:16]([CH3:19])([CH3:18])[CH3:17])=[O:14])[C:6]1[N:7]=[C:8]([NH:11][C:23](=[O:24])[CH2:22][Cl:21])[S:9][CH:10]=1)[CH3:2]
Reactant: CCOC(=O)C(NC(=O)OC(C)(C)C)c1csc(N)n1
Reactant: O=C(Cl)CCl
Solvent: CC(=O)N(C)C
Solvent: O
Product: CCOC(=O)C(NC(=O)OC(C)(C)C)c1csc(NC(=O)CCl)n1
Reaction time: 1 h
Yield: 90.8 %

Procedure:
To a solution of 1.26 g of α-t-butyloxycarbonylamino-α-(2-aminothiazol-4-yl)acetic acid ethyl ester in 5 ml of N,N-dimethylactamide is added 708 mg of chloroacetyl chloride under stirring. After the stirring for further 1 hour at room temperature, the reaction solution is poured into water and extracted with ethyl acetate. The organic layer is washed with saturated sodium bicarbonate aq. solution and then water and dried over anhydrous magnesium sulfate. The distillation of the solvent gives 1.435 g of α-t-butyloxycarbonylamino-α-[2-(chloroacetamido)-thiazol-4-yl]acetic acid ethyl ester as crystals (yield, 90.8%). Melting point: 192°-193° C.
Reaction SMILES: [C:1](Cl)(Cl)=[O:2].[NH2:5][C:6]1[CH:10]=[C:9]([C:11]([CH3:14])([CH3:13])[CH3:12])[O:8][N:7]=1>C(OCC)(=O)C>[N:5]([C:6]1[CH:10]=[C:9]([C:11]([CH3:14])([CH3:13])[CH3:12])[O:8][N:7]=1)=[C:1]=[O:2]
Reactant: CC(C)(C)c1cc(N)no1
Reactant: O=C(Cl)Cl
Solvent: CCOC(C)=O
Product: CC(C)(C)c1cc(N=C=O)no1
Reaction time: 8 h

Procedure:
99 g of phosgene was dissolved in 500 ml of ethyl acetate, then a solution of 71.6 g of 1A in 400 ml of ethyl acetate was added drop-by-drop to the stirred mixture. The mixture was stirred at reflux temperature for five hours, left standing overnight at room temperature, and filtered. The solid was dried at room temperature for two days to give dimeric 3-isocyanato-5-(1,1-dimethylethyl)-isoxazole (3A) m.p.: 165°-167° C.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]2[C@@H:13]3[CH2:14][N:15]([C:18]([O:20][C:21]([CH3:24])([CH3:23])[CH3:22])=[O:19])[CH2:16][CH2:17][C@@H:12]3[N:6]3[CH2:7][CH2:8][NH:9][C:10]([CH:11]=1)=[C:5]23.[Cl:25][C:26]1[CH:31]=[C:30]([Cl:32])[CH:29]=[CH:28][C:27]=1B(O)O>>[Cl:25][C:26]1[CH:31]=[C:30]([Cl:32])[CH:29]=[CH:28][C:27]=1[C:2]1[CH:3]=[C:4]2[C@@H:13]3[CH2:14][N:15]([C:18]([O:20][C:21]([CH3:22])([CH3:23])[CH3:24])=[O:19])[CH2:16][CH2:17][C@@H:12]3[N:6]3[CH2:7][CH2:8][NH:9][C:10]([CH:11]=1)=[C:5]23
Reactant: OB(O)c1ccc(Cl)cc1Cl
Reactant: CC(C)(C)OC(=O)N1CC[C@H]2[C@@H](C1)c1cc(Br)cc3c1N2CCN3
Product: CC(C)(C)OC(=O)N1CC[C@H]2[C@@H](C1)c1cc(-c3ccc(Cl)cc3Cl)cc3c1N2CCN3
Yield: 61.8 %

Procedure:
Tert-butyl (6bR, 10aS)-5-(2,4-dichlorophenyl)-2,3,6b,9,10,10a-hexahydro-1H-pyrido[3′,4′:4,5]pyrrolo[1,2,3-de]quinoxaline-8(7H)-carboxylate (37 mg, 60%) was prepared via coupling of tert-butyl (6bR, 10aS)-5-bromo-2,3,6b,9,10,10a-hexahydro-1H-pyrido[3′,4′:4,5]pyrrolo[1,2,3-de]quinoxaline-8(7H)-carboxylate (50 mg, 0.13 mmol) with 2,4-dichlorophenyl boronic acid (74 mg, 0.39 mmol) as illustrated above using the general procedure for Suzuki coupling. 1H NMR (CDCl3, 300 MHz) δ 1.46 (s, 9H), 1.82-1.96 (m, 2H), 2.74-2.82 (m, 1H), 2.99-3.05 (m, 1H), 3.16-3.22 (m, 2H), 3.33-3.39 (m, 1H), 3.43-3.50 (m, 1H), 3.52-3.57 (m, 1H), 3.62-3.69 (m, 1H), 3.43-3.50 (m, 1H), 3.52-3.57 (m, 1H), 3.62-3.69 (m, 1H), 3.71-3.79 (m, 1H), 3.80-3.85 (m, 1H), 3.89-4.14 (m, 1H), 6.44 (s, 1H), 6.59 (s, 1H), 7.22 (s, 2H), 7.42 (s, 1H) ppm.