Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([O:8][C:9]1[C:13]([O:14][CH2:15][C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)=[C:12]([C:22](=[O:26])[N:23]([CH3:25])[CH3:24])[N:11]([C:27]2[CH:32]=[CH:31][C:30]([OH:33])=[CH:29][CH:28]=2)[C:10]=1[C:34]([O:36][CH2:37][CH3:38])=[O:35])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Cl.Cl[CH2:41][CH2:42][CH2:43][N:44]1[CH2:49][CH2:48][O:47][CH2:46][CH2:45]1.C([O-])([O-])=O.[K+].[K+]>CN(C=O)C>[CH2:1]([O:8][C:9]1[C:13]([O:14][CH2:15][C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)=[C:12]([C:22](=[O:26])[N:23]([CH3:25])[CH3:24])[N:11]([C:27]2[CH:32]=[CH:31][C:30]([O:33][CH2:41][CH2:42][CH2:43][N:44]3[CH2:49][CH2:48][O:47][CH2:46][CH2:45]3)=[CH:29][CH:28]=2)[C:10]=1[C:34]([O:36][CH2:37][CH3:38])=[O:35])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CCOC(=O)c1c(OCc2ccccc2)c(OCc2ccccc2)c(C(=O)N(C)C)n1-c1ccc(O)cc1
Reactant: ClCCCN1CCOCC1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CCOC(=O)c1c(OCc2ccccc2)c(OCc2ccccc2)c(C(=O)N(C)C)n1-c1ccc(OCCCN2CCOCC2)cc1
Yield: 55.4 %

Procedure:
A solution of ethyl 3,4-bis(benzyloxy)-5-(dimethylcarbamoyl)-1-(4-hydroxyphenyl)-1H-pyrrole-2-carboxylate (36) (45 mg, 0.09 mmol), 4-(3-chloropropyl)morpholine hydrochloride (19 mg, 0.10 mmol) and K2CO3 (25 mg, 0.18 mmol) in DMF (1 mL) was stirred at 60° C. for 18 h. The reaction mixture was partitioned between EtOAc (10 mL) and water (5 mL), the organic layer was separated and washed with brine (5 mL), dried (MgSO4), filtered and concentrated in vacuo. The residue was dissolved in MeOH (2 mL) and loaded onto a column of SCX (5 g). The column was washed with MeOH and then the product was eluted with 1% NH3 in MeOH, removal of the solvents in vacuo afforded ethyl 3,4-bis(benzyloxy)-5-(dimethylcarbamoyl)-1-(4-(3-morpholinopropoxy)phenyl)-1H-pyrrole-2-carboxylate (37) (32 mg, 57%) as a yellow oil: m/z 642 (M+H)+ (ES+). 1H NMR (400 MHz, DMSO-d6) δ: 7.47-7.42 (m, 2H), 7.41-7.30 (m, 8H), 7.10-7.05 (m, 2H), 6.99-6.91 (m, 2H), 5.11 (s, 2H), 4.96 (s, 2H), 4.04-3.95 (m, 4H), 3.59-3.52 (m, 5H), 2.72-2.67 (m, 6H), 2.44-2.38 (m, 3H), 2.37-2.32 (m, 5H), 1.92-1.81 (m, 2H), 1.00 (t, J=7.0 Hz, 3H).
Reaction SMILES: [CH3:1][N:2]1[CH:6]=[N:5][CH:4]=[N:3]1.C([Li])CCC.[CH2:12]([N:19]1[CH2:23][C@H:22]([O:24][Si:25]([C:28]([CH3:31])([CH3:30])[CH3:29])([CH3:27])[CH3:26])[CH2:21][C@H:20]1[CH:32]=[O:33])[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1>O1CCCC1.CCCCCC>[CH2:12]([N:19]1[CH2:23][C@H:22]([O:24][Si:25]([C:28]([CH3:29])([CH3:30])[CH3:31])([CH3:27])[CH3:26])[CH2:21][C@H:20]1[CH:32]([C:6]1[N:2]([CH3:1])[N:3]=[CH:4][N:5]=1)[OH:33])[C:13]1[CH:14]=[CH:15][CH:16]=[CH:17][CH:18]=1
Reactant: CC(C)(C)[Si](C)(C)O[C@@H]1C[C@@H](C=O)N(Cc2ccccc2)C1
Reactant: Cn1cncn1
Agent: [Li]CCCC
Solvent: CCCCCC
Solvent: C1CCOC1
Product: Cn1ncnc1C(O)[C@@H]1C[C@@H](O[Si](C)(C)C(C)(C)C)CN1Cc1ccccc1
Temperature: 0 °C
Reaction time: 0.25 h
Yield: 48.9 %

Procedure:
To a solution of 1-methyl-1,2,4-triazole (3.12 g) in tetrahydrofuran (47 ml) at -70° C. was added dropwise n-butyllithium (1.6N) in hexane (25.5 ml) keeping the temperature below -60° C. After 15 minutes at -70° C., the mixture was warmed quickly to 0° C., stirred 5 minutes then recooled to -70° C. and stirred for 30 minutes. To the mixture was added a solution of (2S,4R)-1-benzyl-4-(t-butyldimethylsilyloxy)-2-formylpyrrolidine (10.0 g) in tetrahydrofuran (10 ml) keeping the temperature below -60° C. After 30 minutes the cooling bath was removed and the mixture was warmed to 0° C. over 30 minutes. After a further 2 hours the mixture was quenched with saturated sodium bicarbonate solution and extracted with ethyl acetate (×2). The combined organic layer was washed with brine and water, dried over magnesium sulfate and evaporated under reduced pressure. The residue was column chromatographed on silica gel (300 g, eluting with chloroform-methanol (30:1)) and then again on silica gel (300 g) eluting with ethyl acetate) to give 1-{(2S,4R)-1-benzyl-4-(t-butyldimethylsilyloxy) pyrrolidin-2-yl}-1-(1-methyl-1,2,4-triazol-5-yl) methanol (6.16 g) (as a 4.3:1 mixture of diastereoisomers).
Reaction SMILES: Br[CH2:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]([F:12])([F:11])[F:10])=[CH:5][N:4]=1.[OH:13][C:14]1[CH:19]=[CH:18][N:17]([C:20]2[CH:21]=[CH:22][C:23]3[C:24]4[CH2:33][N:32]([C:34]([O:36][C:37]([CH3:40])([CH3:39])[CH3:38])=[O:35])[CH2:31][CH2:30][C:25]=4[N:26]([CH3:29])[C:27]=3[CH:28]=2)[C:16](=[O:41])[CH:15]=1.C([O-])([O-])=O.[K+].[K+]>C(#N)C.CN(C=O)C.C(Cl)Cl>[CH3:29][N:26]1[C:27]2[CH:28]=[C:20]([N:17]3[CH:18]=[CH:19][C:14]([O:13][CH2:2][C:3]4[CH:8]=[CH:7][C:6]([C:9]([F:12])([F:11])[F:10])=[CH:5][N:4]=4)=[CH:15][C:16]3=[O:41])[CH:21]=[CH:22][C:23]=2[C:24]2[CH2:33][N:32]([C:34]([O:36][C:37]([CH3:40])([CH3:39])[CH3:38])=[O:35])[CH2:31][CH2:30][C:25]1=2
Reactant: FC(F)(F)c1ccc(CBr)nc1
Reactant: Cn1c2c(c3ccc(-n4ccc(O)cc4=O)cc31)CN(C(=O)OC(C)(C)C)CC2
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Solvent: CN(C)C=O
Solvent: ClCCl
Product: Cn1c2c(c3ccc(-n4ccc(OCc5ccc(C(F)(F)F)cn5)cc4=O)cc31)CN(C(=O)OC(C)(C)C)CC2
Yield: 29.8 %

Procedure:
2-(Bromomethyl)-5-(trifluoromethyl)pyridine (140 mg, 0.58 mmol), tert-butyl 7-(4-hydroxy-2-oxopyridin-1(2H)-yl)-5-methyl-3,4-dihydro-1H-pyrido[4,3-b]indole-2(5H)-carboxylate (230 mg, 0.58 mmol) and K2CO3 (160 mg, 1.16 mmol) were stirred in acetonitrile/DMF (3 mL/0.5 mL) for 72 h. The mixture was diluted with methylene chloride, washed with water and concentrated to provide the title compound (96 mg, 29%) as a yellow solid: 1H NMR (300 MHz, CDCl3) δ 8.88 (s, 1H), 8.00 (dd, J=8.2, 2.0 Hz, 1H), 7.63 (d, J=8.2 Hz, 1H), 7.51 (d, J=8.2 Hz, 1H), 7.36 (d, J=7.6 Hz, 1H), 7.28-7.26 (m, 1H), 7.00 (d, J=7.7 Hz, 1H), 6.12 (dd, J=7.6, 2.7 Hz, 1H), 6.04 (d, J=2.7 Hz, 1H), 5.26 (s, 2H), 4.63-4.58 (br m, 2H), 3.87-3.76 (br m, 2H), 3.63 (s, 3H), 2.86-2.76 (br m, 2H), 1.50 (s, 9H).
Reaction SMILES: ClC1C=C(Cl)C=C(Cl)C=1NN.[C:12]([C:14](=[C:23]([CH3:35])[NH:24][NH:25][C:26]1[C:31]([Cl:32])=[CH:30][C:29]([Cl:33])=[CH:28][C:27]=1[Cl:34])[C:15]([NH:17][C:18](OCC)=[O:19])=[O:16])#[N:13]>>[C:12]([C:14]1[C:15](=[O:16])[NH:17][C:18](=[O:19])[N:24]([NH:25][C:26]2[C:31]([Cl:32])=[CH:30][C:29]([Cl:33])=[CH:28][C:27]=2[Cl:34])[C:23]=1[CH3:35])#[N:13]
Reactant: CCOC(=O)NC(=O)C(C#N)=C(C)NNc1c(Cl)cc(Cl)cc1Cl
Agent: NNc1c(Cl)cc(Cl)cc1Cl
Product: Cc1c(C#N)c(=O)[nH]c(=O)n1Nc1c(Cl)cc(Cl)cc1Cl

Procedure:
Following the method of Example 1, N-ethoxycarbonylcyanoacetamide is heated with triethyl orthoacetate and acetic anhydride to give α-cyano-β-ethoxy-β-methyl-N-ethoxycarbonylacrylamide, which in turn is reacted with 2,4,6-trichlorophenylhydrazine. The resulting compound α-cyano-β-methyl-β-(2,4,6-trichlorophenylhydrazino)-N-ethoxycarbonylacrylamide (m.p.=183°-184°) is cyclized, yielding 5-cyano-6-methyl-1-(2,4,6-trichloroanilino)-2,4-pyrimidinedione, m.p.=>305°.
Reaction SMILES: [C:1]([NH:4][C:5]1[S:6][CH:7]=[C:8]([C:10]([OH:12])=O)[N:9]=1)(=[O:3])[CH3:2].C(N1C=CN=C1)(N1C=CN=C1)=O.[NH2:25][C:26]1[CH:44]=[CH:43][C:29]([CH2:30][NH:31][C:32]([NH:34][NH:35][C:36]([O:38][C:39]([CH3:42])([CH3:41])[CH3:40])=[O:37])=[O:33])=[CH:28][CH:27]=1.O>O1CCCC1.CN(C)C=O.C(OCC)(=O)C>[C:1]([NH:4][C:5]1[S:6][CH:7]=[C:8]([C:10]([NH:25][C:26]2[CH:27]=[CH:28][C:29]([CH2:30][NH:31][C:32]([NH:34][NH:35][C:36]([O:38][C:39]([CH3:40])([CH3:41])[CH3:42])=[O:37])=[O:33])=[CH:43][CH:44]=2)=[O:12])[N:9]=1)(=[O:3])[CH3:2]
Reactant: CC(=O)Nc1nc(C(=O)O)cs1
Reactant: CC(C)(C)OC(=O)NNC(=O)NCc1ccc(N)cc1
Agent: O=C(n1ccnc1)n1ccnc1
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Solvent: O
Product: CC(=O)Nc1nc(C(=O)Nc2ccc(CNC(=O)NNC(=O)OC(C)(C)C)cc2)cs1
Temperature: 50 °C
Reaction time: 2 h
Yield: 90.9 %

Procedure:
To a suspension of 2-(acetylamino)-1,3-thiazole-4-carboxylic acid (558.6 mg, 3.000 mmol) in anhydrous tetrahydrofuran (10 ml) were added 1,1′-carbonyldiimidazole (535.2 mg, 3.301 mmol) and anhydrous tetrahydrofuran (10 ml), and the mixture was stirred at 50° C. for 2 hr. tert-Butyl 2-[(4-aminobenzyl)carbamoyl]hydrazinecarboxylate (841.0 mg, 3.000 mmol) was added, and the mixture was stirred for 24 hr. To a solution of 2-(acetylamino)-1,3-thiazole-4-carboxylic acid (280.2 mg, 1.505 mmol) in anhydrous N,N-dimethylformamide (5 ml) was added 1,1′-carbonyldiimidazole (243.2 mg, 1.500 mmol), and the mixture was stirred at 50° C. for 30 min. This solution was added to the mixture obtained above, and the mixture was stirred at 50° C. for 3 hr, and at room temperature for 65 hr. Water and ethyl acetate were added to the reaction mixture and the mixture was stirred. The precipitated solid was filtered, washed with ethyl acetate, and dried under reduced pressure to give tert-butyl 2-{[4-({[2-(acetylamino)-1,3-thiazol-4-yl]carbonyl}amino)benzyl]carbamoyl}hydrazinecarboxylate (1.223 g, 2.728 mmol, yield 90.9%) as a white solid.
Reaction SMILES: Cl[C:2]([O:4][CH2:5][CH3:6])=[O:3].[NH2:7][CH2:8][CH2:9][C:10]1[CH:15]=[CH:14][C:13]([OH:16])=[CH:12][CH:11]=1.[OH-].[Na+]>O>[CH2:5]([O:4][C:2](=[O:3])[NH:7][CH2:8][CH2:9][C:10]1[CH:15]=[CH:14][C:13]([OH:16])=[CH:12][CH:11]=1)[CH3:6]
Reactant: CCOC(=O)Cl
Reactant: NCCc1ccc(O)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: CCOC(=O)NCCc1ccc(O)cc1

Procedure:
According to scheme 1, ethyl chloroformate is added to a solution of tyramine (1), sodium hydroxide, and water to produce the [2-(4-hydroxy-phenyl)-ethyl]carbamic acid ethyl ester (2). The carbamate is treated with cesium carbonate and 4-fluorobenzonitrile in DMF to yield the corresponding biarylether 3. The nitrile functionality of the biaryl; ether 3 is converted to the N-acyl compound 4 by reaction with methyllithium followed by hydrolysis in aqueous sulfuric acid. The N-acyl compound 4 is converted to the acetate 5 by oxidation with m-chloroperbenzoic acid (MCPBA) in a suitable solvent. The acetate 5 is reduced with lithium aluminum hydride to afford the compound 4-[4-(2-methylamino-ethyl)-phenoxy]-phenol (6). The compound 6 is treated with benzaldehyde in the presence of sodium triacetoxyborohydride to produce the reductive amination product 4-{4-[2-(benzyl-methyl-amino)-ethyl]-phenoxy}-phenol 7 of formula I. Compounds of formula I wherein D is acetate and q is 0, may also be prepared according to scheme 2 below.
Reaction SMILES: Cl[C:2]1[N:7]=[C:6](Cl)[CH:5]=[CH:4][N:3]=1.[CH3:9][O:10][C:11]1[CH:12]=[C:13]([CH:15]=[C:16]([O:20][CH3:21])[C:17]=1[O:18][CH3:19])[NH2:14]>>[CH3:21][O:20][C:16]1[CH:15]=[C:13]([NH:14][C:2]2[N:7]=[C:6]([NH:14][C:13]3[CH:15]=[C:16]([O:20][CH3:21])[C:17]([O:18][CH3:19])=[C:11]([O:10][CH3:9])[CH:12]=3)[CH:5]=[CH:4][N:3]=2)[CH:12]=[C:11]([O:10][CH3:9])[C:17]=1[O:18][CH3:19]
Reactant: COc1cc(N)cc(OC)c1OC
Reactant: Clc1ccnc(Cl)n1
Product: COc1cc(Nc2ccnc(Nc3cc(OC)c(OC)c(OC)c3)n2)cc(OC)c1OC
Yield: 15.2 %

Procedure:
A solution of 2,4-dichloropyrimidine (1.0 g, 6.7 mmol), 3,4,5-trimethoxyaniline (2.5 g, 13.4 mmol) and triethylamnine (1.8 ml, 12.6 mmol) was heated at reflux for 5 h. On cooling the resulting precipitate was collected and recrystallised from ethyl acetate to give the title compound (450 mg) as a purple solid m.p. 180°. MS m/z 443 (M+H)+.
Reaction SMILES: C(OC([NH:8][CH2:9][CH:10]([S:20][C:21](=[S:37])[CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][CH3:36])[CH2:11][NH:12]C(OC(C)(C)C)=O)=O)(C)(C)C>CCOCC.Cl>[NH2:12][CH2:11][CH:10]([S:20][C:21](=[S:37])[CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][CH3:36])[CH2:9][NH2:8]
Reactant: CCCCCCCCCCCCCCCC(=S)SC(CNC(=O)OC(C)(C)C)CNC(=O)OC(C)(C)C
Agent: Cl
Solvent: CCOCC
Product: CCCCCCCCCCCCCCCC(=S)SC(CN)CN
Temperature: 25 °C
Yield: 59 %

Procedure:
1,3-[di(tert-butoxycarbonylamino)]-2-tetradecylthioacetylthiopropane (example 15d) (0.300 g, 0.52 mmol) was dissolved in ether saturated in gaseous hydrochloric acid (55 ml). The mixture was stirred at room temperature. After 96 hours of reaction, the precipitate which formed was filtered, washed several times with diethyl ether and dried to give the desired compound in the form of a white powder.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH2:9][C:10]([OH:12])=O)[CH:5]=[C:6]([F:8])[CH:7]=1.[NH2:13][C@H:14]([C:16]([NH:18][CH:19]1[N:25]=[C:24]([C:26]2[CH:31]=[CH:30][C:29]([F:32])=[CH:28][CH:27]=2)[C:23]2[CH:33]=[CH:34][CH:35]=[CH:36][C:22]=2[N:21]([CH3:37])[C:20]1=[O:38])=[O:17])[CH3:15]>>[F:8][C:6]1[CH:5]=[C:4]([CH2:9][C:10]([NH:13][C@H:14]([C:16]([NH:18][CH:19]2[N:25]=[C:24]([C:26]3[CH:31]=[CH:30][C:29]([F:32])=[CH:28][CH:27]=3)[C:23]3[CH:33]=[CH:34][CH:35]=[CH:36][C:22]=3[N:21]([CH3:37])[C:20]2=[O:38])=[O:17])[CH3:15])=[O:12])[CH:3]=[C:2]([F:1])[CH:7]=1
Reactant: C[C@H](N)C(=O)NC1N=C(c2ccc(F)cc2)c2ccccc2N(C)C1=O
Reactant: O=C(O)Cc1cc(F)cc(F)c1
Product: C[C@H](NC(=O)Cc1cc(F)cc(F)c1)C(=O)NC1N=C(c2ccc(F)cc2)c2ccccc2N(C)C1=O

Procedure:
Following General Procedure D above using 3,5-difluorophenylacetic acid (Oakwood Products, Inc.) and 3-(L-alaninyl)-amino-2,3-dihydro-1-methyl-5-(4-fluorophenyl)-1H-1,4-benzodiazepin-2-one (Example 8-K), the title compound was prepared as an off-white solid.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([SH:8])[CH:5]=[CH:6][CH:7]=1.[C:9]([OH:13])(=[O:12])[CH:10]=[CH2:11]>CCOCC>[F:1][C:2]1[CH:3]=[C:4]([S:8][CH2:11][CH2:10][C:9]([OH:13])=[O:12])[CH:5]=[CH:6][CH:7]=1
Reactant: Fc1cccc(S)c1
Reactant: C=CC(=O)O
Solvent: CCOCC
Product: O=C(O)CCSc1cccc(F)c1
Temperature: 25 °C
Reaction time: 20.2 h
Yield: 80.3 %

Procedure:
3-Fluorothiophenol (5.39 g, 42 mmol) was placed in a flask with acrylic acid (3.73 g, 52 mmol) and stirred at room temperature for 20.2 hours. The reaction mixture solidified, was dissolved in ether and extracted with 10% Na2CO3. The aqueous layer was acidified with concentrated hydrochloric acid, extracted with ether, washed with brine, dried over MgSO4, and concentrated in vacuo to give the 3-(3-fluorophenylthio)propanoic acid (6.75 g), contaminated with some acrylic acid, as a white solid which was used without further purification in the next step.
Reaction SMILES: [CH3:1][N:2]([CH2:6][CH:7]([N:9]1[C:22]2[CH:21]=[C:20]([C:23]#[N:24])[CH:19]=[CH:18][C:17]=2[S:16][C:15]2[C:10]1=[CH:11][CH:12]=[CH:13][CH:14]=2)[CH3:8])[CH2:3][CH2:4][CH3:5].C(N(CC)CC)C.[SH2:32]>N1C=CC=CC=1.C(OCC)(=O)C>[CH3:1][N:2]([CH2:6][CH:7]([N:9]1[C:22]2[CH:21]=[C:20]([C:23](=[S:32])[NH2:24])[CH:19]=[CH:18][C:17]=2[S:16][C:15]2[C:10]1=[CH:11][CH:12]=[CH:13][CH:14]=2)[CH3:8])[CH2:3][CH2:4][CH3:5]
Reactant: CCCN(C)CC(C)N1c2ccccc2Sc2ccc(C#N)cc21
Reactant: S
Solvent: CCOC(C)=O
Solvent: CCN(CC)CC
Solvent: c1ccncc1
Product: CCCN(C)CC(C)N1c2ccccc2Sc2ccc(C(N)=S)cc21
Temperature: 20 °C
Reaction time: 16 h

Procedure:
A solution of 10-[(2RS)-1-(N-methyl-N-propylamino)-2-propyl]-2-phenothiazinecarbonitrile (4.3 g) and triethylamine (1.77 cc) in pyridine (86 cc) is treated with hydrogen sulphide and left stirred for 16 hours at a temperature in the region of 20° C. The green solution obtained is diluted with ethyl acetate (200 cc), washed with distilled water (5×40 cc), dried over magnesium sulphate, filtered and concentrated to dryness under reduced pressure (30 mm Hg; 4 kPa) at 40° C. The residual oil (5.4 g) is purified by chromatography on a column (height: 30 cm; diameter: 5.5 cm) of silica gel (0.04-0.063 mm) with a slight excess pressure of nitrogen (40 kPa), eluting with a mixture (97.5:2.5 by volume) (5 liters) of methylene chloride and methanol and collecting 100-cc fractions. The combined fractions 13 to 44 are concentrated to dryness under reduced pressure (30 mm Hg; 4 kPa) at 40° C. The residual yellow oil (4.37 g) is dissolved in ethanol (12 cc) under reflux and treated, with stirring, with a solution of fumaric acid (1.4 g) in ethanol (15 cc) under reflux. After 2 hours, stirring at a temperature in the region of 5° C., the solid formed is drained, washed with ethanol (5 cc) and dried under reduced pressure (5 mm Hg; 0.68 kPa) at 40° C. 10-[(2RS)-1-(N-Methyl-N-propylamino)-2-propyl]-2-phenothiazinecarbothioamide acid fumarate (4.35 g) is thereby obtained in the form of yellow crystals, m.p. 204° C.
Reaction SMILES: C([Li])CCC.C(NC(C)C)(C)C.[C:13]([OH:18])(=[O:17])[CH:14]([CH3:16])[CH3:15].Br[CH2:20][CH2:21][CH2:22][CH2:23][O:24][CH2:25][CH2:26][C:27]1[CH:32]=[CH:31][C:30]([N:33]2[CH2:38][CH2:37][O:36][CH2:35][CH2:34]2)=[CH:29][CH:28]=1>CCCCCC.C1COCC1>[CH3:15][C:14]([CH3:16])([CH2:20][CH2:21][CH2:22][CH2:23][O:24][CH2:25][CH2:26][C:27]1[CH:32]=[CH:31][C:30]([N:33]2[CH2:38][CH2:37][O:36][CH2:35][CH2:34]2)=[CH:29][CH:28]=1)[C:13]([OH:18])=[O:17]
Reactant: CC(C)C(=O)O
Reactant: BrCCCCOCCc1ccc(N2CCOCC2)cc1
Agent: [Li]CCCC
Solvent: CC(C)NC(C)C
Solvent: CCCCCC
Solvent: C1CCOC1
Product: CC(C)(CCCCOCCc1ccc(N2CCOCC2)cc1)C(=O)O
Reaction time: 1 h
Yield: 99.9 %

Procedure:
n-Butyllithium in hexane (1.53M, 113.5 ml) was added dropwise to N,N-diisopropylamine (17.9 g) in THF (100 ml) at -78° under nitrogen. The mixture was warmed to 0°, stirred for 1 h and treated dropwise with isobutyric acid (7.65 g) in THF (20 ml). The resulting suspension was stirred at room temperature for 3 h, and the product of stage (ii) (20.0 g) was added dropwise. The reaction mixture was stirred for 16 h at room temperature and the solvent was evaporated. The resultant oil was partitioned between EA (250 ml) and water (250 ml). The aqueous layer was acidified to pH 6 with 2N aqueous hydrochloric acid and the organic extract was separated. The aqueous layer was extracted with EA (250 ml) and the combined extracts were concentrated to leave the title compound as an orange oil (20.4 g). T.l.c. (ER) Rf 0.53.
Reaction SMILES: Cl[CH2:2][C:3]1[N:4]=[C:5]2[CH:10]=[CH:9][CH:8]=[CH:7][N:6]2[CH:11]=1.[CH3:12][OH:13].C[O-].[Na+]>O>[CH3:12][O:13][CH2:2][C:3]1[N:4]=[C:5]2[CH:10]=[CH:9][CH:8]=[CH:7][N:6]2[CH:11]=1
Reactant: ClCc1cn2ccccc2n1
Reactant: CO
Agent: C[O-]
Agent: [Na+]
Solvent: O
Product: COCc1cn2ccccc2n1
Temperature: 50 °C
Reaction time: 6 h
Yield: 88 %

Procedure:
[step 2] To 2-(chloromethyl)imidazo[1,2-a]pyridine (4.04 g, 24 mmol) obtained in step 1 were added methanol (121 mL) and sodium methoxide (3.93 g, 73 mmol), and the mixture was stirred at 50° C. for 6 hr. The reaction was discontinued with water, and the mixture was extracted with chloroform and the extract was dried over sodium sulfate. Filtration and concentration under reduced pressure gave 2-(methoxymethyl)imidazo[1,2-a]pyridine (3.45 g, 88%).
Reaction SMILES: Cl[C:2]1[CH:7]=[CH:6][C:5]([S:8]([CH:11]([CH3:13])[CH3:12])(=[O:10])=[O:9])=[CH:4][C:3]=1[N+:14]([O-:16])=[O:15].[NH2:17][CH2:18][CH2:19][N:20]1[CH2:24][CH2:23][CH2:22][CH2:21]1>C(O)C>[CH:11]([S:8]([C:5]1[CH:6]=[CH:7][C:2]([NH:17][CH2:18][CH2:19][N:20]2[CH2:24][CH2:23][CH2:22][CH2:21]2)=[C:3]([N+:14]([O-:16])=[O:15])[CH:4]=1)(=[O:10])=[O:9])([CH3:13])[CH3:12]
Reactant: CC(C)S(=O)(=O)c1ccc(Cl)c([N+](=O)[O-])c1
Reactant: NCCN1CCCC1
Solvent: CCO
Product: CC(C)S(=O)(=O)c1ccc(NCCN2CCCC2)c([N+](=O)[O-])c1

Procedure:
A mixture of 1-chloro-4-(isopropylsulfonyl)-2-nitrobenzene (Step C of Example 1, 200 mg, 0.76 mmol) and 1-(2-aminoethyl)pyrrolidine (0.1 mL, 0.80 mmol) in ethanol (1 mL) was microwaved for 15 min at 130° C. The reaction was quenched with water and extracted three times with ethyl acetate. The combined organic layers were dried over MgSO4 and filtered. The filtrate was evaporated under reduced pressure. The residue was crude product as a yellow solid.
Reaction SMILES: C([O:8][CH:9]1[CH2:13][N:12]([C:14](=[O:35])[CH2:15][C:16]2[CH:21]=[CH:20][C:19]([NH:22][C:23]([NH:25][C:26]3[CH:31]=[CH:30][CH:29]=[CH:28][C:27]=3[CH3:32])=[O:24])=[C:18]([O:33][CH3:34])[CH:17]=2)[CH:11]([CH2:36][O:37][C:38]2[CH:46]=[CH:45][C:41]([C:42]([O-:44])=[O:43])=[CH:40][C:39]=2[O:47][CH3:48])[CH2:10]1)C1C=CC=CC=1.[CH3:49][C:50](O)=O.CCO>[Pd]>[OH:8][CH:9]1[CH2:13][N:12]([C:14](=[O:35])[CH2:15][C:16]2[CH:21]=[CH:20][C:19]([NH:22][C:23]([NH:25][C:26]3[CH:31]=[CH:30][CH:29]=[CH:28][C:27]=3[CH3:32])=[O:24])=[C:18]([O:33][CH3:34])[CH:17]=2)[CH:11]([CH2:36][O:37][C:38]2[CH:46]=[CH:45][C:41]([C:42]([O:44][CH2:49][CH3:50])=[O:43])=[CH:40][C:39]=2[O:47][CH3:48])[CH2:10]1
Reactant: COc1cc(CC(=O)N2CC(OCc3ccccc3)CC2COc2ccc(C(=O)[O-])cc2OC)ccc1NC(=O)Nc1ccccc1C
Reactant: CC(=O)O
Agent: [Pd]
Solvent: CCO
Product: CCOC(=O)c1ccc(OCC2CC(O)CN2C(=O)Cc2ccc(NC(=O)Nc3ccccc3C)c(OC)c2)c(OC)c1
Reaction time: 5 h
Yield: 24 %

Procedure:
A stirred mixture of 4-[4-benzyloxy-1-[3-methoxy-4-[N′-(2-methylphenyl)ureido]phenylacetyl]-2-pyrrolidinylmethoxy]-3-methoxybenzoate (440 mg, 0.645 mmol) and 5% Pd/C (400 mg) in AcOH:EtOH (1:1, v/v, 100 mL) was hydrogenated at 1 atm for 5 hr. The mixture was filtered to remove the catalyst and the filtrate was concentrated in vacuo. The residue was chromatographed on silica-gel with CHCl3:EtOH (10:1, v/v) as eluent to give 90 mg (24%) ethyl 4-[4-hydroxy-1-[3-methoxy-4-[N′-(2-methylphenyl)ureido]phenylacetyl]-2-pyrrolidinylmethoxy]-3-methoxybenzoate as a pale yellow oil. 1H-NMR (CDCl3) δ 1.39 (3 H, t, J=7.3 Hz), 2.04–2.37 (total 5 H, m), 3.44–4.70 (16 H, series of m), 6.63 (1 H, s), 6.70–6.80 (2 H, m), 6.84 (1 H, d, J=8.3 Hz), 7.11 (1H, t, J=7.8 Hz), 7.20–7.24 (3 H, m), 7.45 (1 H, d, J=2.0 Hz), 7.59 (2 H,dd, J=8.3, 2.0 Hz), 8.01 (1 H, d, J=7.8 Hz).
Reaction SMILES: CC1C=CC(S(O[CH2:12][C@@H:13]([NH:21][C:22]([O:24][C:25]([CH3:28])([CH3:27])[CH3:26])=[O:23])[CH2:14][C@H:15]2[CH2:20][CH2:19][CH2:18][O:17][CH2:16]2)(=O)=O)=CC=1.[N-:29]=[N+:30]=[N-:31].[Na+]>CN(C=O)C.CCOC(C)=O>[N:29]([CH2:12][C@@H:13]([NH:21][C:22](=[O:23])[O:24][C:25]([CH3:28])([CH3:27])[CH3:26])[CH2:14][C@H:15]1[CH2:20][CH2:19][CH2:18][O:17][CH2:16]1)=[N+:30]=[N-:31]
Reactant: [N-]=[N+]=[N-]
Reactant: Cc1ccc(S(=O)(=O)OC[C@H](C[C@H]2CCCOC2)NC(=O)OC(C)(C)C)cc1
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)N[C@H](CN=[N+]=[N-])C[C@H]1CCCOC1
Temperature: 25 °C
Yield: 63.7 %

Procedure:
The solution of (S)-2-(tert-butoxycarbonylamino)-3-((R)-tetrahydro-2H-pyran-3-yl)propyl 4-methylbenzenesulfonate (132 mg, 0.32 mmol) and NaN3 (62 mg, 0.95 mmol) in anhydrous DMF was heated to 80° C. under N2 atmosphere for 1.5 hr, cooled to rt and diluted with EtOAc, and washed with H2O (3×20 mL), followed by brine, and dried over anhydrous Na2SO4, and filtered, and concentrated under reduced pressure. The resulted slurry was purified through flash chromatography on silica gel (eluted with gradient system: 0-30% EtOAc in hexane) to afford tert-butyl (S)-1-azido-3-((R)-tetrahydro-2H-pyran-3-yl)propan-2-ylcarbamate 58 mg, yield 64%. MS ESI +ve m/z 307 (M+Na).
Reaction SMILES: BrC1C=CC(CC[C@@](C)(S(C)(=O)=O)C(OCC)=O)=CC=1.B1(B2OC(C)(C)C(C)(C)O2)OC(C)(C)C(C)(C)O1.[CH3:39][C:40]([S:63]([CH3:66])(=[O:65])=[O:64])([CH2:46][CH2:47][C:48]1[CH:53]=[CH:52][C:51]([B:54]2[O:58][C:57]([CH3:60])([CH3:59])[C:56]([CH3:62])([CH3:61])[O:55]2)=[CH:50][CH:49]=1)[C:41]([O:43][CH2:44][CH3:45])=[O:42]>>[CH3:39][C@@:40]([S:63]([CH3:66])(=[O:64])=[O:65])([CH2:46][CH2:47][C:48]1[CH:49]=[CH:50][C:51]([B:54]2[O:58][C:57]([CH3:59])([CH3:60])[C:56]([CH3:62])([CH3:61])[O:55]2)=[CH:52][CH:53]=1)[C:41]([O:43][CH2:44][CH3:45])=[O:42]
Reactant: CCOC(=O)C(C)(CCc1ccc(B2OC(C)(C)C(C)(C)O2)cc1)S(C)(=O)=O
Agent: CC1(C)OB(B2OC(C)(C)C(C)(C)O2)OC1(C)C
Agent: CCOC(=O)[C@@](C)(CCc1ccc(Br)cc1)S(C)(=O)=O
Product: CCOC(=O)[C@@](C)(CCc1ccc(B2OC(C)(C)C(C)(C)O2)cc1)S(C)(=O)=O
Yield: 93 %

Procedure:
The title compound (10.5 g, 93%) was prepared from ethyl(2R)-4-(4-bromophenyl)-2-methyl-2-(methylsulfonyl)butanoate, (10.0 g, 27.5 mmol) and bis(pinacolato)diborane (7.69 g, 30.3 mmol) by a procedure analogous to that described for (+/−)-ethyl 2-methyl-2-(methylsulfonyl)-4-[4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl]butanoate as described in Preparation 3 step A.