Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([C:5]1[N:14]([CH2:15][C:16]2[CH:21]=[CH:20][C:19]([N:22]3[CH:26]=[CH:25][CH:24]=[C:23]3[C:27]3[NH:31][N:30]=[N:29][N:28]=3)=[C:18]([N+:32]([O-])=O)[CH:17]=2)[C:8]2=[N:9][CH:10]=[CH:11][C:12]([CH3:13])=[C:7]2[N:6]=1)[CH2:2][CH2:3][CH3:4]>[Pd].CO>[NH2:32][C:18]1[CH:17]=[C:16]([CH:21]=[CH:20][C:19]=1[N:22]1[CH:26]=[CH:25][CH:24]=[C:23]1[C:27]1[NH:31][N:30]=[N:29][N:28]=1)[CH2:15][N:14]1[C:8]2=[N:9][CH:10]=[CH:11][C:12]([CH3:13])=[C:7]2[N:6]=[C:5]1[CH2:1][CH2:2][CH2:3][CH3:4]
Reactant: CCCCc1nc2c(C)ccnc2n1Cc1ccc(-n2cccc2-c2nnn[nH]2)c([N+](=O)[O-])c1
Agent: [Pd]
Solvent: CO
Product: CCCCc1nc2c(C)ccnc2n1Cc1ccc(-n2cccc2-c2nnn[nH]2)c(N)c1
Temperature: 25 °C
Reaction time: 5 h
Yield: 95.9 %

Procedure:
A mixture of 2-butyl-7-methyl-3-[3-nitro-4-[2-(1H-tetrazol-5-yl)-1-pyrrolyl]benzyl]-3H-imidazo[4,5-b]pyridine (145 mg), 10% palladium on carbon (30 mg), and methanol (5 ml) was stirred at room temperature for 5 hours under hydrogen atmosphere (4 atom). After vacuum filtration, the filtrate was evaporated in vacuo to give a yellow residue of 3-[3-amino-4-[2-(1H-tetrazol-5-yl)-1-pyrrolyl]benzyl]-2-butyl-7-methyl-3H-imidazo[4,5-b]pyridine (130 mg). This residue was treated with acetic anhydride (1 ml) and pyridine (2 ml) at room temperature for 2 hours. The reaction mixture was evaporated in vacuo and purified by preparative thin layer chromatography (ethyl acetate-acetic acid=19:1) to give a brownish viscous oil (65 ml). To a solution of the oil in ethanol (2 ml) was added a solution of sodium hydrogencarbonate (12.8 mg) in water (1 ml) and the mixture was evaporated in vacuo. The residue was dissolved in water (2 ml) and lyophilized to afford sodium salt of 3-[3-acetamido-4-[2-(1H-tetrazol-5-yl)-1-pyrrolyl]benzyl]-2-butyl-7-methyl-3H-imidazo[4,5-b]pyridine (65 mg) as an amorphous powder.
Reaction SMILES: CO[C:3]1[CH:8]=[C:7](/[CH:9]=[CH:10]/[C:11]([CH2:13][C:14](/[CH:16]=[CH:17]/[C:18]2[CH:23]=[CH:22][C:21](O)=[C:20]([O:25]C)C=2)=O)=O)[CH:6]=[CH:5][C:4]=1O.[OH2:28]>>[C:20]([OH:25])(=[O:28])[CH2:21][CH2:22][CH2:23][CH2:18][CH2:17][CH2:16][CH2:14]/[CH:13]=[CH:11]\[CH2:10][CH2:9][CH2:7][CH2:6][CH2:5][CH2:4][CH2:3][CH3:8]
Reactant: O
Reactant: COc1cc(/C=C/C(=O)CC(=O)/C=C/c2ccc(O)c(OC)c2)ccc1O
Product: CCCCCCCC/C=C\CCCCCCCC(=O)O

Procedure:
220 g HALAD™ 344 (water soluble polymer)
Reaction SMILES: [CH2:1]([O:3][C:4]([CH:6]1[C:39]2[C:34](=[CH:35][CH:36]=[CH:37][CH:38]=2)[C:8]2([CH2:13][CH2:12][N:11]([C:14](=[O:33])[CH:15]([NH:25]C(OC(C)(C)C)=O)[CH2:16][CH2:17][CH2:18][C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=3)[CH2:10][CH2:9]2)[CH2:7]1)=[O:5])[CH3:2].C(O)(C(F)(F)F)=O.[C:47]([NH:54][C:55]([CH3:60])([C:57](O)=[O:58])[CH3:56])([O:49][C:50]([CH3:53])([CH3:52])[CH3:51])=[O:48].C(Cl)CCl.C1C=CC2N(O)N=NC=2C=1.CN1CCOCC1>>[CH2:1]([O:3][C:4]([CH:6]1[C:39]2[C:34](=[CH:35][CH:36]=[CH:37][CH:38]=2)[C:8]2([CH2:13][CH2:12][N:11]([C:14](=[O:33])[CH:15]([NH:25][C:57](=[O:58])[C:55]([NH:54][C:47]([O:49][C:50]([CH3:53])([CH3:52])[CH3:51])=[O:48])([CH3:60])[CH3:56])[CH2:16][CH2:17][CH2:18][C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=3)[CH2:10][CH2:9]2)[CH2:7]1)=[O:5])[CH3:2]
Reactant: CC(C)(C)OC(=O)NC(C)(C)C(=O)O
Reactant: CCOC(=O)C1CC2(CCN(C(=O)C(CCCc3ccccc3)NC(=O)OC(C)(C)C)CC2)c2ccccc21
Agent: On1nnc2ccccc21
Solvent: ClCCCl
Solvent: O=C(O)C(F)(F)F
Solvent: CN1CCOCC1
Product: CCOC(=O)C1CC2(CCN(C(=O)C(CCCc3ccccc3)NC(=O)C(C)(C)NC(=O)OC(C)(C)C)CC2)c2ccccc21
Yield: 62.1 %

Procedure:
The title compound from Step A (155 mg, 0.29 mmol) was treated with TFA as in Step A and the residue was reacted with BOC-α-methyl alanine (73.5 mg, 0.377 mmol), EDC (72.0 mg, 0.377 mmol), HOBT (53 mg, 0.377 mmol), NMM (0.032 ml, 0.290 mmol) according to the procedure used for Example 1, Step A. Flash chromatography provided the title compound (112 mg, 0.18 mmol).
Reaction SMILES: [CH3:1][C:2]([CH3:23])([CH3:22])[C:3](=[O:21])[CH2:4][N:5]1[CH2:12][CH:11]2[O:13][CH:7]([CH2:8][N:9](C(OC(C)(C)C)=O)[CH2:10]2)[CH2:6]1.Cl.C(#N)C.C([O-])([O-])=O.[K+].[K+]>C(OCC)(=O)C>[CH3:1][C:2]([CH3:23])([CH3:22])[C:3](=[O:21])[CH2:4][N:5]1[CH2:12][CH:11]2[O:13][CH:7]([CH2:8][NH:9][CH2:10]2)[CH2:6]1
Reactant: CC(C)(C)OC(=O)N1CC2CN(CC(=O)C(C)(C)C)CC(C1)O2
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Solvent: CCOC(C)=O
Product: CC(C)(C)C(=O)CN1CC2CNCC(C1)O2
Temperature: 0 °C
Reaction time: 5 h
Yield: 86.5 %

Procedure:
A solution of tert-butyl 7-(3,3-dimethyl-2-oxoburyl)-9-oxa-3,7-diazabicyclo[3.3.1]nonane-3-carboxylate (from step (i) above; 0.265 g, 0.812 mmol) in ethyl acetate (10 mL) was treated, at 0° C., with ethyl acetate saturated with gaseous hydrochloric acid. The mixture was stirred at 0° C. for 5 h, and then evaporated. Acetonitrile (15 mL) and K2CO3 (1 g, 7.2 mmol) were added, and the mixture was stirred overnight before being filtered and evaporated to yield 0.159 g (86%) of the sub-title compound.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:13]=[CH:12][C:6]([O:7][CH2:8][CH:9]2[CH2:11][O:10]2)=[CH:5][CH:4]=1.Br.Br.[F:16][C:17]1[CH:22]=[CH:21][C:20]([CH2:23][N:24]2[C:28]3[CH:29]=[CH:30][CH:31]=[CH:32][C:27]=3[N:26]=[C:25]2[NH:33][CH:34]2[CH2:39][CH2:38][NH:37][CH2:36][CH2:35]2)=[CH:19][CH:18]=1.C(=O)([O-])[O-].[Na+].[Na+].CO>C1C=CC=CC=1>[F:16][C:17]1[CH:22]=[CH:21][C:20]([CH2:23][N:24]2[C:28]3[CH:29]=[CH:30][CH:31]=[CH:32][C:27]=3[N:26]=[C:25]2[NH:33][CH:34]2[CH2:35][CH2:36][N:37]([CH2:11][CH:9]([CH2:8][O:7][C:6]3[CH:12]=[CH:13][C:3]([O:2][CH3:1])=[CH:4][CH:5]=3)[OH:10])[CH2:38][CH2:39]2)=[CH:19][CH:18]=1
Reactant: COc1ccc(OCC2CO2)cc1
Reactant: Fc1ccc(Cn2c(NC3CCNCC3)nc3ccccc32)cc1
Agent: Br
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: c1ccccc1
Solvent: CO
Product: COc1ccc(OCC(O)CN2CCC(Nc3nc4ccccc4n3Cc3ccc(F)cc3)CC2)cc1
Yield: 51 %

Procedure:
A mixture of 3.6 parts of [(4-methoxyphenoxy)methyl]oxirane, 4.9 parts of 1-[(4-fluorophenyl)methyl]-N-(4-piperidinyl)-1H-benzimidazol-2-amine dihydrobromide, 2.1 parts of sodium carbonate, 40 parts of methanol and 90 parts of benzene is stirred and refluxed overnight. The reaction mixture is filtered and the filtrate is evaporated. The residue is crystallized from a mixture of 2-propanone and 2,2'-oxybispropane. The product is filtered off and dried, yielding 2.6 parts (51%) of 4-[1-(4-fluorophenylmethyl)-1H-benzimidazol-2-ylamino]-α-(4-methoxyphenoxymethyl)-1-piperidineethanol; mp. 174.5° C.
Reaction SMILES: [O:1]([C:8]1[CH:13]=[CH:12][C:11](B(O)O)=[CH:10][CH:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Br[C:18]1[C:19]([NH2:24])=[N:20][CH:21]=[CH:22][CH:23]=1.C(=O)([O-])[O-].[Na+].[Na+]>COCCOC.O.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>[O:1]([C:8]1[CH:13]=[CH:12][C:11]([C:18]2[C:19]([NH2:24])=[N:20][CH:21]=[CH:22][CH:23]=2)=[CH:10][CH:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: Nc1ncccc1Br
Reactant: OB(O)c1ccc(Oc2ccccc2)cc1
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: O
Solvent: COCCOC
Product: Nc1ncccc1-c1ccc(Oc2ccccc2)cc1
Temperature: 80 °C
Reaction time: 20 h
Yield: 89.2 %

Procedure:
A mixture of 4-phenoxyphenylboronic acid (40.2 g), 3-bromopyridin-2-amine (25 g), tetrakis(triphenylphosphine)palladium(0) (5.01 g) and sodium carbonate (30.6 g) in DME (722 mL) and water (145 mL) was stirred at 80° C. under N2 for 20 hr. NH silica gel was added and the mixture was concentrated in vacuo. The residue was purified by column chromatography (NH silica gel, eluted with EtOAc in hexane) to give a white solid. The solid was crystallized from EtOAc and hexane to give the title compound (33.8 g) as a white solid.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[NH:8][C:9](=[S:23])[NH:10][C:11]1[S:12][CH:13]=[C:14]([C:16](=O)[C:17]([O:19][CH2:20][CH3:21])=[O:18])[N:15]=1.[S:24]1[CH2:30][C:28](=[O:29])[N:27]([CH2:31][C:32]([OH:34])=[O:33])[C:25]1=[S:26].[Cl-].[NH4+].N>C(O)C>[CH2:20]([O:19][C:17]([C:16](=[C:30]1[S:24][C:25](=[S:26])[N:27]([CH2:31][C:32]([OH:34])=[O:33])[C:28]1=[O:29])[C:14]1[N:15]=[C:11]([NH:10][C:9]([NH:8][C:3]2[CH:4]=[CH:5][CH:6]=[CH:7][C:2]=2[F:1])=[S:23])[S:12][CH:13]=1)=[O:18])[CH3:21]
Reactant: CCOC(=O)C(=O)c1csc(NC(=S)Nc2ccccc2F)n1
Reactant: O=C(O)CN1C(=O)CSC1=S
Agent: N
Agent: [Cl-]
Agent: [NH4+]
Solvent: CCO
Product: CCOC(=O)C(=C1SC(=S)N(CC(=O)O)C1=O)c1csc(NC(=S)Nc2ccccc2F)n1

Procedure:
Following a procedure similar to that described in Example 1, the desired compound was prepared from 7 g of ethyl 2-(3-o-fluorophenylthioureido)thiazol-4-ylglyoxylate, 3.8g of rhodanine-3-acetic acid, 2 g of ammonium chloride, ml of 28% v/v aqueous ammonia and 100 ml of ethanol. The resulting product was a yellow powder having the following physical properties.
Reaction SMILES: ClC1C=C2[C:8](=[CH:9][CH:10]=1)[N:7](S(C1C=CC=CC=1)(=O)=O)C(C(OCC)=O)=C2S(Cl)(=O)=O.[Br:29][C:30]1[CH:31]=[C:32]2[C:36](=[CH:37][CH:38]=1)[N:35](S(C1C=CC=CC=1)(=O)=O)[C:34]([C:48]([O:50]CC)=O)=[C:33]2[S:53](Cl)(=[O:55])=[O:54].[NH:57]1CCOCC1.N1CCC1>>[N:7]1([S:53]([C:33]2[C:32]3[C:36](=[CH:37][CH:38]=[C:30]([Br:29])[CH:31]=3)[NH:35][C:34]=2[C:48]([NH2:57])=[O:50])(=[O:54])=[O:55])[CH2:8][CH2:9][CH2:10]1
Reactant: C1COCCN1
Reactant: CCOC(=O)c1c(S(=O)(=O)Cl)c2cc(Cl)ccc2n1S(=O)(=O)c1ccccc1
Reactant: CCOC(=O)c1c(S(=O)(=O)Cl)c2cc(Br)ccc2n1S(=O)(=O)c1ccccc1
Agent: C1CNC1
Product: NC(=O)c1[nH]c2ccc(Br)cc2c1S(=O)(=O)N1CCC1

Procedure:
Following the procedures described in Steps D and E of Example 1, replacing in Step D ethyl 5-chloro-3-(chlorosulfonyl)-1-(phenylsulfonyl)-1H-indole-2-carboxylate with ethyl 5-bromo-3-(chlorosulfonyl)-1-(phenylsulfonyl)-1H-indole-2-carboxylate, and morpholine with azetidine, the title compound was obtained. HRMS (ES) exact mass calculated for C12H13BrN3O3S (M+H+): 357.9856. Found 357.9859.
Reaction SMILES: [CH2:1]([O:8][C:9](=[O:33])[C@H:10]([CH3:32])[NH:11][C:12](=[O:31])[C@H:13]([CH3:30])[N:14]([C:16](=[O:29])[C@H:17]([CH:26]([CH3:28])[CH3:27])[NH:18]C(OC(C)(C)C)=O)[CH3:15])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.FC(F)(F)C(O)=O.C(=O)(O)[O-].[Na+]>ClCCl>[CH2:1]([O:8][C:9](=[O:33])[C@H:10]([CH3:32])[NH:11][C:12](=[O:31])[C@H:13]([CH3:30])[N:14]([C:16](=[O:29])[C@H:17]([CH:26]([CH3:28])[CH3:27])[NH2:18])[CH3:15])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CC(C)[C@H](NC(=O)OC(C)(C)C)C(=O)N(C)[C@@H](C)C(=O)N[C@@H](C)C(=O)OCc1ccccc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CC(C)[C@H](N)C(=O)N(C)[C@@H](C)C(=O)N[C@@H](C)C(=O)OCc1ccccc1
Temperature: -15 °C

Procedure:
A stirred solution of 17 g (0.0367 mole) Boc-L-valyl-N-methyl-L-alanyl-L-alanine benzyl ester in 170 ml of dry dichloromethane was cooled at -10° C. as 85 ml of trifluoroacetic acid, previously cooled at -15° C., was added. After 16 hours -5° C., the reaction was carefully poured with good stirring into a mixture of 93 g of sodium bicarbonate, ice, and 250 ml of dichloromethane. The organic layer was separated and the aqueous layer was extracted with another 75 ml of dichloromethane. The combined organic layers were washed with 3×75 ml of saturated sodium bicarbonate solution, dried over magnesium sulfate, and evaporated to give 12.8 g (96% of theory) of crude product which was used in step 5 without further purification. FAB m.s. showed a molecular ion peak at 364.
Reaction SMILES: FC(F)(F)C(O)=O.[Cl:8][C:9]1[C:10]([F:38])=[C:11]([CH:15]2[C:19]([C:22]3[CH:27]=[CH:26][C:25]([Cl:28])=[CH:24][C:23]=3[F:29])([C:20]#[N:21])[CH:18]([CH2:30][C:31]([CH3:34])([CH3:33])[CH3:32])[NH:17][CH:16]2[C:35]([OH:37])=O)[CH:12]=[CH:13][CH:14]=1.Cl.[NH:40]1[CH2:43][CH:42]([OH:44])[CH2:41]1.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C>C(Cl)Cl>[Cl:8][C:9]1[C:10]([F:38])=[C:11]([CH:15]2[CH:16]([C:35]([N:40]3[CH2:43][CH:42]([OH:44])[CH2:41]3)=[O:37])[NH:17][CH:18]([CH2:30][C:31]([CH3:32])([CH3:34])[CH3:33])[C:19]2([C:22]2[CH:27]=[CH:26][C:25]([Cl:28])=[CH:24][C:23]=2[F:29])[C:20]#[N:21])[CH:12]=[CH:13][CH:14]=1
Reactant: CC(C)(C)CC1NC(C(=O)O)C(c2cccc(Cl)c2F)C1(C#N)c1ccc(Cl)cc1F
Reactant: OC1CNC1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Product: CC(C)(C)CC1NC(C(=O)N2CC(O)C2)C(c2cccc(Cl)c2F)C1(C#N)c1ccc(Cl)cc1F
Yield: 89 %

Procedure:
In a manner similar to the method described in Examples 1e, rac-(2R,3S,4R,5S)-3-(3-chloro-2-fluoro-phenyl)-4-(4-chloro-2-fluoro-phenyl)-4-cyano-5-(2,2-dimethyl-propyl)-pyrrolidine-2-carboxylic acid trifluoroacetic acid prepared in Example 52c (0.25 g, 0.43 mmol) was reacted with azetidin-3-ol hydrochloride (Matrix) (0.25 g, 2.7 mmol), HATU (0.4 g, 1 mmol) and iPr2NEt (0.6 g, 4.6 mmol) in CH2Cl2 at room temperature for 20 h to give rac-(2S,3R,4S,5R)-4-(3-chloro-2-fluoro-phenyl)-3-(4-chloro-2-fluoro-phenyl)-2-(2,2-dimethyl-propyl)-5-(3-hydroxy-azetidine-1-carbonyl)-pyrrolidine-3-carbonitrile as a white solid (0.2 g, 89%).
Reaction SMILES: [CH:1]([O:4][C:5](=[O:23])[NH:6][C:7]1[CH:8]=[C:9]2[N:15]=[C:14]([C:16]3[CH:21]=[CH:20][CH:19]=[C:18]([NH2:22])[CH:17]=3)[NH:13][C:10]2=[N:11][CH:12]=1)([CH3:3])[CH3:2].[CH3:24][S:25](Cl)(=[O:27])=[O:26].N1C=CC=CC=1.Cl>CN1C(=O)CCC1>[CH:1]([O:4][C:5](=[O:23])[NH:6][C:7]1[CH:8]=[C:9]2[N:15]=[C:14]([C:16]3[CH:21]=[CH:20][CH:19]=[C:18]([NH:22][S:25]([CH3:24])(=[O:27])=[O:26])[CH:17]=3)[NH:13][C:10]2=[N:11][CH:12]=1)([CH3:3])[CH3:2]
Reactant: CS(=O)(=O)Cl
Reactant: CC(C)OC(=O)Nc1cnc2[nH]c(-c3cccc(N)c3)nc2c1
Agent: Cl
Solvent: c1ccncc1
Solvent: CN1CCCC1=O
Product: CC(C)OC(=O)Nc1cnc2[nH]c(-c3cccc(NS(C)(=O)=O)c3)nc2c1
Temperature: 0 °C
Reaction time: 1 h

Procedure:
45 mg of the product from example 5-1 were dissolved in 1 ml dry NMP and cooled to 0° C. 18.3 mg methylsulfonylchloride were added and the mixture was stirred for 1 hr at 0° C. and another hr at room temperature. 12 μl (1 equivalent) pyridine were added and stirring was continued for another 60 min. After addition of 0.1 ml conc. HCl, the solvent was removed under vacuum and the residue purified by chromatography on C-18 RP silica in methanol water mixtures.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([S:9](Cl)(=[O:11])=[O:10])=[CH:5][CH:4]=1.[CH3:13][O:14][C:15]1[C:24]2[C:19](=[CH:20][CH:21]=[CH:22][CH:23]=2)[CH:18]=[CH:17][CH:16]=1.ClC1C=CC=CC=1Cl.Cl>[N+](C)([O-])=O>[CH3:13][O:14][C:15]1[C:24]2[C:19](=[CH:20][CH:21]=[CH:22][CH:23]=2)[C:18]([S:9]([C:6]2[CH:5]=[CH:4][C:3]([O:2][CH3:1])=[CH:8][CH:7]=2)(=[O:11])=[O:10])=[CH:17][CH:16]=1
Reactant: COc1ccc(S(=O)(=O)Cl)cc1
Reactant: COc1cccc2ccccc12
Agent: Cl
Solvent: Clc1ccccc1Cl
Solvent: C[N+](=O)[O-]
Product: COc1ccc(S(=O)(=O)c2ccc(OC)c3ccccc23)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 88 %

Procedure:
p-Methoxybenzenesulfonyl chloride, 2.0 mol, anhydrous stannic chloride, 2.25 mol, 1-methoxynaphthalene, 2.25 mol, and 3 1 of o-dichlorobenzene were mixed at room temperature under nitrogen. The mixture was stirred at room temperature overnight (ca 7 hours needed) and decomposed with 3N hydrochloric acid. The organic layer was diluted with 1250 ml of nitromethane and washed with 2 portions of 1N hydrochloric acid followed by pure water. The organic layer was treated with magnesium sulfate, filtered, evaporated, extracted with hot toluene and dried at 120° C. for two hours to give 577 g, 88% yield, m.p. 160°-162° C.
Reaction SMILES: [C:1]([O:5][C:6](=[O:20])[CH2:7][CH2:8][C:9]1[C:14]([CH3:15])=[CH:13][C:12]([C:16](=O)[NH2:17])=[CH:11][C:10]=1[CH3:19])([CH3:4])([CH3:3])[CH3:2].C(N(CC)CC)C.FC(F)(F)C(OC(=O)C(F)(F)F)=O>C(Cl)Cl>[C:1]([O:5][C:6](=[O:20])[CH2:7][CH2:8][C:9]1[C:10]([CH3:19])=[CH:11][C:12]([C:16]#[N:17])=[CH:13][C:14]=1[CH3:15])([CH3:4])([CH3:3])[CH3:2]
Reactant: Cc1cc(C(N)=O)cc(C)c1CCC(=O)OC(C)(C)C
Solvent: ClCCl
Solvent: O=C(OC(=O)C(F)(F)F)C(F)(F)F
Solvent: CCN(CC)CC
Product: Cc1cc(C#N)cc(C)c1CCC(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 1 h
Yield: 64.3 %

Procedure:
To an ice-cooled solution of 3-(4-carbamoyl-2,6-dimethyl-phenyl)-propionic acid tert-butyl ester (7.00 g, 25.2 mmol) and triethylamine (7.66 g, 75.7 mmol) in DCM (100 mL), trifluoroacetic anhydride (6.06 g, 28.8 mmol) is added slowly so that the reaction temperature stays below 15° C. The clear yellow solution is stirred at rt for 1 h before it is washed twice with water (100 mL) and concentrated. The crude product is purified by recrystallisation from methanol to give 3-(4-cyano-2,6-dimethyl-phenyl)-propionic acid tert-butyl ester (4.2 g) as a white solid, 1H NMR (CDCl3): δ 1.48 (s, 9H), 2.33-2.37 (m, 2H), 2.38 (s, 6H), 2.94-3.01 (m, 2H), 7.31 (s, 2H).
Reaction SMILES: [Li]CCCC.[CH2:6]([C:9]1[CH:10]=[N:11][C:12]([C:15]2[CH:20]=[CH:19][C:18]([CH2:21][CH2:22][C:23]3[CH:28]=[C:27]([F:29])[CH:26]=[C:25]([F:30])[CH:24]=3)=[CH:17][CH:16]=2)=[N:13][CH:14]=1)[CH2:7][CH3:8].[CH3:31][N:32](CCN(C)C)C.II>C1COCC1.C(OCC)C.O>[CH2:6]([C:9]1[CH:14]=[N:13][C:12]([C:15]2[CH:20]=[CH:19][C:18]([CH2:21][CH2:22][C:23]3[CH:24]=[C:25]([F:30])[C:26]([C:31]#[N:32])=[C:27]([F:29])[CH:28]=3)=[CH:17][CH:16]=2)=[N:11][CH:10]=1)[CH2:7][CH3:8]
Reactant: CN(C)CCN(C)C
Reactant: CCCc1cnc(-c2ccc(CCc3cc(F)cc(F)c3)cc2)nc1
Agent: II
Agent: [Li]CCCC
Solvent: O
Solvent: CCOCC
Solvent: C1CCOC1
Product: CCCc1cnc(-c2ccc(CCc3cc(F)c(C#N)c(F)c3)cc2)nc1
Temperature: 170 °C
Reaction time: 0.5 h

Procedure:
0.1 m of n-BuLi (1,5 M in hexane) is added dropwise to a solution of 0.1 m of 1-[p-(5-n-propyl-2-pyrimidinyl)-phenyl]-2-(3,5-difluorophenyl)ethane (prepared in accordance with scheme 1) and 0.1 m of TMEDA in 300 ml of THF at approximately -90° . Stirring is carried out for a further 30 min at this temperature and then a solution of 0.1 m of I2 in 70 ml of THF is slowly added. After addition is complete, the solution is allowed to heat up to -20° and hydrolyzation is carried out with H2O. The product is completely dissolved by adding diethyl ether and excess I2 is removed by washing with sodium thiosulfate solution and H2O. After evaporating down, the product is left behind as a residue and without further purification, is heated with 0.12 m of (CuCN)x and 100 ml of NMP for 4 h at 170° C. in an oil bath. After this time, water and CH2CH2 are added to the cooled reaction mixture, and the organic phase is washed, dried and evaporated down. The pure product can be obtained by chromatography and crystallization. 1-[p-(5-n-propyl-2-pyrimidinyl)-phenyl]-2-(4-cyano-3,5difluorophenyl)ethane is obtained.
Reaction SMILES: [Cl:1][C:2]1[CH:11]=[C:10](I)[C:5]([C:6]([O:8][CH3:9])=[O:7])=[C:4]([F:13])[CH:3]=1.[C:14]([Cu])#[N:15].CCOC(C)=O>CN(C=O)C>[Cl:1][C:2]1[CH:3]=[C:4]([F:13])[C:5]([C:6]([O:8][CH3:9])=[O:7])=[C:10]([C:14]#[N:15])[CH:11]=1
Reactant: N#C[Cu]
Reactant: COC(=O)c1c(F)cc(Cl)cc1I
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: COC(=O)c1c(F)cc(Cl)cc1C#N
Temperature: 110 °C
Yield: 22.3 %

Procedure:
Methyl 4-chloro-2-fluoro-6-iodobenzoate (1.99 g, 10.6 mmol) was dissolved in DMF (12 mL). CuCN (2.84 g, 31.7 mmol) was added and the suspension was heated under microwave at 110° C. for 18 min. EtOAc was added and the suspension was filtered through a piece of filter paper. The filtrate was washed three times with water. The aqueous layers were combined and extracted once with EtOAc. The organic layers were combined, dried over Na2SO4 and concentrated. The residue was purified on a silica gel column (heptane:EtOAc 1:0 to 9:1) to give the product as a colorless solid (505 mg). 1H NMR (400 MHz, CDCl3) δ ppm 7.56 (s, 1H), 7.40 (d, 1H, J=8 Hz), 4.00 (s, 3H); 13C NMR (100 MHz, CDCl3) δ ppm 161.78 (d, J=58 Hz), 159.44, 139.16 (d, J=11 Hz), 129.96, 121.99, 121.74, 115.48, 114.72, 53.04.
Reaction SMILES: C([C:3]1([NH2:10])[C:8]([Br:9])=[CH:7][N:6]=[CH:5][CH2:4]1)C.[CH3:11][C:12]([CH:19]1[CH2:24][CH2:23][C:22](=O)[CH2:21][CH2:20]1)([CH3:18])[CH2:13][C:14]([CH3:17])([CH3:16])[CH3:15].[CH:26](OC(C)C)(C)[CH3:27]>>[CH2:26]([C:5]1[CH:4]=[C:3]([NH:10][C@H:22]2[CH2:23][CH2:24][C@@H:19]([C:12]([CH3:18])([CH3:11])[CH2:13][C:14]([CH3:17])([CH3:16])[CH3:15])[CH2:20][CH2:21]2)[C:8]([Br:9])=[CH:7][N:6]=1)[CH3:27]
Reactant: CCC1(N)CC=NC=C1Br
Reactant: CC(C)(C)CC(C)(C)C1CCC(=O)CC1
Reactant: CC(C)OC(C)C
Product: CCc1cc(N[C@H]2CC[C@@H](C(C)(C)CC(C)(C)C)CC2)c(Br)cn1

Procedure:
As Example 75, but using 2.01 g (10 mmol) of 4-ethyl-4-amino-5-bromopyridine instead of 2-ethyl-3-bromo-4-aminopyridine and 4.2 g (20 mmol) of 4-(1,1,3,3-tetramethylbutyl)cyclohexanone instead of 4-phenylcyclohexanone. Yield: 1.9 g (48%); Rf =0.39 (diisopropyl ether)
Reaction SMILES: [CH2:1]([NH:13][C:14]([N:16]1[CH:20]=[CH:19]N=[CH:17]1)=[O:15])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH3:12].CNC[C@@H:24]([C@H:26]([C@@H:28]([C@@H:30](CO)[OH:31])[OH:29])[OH:27])[OH:25].C[OH:35]>>[CH2:1]([NH:13][C:14]([N:16]([CH3:17])[CH2:20][C@@H:19]([C@H:24]([C@@H:26]([C@@H:28]([CH2:30][OH:31])[OH:29])[OH:27])[OH:25])[OH:35])=[O:15])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH3:12]
Reactant: CNC[C@H](O)[C@@H](O)[C@H](O)[C@H](O)CO
Reactant: CO
Reactant: CCCCCCCCCCCCNC(=O)n1ccnc1
Product: CCCCCCCCCCCCNC(=O)N(C)C[C@H](O)[C@@H](O)[C@H](O)[C@H](O)CO
Yield: 80 %

Procedure:
42 g of 1-N-(dodecylaminocarbonyl)imidazole and 32 g of N-methyl-D-glucamine were suspended, under an inert atmosphere, in 400 cm3 of methanol. The reaction mixture was kept stirring at reflux for 4 hours. The reaction mixture was cooled with an ice bath and the precipitate was then filtered off. It was washed with 500 cm3 of water and then dried. 49 g (80% yield) of N-dodecylaminocarbonyl-N-methyl-D-glucamine were obtained in the form of a white powder.
Reaction SMILES: [Cl:1][C:2]1[CH:13]=[CH:12][C:5]2[C:6](=[O:11])O[C:8](=O)[NH:9][C:4]=2[CH:3]=1.[H-].[Na+].BrC[C:18]([O:20][CH2:21][CH3:22])=[O:19].[NH3:23].Cl>CN(C)C=O>[C:6]([C:5]1[CH:12]=[CH:13][C:2]([Cl:1])=[CH:3][C:4]=1[NH:9][CH2:8][C:18]([O:20][CH2:21][CH3:22])=[O:19])(=[O:11])[NH2:23]
Reactant: CCOC(=O)CBr
Reactant: N
Reactant: O=c1[nH]c2cc(Cl)ccc2c(=O)o1
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CCOC(=O)CNc1cc(Cl)ccc1C(N)=O
Temperature: 5 °C
Reaction time: 0.5 h

Procedure:
To a solution of 7-chloro-2H-3,1-benzoxazine-2,4(1H)-dione (330 g) in N,N-dimethylformamide (3.3 l) was added sodium hydride (60% in mineral oil, 86.8 g) below 20° C. and the mixture was stirred at 5° C. for 30 minutes. To this solution was added ethyl bromoacetate (222 ml) at 10° C. over a 30-minute period and the resulting mixture was stirred at room temperature for 1.5 hours. To this reaction mixture was added 28% aqueous ammonia (696 ml) below 10° C. and the resulting mixture was stirred at 5° C. for 20 minutes. The mixture was poured into 1N hydrochloric acid (16.5 l). The precipitates were collected by filtration, and washed in turn with water (3 times) and diethyl ether to give ethyl N-(2-carbamoyl-5-chlorophenyl)aminoacetate (360 g).
Reaction SMILES: [Br:1][C:2]1[C:3]([Cl:13])=[C:4]2[C:9](=[CH:10][CH:11]=1)[NH:8][C:7](=O)[CH2:6][CH2:5]2.COC1C=CC(P2(SP(C3C=CC(OC)=CC=3)(=S)S2)=[S:23])=CC=1>C1(C)C=CC=CC=1>[Br:1][C:2]1[C:3]([Cl:13])=[C:4]2[C:9](=[CH:10][CH:11]=1)[NH:8][C:7](=[S:23])[CH2:6][CH2:5]2
Reactant: COc1ccc(P2(=S)SP(=S)(c3ccc(OC)cc3)S2)cc1
Reactant: O=C1CCc2c(ccc(Br)c2Cl)N1
Solvent: Cc1ccccc1
Product: S=C1CCc2c(ccc(Br)c2Cl)N1
Temperature: 100 °C

Procedure:
To a stirred solution of 6-bromo-5-chloro-3,4-dihydroquinolin-2(1H)-one (143-5; 1.2 g, 0.0046 mol) in toluene (20 mL) was added Lawesson's reagent (1.8 g, 0.0046 mol). Reaction mass was refluxed at 100° C. for 12 h. The reaction mixture was concentrated and directly purified by silica gel column chromatography to obtain title compound 6-bromo-5-chloro-3,4-dihydroquinoline-2(1H)-thione. MS (M+1): 277.8.