Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C[O:2][C:3]([C:5]1[CH:6]=[C:7]2[C:11](=[CH:12][CH:13]=1)[CH2:10][C@H:9]([NH:14][C:15]([O:17][CH2:18][C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1)=[O:16])[CH2:8]2)=O.[BH4-].[Li+]>C1COCC1.CO>[OH:2][CH2:3][C:5]1[CH:6]=[C:7]2[C:11](=[CH:12][CH:13]=1)[CH2:10][C@H:9]([NH:14][C:15](=[O:16])[O:17][CH2:18][C:19]1[CH:20]=[CH:21][CH:22]=[CH:23][CH:24]=1)[CH2:8]2
Reactant: COC(=O)c1ccc2c(c1)C[C@@H](NC(=O)OCc1ccccc1)C2
Agent: [BH4-]
Agent: [Li+]
Solvent: C1CCOC1
Solvent: CO
Product: O=C(N[C@H]1Cc2ccc(CO)cc2C1)OCc1ccccc1
Reaction time: 8 h

Procedure:
(S)-methyl-2-(benzyloxycarbonylamino)-2,3-dihydro-1H-indene-5-carboxylate (15.37 mmol, 5.00 g) was dissolved in THF (50 mL) and the vessel purged with nitrogen. Lithium Borohydride (2M, 30.7 mmol, 15.37 mL) was added dropwise followed by methanol (30.7 mmol, 0.985 g). The solution was stirred at room temperature for 6 h before additional lithium borohydride (2M, 15.35 mmol, 7.69 mL) was added. Stirring was continued overnight. A further amount of lithium borohydride was added (2M, 15.35 mmol, 7.69 mL) and stirring continued for 1 h. The reaction was quenched with MeOH then water and concentrated to a light brown residue. This was partitioned between EtOAc (150 mL) and 1N HCl (150 mL) and the phases mixed and separated. The aqueous layer was twice extracted with ethylacetate and combined organics dried, filtered and concentrated to give a brown gum which was dissolved in MeOH (100 mL) and stirred with activated carbon. Filtration through a dicalite pad followed by concentration and purification on silica eluting with 0-2% MeOH/DCM gave (S)-benzyl 5-(hydroxymethyl)-2,3-dihydro-1H-inden-2-ylcarbamate as a beige solid (2.2, 48%). 1H NMR (400 MHz, CDCl3) δ 1.66 (t, 1H) 2.81 (m, 2H) 3.28 (m, 2H) 4.52 (bs, 1H) 4.65 (d, 2H) 4.95 (bs, 1H) 5.09 (bs, 2H) 7.15-7.37 (bm, 8H).
Reaction SMILES: [H-].[Na+].[C:3]1(=[O:10])[NH:8][C:7](=[O:9])[CH2:6][CH2:5][CH2:4]1.Br[CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH:21]=[CH2:22].O>CS(C)=O>[CH2:22]([N:8]1[C:7](=[O:9])[CH2:6][CH2:5][CH2:4][C:3]1=[O:10])[CH2:21][CH2:20][CH2:19][CH2:18][CH2:17][CH2:16][CH2:15][CH2:14][CH:13]=[CH2:12]
Reactant: C=CCCCCCCCCCBr
Reactant: O=C1CCCC(=O)N1
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CS(C)=O
Product: C=CCCCCCCCCCN1C(=O)CCCC1=O
Reaction time: 0.33 h
Yield: 58.6 %

Procedure:
This example illustrates a synthesis of N-(11,10-Oxidoundecyl)glutarimide (inventive compound no. 1611). Sodium hydride (95%) (168 mg, 7 mmol) was added to a solution of glutarimide (565.6 mg, 5 mmol) in dimethyl sulfoxide (15 mL). After 20 minutes of stirring, 1-bromundec-10-ene (1.165 g, 5 mmol) was added and stirred for 12 hours at room temperature. The reaction mixture was then poured into a separatory funnel containing 100 mL of water and extracted with dichlormethane (5×75 mL). The organic extracts were combined, washed with water (50 mL) and brine (50 mL), dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The crude product obtained was further purified by flash chromatography over silica gel using 20% ethyl acetate/hexane eluant to yield 0.777 g (58.6% yield) N-(10-Undecenyl)glutarimide (inventive compound no. 1610).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([Cl:8])[C:5]([O:9][CH2:10][C:11]#[CH:12])=[CH:4][C:3]=1[N:13]1[C:22](=[O:23])[N:16]2[CH2:17][CH2:18][CH2:19][CH:20](O)[C:15]2=[N:14]1.C(N(S(F)(F)[F:30])CC)C>ClCCl>[Cl:1][C:2]1[CH:7]=[C:6]([Cl:8])[C:5]([O:9][CH2:10][C:11]#[CH:12])=[CH:4][C:3]=1[N:13]1[C:22](=[O:23])[N:16]2[CH2:17][CH2:18][CH2:19][CH:20]([F:30])[C:15]2=[N:14]1
Reactant: C#CCOc1cc(-n2nc3n(c2=O)CCCC3O)c(Cl)cc1Cl
Reactant: CCN(CC)S(F)(F)F
Solvent: ClCCl
Product: C#CCOc1cc(-n2nc3n(c2=O)CCCC3F)c(Cl)cc1Cl
Temperature: -78 °C
Reaction time: 4 h
Yield: 90.2 %

Procedure:
To a solution of 300 mg (0.847 mmol) of 5,6,7,8-tetrahydro-2-[2,4-dichloro-5-(2-propynyloxy)phenyl]-8-hydroxy-1,2,4-triazolo[4,3-α]pyridin-3(2H)-one in 10 mL of dichloromethane was added 123 mL (0.930 mmol) of diethylaminosulfur trifluoride (DAST) at -78° C. The reaction mixture was stirred at -78° C. for 4h. The mixture was warmed to room temperature, quenched with ice, and extracted with dichloromethane. The organic layers were dried (MgSO4), and concentrated under reduced pressure. The crude product was flash chromatographed over silica gel, eluting with a 98:2 v:v mixture of dichloromethane and methanol to give 272 mg of the title product of Step 4 as a yellow solid. 19F NMR (CDCl3, 300 MHz) δ-172; 1H NMR (CDCl3, 300 MHz) δ 7.55 (s,1H), 7.2 (s,1H), 5.6, 5.5 (2m, J=70 Hz,1H), 4.8 (s,2H), 4.0 (m,1H), 3.55 (m,1H), 2.6 (m,1H), 2.5-1.8 (m,4H).
Reaction SMILES: Br[CH2:2][C:3]([NH:5][CH2:6][C:7]#[CH:8])=[O:4].[N+:9]([C:12]1[N:13](CC#C)[CH:14]=[CH:15][N:16]=1)([O-:11])=[O:10].C([O-])([O-])=O.[K+].[K+]>CN(C=O)C.O>[N+:9]([C:12]1[N:13]([CH2:2][C:3]([NH:5][CH2:6][C:7]#[CH:8])=[O:4])[CH:14]=[CH:15][N:16]=1)([O-:11])=[O:10]
Reactant: C#CCNC(=O)CBr
Reactant: C#CCn1ccnc1[N+](=O)[O-]
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: C#CCNC(=O)Cn1ccnc1[N+](=O)[O-]
Reaction time: 8 h
Yield: 17.6 %

Procedure:
To a round bottom flask was added alkyne 18 (1.56 g, 8.84 mmol), 2-nitroimidazole 10 (1 g, 8.84 mmol) and K2CO3 (1.22 g, 8.84 mmol) in DMF (10 mL). The reaction was stirred overnight. The reaction was diluted with water (100 mL) and the resultant precipitate (1.2 g) was filtered off and washed with water (2×40 mL). The aqueous layer was extracted into EtOAc. The organic layer was concentrated to dryness and combined with the precipitate. The material was purified on a silica gel cartridge using EtOAc:Hex as the eluent to afford a 19 white solid (324 mg, 18%). Mass Spec (lo-res): Calc'd for C8H8N4O3: 208.06; found: 209.10 (M+H).
Reaction SMILES: [C:1]([C:3]1[CH:8]=[CH:7][C:6]([N:9]([CH2:14][CH:15]2[CH2:17][CH2:16]2)[CH2:10][C:11]([OH:13])=O)=[CH:5][C:4]=1[C:18]([F:21])([F:20])[F:19])#[N:2].[C:22]1([C@@H:28]([NH2:30])[CH3:29])[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1>>[C:1]([C:3]1[CH:8]=[CH:7][C:6]([N:9]([CH2:14][CH:15]2[CH2:17][CH2:16]2)[CH2:10][C:11]([NH:30][C@H:28]([C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)[CH3:29])=[O:13])=[CH:5][C:4]=1[C:18]([F:21])([F:20])[F:19])#[N:2]
Reactant: C[C@H](N)c1ccccc1
Reactant: N#Cc1ccc(N(CC(=O)O)CC2CC2)cc1C(F)(F)F
Product: C[C@H](NC(=O)CN(CC1CC1)c1ccc(C#N)c(C(F)(F)F)c1)c1ccccc1

Procedure:
Synthesized as described for Example 91C using N-[4-cyano-3-(trifluoromethyl)phenyl]-N-(cyclopropylmethyl)glycine and (1S)-1-phenylethanamine: MS (APCI) m/z 402 (M+1).
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[S:6][C:7]([C:10]#[C:11][CH2:12][NH:13][C:14]([O:16][C:17]([CH3:20])([CH3:19])[CH3:18])=[O:15])=[CH:8][CH:9]=1)=[O:4]>[Pd].CO>[CH3:1][O:2][C:3]([C:5]1[S:6][C:7]([CH2:10][CH2:11][CH2:12][NH:13][C:14]([O:16][C:17]([CH3:20])([CH3:19])[CH3:18])=[O:15])=[CH:8][CH:9]=1)=[O:4]
Reactant: COC(=O)c1ccc(C#CCNC(=O)OC(C)(C)C)s1
Agent: [Pd]
Solvent: CO
Product: COC(=O)c1ccc(CCCNC(=O)OC(C)(C)C)s1
Reaction time: 16 h
Yield: 92.4 %

Procedure:
A mixture of 5-(3-tert-butoxycarbonylamino-prop-1-ynyl)-thiophene-2-carboxylic acid methyl ester (2.06 g) and 10% palladium on carbon (1.03 g) in 50 mL MeOH was hydrogenated on a Parr shaker at 50 psi H2 for 16 h. The reaction was filtered through Celite with the aid of MeOH and the filtrate was concentrated in vacuo to afford the title compound as a solid (1.93 g). MS 317 (M+18).
Reaction SMILES: [CH:1]1[CH:6]=[CH:5][C:4]([C:7]([C:9]2[CH:14]=[CH:13][C:12]([C:15]([OH:17])=O)=[CH:11][CH:10]=2)=[O:8])=[CH:3][CH:2]=1.Cl.CN(C)CCCN=C=NCC.C(N(C(C)C)C(C)C)C.[NH2:39][C:40]([CH3:55])([CH2:43][O:44][C:45]1[CH:50]=[CH:49][CH:48]=[CH:47][C:46]=1[C:51]([F:54])([F:53])[F:52])[C:41]#[N:42]>ClCCl.CN(C)C1C=CN=CC=1>[C:7]([C:9]1[CH:10]=[CH:11][C:12]([C:15]([NH:39][C:40]([C:41]#[N:42])([CH3:55])[CH2:43][O:44][C:45]2[CH:50]=[CH:49][CH:48]=[CH:47][C:46]=2[C:51]([F:53])([F:54])[F:52])=[O:17])=[CH:13][CH:14]=1)(=[O:8])[C:4]1[CH:3]=[CH:2][CH:1]=[CH:6][CH:5]=1
Reactant: O=C(O)c1ccc(C(=O)c2ccccc2)cc1
Reactant: CC(N)(C#N)COc1ccccc1C(F)(F)F
Agent: CCN=C=NCCCN(C)C
Agent: CN(C)c1ccncc1
Agent: Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: CC(C#N)(COc1ccccc1C(F)(F)F)NC(=O)c1ccc(C(=O)c2ccccc2)cc1
Temperature: 25 °C
Reaction time: 0.33 h
Yield: 66.9 %

Procedure:
330 mg of benzophenone-4-carboxylic acid are dissolved in 6 ml of dichloromethane, then 283 mg of N-(3-dimethylaminopropyl)-N′-ethylcarbodiimide hydrochloride, 18 mg of 4-dimethylaminopyridine and 222 mg of ethyldiisopropylamine are added, and stirred for 20 minutes at room temperature. 300 mg of 2-amino-2-methyl-3-(2-trifluoromethylphenoxy)-propionitrile are subsequently added, and the mixture stirred for a further 40 hours. Afterwards, the mixed solution is washed with an aqueous sodium bicarbonate solution, then with a 1 n hydrochloric acid solution and finally with a saturated sodium chloride solution. The organic phase is then separated, dried with sodium sulphate, filtered and concentrated by evaporation. After recrystallisation in diethylether, the residue yields 372 mg of the title compound with a melting point of 121-123° C.
Reaction SMILES: Cl.[C:2]1([N:8]([CH2:33][CH2:34][C:35]([O:37]CC)=[O:36])[C:9]([C:11]2[CH:32]=[CH:31][C:14]3[N:15]([CH3:30])[C:16]([CH2:18][N:19]([C:21]4[CH:26]=[CH:25][C:24]([C:27](=[NH:29])[NH2:28])=[CH:23][CH:22]=4)[CH3:20])=[N:17][C:13]=3[CH:12]=2)=[O:10])[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[OH-].[Na+]>>[C:2]1([N:8]([CH2:33][CH2:34][C:35]([OH:37])=[O:36])[C:9]([C:11]2[CH:32]=[CH:31][C:14]3[N:15]([CH3:30])[C:16]([CH2:18][N:19]([C:21]4[CH:26]=[CH:25][C:24]([C:27](=[NH:28])[NH2:29])=[CH:23][CH:22]=4)[CH3:20])=[N:17][C:13]=3[CH:12]=2)=[O:10])[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CCOC(=O)CCN(C(=O)c1ccc2c(c1)nc(CN(C)c1ccc(C(=N)N)cc1)n2C)c1ccccc1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Product: CN(Cc1nc2cc(C(=O)N(CCC(=O)O)c3ccccc3)ccc2n1C)c1ccc(C(=N)N)cc1
Yield: 80 %

Procedure:
Prepared analogously to Example 26 from 1-methyl-2-[N-(4-amidinophenyl)-N-methylaminomethyl]benzimidazol-5-yl-carboxylic acid-N-phenyl-N-(2-ethoxycarbonylethyl)amide hydrochloride and sodium hydroxide solution. Yield: 80% of theory, C27H28N6O3 (484.6); EKA mass spectrum: (M+H)+=485; (M+H+Na)++=254; (M+Na)+=507; (M+2Na)+=265.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([CH:21]=[CH:22][CH:23]=1)[O:5][C:6]1[CH:7]=[CH:8][C:9]2[N:13]=[C:12]([NH:14][C:15]([CH:17]3[CH2:19][CH2:18]3)=[O:16])[NH:11][C:10]=2[CH:20]=1.[C:24]([C:26]1([C:29]2[CH:30]=[C:31]([CH:35]=[CH:36][CH:37]=2)[C:32](O)=[O:33])[CH2:28][CH2:27]1)#[N:25].Cl.C(N=C=NCCCN(C)C)C>CN(C)C1C=CN=CC=1.N1C=CC=CC=1>[C:24]([C:26]1([C:29]2[CH:30]=[C:31]([CH:35]=[CH:36][CH:37]=2)[C:32]([NH:1][C:2]2[CH:23]=[CH:22][CH:21]=[C:4]([O:5][C:6]3[CH:7]=[CH:8][C:9]4[N:13]=[C:12]([NH:14][C:15]([CH:17]5[CH2:19][CH2:18]5)=[O:16])[NH:11][C:10]=4[CH:20]=3)[CH:3]=2)=[O:33])[CH2:27][CH2:28]1)#[N:25]
Reactant: Nc1cccc(Oc2ccc3nc(NC(=O)C4CC4)[nH]c3c2)c1
Reactant: N#CC1(c2cccc(C(=O)O)c2)CC1
Agent: CCN=C=NCCCN(C)C
Agent: CN(C)c1ccncc1
Agent: Cl
Solvent: c1ccncc1
Product: N#CC1(c2cccc(C(=O)Nc3cccc(Oc4ccc5nc(NC(=O)C6CC6)[nH]c5c4)c3)c2)CC1
Yield: 43.5 %

Procedure:
Using N-[6-(3-aminophenoxy)-1H-benzimidazol-2-yl]cyclopropanecarboxamide (159 mg, 515 μmol) produced in Example C1(vi), 3-(1-cyanocyclopropyl)benzoic acid (210 mg, 1.12 mmol), pyridine (5 mL), 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (307 mg, 1.60 mmol) and N,N-dimethylpyridine-4-amine (58.1 mg, 47.6 μmol) as starting materials, and in the same manner as in Example C1(vii), the title compound (107 mg, 43%) was obtained as colorless crystals.
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[N:5]([CH2:12][CH2:13][CH2:14][O:15][C:16]2[CH:33]=[CH:32][C:19]3[N:20]([CH2:30][CH3:31])[C:21](=[O:29])[C:22]([CH3:28])([CH3:27])[C:23](=[O:26])[N:24]([CH3:25])[C:18]=3[CH:17]=2)[C:4](=[O:34])[C:3]=1[C:35]1[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=1>[Pd].C(O)C.C(OCC)(=O)C>[CH2:30]([N:20]1[C:21](=[O:29])[C:22]([CH3:28])([CH3:27])[C:23](=[O:26])[N:24]([CH3:25])[C:18]2[CH:17]=[C:16]([O:15][CH2:14][CH2:13][CH2:12][N:5]3[C:6]4[C:11](=[CH:10][CH:9]=[CH:8][CH:7]=4)[CH2:2][CH:3]([C:35]4[CH:36]=[CH:37][CH:38]=[CH:39][CH:40]=4)[C:4]3=[O:34])[CH:33]=[CH:32][C:19]1=2)[CH3:31]
Reactant: CCN1C(=O)C(C)(C)C(=O)N(C)c2cc(OCCCn3c(=O)c(-c4ccccc4)c(Cl)c4ccccc43)ccc21
Agent: [Pd]
Solvent: CCOC(C)=O
Solvent: CCO
Product: CCN1C(=O)C(C)(C)C(=O)N(C)c2cc(OCCCN3C(=O)C(c4ccccc4)Cc4ccccc43)ccc21
Reaction time: 6 h
Yield: 55.9 %

Procedure:
10% Palladium on carbon (20 mg) was added to an ethanol/ethyl acetate solution (1:1, 4 ml) of 7-[3-(4-chloro-2-oxo-3-phenyl-2H-quinoline-1-yl)propoxy]-1-ethyl-3,3,5-trimethyl-1,5-dihydrobenzo[b][1,4]diazepine-2,4-dione (0.19 g). The mixture was subjected to catalytic reduction at 50° C. under normal pressure for 6 hours. The reaction mixture was subjected to celite filtration to remove the catalyst. The filtrate was condensed under reduced pressure. The residue was purified by silica gel column chromatography (hexane:ethyl acetate=1:1). The purified product was condensed under reduced pressure, and the residue was recrystallized from ether/hexane, thereby obtaining the title compound (0.1 g) as a white powder.
Reaction SMILES: [H-].[Na+].[CH2:3]([OH:10])[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1.CN(C=O)C.[Br:16][C:17]1[CH:22]=[C:21]([F:23])[CH:20]=[C:19](F)[CH:18]=1>C1COCC1>[CH2:3]([O:10][C:19]1[CH:18]=[C:17]([Br:16])[CH:22]=[C:21]([F:23])[CH:20]=1)[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1
Reactant: Fc1cc(F)cc(Br)c1
Reactant: OCc1ccccc1
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CN(C)C=O
Product: Fc1cc(Br)cc(OCc2ccccc2)c1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 64.3 %

Procedure:
Sodium hydride (80% oil dispersion, 6.0 g, 201 mmol) was added slowly to a solution of benzyl alcohol (16 mL, 155 mmol) in THF (310 mL) at 0° C. DMF (300 mL) was added slowly and the reaction mixture was stirred until all of the NaH dissolved and gas evolution ceased. A solution of 1-bromo-3,5-difluorobenzene (30 g, 155 mmol) in THF (30 mL) was added and the reaction mixture was stirred for 30 min at ambient temperature. The reaction was quenched with saturated aqueous NH4Cl, and the reaction mixture was extracted 3 times with ethyl acetate. The combined organic layers were washed with saturated aqueous NH4Cl and brine, dried over MgSO4, filtered, and concentrated in vacuo to give a yellow liquid. 3-benzyloxy-5-fluorobromobenzene (28 g) was isolated by chromatography on silica gel (5% ethyl acetate, hexanes). Step 2. 4-[(3-benzyloxy-5-fluorophen-1-yl)oxomethyl]tetrahydropyran.
Reaction SMILES: [OH:1][C:2]1[C:11]2[C:6](=[CH:7][C:8]([C:12]([F:15])([F:14])[F:13])=[CH:9][CH:10]=2)[N:5]=[CH:4][C:3]=1[C:16](Cl)=[O:17].[NH2:19][C:20]1[S:21][CH:22]=[CH:23][N:24]=1>>[S:21]1[CH:22]=[CH:23][N:24]=[C:20]1[NH:19][C:16]([C:3]1[CH:4]=[N:5][C:6]2[C:11]([C:2]=1[OH:1])=[CH:10][CH:9]=[C:8]([C:12]([F:15])([F:14])[F:13])[CH:7]=2)=[O:17]
Reactant: Nc1nccs1
Reactant: O=C(Cl)c1cnc2cc(C(F)(F)F)ccc2c1O
Product: O=C(Nc1nccs1)c1cnc2cc(C(F)(F)F)ccc2c1O
Yield: 56.6 %

Procedure:
Using the procedure of Step B of Example 1, 3.7 g of the acid chloride of Step A and 1.35 g of 2-amino-thiazole were reacted to obtain 2.58 g of N-[2-thiazolyl]-4-hydroxy- 7-trifluoromethyl-3-quinoline-carboxamide melting above 369° C.
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[CH:9][CH:8]=[CH:7][C:3]=1[C:4]([OH:6])=O.[N:11]1[CH:16]=[CH:15][C:14]([CH:17]([C:20]2[CH:21]=[N:22][C:23]([C:26]([F:29])([F:28])[F:27])=[N:24][CH:25]=2)[CH2:18][NH2:19])=[CH:13][CH:12]=1>>[Cl:1][C:2]1[CH:10]=[CH:9][CH:8]=[CH:7][C:3]=1[C:4]([NH:19][CH2:18][CH:17]([C:14]1[CH:15]=[CH:16][N:11]=[CH:12][CH:13]=1)[C:20]1[CH:21]=[N:22][C:23]([C:26]([F:28])([F:29])[F:27])=[N:24][CH:25]=1)=[O:6]
Reactant: O=C(O)c1ccccc1Cl
Reactant: NCC(c1ccncc1)c1cnc(C(F)(F)F)nc1
Product: O=C(NCC(c1ccncc1)c1cnc(C(F)(F)F)nc1)c1ccccc1Cl

Procedure:
From 2-chlorobenzoic acid and 2-(pyridin-4-yl)-2-(2-(trifluoromethyl)pyrimidin-5-yl)ethanamine. LCMS (MH+): m/z=407.1, tR (minutes, Method F)=2.25
Reaction SMILES: [NH:1]1[C:5]2=[CH:6][N:7]=[CH:8][CH:9]=[C:4]2[CH:3]=[CH:2]1.[Br:10][C:11]1[CH:19]=[C:18]([Cl:20])[C:14]([C:15](Cl)=[O:16])=[C:13]([Cl:21])[CH:12]=1>>[Br:10][C:11]1[CH:12]=[C:13]([Cl:21])[C:14]([C:15]([C:3]2[C:4]3[C:5](=[CH:6][N:7]=[CH:8][CH:9]=3)[NH:1][CH:2]=2)=[O:16])=[C:18]([Cl:20])[CH:19]=1
Reactant: O=C(Cl)c1c(Cl)cc(Br)cc1Cl
Reactant: c1cc2cc[nH]c2cn1
Product: O=C(c1c(Cl)cc(Br)cc1Cl)c1c[nH]c2cnccc12

Procedure:
(4-Bromo-2,6-dichlorophenyl)(1H-pyrrolo[2,3-c]pyridin-3-yl)methanone was prepared from 1H-Pyrrolo[2,3-c]pyridine and 4-bromo-2,6-dichloro benzoyl chloride (Compound No. 10).
Reaction SMILES: [H-].[Na+].[Cl:3][C:4]1[C:12]2[N:11]=[C:10]3[N:13]([C:17]4[CH:22]=[CH:21][C:20]([Cl:23])=[CH:19][C:18]=4[C:24]([F:27])([F:26])[F:25])[CH2:14][CH2:15][CH2:16][N:9]3[C:8]=2[C:7]([CH:28]([CH:30]2[CH2:32][CH2:31]2)[OH:29])=[CH:6][CH:5]=1.[CH3:33]I>CN(C)C=O.O>[Cl:3][C:4]1[C:12]2[N:11]=[C:10]3[N:13]([C:17]4[CH:22]=[CH:21][C:20]([Cl:23])=[CH:19][C:18]=4[C:24]([F:25])([F:27])[F:26])[CH2:14][CH2:15][CH2:16][N:9]3[C:8]=2[C:7]([CH:28]([CH:30]2[CH2:32][CH2:31]2)[O:29][CH3:33])=[CH:6][CH:5]=1
Reactant: OC(c1ccc(Cl)c2nc3n(c12)CCCN3c1ccc(Cl)cc1C(F)(F)F)C1CC1
Reactant: CI
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: COC(c1ccc(Cl)c2nc3n(c12)CCCN3c1ccc(Cl)cc1C(F)(F)F)C1CC1
Reaction time: 0.08 h
Yield: 77.2 %

Procedure:
Sodium hydride (60% in oil, 52.4 mg, 1.31 mmol) was added to a stirred solution of {9-chloro-1-[4-chloro-2-(trifluoromethyl)phenyl]-1,2,3,4-tetrahydropyrimido[1,2-a]benzimidazol-6-yl}(cyclopropyl)methanol (500 mg, 1.09 mmol) in N,N-dimethylformamide (4.0 mL) at room temperature. After stirring 5 min, methyl iodide (232 mg, 1.64 mmol) was added to the mixture, and the mixture was stirred at room temperature for 3 hr. The mixture was diluted with water, and extracted with ethyl acetate. The combined organic layer was washed with brine, dried over anhydrous magnesium sulfate, filtered, and concentrated in vacuo. The residue was recrystallized from ethyl acetate/n-hexane to give the title compound as a colorless crystal (396 mg, 0.842 mmol, 77%).
Reaction SMILES: Cl[CH2:2][CH2:3][CH2:4][CH2:5][S:6]([NH:9][CH3:10])(=[O:8])=[O:7].[I-].[Na+].[C-:13]#[N:14].[Na+]>CN(C=O)C>[C:13]([CH2:2][CH2:3][CH2:4][CH2:5][S:6]([NH:9][CH3:10])(=[O:8])=[O:7])#[N:14]
Reactant: [C-]#N
Reactant: CNS(=O)(=O)CCCCCl
Agent: [I-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CNS(=O)(=O)CCCCC#N
Temperature: 60 °C
Reaction time: 8 h

Procedure:
A solution of 4-chloro-N-methylbutane-1-sulfonamide (Example 5; 86.7 mmol), and sodium iodide (95.4 mmol) in DMF (175 ml) was stirred for 10 min at room temperature. Sodium cyanide (191 mmol) was added and the mixture was stirred overnight at 60° C. The mixture was filtered off and the filtrate was extracted with AcOEt/water. The crude product was concentrated and was used without further purification in the next step (Examples 10 and 20).
Reaction SMILES: [Cl:1][CH2:2][C:3]([C:7]1[CH:12]=[CH:11][C:10]([F:13])=[CH:9][C:8]=1[F:14])([OH:6])[CH2:4]Cl.[OH-].[K+]>C1(C)C=CC=CC=1>[Cl:1][CH2:2][C:3]1([C:7]2[CH:12]=[CH:11][C:10]([F:13])=[CH:9][C:8]=2[F:14])[O:6][CH2:4]1
Reactant: OC(CCl)(CCl)c1ccc(F)cc1F
Agent: [K+]
Agent: [OH-]
Solvent: Cc1ccccc1
Product: Fc1ccc(C2(CCl)CO2)c(F)c1
Temperature: 25 °C
Reaction time: 3 h
Yield: 50.1 %

Procedure:
To 1.7 l of toluene solution of 433 g of 1,3-dichloro-2-(2,4-difluorophenyl)-2-propanol was added 870 ml of 20% aqueous solution of potassium hydroxide. After the resulting liquid was stirred at room temperature for 3 hours, the organic layer was separated therefrom. The aqueous layer was extracted twice with 1 l of ethyl acetate. The organic layers were combined and dried over anhydrous sodium sulfate. The resulting organic layer was filtered and the solvent was removed under reduced pressure. Thus obtained concentrate was distilled under reduced pressure to give 184 g of the desired compound.
Reaction SMILES: [C:1]1([C:11]([OH:13])=[O:12])[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][CH:2]=1.O[CH2:15][CH2:16][O:17][C:18](=[O:22])[C:19]([CH3:21])=[CH2:20].C1(C)C=CC(S(O)(=O)=O)=CC=1.CN(C1C=CC=CN=1)C.C1(N=C=NC2CCCCC2)CCCCC1>ClCCl>[C:18]([O:17][CH2:16][CH2:15][O:12][C:11]([C:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][CH:2]=1)=[O:13])(=[O:22])[C:19]([CH3:21])=[CH2:20]
Reactant: C=C(C)C(=O)OCCO
Reactant: O=C(O)c1cccc2ccccc12
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: CN(C)c1ccccn1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: ClCCl
Product: C=C(C)C(=O)OCCOC(=O)c1cccc2ccccc12
Temperature: 0 °C
Reaction time: 0.25 h

Procedure:
A mixture of 1-napthoic acid (8.0 g, 46 mmol), 2-hydroxyethylmethacrylate (18.1 g, 139 mmol), dimethylamino-pyridine p-toluenesulfonic acid salt (5.5 g, 19 mmol), and anhydrous dichloromethane (45 mL) was cooled to 0° C. under nitrogen, and 1,3-dicyclohexyl-carbodiimide (12.5 g, 60 mmol) were added. After 15 min, the reaction mixture was warmed to ambient and stirred for 3 h. The precipitated urea by-product was filtered, and the filtrate was washed successively with 10% aqueous HCl, 10% aqueous NaHCO3, water, and brine. The organic layer was dried (Na2SO4) and concentrated to deposit a gold oil. The product was purified by column chromatography to provide 8.2 g (62% of theory) of a pale yellow oil. 1H NMR (CDCl3): δ 1.90 (s, 3H), 1.55 (m, 2H), 1.70 (m, 2H), 5.60 (s, 1H), 6.20 (s, 1H), 7.55 (m, 3H), 7.90 (d, 1H), 8.05 (d, 1H), 8.20 (d, 1H), 8.90 (d, 1H).
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][C:20]([OH:22])=O)=[O:7])([CH3:4])([CH3:3])[CH3:2].C(N1C=CN=C1)(N1C=CN=C1)=O.[CH3:35][N:36]([CH3:41])[CH2:37][CH2:38][CH2:39][NH2:40]>C1COCC1>[C:1]([O:5][C:6](=[O:7])[NH:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][C:20](=[O:22])[NH:40][CH2:39][CH2:38][CH2:37][N:36]([CH3:41])[CH3:35])([CH3:2])([CH3:3])[CH3:4]
Reactant: CC(C)(C)OC(=O)NCCCCCCCCCCCC(=O)O
Reactant: CN(C)CCCN
Agent: O=C(n1ccnc1)n1ccnc1
Solvent: C1CCOC1
Product: CN(C)CCCNC(=O)CCCCCCCCCCCNC(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 3 h
Yield: 33.5 %

Procedure:
A mixture of 12-tert-butoxycarbonylaminododecanoic acid (3) (205 mg, 0.65 mmol) and 1,1′-Carbonyldiimidazole (114 mg, 0.70 mmol) in anhydrous THF (5 mL) was stirred at room temperature for 3 hours. 3-(Dimethylamino)propylamine (163 mL, 1.30 mmol) was then added via syringe and the reaction mixture stirred at room temperature for a further 24 hours. The solvent was then removed by rotary evaporation and the residue subjected to Biotage silica gel column chromatography (ethyl acetate/dichloromethane 5% to 75%, then methanol/dichloromethane 8%) to give the desired amide 4 (87.0 mg, 34%) as a white solid: 1H NMR (500 MHz, CDCl3) δ 1.27 (m, 14H), 1.45 (s, 9H), 1.47 (m, 2H), 1.60 (m, 2H), 1.69 (m, 2H), 2.16 (t, 2H), 2.29 (s, 6H), 2.45 (t, 2H), 3.10 (m, 2H), 3.32 (m, 2H), 4.50 (br, 1H), 6.91 (br, 1H). m/z (ESI) 400 [C22H45N3O3+H]+.