Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]1([CH:10]=[CH:11][C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[CH:6]=[CH:5][C:4]([C:7](O)=[O:8])=[CH:3][CH:2]=1.S(Cl)([Cl:20])=O.C1(C)C=CC=CC=1>CN(C)C=O>[C:1]1([CH:10]=[CH:11][C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[CH:6]=[CH:5][C:4]([C:7]([Cl:20])=[O:8])=[CH:3][CH:2]=1
Reactant: O=C(O)c1ccc(C=Cc2ccccc2)cc1
Reactant: O=S(Cl)Cl
Solvent: CN(C)C=O
Solvent: Cc1ccccc1
Product: O=C(Cl)c1ccc(C=Cc2ccccc2)cc1
Yield: 83.8 %

Procedure:
15.1 g (67.4 mmols) of stilbene-4-carboxylic acid, 10.0 g (84.25 mmols) of thionyl chloride, 150 ml of toluene and 0.18 ml of N,N-dimethylformamide are stirred at 70° C. for 3 hours. The reaction mixture is then evaporated and the crude product is recrystallised from n-hexane/cyclohexane. 13.7 g (84% of theory) of stilbene-4-carboxylic acid chloride are obtained in the form of white crystals; melting point 131.2° C.
Reaction SMILES: [Br:1][C:2]1[N:3]=[C:4]([CH:19]2[O:23][CH2:22][CH2:21][O:20]2)[N:5]([CH2:8][C:9]2[C:17]([Cl:18])=[CH:16][C:12]3[O:13][CH2:14][O:15][C:11]=3[CH:10]=2)[C:6]=1Br.[O:24]1CCC[CH2:25]1.C([Mg]Br)C.CN(C)C=O>C(OC(C)C)(C)C>[Br:1][C:2]1[N:3]=[C:4]([CH:19]2[O:23][CH2:22][CH2:21][O:20]2)[N:5]([CH2:8][C:9]2[C:17]([Cl:18])=[CH:16][C:12]3[O:13][CH2:14][O:15][C:11]=3[CH:10]=2)[C:6]=1[CH:25]=[O:24]
Reactant: C1CCOC1
Reactant: Clc1cc2c(cc1Cn1c(C3OCCO3)nc(Br)c1Br)OCO2
Agent: CC[Mg]Br
Solvent: CC(C)OC(C)C
Solvent: CN(C)C=O
Product: O=Cc1c(Br)nc(C2OCCO2)n1Cc1cc2c(cc1Cl)OCO2
Reaction time: 0.33 h

Procedure:
10 g of the product obtained in Stage 3 above is introduced into 200 ml of anhydrous tetrahydrofuran. 10 ml of ethyl magnesium bromide (3M solution in ethyl ether) is added and the reaction medium is left under agitation for 20 minutes at ambient temperature. Then an excess of anhydrous dimethylformamide is added. After 2 hours at ambient temperature, hydrolysis is carried out with 200 ml of 1N hydrochloric acid and extraction is carried out 3 times with 300 ml of ethyl acetate. The organic phase is washed with saturated sodium chloride then dried and evaporated to dryness. The residue obtained is impasted in isopropyl ether. In this way 7.6 g of expected product is obtained, which is used without purification for the following stage.
Reaction SMILES: Cl[C:2]1[CH:7]=[C:6]([C:8]2[N:13]=[C:12]([C:14]([F:17])([F:16])[F:15])[CH:11]=[C:10]([C:18]3[CH:23]=[CH:22][C:21]([C:24]([F:27])([F:26])[F:25])=[CH:20][CH:19]=3)[N:9]=2)[CH:5]=[CH:4][N:3]=1.[C:28]([NH:32][S:33]([C:36]1[CH:37]=[C:38](B(O)O)[CH:39]=[CH:40][CH:41]=1)(=[O:35])=[O:34])([CH3:31])([CH3:30])[CH3:29]>>[C:28]([NH:32][S:33]([C:36]1[CH:37]=[CH:38][CH:39]=[C:40]([C:2]2[CH:7]=[C:6]([C:8]3[N:13]=[C:12]([C:14]([F:17])([F:16])[F:15])[CH:11]=[C:10]([C:18]4[CH:23]=[CH:22][C:21]([C:24]([F:27])([F:26])[F:25])=[CH:20][CH:19]=4)[N:9]=3)[CH:5]=[CH:4][N:3]=2)[CH:41]=1)(=[O:35])=[O:34])([CH3:31])([CH3:29])[CH3:30]
Reactant: FC(F)(F)c1ccc(-c2cc(C(F)(F)F)nc(-c3ccnc(Cl)c3)n2)cc1
Reactant: CC(C)(C)NS(=O)(=O)c1cccc(B(O)O)c1
Product: CC(C)(C)NS(=O)(=O)c1cccc(-c2cc(-c3nc(-c4ccc(C(F)(F)F)cc4)cc(C(F)(F)F)n3)ccn2)c1

Procedure:
The title compound was prepared from 2-(2-chloro-pyridin-4-yl)-4-trifluoromethyl-6-(4-trifluoromethyl-phenyl)-pyrimidine (example E.6) (0.404 g, 1.0 mmol) and commercially available 3-(tert.-butylsulfamoyl)-phenylboronic acid (0.31 g, 1.2 mmol) according to the general procedure VI. Obtained as an off-white solid (0.51 g, 88%). MS (ISP) 581.3 [(M+H)+]; mp 211° C.
Reaction SMILES: CS(Cl)(=O)=O.[NH:6]([C:13]1[N:18]=[C:17]([C:19]2[N:23]([CH3:24])[C:22]([CH2:25][C:26]([CH3:29])(O)[CH3:27])=[N:21][CH:20]=2)[CH:16]=[CH:15][N:14]=1)[C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1.C(N(CC)CC)C>C(Cl)Cl>[CH3:24][N:23]1[C:19]([C:17]2[CH:16]=[CH:15][N:14]=[C:13]([NH:6][C:7]3[CH:8]=[CH:9][CH:10]=[CH:11][CH:12]=3)[N:18]=2)=[CH:20][N:21]=[C:22]1[CH:25]=[C:26]([CH3:29])[CH3:27]
Reactant: Cn1c(-c2ccnc(Nc3ccccc3)n2)cnc1CC(C)(C)O
Agent: CS(=O)(=O)Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CC(C)=Cc1ncc(-c2ccnc(Nc3ccccc3)n2)n1C
Reaction time: 3 h
Yield: 41.4 %

Procedure:
Methanesulphonyl chloride (151 μl, 1.96 mmol), was added to a solution of 2-anilino-4-(1-methyl-2-(2-methyl-2-hydroxypropyl)imidazol-5-yl)pyrimidine (Method 97; 600 mg, 1.86 mmol), and triethylamine (777 μl, 5.58 mmol), in DCM (10 ml), at ambient temperature under nitrogen. The mixture was stirred for 3 hours then adsorbed directly onto silica gel and purified by chromatography eluting with EtOAc to give the title compound (235 mg, 42%). NMR: 1.98 (s, 3H), 2.14 (s, 3H), 3.99 (s, 3H), 6.24 (s, 1H), 6.98 (t, 1H), 7.10 (d, 1H), 7.28 (dd, 2H), 7.69-7.72 (m, 3H), 8.40 (d, 1H), 9.42 (s, 1H); m/z: 306.
Reaction SMILES: [C:1]([O:5][C:6](=[O:16])[N:7]([C@H:9]1[CH2:14][CH2:13][C@H:12]([OH:15])[CH2:11][CH2:10]1)[CH3:8])([CH3:4])([CH3:3])[CH3:2].[Br:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22]Br>>[C:1]([O:5][C:6](=[O:16])[N:7]([C@H:9]1[CH2:10][CH2:11][C@H:12]([O:15][CH2:22][CH2:21][CH2:20][CH2:19][CH2:18][Br:17])[CH2:13][CH2:14]1)[CH3:8])([CH3:4])([CH3:2])[CH3:3]
Reactant: CN(C(=O)OC(C)(C)C)[C@H]1CC[C@H](O)CC1
Reactant: BrCCCCCBr
Product: CN(C(=O)OC(C)(C)C)[C@H]1CC[C@H](OCCCCCBr)CC1

Procedure:
In analogy to examples 1.4 and 1.5, trans-(4-Hydroxy-cyclohexyl)-methyl-carbamic acid tert-butyl ester was reacted with 1,5-dibromopentane to yield trans-[4-(5-Bromo-pentyloxy)-cyclohexyl]-methyl-carbamic acid tert-butyl ester which was reacted with N-allylmethylamine to yield trans-(4-[5-(Allyl-methyl-amino)-pentyloxy]-cyclohexyl)-methyl-carbamic acid tert-butyl ester as white oil, MS: 369 (MH+).
Reaction SMILES: [Cl:1][C:2]1[CH:11]=[C:10]2[C:5]([CH2:6][CH2:7][CH2:8][C:9]2=[O:12])=[C:4]([O:13]C)[C:3]=1[F:15].[Cl-].[Al+3].[Cl-].[Cl-]>C1(C)C(C)=CC=CC=1>[Cl:1][C:2]1[CH:11]=[C:10]2[C:5]([CH2:6][CH2:7][CH2:8][C:9]2=[O:12])=[C:4]([OH:13])[C:3]=1[F:15]
Reactant: COc1c(F)c(Cl)cc2c1CCCC2=O
Agent: [Al+3]
Agent: [Cl-]
Solvent: Cc1ccccc1C
Product: O=C1CCCc2c1cc(Cl)c(F)c2O
Temperature: 25 °C
Yield: 89.2 %

Procedure:
To a stirred solution of 7-chloro-6-fluoro-5-methoxy-3,4-dihydro-2H-naphthalen-1-one (1.04 g, 4.7 mmol) in xylene (35 mL) was added anhydrous aluminum chloride (1.93 g, 14.5 mmol) at room temperature. The reaction mixture was then heated at reflux for 1 hour. After being cooled to room temperature, the reaction mixture was slowly poured into ice water with continuous stirring. The resulting solution was extracted with ethyl acetate (50 mL×3). The collected organic layers were then washed with saturated sodium bicarbonate solution and water, dried with anhydrous sodium sulfate, filtered, and concentrated in vacuo to give the crude residue, which was washed with ether to afford 7-chloro-6-fluoro-5-hydroxy-3,4-dihydro-2H-naphthalen-1-one (0.90 g, 89%), which was used in the next step without further purification. MS cald. for C10H8ClFO2 214, obsd. 215 [(M+H)+].
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]([CH:9]=[CH:10][CH:11]=1)[C:5]([O:7][CH3:8])=[O:6].C([O-])([O-])=O.[K+].[K+].Cl[CH2:19][C:20]([N:22]([CH3:24])[CH3:23])=[O:21].Cl>CN(C=O)C>[CH3:23][N:22]([CH3:24])[C:20](=[O:21])[CH2:19][O:1][C:2]1[CH:3]=[C:4]([CH:9]=[CH:10][CH:11]=1)[C:5]([O:7][CH3:8])=[O:6]
Reactant: COC(=O)c1cccc(O)c1
Reactant: CN(C)C(=O)CCl
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: COC(=O)c1cccc(OCC(=O)N(C)C)c1
Reaction time: 1 h
Yield: 93.6 %

Procedure:
A mixture of methyl 3-hydroxybenzoate (Aldrich) (1.52 g, 10 mmol) and K2CO3 (1.38 g, 10 mmol) in DMF (10 mL) was stirred for 1 h. 2-Chloro-N,N-dimethylacetamide (Merck) (1.03 mL, 10 mmol) was added and the mixture was stirred for 1 h at RT and then stood at RT for 6 days. The mixture was then acidified with 2M HCl and extracted with EtOAc. The aqueous layer was extracted twice more with EtOAc and the combined organic solutions were washed with 2M HCl (×3), aq. sat NaHCO3, brine, dried (MgSO4) and evaporated under reduced pressure to give the title compound (2.22 g, 94%) as a white solid. LCMS (System A) RT=0.80 min, 91%, ES+ve m/z 238 (M+H)+.
Reaction SMILES: [Cl:1][C:2]1[N:7]=[C:6](/[CH:8]=C(/C2C=C(NS(C3C(F)=CC=CC=3F)(=O)=O)C=CC=2)\O)[CH:5]=[CH:4][N:3]=1.[Cl:29][C:30]1[C:39]([NH:40][C:41]([O:43][CH2:44][CH:45]=[CH2:46])=[O:42])=[CH:38][CH:37]=[CH:36][C:31]=1[C:32]([O:34]C)=O.ClC1N=C(C)C=CN=1>>[Cl:29][C:30]1[C:31](/[C:32](/[OH:34])=[CH:8]\[C:6]2[CH:5]=[CH:4][N:3]=[C:2]([Cl:1])[N:7]=2)=[CH:36][CH:37]=[CH:38][C:39]=1[NH:40][C:41](=[O:42])[O:43][CH2:44][CH:45]=[CH2:46]
Reactant: O=S(=O)(Nc1cccc(/C(O)=C/c2ccnc(Cl)n2)c1)c1c(F)cccc1F
Reactant: C=CCOC(=O)Nc1cccc(C(=O)OC)c1Cl
Agent: Cc1ccnc(Cl)n1
Product: C=CCOC(=O)Nc1cccc(/C(O)=C\c2ccnc(Cl)n2)c1Cl
Yield: 79.6 %

Procedure:
Following a procedure analogous to the procedure described in Intermediate 5, Step B using methyl 2-chloro-3-{[(2-propen-1-yloxy)carbonyl]amino}benzoate (30 g, 0.11 mol) and 2-chloro-4-methylpyrimidine (15.8 g, 0.12 mol) the title compound of Step B was prepared (29 g, 79.6% yield). 1H NMR (400 MHz, CDCl3) δ ppm 13.52-13.58 (br, 0.9H), 8.41-8.42 (m, 1H), 8.22-8.27 (m, 1H), 7.28-7.35 (m, 2.2H), 7.21-7.24 (m, 1.2H), 6.85-6.88 (m, 1H), 5.91-6.02 (m, 1H), 5.73 (s, 1H), 5.23-5.40 (m, 2H), 4.66-4.70 (m, 2H).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([CH2:11][C:12](O)=O)(=[O:10])=[O:9])=[CH:4][CH:3]=1.[CH3:15][C:16]1[CH:23]=[CH:22][C:19](C=O)=[CH:18][CH:17]=1>>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([S:8](/[CH:11]=[CH:12]/[C:19]2[CH:22]=[CH:23][C:16]([CH3:15])=[CH:17][CH:18]=2)(=[O:10])=[O:9])=[CH:4][CH:3]=1
Reactant: Cc1ccc(C=O)cc1
Reactant: O=C(O)CS(=O)(=O)c1ccc(Cl)cc1
Product: Cc1ccc(/C=C/S(=O)(=O)c2ccc(Cl)cc2)cc1
Yield: 60 %

Procedure:
A solution of 4-chlorophenyl sulfonylacetic acid (0.01 mol) and 4-methylbenzaldehyde (0.01 mol) was subjected to Procedure 1, Part B. The title compound was obtained in 60-64% yield.
Reaction SMILES: C([NH:8][C@H:9]([C:13]([OH:15])=O)[CH2:10][CH2:11][OH:12])(OC(C)(C)C)=O.C1C=C2N=NN(O)C2=CC=1.O.N=C=N.[NH2:30][CH2:31][CH2:32][CH2:33][C:34]#[C:35][C:36]1[CH:37]=[C:38]([CH:53]=[CH:54][CH:55]=1)[O:39][CH:40]1[CH2:45][CH2:44][N:43](C(OC(C)(C)C)=O)[CH2:42][CH2:41]1.CC[NH+](CC)CC.CC[NH+](CC)CC.C([O-])([O-])=O>CN(C=O)C.C(Cl)Cl>[NH2:8][C@@H:9]([CH2:10][CH2:11][OH:12])[C:13]([NH:30][CH2:31][CH2:32][CH2:33][C:34]#[C:35][C:36]1[CH:55]=[CH:54][CH:53]=[C:38]([O:39][CH:40]2[CH2:45][CH2:44][NH:43][CH2:42][CH2:41]2)[CH:37]=1)=[O:15]
Reactant: CC(C)(C)OC(=O)N1CCC(Oc2cccc(C#CCCCN)c2)CC1
Reactant: CC(C)(C)OC(=O)N[C@@H](CCO)C(=O)O
Agent: CC[NH+](CC)CC
Agent: N=C=N
Agent: O=C([O-])[O-]
Solvent: ClCCl
Solvent: CN(C)C=O
Solvent: O
Product: N[C@@H](CCO)C(=O)NCCCC#Cc1cccc(OC2CCNCC2)c1
Reaction time: 0.17 h

Procedure:
To a solution of N-Boc-L-Homoserine (16 mg, 0.075 mmol, 1.5 eq) and HOBT hydrate (12 mg, 0.085 mmol, 1.7 eq) in DMF (2 mL) was added PS-carbodiimide (also known as N-Cyclohexylcarbodiimide-N′-propoxymethyl polystyrene, purchased from Biotage) (80 mg, 1.25 mmol/g resin, 0.1 mmol, 2.0 eq). After 10 minutes, a solution of tert-butyl 4-(3-(5-aminopent-1-ynyl)phenoxy)piperidine-1-carboxylate (0.25 mL of a 0.2 M solution in DCM, 0.05 mmol, 1.0 eq) was added and the resulting solution stirred overnight. To the resulting solution was then added MP-carbonate resin (95 mg, 2.64 mmol/g resin, 0.25 mmols, 5 eq), the suspension stirred 2 hrs, filtered, the resin washed with DCM and the filtrate concentrated by rotovap. The residue was taken up in 20% TFA/DCM (2 mL) and stirred 1 hr, methanol (1 mL) was added, and the resulting solution concentrated by rotovap. The resulting residue was purified by HPLC to yield (S)-2-amino-4-hydroxy-N-(5-(3-(piperidin-4-yloxy)phenyl)pent-4-ynyl)butanamide as a gum. ESI-MS (m/z): Calculated for C20H29N3O3: 360.2 (M+1); Measured: 360.2.
Reaction SMILES: [Br:1][C:2]1[CH:18]=[CH:17][C:16]([O:19][CH3:20])=[CH:15][C:3]=1[CH2:4][CH:5]1[CH2:10][CH2:9][N:8]([CH2:11][CH2:12][CH2:13][NH2:14])[CH2:7][CH2:6]1.Br[CH2:22][C:23]1[CH:32]=[CH:31][CH:30]=[CH:29][C:24]=1[C:25](OC)=[O:26].C(N(CC)CC)C>C1(C)C=CC=CC=1.C(OCC)(=O)C>[Br:1][C:2]1[CH:18]=[CH:17][C:16]([O:19][CH3:20])=[CH:15][C:3]=1[CH2:4][CH:5]1[CH2:10][CH2:9][N:8]([CH2:11][CH2:12][CH2:13][N:14]2[CH2:22][C:23]3[C:24](=[CH:29][CH:30]=[CH:31][CH:32]=3)[C:25]2=[O:26])[CH2:7][CH2:6]1
Reactant: COC(=O)c1ccccc1CBr
Reactant: COc1ccc(Br)c(CC2CCN(CCCN)CC2)c1
Solvent: Cc1ccccc1
Solvent: CCN(CC)CC
Solvent: CCOC(C)=O
Product: COc1ccc(Br)c(CC2CCN(CCCN3Cc4ccccc4C3=O)CC2)c1

Procedure:
A solution (5 ml) of 3-[4-(2-bromo-5-methoxybenzyl)-1-piperidinyl]propylamine (400.0 mg, 1.179 mmol), methyl 2-(bromomethyl)benzoate (400.0 mg, 1.746 mmol) and triethylamine (200.0 mg, 1.976 mmol) in toluene was stirred with heating under reflux for 5 hours. The reaction solution was diluted with ethyl acetate and the triethylamine hydrobromide produced during the reaction was filtered off. Then, the solvent was distilled off under reduced pressure and the residue was purified by a silica gel column chromatography (hexane/ethyl acetate=3/1˜ethyl acetate˜triethylamine/ethyl acetate=1/19) to obtain the title compound (439.3 mg, 0.960 mmol) in a yield of 82%.
Reaction SMILES: CS[C:3]1[S:4][CH2:5][C:6](=[O:8])[N:7]=1.[NH:9]1[CH2:15][CH2:14][CH2:13][NH:12][CH2:11][CH2:10]1>>[N:9]1([C:3]2[S:4][CH2:5][C:6](=[O:8])[N:7]=2)[CH2:15][CH2:14][CH2:13][NH:12][CH2:11][CH2:10]1
Reactant: C1CNCCNC1
Reactant: CSC1=NC(=O)CS1
Product: O=C1CSC(N2CCCNCC2)=N1

Procedure:
2-[1,4]-Diazepan-1-yl-thiazol-4-one was prepared from 2-Methylsulfanyl-thiazol-4-one and [1,4]diazepane following General Procedure E
Reaction SMILES: C([O:8][N:9]([CH2:22][C:23]([NH:25][C@H:26]([C:28]1[CH:33]=[CH:32][C:31]([CH3:34])=[CH:30][CH:29]=1)[CH3:27])=[O:24])[C:10]([NH:12][C:13]1[CH:18]=[CH:17][C:16]([C:19](=[NH:21])[NH2:20])=[CH:15][CH:14]=1)=[O:11])C1C=CC=CC=1.C([O-])=O.[NH4+]>CO.[Pd]>[C:19]([C:16]1[CH:15]=[CH:14][C:13]([NH:12][C:10](=[O:11])[N:9]([CH2:22][C:23]([NH:25][C@H:26]([C:28]2[CH:33]=[CH:32][C:31]([CH3:34])=[CH:30][CH:29]=2)[CH3:27])=[O:24])[OH:8])=[CH:18][CH:17]=1)(=[NH:20])[NH2:21]
Reactant: Cc1ccc([C@H](C)NC(=O)CN(OCc2ccccc2)C(=O)Nc2ccc(C(=N)N)cc2)cc1
Agent: [Pd]
Agent: O=C[O-]
Agent: [NH4+]
Solvent: CO
Product: Cc1ccc([C@H](C)NC(=O)CN(O)C(=O)Nc2ccc(C(=N)N)cc2)cc1
Yield: 63.6 %

Procedure:
The compound of example 46 (104 mg, 0.2 mmol) was hydrogenated by means of ammonium formate (143 mg) and Pd/C (30 mg; 10%) in methanol (10 ml) at room temperature. After 16 h (LC-MS control) the mixture was filtered off and the solvent was removed. Remaining traces of formate were removed in high vacuo at elevated temperature. 47 mg (57%) of the title compound were obtained. MS 370.10 (M+1)+
Reaction SMILES: [S:1]1[CH:5]=[CH:4][CH:3]=[CH:2]1.[C:6](Cl)(=[O:12])[CH2:7][CH2:8][CH2:9][CH2:10][CH3:11].Cl[Sn](Cl)(Cl)Cl.Cl>C1C=CC=CC=1>[C:6]([C:2]1[S:1][CH:5]=[CH:4][CH:3]=1)(=[O:12])[CH2:7][CH2:8][CH2:9][CH2:10][CH3:11]
Reactant: c1ccsc1
Reactant: CCCCCC(=O)Cl
Agent: Cl
Agent: Cl[Sn](Cl)(Cl)Cl
Solvent: c1ccccc1
Product: CCCCCC(=O)c1cccs1
Yield: 77.1 %

Procedure:
In a 5 liter-five-necked flask, 187.3 g (2.23 mol) of thiophene, 300 g (2.23 mol) of n-hexanoyl chloride and 2.7 liter of dry benzene were placed and cooled below 0° C. To the mixture under stirring, 237.9 g (9.13×10-1 mol) of SnCl4 was added dropwise in 1 hour below 0° C. The mixture was stirred for 30 min. below 0° C., followed by stirring for 3.5 hours while being gradually restored to room temperature. After the reaction, 2 liter of 10% HCl was added to the reaction mixture, followed by stirring for 10 min. The separated organic layer was successively washed three times with 500 ml each of 10% HCl, water, 5% Na2CO3 and water, followed by drying with CaCl2 and distilling-off of the solvent to obtain 408 g of a crude product. The crude product was subjected to reduced-pressure distillation in an atmosphere of nitrogen to obtain 313.4 g of a pure product (yield: 77.2%).
Reaction SMILES: Br[CH2:2][C:3]1[NH:8][C:7]([C:9]2[CH:14]=[N:13][CH:12]=[CH:11][N:10]=2)=[N:6][CH:5]([C:15]2[CH:20]=[CH:19][C:18]([F:21])=[CH:17][C:16]=2[Cl:22])[C:4]=1[C:23]([O:25][CH2:26][CH3:27])=[O:24].Cl.[NH:29]1[CH2:34][CH2:33][O:32][CH:31]([CH2:35][C:36]([OH:38])=[O:37])[CH2:30]1>>[Cl:22][C:16]1[CH:17]=[C:18]([F:21])[CH:19]=[CH:20][C:15]=1[CH:5]1[N:6]=[C:7]([C:9]2[CH:14]=[N:13][CH:12]=[CH:11][N:10]=2)[NH:8][C:3]([CH2:2][N:29]2[CH2:34][CH2:33][O:32][CH:31]([CH2:35][C:36]([OH:38])=[O:37])[CH2:30]2)=[C:4]1[C:23]([O:25][CH2:26][CH3:27])=[O:24]
Reactant: O=C(O)CC1CNCCO1
Reactant: CCOC(=O)C1=C(CBr)NC(c2cnccn2)=NC1c1ccc(F)cc1Cl
Agent: Cl
Product: CCOC(=O)C1=C(CN2CCOC(CC(=O)O)C2)NC(c2cnccn2)=NC1c1ccc(F)cc1Cl
Yield: 31.6 %

Procedure:
Ethyl 6-(bromomethyl)-4-(2-chloro-4-fluorophenyl)-2-(pyrazin-2-yl)-1,4-dihydropyrimidine-5-carboxylate (1 g, 2.2 mmol) was reacted with 2-(morpholin-2-yl)acetic acid hydrochloride (0.4 g, 2.2 mmol) according to the procedure as described in Example 1, Step C to give the title compound as a yellow solid (0.36 g, 32%). The compound was characterized by the following spectroscopic data:
Reaction SMILES: [CH3:1][S:2]([O:5]S(C)(=O)=O)(=[O:4])=[O:3].[C:10]([O:14][C:15](=[O:25])[NH:16][C:17]1[CH:22]=[CH:21][C:20]([CH2:23]O)=[CH:19][N:18]=1)([CH3:13])([CH3:12])[CH3:11].C(N(CC)CC)C>C(Cl)Cl.CCOC(C)=O.O>[C:10]([O:14][C:15]([NH:16][C:17]1[N:18]=[CH:19][C:20]([CH2:23][O:5][S:2]([CH3:1])(=[O:4])=[O:3])=[CH:21][CH:22]=1)=[O:25])([CH3:13])([CH3:12])[CH3:11]
Reactant: CS(=O)(=O)OS(C)(=O)=O
Reactant: CC(C)(C)OC(=O)Nc1ccc(CO)cn1
Solvent: O
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CC(C)(C)OC(=O)Nc1ccc(COS(C)(=O)=O)cn1
Temperature: 5 °C
Reaction time: 1 h
Yield: 91.9 %

Procedure:
Methanesulfonic anhydride (0.854 g, 4.9 mmol, 1.1 equiv) was added portionwise to a cold (5° C.) mixture of (5-hydroxymethyl-pyridin-2-yl)-carbamic acid tert-butyl ester (Step 26.4) (1 g, 4.5 mmol) and triethylamine (0.75 mL, 5.4 mmol, 1.2 equiv) in DCM (20 mL), under an argon atmosphere. The reaction mixture was allowed to stir for 1 h at 5° C., diluted with EtOAc and H2O, and extracted with EtOAc. The organic phase was washed with H2O and brine, dried (Na2SO4), filtered and concentrated to provide 1.25 g of the title compound as a white solid: tR=2.60 min (System 1).
Reaction SMILES: [CH3:1][N:2]([CH3:19])[C:3]1[CH:18]=[CH:17][CH:16]=[CH:15][C:4]=1[CH2:5][S:6][C:7]1[NH:8][C:9]([CH3:14])([CH3:13])[C:10](=[O:12])[N:11]=1.[H-].[Na+].CI.[C:24](OCC)(=O)C>CN(C)C=O.O>[CH3:24][N:11]1[C:10](=[O:12])[C:9]([CH3:14])([CH3:13])[N:8]=[C:7]1[S:6][CH2:5][C:4]1[CH:15]=[CH:16][CH:17]=[CH:18][C:3]=1[N:2]([CH3:1])[CH3:19]
Reactant: CCOC(C)=O
Reactant: CN(C)c1ccccc1CSC1=NC(=O)C(C)(C)N1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Solvent: CI
Product: CN1C(=O)C(C)(C)N=C1SCc1ccccc1N(C)C
Reaction time: 0.25 h

Procedure:
To a solution of 0.5 g of 2-(2-dimethylaminobenzylthio)-5,5-dimethylimidazolin-4-one in 20 mL of N,N-dimethylformamide, there was added 60% sodium hydride in 0.09 g of mineral oil at -10° C. After the mixture was stirred for 15 minutes, 1 mL of methyl iodide was added to the mixture, and the stirring was continued for one hour. To the reaction mixture, there were added 100 mL of ethyl acetate (AcOEt) and 100 mL of water. The AcOEt layer was separated. The separated AcOEt layer was washed three times with 50 mL of brine, dried over magnesium sulfate (MgSO4), and concentrated in vacuo. The residue was purified by column chromatography (using CHCl3 as a developing solvent), to give the desired compound in the form of a syrup. The yield of this compound was 0.41 g with a yield ratio of 78.1%.
Reaction SMILES: [CH2:1]([N:3]([CH2:16][CH3:17])[C:4]([C:6]1[CH:15]=[CH:14][C:9]([C:10]([O:12]C)=[O:11])=[CH:8][CH:7]=1)=[O:5])[CH3:2].[OH-].[Na+].O.C(OCC)(=O)C>CO>[CH2:16]([N:3]([CH2:1][CH3:2])[C:4]([C:6]1[CH:15]=[CH:14][C:9]([C:10]([OH:12])=[O:11])=[CH:8][CH:7]=1)=[O:5])[CH3:17]
Reactant: CCN(CC)C(=O)c1ccc(C(=O)OC)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CO
Solvent: CCOC(C)=O
Product: CCN(CC)C(=O)c1ccc(C(=O)O)cc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 57.5 %

Procedure:
In 25 ml of methanol was dissolved 5.44 g of methyl 4-[(diethylamino)carbonyl]-benzoate. After adding 25 ml of 1 mol/L aqueous solution of sodium hydroxide at 0-5° C., the mixture was stirred at ambient temperature for 2 hours. The reaction mixture was poured into a mixture of water and ethyl acetate, and the aqueous layer was separated. The aqueous layer was mixed with ethyl acetate, pH was adjusted to 1.5 with 6 mol/L hydrochloric acid, and the organic layer was separated. The organic layer was washed successively with water and saturated aqueous solution of sodium chloride and dried over magnesium sulfate, and the solvent was distilled off under reduced pressure. Diisopropyl ether was added to the residue, and the deposited crystal was collected by filtration to obtain 2.94 g of 4-[(diethylamino)carbonyl]-benzoic acid as a colorless crystalline product.
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][C:7]([NH2:10])=[C:6]([NH2:11])[CH:5]=1)([O-:3])=[O:2].Cl.[C:13]([CH:15]([C:21]1[N:26]=[C:25]([CH3:27])[CH:24]=[C:23]([C:28]([F:31])([F:30])[F:29])[N:22]=1)[C:16](OCC)=O)#[N:14]>C(O)(=O)C>[CH3:27][C:25]1[CH:24]=[C:23]([C:28]([F:31])([F:29])[F:30])[N:22]=[C:21]([C:15](=[C:16]2[NH:10][C:7]3[CH:8]=[CH:9][C:4]([N+:1]([O-:3])=[O:2])=[CH:5][C:6]=3[NH:11]2)[C:13]#[N:14])[N:26]=1
Reactant: CCOC(=O)C(C#N)c1nc(C)cc(C(F)(F)F)n1
Reactant: Nc1ccc([N+](=O)[O-])cc1N
Agent: Cl
Solvent: CC(=O)O
Product: Cc1cc(C(F)(F)F)nc(C(C#N)=C2Nc3ccc([N+](=O)[O-])cc3N2)n1
Temperature: 100 °C
Yield: 50.9 %

Procedure:
4-Nitro-1,2-phenylenediamine (50 mg; 0.32 mmol) and ethyl 2-cyano-2-[4-methyl-6-(trifluoromethyl)pyrimidin-2-yl]acetate hydrochloride salt (101 mg; 0.32 mmol) were heated at 198° C. in a microwave for 3 min. Acetic acid (1.5 mL) was added to the crude material and the mixture heated at 100° C. for 6 hr. The solid was collected by filtration, washed with acetonitrile, and dried under high vacuum to give 2-[4-methyl-6-(trifluoromethyl)pyrimidin-2-yl]-2-(5-nitro-1H-benzimidazol-2(3H)-ylidene)acetonitrile (59 mg) as a yellow solid. 2-[4-Methyl-6-(trifluoromethyl)pyrimidin-2-yl]-2-(5-nitro-1H-benzimidazol-2(3H)-ylidene)acetonitrile (55 mg; 0.15 mmol) in DMF (3 mL) was hydrogenated over 10% palladium on carbon (11 mg). The mixture was filtered through diatomaceous earth, washing with methanol, and the filtrate was concentrated to give 2-(5-amino-1H-benzimidazol-2(3H)-ylidene)-2-[4-methyl-6-(trifluoromethyl)pyrimidin-2-yl]acetonitrile, which was dissolved in DMF (1 mL) and added to a solution of N-methyl-L-proline (19.3 mg; 0.16 mmol), HBTU (56.8 mg; 0.15 mmol), and DIPEA (104.5 μL; 0.60 mmol) in DMF (1 mL). The mixture was stirred for 5 hr and then partitioned between EA and water. The EA phase was dried and concentrated to give 2-{5-[(S)-(1-methylpyrrolidin-2-yl)carbonylamino]-1H-benzimidazol-2 (3H)-ylidene}-2-[4-methyl-6-(trifluoromethyl)pyrimidin-2-yl]acetonitrile (65 mg) as a brown oil. 2-{5-[(S)-(1-Methylpyrrolidin-2-yl)-carbonylamino]-1H-benzimidazol-2(3H)-ylidene}-2-[4-methyl-6-(trifluoromethyl)pyrimidin-2-yl]-acetonitrile (65 mg) was dissolved in concentrated sulfuric acid and stirred at room temperature overnight. The mixture was diluted with ice-water and acetonitrile and, after coming to room temperature, was purified by reverse phase preparative HPLC using a Peeke Ultro 120, 7 μm, C18Q, 250×30 mm column at a flow rate of 42 mL/min and mobile phases of 95% water, 5% acetonitrile (with 0.01% hydrochloric acid) and 5% water, 95% acetonitrile (with 0.01% hydrochloric acid) to give 2-{5-[(S)-(1-methylpyrrolidin-2-yl)carbonylamino]-1H-benzimidazol-2 (3H)-ylidene}-2-[4-methyl-6-(trifluoromethyl)pyrimidin-2-yl]acetamide hydrochloride salt (18 mg) as a yellow solid.