Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][CH:6]=[C:5]2[C:11]([C@@H:13]1[CH2:15][C@H:14]1[C:16]([OH:18])=O)=[O:12].C(C1NC=CN=1)([C:21]1[NH:22][CH:23]=CN=1)=O.CNC>O1CCCC1>[CH3:21][N:22]([CH3:23])[C:16]([C@@H:14]1[CH2:15][C@H:13]1[C:11]([C:5]1[C:4]2[C:8](=[CH:9][CH:10]=[C:2]([F:1])[CH:3]=2)[NH:7][CH:6]=1)=[O:12])=[O:18]
Reactant: O=C(O)[C@@H]1C[C@H]1C(=O)c1c[nH]c2ccc(F)cc12
Reactant: O=C(c1ncc[nH]1)c1ncc[nH]1
Agent: CNC
Solvent: C1CCOC1
Product: CN(C)C(=O)[C@@H]1C[C@H]1C(=O)c1c[nH]c2ccc(F)cc12
Reaction time: 3 h

Procedure:
A solution of trans-2-(5-fluoro-3-indolylcarbonyl)cyclopropanecarboxylic acid (1.5 g, 6 mmol) and carbonyl diimidazole in tetrahydrofuran was stirred for 0.5 hr. A solution of dimethylamine in tetrahydrofuran (3 ml, 2 M solution, 6 mmol) was added and the solution stirred for 3 hr. The solution was concentrated in vacuo and the residue dissolved in ethyl acetate. The organic solution was washed with 1 N HCl and saturated sodium bicarbonate solution. The solution was dried over sodium sulfate and concentrated in vacuo. The residue was triturated with isopropyl ether to give 1.5 g of trans-2-(5-fluoro-3-indolylcarbonyl)cyclopropanecarboxylic acid dimethylamide, mp 239-241° C. LC/MS mw=274; retention time 1.23 min. Mol wt calc1d for C15H15F N2O2: 274.
Reaction SMILES: Cl[CH2:2][CH2:3][CH2:4][CH2:5][S:6][C:7]1[N:12]2[CH:13]=[C:14]([CH3:16])[N:15]=[C:11]2[CH:10]=[CH:9][CH:8]=1.[S:17]1[CH2:21][C:20](=[O:22])[NH:19][C:18]1=[O:23].C1CCN2C(=NCCC2)CC1>>[CH3:16][C:14]1[N:15]=[C:11]2[CH:10]=[CH:9][CH:8]=[C:7]([S:6][CH2:5][CH2:4][CH2:3][CH2:2][N:19]3[C:20](=[O:22])[CH2:21][S:17][C:18]3=[O:23])[N:12]2[CH:13]=1
Reactant: O=C1CSC(=O)N1
Reactant: Cc1cn2c(SCCCCCl)cccc2n1
Solvent: C1CCC2=NCCCN2CC1
Product: Cc1cn2c(SCCCCN3C(=O)CSC3=O)cccc2n1

Procedure:
Using 0.76 g (3.0 mmol) of 5-(4-chlorobutylthio)-2-methylimidazo[1,2-a]pyridine, 0.35 g (3.0 mmol) of thiazolidine-2,4-dione and 0.45 ml (3.0 mmol) of 1,8-diazabicyclo[5.4.0]-7-undecene, the same procedure as in Reference Example 2 was followed, to yield 0.78 g (77.7%, light yellow oily substance) of the desired product.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([C:8]2[N:9]=[C:10]3[N:14]([C:15]=2[C:16]2[CH:21]=[CH:20][N:19]=[C:18]([NH:22][C:23]4[CH:28]=[CH:27][CH:26]=[C:25]([CH2:29][CH2:30][N:31]5[CH2:36][CH2:35][O:34][CH2:33][CH2:32]5)[CH:24]=4)[N:17]=2)[CH:13]=[CH:12][S:11]3)[CH:5]=[CH:6][CH:7]=1.NC1C=C(C2N=C3N(C=2C2C=CN=C(NC4C=CC=C(OCCCN5CCOCC5)C=4)N=2)C=CS3)C=CC=1.[CH3:75][C:76]1[CH:84]=[CH:83][CH:82]=[CH:81][C:77]=1[C:78](Cl)=[O:79].FC1C=CC=C(F)C=1C(Cl)=O>>[CH3:75][C:76]1[CH:84]=[CH:83][CH:82]=[CH:81][C:77]=1[C:78]([NH:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([C:8]2[N:9]=[C:10]3[N:14]([C:15]=2[C:16]2[CH:21]=[CH:20][N:19]=[C:18]([NH:22][C:23]4[CH:28]=[CH:27][CH:26]=[C:25]([CH2:29][CH2:30][N:31]5[CH2:36][CH2:35][O:34][CH2:33][CH2:32]5)[CH:24]=4)[N:17]=2)[CH:13]=[CH:12][S:11]3)[CH:3]=1)=[O:79]
Reactant: Nc1cccc(-c2nc3sccn3c2-c2ccnc(Nc3cccc(CCN4CCOCC4)c3)n2)c1
Reactant: Cc1ccccc1C(=O)Cl
Agent: Nc1cccc(-c2nc3sccn3c2-c2ccnc(Nc3cccc(OCCCN4CCOCC4)c3)n2)c1
Agent: O=C(Cl)c1c(F)cccc1F
Product: Cc1ccccc1C(=O)Nc1cccc(-c2nc3sccn3c2-c2ccnc(Nc3cccc(CCN4CCOCC4)c3)n2)c1

Procedure:
The title compound was prepared as described in EXAMPLE 297, with the following substitutions: 4-(6-(3-aminophenyl)imidazo[2,1-b]thiazol-5-yl)-N-(3-(2-morpholinoethyl)phenyl)pyrimidin-2-amine for 4-(6-(3-aminophenyl)imidazo[2,1-b]thiazol-5-yl)-N-(3-(3-morpholinopropoxy)phenyl)pyrimidin-2-amine and 2-methylbenzoyl chloride for 2,6-difluorobenzoyl chloride. (ESI(+)) m/e 616 (M+H)+; (ESI(−)) m/e 614 (M−H)−; 1H-NMR (300 MHz, DMSO-d6) □ 10.40 (s, 1H), 9.61 (s, 1H), 8.81 (d, 1H), 8.29 (d, 1H), 8.06 (s, 1H), 7.84 (d, 1H), 7.25-7.64 (m, 9H), 7.21 (t, 1H), 6.86 (d, 1H), 6.65 (d, 1H), 3.53-3.62 (m, 4H), 3.17 (d, 2H), 2.67-2.77 (m, 2H), 2.36-2.44 (m, 7H).
Reaction SMILES: [NH2:1][C:2]1[N:7]=[C:6]([CH3:8])[CH:5]=[C:4]([CH3:9])[N:3]=1.[CH3:10][C:11]1([CH3:26])[CH2:15][C:14]2[CH:16]=[CH:17][CH:18]=[C:19]([S:20]([N:23]=[C:24]=[O:25])(=[O:22])=[O:21])[C:13]=2[O:12]1>O1CCCC1>[CH3:9][C:4]1[CH:5]=[C:6]([CH3:8])[N:7]=[C:2]([NH:1][C:24]([NH:23][S:20]([C:19]2[C:13]3[O:12][C:11]([CH3:26])([CH3:10])[CH2:15][C:14]=3[CH:16]=[CH:17][CH:18]=2)(=[O:21])=[O:22])=[O:25])[N:3]=1
Reactant: Cc1cc(C)nc(N)n1
Reactant: CC1(C)Cc2cccc(S(=O)(=O)N=C=O)c2O1
Solvent: C1CCOC1
Product: Cc1cc(C)nc(NC(=O)NS(=O)(=O)c2cccc3c2OC(C)(C)C3)n1
Temperature: 25 °C
Reaction time: 4 h
Yield: 54.5 %

Procedure:
To a solution of 1.2 g of 2-amino-4,6-dimethylpyrimidine in 25 ml of tetrahydrofuran was added 2.5 g of 2,3-dihydro-2,2-dimethyl-7-benzofuransulfonyl isocyanate prepared above. After a slight exotherm the solution was stirred at room temperature for 4 hours. The solution was concentrated in vacuo to give a viscous oil that precipitated a solid from 10 ml of acetonitrile. The solid was recrystallized from acetonitrile to give 2 g of N-[(4,6-dimethylpyrimidin-2-yl)aminocarbonyl]-2,3-dihydro-2,2-dimethyl-7-benzofuransulfonamide, m.p. 203°-206° C. The IR spectrum showed a carbonyl absorption at 1680 cm-1 indicative of a sulfonylurea.
Reaction SMILES: [Br:1][C:2]1[CH:9]=[CH:8][C:5]([CH:6]=O)=[CH:4][CH:3]=1.[CH3:10][O:11][CH:12]([O:15][CH3:16])[CH2:13][NH2:14].O.C1(C)C=CC(S(O)(=O)=O)=CC=1.[BH4-].[Na+]>C1(C)C=CC=CC=1.C(O)(=O)C>[Br:1][C:2]1[CH:9]=[CH:8][C:5]([CH2:6][NH:14][CH2:13][CH:12]([O:15][CH3:16])[O:11][CH3:10])=[CH:4][CH:3]=1
Reactant: O=Cc1ccc(Br)cc1
Reactant: COC(CN)OC
Agent: Cc1ccc(S(=O)(=O)O)cc1
Agent: [BH4-]
Agent: [Na+]
Solvent: O
Solvent: CC(=O)O
Solvent: Cc1ccccc1
Product: COC(CNCc1ccc(Br)cc1)OC
Temperature: 25 °C
Reaction time: 4 h
Yield: 81.7 %

Procedure:
50 g (270.2 mmol) 4-bromobenzaldehyde were dissolved in 200 ml of toluene and 28.4 g (270.2 mmol) aminoacetaldehyde dimethylacetal were added. After the addition of 5.1 g (27.0 mmol) p-toluenesulfonic acid monohydrate, the reaction mixture was heated under reflux in a Dean Stark apparatus. After 4 h, the reaction was cooled to room temperature and washed with saturated sodium hydrogen carbonate-solution (2×) and water. The combined aqueous layers were extracted with Toluene and the combined organic layers were dried over magnesium sulfate and evaporated. The residue was dissolved in 200 ml of ethanol and 5.11 g (135.1 mmol) of sodium borohydride were added in small portions. After stirring for 2 h at room temperature and standing overnight, 5.0 ml acetic acid were added and the solvent was removed i. vac. The residue was taken up in dichloromethane and washed (2×) with water. After drying over magnesium sulfate and evaporation, 60.5 g of the title compound were obtained (crude product), which were used without further purification. Rt=0.80 min (Method C). Detected mass: 274.1/276.1 (M+H+).
Reaction SMILES: [O:1]1[C:13]2[C:12]3[CH:11]=[CH:10][CH:9]=[CH:8][C:7]=3[NH:6][C:5](=O)[C:4]=2[CH:3]=[CH:2]1.O=P(Cl)(Cl)[Cl:17]>>[Cl:17][C:5]1[C:4]2[CH:3]=[CH:2][O:1][C:13]=2[C:12]2[CH:11]=[CH:10][CH:9]=[CH:8][C:7]=2[N:6]=1
Reactant: O=c1[nH]c2ccccc2c2occc12
Reactant: O=P(Cl)(Cl)Cl
Product: Clc1nc2ccccc2c2occc12

Procedure:
First, the known compound 5H-furo[3,2-c]quinolin-4-one (compound 1) is reacted with POCl3 to produce 4-chlorofuro[3,2-c]quinoline (compound 2). Compound 2 is further reacted with 3-aminoacetophenone in a solution of EtOH-H2 (2:1) to yield 1-[3-chlorofuro[3,2-c]quinolin-4-ylamino]phenyl)ethanone (compound 3).
Reaction SMILES: C(OC([N:8]1[CH2:13][CH2:12][N:11]([C:14]2[C:23]3[C:18](=[CH:19][CH:20]=[C:21]([OH:24])[CH:22]=3)[CH:17]=[CH:16][N:15]=2)[CH2:10][CH2:9]1)=O)(C)(C)C.[ClH:25].C(OCC)(=O)C>>[ClH:25].[OH:24][C:21]1[CH:22]=[C:23]2[C:18]([CH:17]=[CH:16][N:15]=[C:14]2[N:11]2[CH2:12][CH2:13][NH:8][CH2:9][CH2:10]2)=[CH:19][CH:20]=1
Reactant: CC(C)(C)OC(=O)N1CCN(c2nccc3ccc(O)cc23)CC1
Agent: Cl
Solvent: CCOC(C)=O
Product: Oc1ccc2ccnc(N3CCNCC3)c2c1
Temperature: 25 °C
Yield: 78 %

Procedure:
A mixture of 70 mg of 1-(4-tert-butoxycarbonylpiperazin-1-yl)-7-hydroxyisoquinoline as synthesized in the above step and 3 ml of 4N hydrochloric acid-ethyl acetate solution was stirred for an hour at room temperature. So formed crystalline product was recovered by filtration and washed with ethyl acetate to provide 43 mg (yield: 78%) of 7-hydroxy-1-piperazin-1-ylisoquinoline hydrochloride.
Reaction SMILES: NOS(O)(=O)=O.[NH:7]1[C:15]2[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=2)[CH:9]=[CH:8]1.CC(C)([O-])C.[K+].[NH2:22]OS(O)(=O)=O.N1C2C(=CC=CC=2)C=C1.CN1CCCC1=O.CC(C)([O-])C.[K+].CN1CCCC1=O>CN1CCCC1=O.CC(C)([O-])C.[K+].CN1CCCC1=O>[N:7]1([NH2:22])[C:15]2[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=2)[CH:9]=[CH:8]1
Reactant: NOS(=O)(=O)O
Reactant: c1ccc2[nH]ccc2c1
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: CN1CCCC1=O
Product: Nn1ccc2ccccc21
Reaction time: 3.08 h
Yield: 90.2 %

Procedure:
A solution of 33.8 kg (32.8 kg corrected for 97% purity) of hydroxylamine-O-sulfonic acid (HOSA) and 15.8 kg (15.6 kg corrected for 99% purity) of indole in 120.2 kg of N-methylpyrrolidinone (NMP), is prepared and chilled to 0–5° C. A second solution is prepared from 67.0 kg (63.7 kg corrected for 95% purity) of potassium tert-butoxide and 122.6 kg of NMP. An amination vessel is charged with 47.0 kg of NMP and an initial charge of 2.2 kg of the potassium tert-butoxide/NMP solution. The HOSA/indole/NMP solution and the remaining potassium tert-butoxide/NMP solution are then simultaneously and proportionally metered using a metering pumping system consisting of a dual head plunger pump together with coriolis mass flow meters into the amination vessel over a period of 185 minutes while maintaining a reaction temperature of 20–30° C. to yield a solution containing 15.9 kg (90.2% yield) of 1H-indol-1-amine as determined by external standard HPLC assay.
Reaction SMILES: Cl.[CH3:2][O:3][CH2:4][C:5]1[O:9][C:8]([CH2:10][N:11]2[C:16]3[CH:17]=[C:18]([C:20]4[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=4)[S:19][C:15]=3[C:14](=[O:26])[N:13]([CH:27]3[CH2:32][CH2:31][NH:30][CH2:29][CH2:28]3)[C:12]2=[O:33])=[N:7][N:6]=1.[CH2:34]([O:36][C:37]1[C:46]([O:47][CH3:48])=[CH:45][C:44]2[C:43]([C:49]3[CH:57]=[CH:56][C:52]([C:53](O)=[O:54])=[CH:51][CH:50]=3)=[N:42][C@@H:41]3[CH2:58][CH2:59][S:60][CH2:61][C@@H:40]3[C:39]=2[CH:38]=1)[CH3:35].CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C>C(Cl)Cl>[CH2:34]([O:36][C:37]1[C:46]([O:47][CH3:48])=[CH:45][C:44]2[C:43]([C:49]3[CH:50]=[CH:51][C:52]([C:53]([N:30]4[CH2:31][CH2:32][CH:27]([N:13]5[C:14](=[O:26])[C:15]6[S:19][C:18]([C:20]7[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=7)=[CH:17][C:16]=6[N:11]([CH2:10][C:8]6[O:9][C:5]([CH2:4][O:3][CH3:2])=[N:6][N:7]=6)[C:12]5=[O:33])[CH2:28][CH2:29]4)=[O:54])=[CH:56][CH:57]=3)=[N:42][C@@H:41]3[CH2:58][CH2:59][S:60][CH2:61][C@@H:40]3[C:39]=2[CH:38]=1)[CH3:35]
Reactant: COCc1nnc(Cn2c(=O)n(C3CCNCC3)c(=O)c3sc(-c4ccccc4)cc32)o1
Reactant: CCOc1cc2c(cc1OC)C(c1ccc(C(=O)O)cc1)=N[C@@H]1CCSC[C@H]21
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: CCOc1cc2c(cc1OC)C(c1ccc(C(=O)N3CCC(n4c(=O)c5sc(-c6ccccc6)cc5n(Cc5nnc(COC)o5)c4=O)CC3)cc1)=N[C@@H]1CCSC[C@H]21

Procedure:
1-{[5-(methoxymethyl)-1,3,4-oxadiazol-2-yl]methyl}-6-phenyl-3-(piperidin-4-yl)thieno[3,2-d]pyrimidine-2,4(1H,3H)-dione hydrochloride (250 mg; compound B33) is reacted with 4-[(4aR,10bR)-9-ethoxy-8-methoxy-3,4,4a,10b-tetrahydro-1H-thiopyrano[4,3-c]isoquinolin-6-yl]benzoic acid (223 mg; compound C10) and HBTU (232 mg) in DCM (15 ml) in the presence of DIPEA (0.36 ml) according to the procedure described in example 2 to afford the title compound after purification by flash column chromatography [silica gel, eluation gradient: DCM/MeOH, 1/0 to 3/2 (v/v)] and preparative HPLC as a solid.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4](B(O)O)[C:5]([F:8])=[N:6][CH:7]=1.Cl[C:13]1[N:18]=[C:17]([CH3:19])[N:16]=[C:15]([N:20]([CH2:30][C:31]2[CH:36]=[CH:35][C:34]([O:37][CH3:38])=[CH:33][CH:32]=2)[CH2:21][C:22]2[CH:27]=[CH:26][C:25]([O:28][CH3:29])=[CH:24][CH:23]=2)[N:14]=1.C([O-])(=O)C.[K+]>C(O)C.O.CC(P(C(C)(C)C)C1C=CC(N(C)C)=CC=1)(C)C.CC(P(C(C)(C)C)C1C=CC(N(C)C)=CC=1)(C)C.Cl[Pd]Cl>[Cl:1][C:2]1[CH:3]=[C:4]([C:13]2[N:18]=[C:17]([CH3:19])[N:16]=[C:15]([N:20]([CH2:21][C:22]3[CH:23]=[CH:24][C:25]([O:28][CH3:29])=[CH:26][CH:27]=3)[CH2:30][C:31]3[CH:32]=[CH:33][C:34]([O:37][CH3:38])=[CH:35][CH:36]=3)[N:14]=2)[C:5]([F:8])=[N:6][CH:7]=1
Reactant: OB(O)c1cc(Cl)cnc1F
Reactant: COc1ccc(CN(Cc2ccc(OC)cc2)c2nc(C)nc(Cl)n2)cc1
Agent: Cl[Pd]Cl
Agent: CC(=O)[O-]
Agent: CN(C)c1ccc(P(C(C)(C)C)C(C)(C)C)cc1
Solvent: CCO
Solvent: O
Product: COc1ccc(CN(Cc2ccc(OC)cc2)c2nc(C)nc(-c3cc(Cl)cnc3F)n2)cc1
Temperature: 100 °C
Reaction time: 16 h
Yield: 55.4 %

Procedure:
A mixture of 5-chloro-2-fluoropyridin-3-ylboronic acid (Combi Blocks, 2.507 g, 14.30 mmol), 4-chloro-N,N-bis(4-methoxybenzyl)-6-methyl-1,3,5-triazin-2-amine (5.24 g, 13.62 mmol), bis-(di-tert-butyl(4-dimethylaminophenyl)phosphine)dichloropalladium(II) (0.482 g, 0.681 mmol), and potassium acetate (4.10 g, 41.8 mmol) in ethanol (100 mL) and water (10 mL) was degassed and stirred under N2 at 100° C. for 16 h. The reaction mixture was then cooled to ambient temperature, concentrated in vacuo, and the residue was partitioned between water (50 mL) and EtOAc (50 mL). The aqueous phase was extracted with EtOAc (2×20 mL), and the combined organic layers were washed with saturated aqueous sodium chloride (100 mL). The organic phase was dried over sodium sulfate, filtered and concentrated. Chromatographic purification of the residue (silica gel, 15 to 50% EtOAc/hexanes) gave 4-(5-chloro-2-fluoropyridin-3-yl)-N,N-bis(4-methoxybenzyl)-6-methyl-1,3,5-triazin-2-amine (3.62 g, 7.54 mmol, 55.4% yield). m/z (ESI, +ve ion) 480 (M+H)+.
Reaction SMILES: [F:1][C:2]1[CH:3]=[CH:4][CH:5]=[C:6]([NH2:11])[C:7]=1[C:8]([NH2:10])=[O:9].Cl[C:13]1[S:14][C:15]([CH3:18])=[CH:16]N=1>>[CH3:18][C:15]1[S:14][C:13]2=[N:11][C:6]3[C:7]([C:8](=[O:9])[N:10]2[CH:16]=1)=[C:2]([F:1])[CH:3]=[CH:4][CH:5]=3
Reactant: NC(=O)c1c(N)cccc1F
Reactant: Cc1cnc(Cl)s1
Product: Cc1cn2c(=O)c3c(F)cccc3nc2s1
Yield: 82.3 %

Procedure:
10.8 g of 6-fluoroanthanilamide and 9.4 g of 2-chloro-5-methylthiazole were stirred for 7 hours at 150° C. After working up in the conventional manner there was obtained 13.5 g (83%) of the above compound; m.p. 245°-246° C.
Reaction SMILES: [C:1]([C:3]1[N:7]2[CH2:8][CH2:9][N:10]([C:12]([O:14][C:15]([CH3:18])([CH3:17])[CH3:16])=[O:13])[CH2:11][C:6]2=[C:5]([C:19]([O:21]CC)=[O:20])[C:4]=1[C:24]1[CH:29]=[CH:28][CH:27]=[C:26]([F:30])[CH:25]=1)#[N:2].C(O)C.[OH-].[Li+].S(=O)(=O)(O)O>ClCCl.O1CCCC1.O>[C:15]([O:14][C:12]([N:10]1[CH2:9][CH2:8][N:7]2[C:3]([C:1]#[N:2])=[C:4]([C:24]3[CH:29]=[CH:28][CH:27]=[C:26]([F:30])[CH:25]=3)[C:5]([C:19]([OH:21])=[O:20])=[C:6]2[CH2:11]1)=[O:13])([CH3:18])([CH3:16])[CH3:17]
Reactant: CCOC(=O)c1c(-c2cccc(F)c2)c(C#N)n2c1CN(C(=O)OC(C)(C)C)CC2
Agent: O=S(=O)(O)O
Agent: [Li+]
Agent: [OH-]
Solvent: ClCCl
Solvent: CCO
Solvent: O
Product: CC(C)(C)OC(=O)N1CCn2c(C#N)c(-c3cccc(F)c3)c(C(=O)O)c2C1
Temperature: 60 °C
Yield: 92.5 %

Procedure:
To a suspension of 1.24 g (3.00 mmol) of 2-tert-butyl 8-ethyl 6-cyano-7-(3-fluorophenyl)-3,4-dihydropyrrolo[1,2-a]pyrazine-2,8(1H)-dicarboxylate in 15 ml of a mixture of ethanol, water and tetrahydrofuran (1:1:1) is added 0.086 g (3.6 mmol) of lithium hydroxide, and the mixture is heated at 60° C. for 1 day. The mixture is then taken up in 60 ml of dichloromethane and is acidified by addition of aqueous 1N sulfuric acid. The organic phase is separated out and dried over sodium sulfate, and the solvent is evaporated off under reduced pressure to give a solid, which is triturated in acetonitrile to give 1.07 g of 2-(tert-butyloxycarbonyl)-6-cyano-7-(3-fluorophenyl)-1,2,3,4-tetrahydropyrrolo[1,2-a]pyrazine-8-carboxylic acid in the form of a white powder.
Reaction SMILES: [CH3:1][O:2][N:3]=[CH:4][C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1.C([BH3-])#N.[Na+]>CO>[CH3:1][O:2][NH:3][CH2:4][C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1
Reactant: CON=Cc1ccccc1
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CO
Product: CONCc1ccccc1

Procedure:
The procedure of Example VI is repeated using 15.0 g of O-methylbenzaldoxime, and 20.0 g of sodium cyanoborohydride in 100 ml of methanol. Bulb to bulb distillation of the crude product affords the title compound as a colorless liquid.
Reaction SMILES: [F:1][C:2]1[C:10]2[N:9]=[C:8]([C:11]([N:13]([CH2:35][CH:36]([CH3:38])[CH3:37])[C@H:14]3[CH2:19][C@@H:18]([C:20]([N:22]4[CH2:27][CH2:26][O:25][CH2:24][CH2:23]4)=[O:21])[CH2:17][N:16](C(OC(C)(C)C)=O)[CH2:15]3)=[O:12])[N:7]([CH2:39][CH2:40][CH2:41][CH2:42][O:43][CH3:44])[C:6]=2[CH:5]=[CH:4][CH:3]=1.C(OCC)(=O)C.[ClH:51]>>[ClH:51].[ClH:51].[F:1][C:2]1[C:10]2[N:9]=[C:8]([C:11]([N:13]([CH2:35][CH:36]([CH3:37])[CH3:38])[C@H:14]3[CH2:19][C@@H:18]([C:20]([N:22]4[CH2:27][CH2:26][O:25][CH2:24][CH2:23]4)=[O:21])[CH2:17][NH:16][CH2:15]3)=[O:12])[N:7]([CH2:39][CH2:40][CH2:41][CH2:42][O:43][CH3:44])[C:6]=2[CH:5]=[CH:4][CH:3]=1
Reactant: COCCCCn1c(C(=O)N(CC(C)C)[C@H]2C[C@@H](C(=O)N3CCOCC3)CN(C(=O)OC(C)(C)C)C2)nc2c(F)cccc21
Agent: Cl
Solvent: CCOC(C)=O
Product: COCCCCn1c(C(=O)N(CC(C)C)[C@@H]2CNC[C@H](C(=O)N3CCOCC3)C2)nc2c(F)cccc21
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
tert-Butyl (3S,5R)-3-{{{4-fluoro-1-(4-methoxybutyl)-1H-benzimidazol-2-yl}carbonyl}(2-methylpropyl)amino}-5-(morpholin-4-ylcarbonyl)piperidine-1-carboxylate (75 mg) was dissolved in 3M hydrogen chloride-ethyl acetate (2 ml), and the mixture was stirred at room temperature for 30 min and concentrated to give the object product (67 mg).
Reaction SMILES: [CH3:1][O:2][C:3]1[C:10]([O:11][CH3:12])=[C:9]([O:13][CH3:14])[CH:8]=[CH:7][C:4]=1C=O.ClC1C=CC=C(C(OO)=[O:23])C=1>C(Cl)Cl>[CH3:1][O:2][C:3]1[C:10]([O:11][CH3:12])=[C:9]([O:13][CH3:14])[CH:8]=[CH:7][C:4]=1[OH:23]
Reactant: COc1ccc(C=O)c(OC)c1OC
Reactant: O=C(OO)c1cccc(Cl)c1
Solvent: ClCCl
Product: COc1ccc(O)c(OC)c1OC
Temperature: 50 °C
Reaction time: 3 h
Yield: 51.1 %

Procedure:
2,3,4-Trimethoxybenzaldehyde (5 g) was suspended in anhydrous methylene chloride (50 ml), followed by addition of m-chloroperbenzoic acid (10 g; purity of 70%) to heat and stir the resulting mixture at 50° C. for 3 hours. After distilling off the solvents under reduced pressure, the residue was dissolved in ethyl acetate (100 ml) and washed in an aqueous saturated sodium hydrogen carbonate solution, in water and in an aqueous saturated sodium chloride solution, and dried over anhydrous magnesium sulfate. Then, the solvents were distilled off under reduced pressure. To the residue were added dioxane (15 ml) and a 3N sodium hydroxide solution (15 ml), prior to stirring at room temperature for 30 minutes and adjustment to acidity with dilute hydrochloric acid, followed by ethyl acetate extraction three times. The organic phase was washed in water and in an aqueous saturated sodium chloride solution and dried over anhydrous magnesium sulfate, followed by distillation of the solvents under reduced pressure. The residue was purified by silica gel column chromatography (developing solvent: hexane:ethyl acetate=3:1), to recover 2,3,4-trimethoxyphenol (2.4 g; yield of 51%). By 1H-NMR (90 MHz, CDCl3), the compound has the peaks shown below.
Reaction SMILES: [CH2:1]([C:8]1[CH:17]=[CH:16][C:11]2[NH:12][C:13](=[S:15])[NH:14][C:10]=2[CH:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH3:18][C:19]([CH:21]=[CH2:22])=[O:20]>>[CH2:1]([C:8]1[CH:17]=[CH:16][C:11]2[N:12]([CH2:22][CH2:21][C:19](=[O:20])[CH3:18])[C:13](=[S:15])[NH:14][C:10]=2[CH:9]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: S=c1[nH]c2ccc(Cc3ccccc3)cc2[nH]1
Reactant: C=CC(C)=O
Product: CC(=O)CCn1c(=S)[nH]c2cc(Cc3ccccc3)ccc21

Procedure:
16 g (66.7 mmoles) of 5-benzyl-benzimidazoline-2-thione are stirred in 30 ml of methylvinylketone for 25 hours. The excess of the detone is distilled off under vacuum (0.1 to 0.2 bars), 50 ml of isopropanol are poured onto the residue, then the solvent is distilled off. Upon pouring ether onto the residue, crystalls are obtained. These are filtered off, and recrystallized from acetonitrile, then ethanol. The title product thus obtained melts at a temperature of 141°-142° C.
Reaction SMILES: C(OC([N:8]([CH2:22][C:23]1[CH:28]=[CH:27][CH:26]=[C:25]([F:29])[CH:24]=1)[CH2:9][CH2:10][O:11]S(C1C=CC(C)=CC=1)(=O)=O)=O)(C)(C)C.[O:30]1[C:34]2[CH:35]=[CH:36][S:37][C:33]=2[C:32]([C:38]2[CH:39]=[C:40](O)[CH:41]=[CH:42][CH:43]=2)=[N:31]1>>[F:29][C:25]1[CH:24]=[C:23]([CH:28]=[CH:27][CH:26]=1)[CH2:22][NH:8][CH2:9][CH2:10][O:11][C:42]1[CH:41]=[CH:40][CH:39]=[C:38]([C:32]2[C:33]3[S:37][CH:36]=[CH:35][C:34]=3[O:30][N:31]=2)[CH:43]=1
Reactant: Oc1cccc(-c2noc3ccsc23)c1
Reactant: Cc1ccc(S(=O)(=O)OCCN(Cc2cccc(F)c2)C(=O)OC(C)(C)C)cc1
Product: Fc1cccc(CNCCOc2cccc(-c3noc4ccsc34)c2)c1

Procedure:
The title compound is prepared from a mixture of toluene-4-sulfonic acid 2-[tert-butoxycarbonyl-(3-fluoro-benzyl)-amino]-ethyl ester and 3-thieno[2,3-d]isoxazol-3-yl-phenol essentially as described in Example 3, Scheme I, Step F. It is understood by one skilled in the art that the nitrogen may be deprotected by acid hydrolysis, to give the final, desired compound.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C:9]2[N:13]([CH2:14][CH:15]3[CH2:20][CH2:19][CH2:18][CH2:17][CH2:16]3)[C:12]3[CH:21]=[C:22]([F:26])[C:23]([F:25])=[CH:24][C:11]=3[N:10]=2)=[C:6]([OH:8])[CH:7]=1.C(=O)([O-])[O-].[Cs+].[Cs+].Br[CH2:34][CH:35]1[CH2:40][CH2:39][CH2:38][CH2:37][CH2:36]1>CC(C)=O>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C:9]2[N:13]([CH2:14][CH:15]3[CH2:16][CH2:17][CH2:18][CH2:19][CH2:20]3)[C:12]3[CH:21]=[C:22]([F:26])[C:23]([F:25])=[CH:24][C:11]=3[N:10]=2)=[C:6]([O:8][CH2:34][CH:35]2[CH2:40][CH2:39][CH2:38][CH2:37][CH2:36]2)[CH:7]=1
Reactant: Oc1cc(Cl)ccc1-c1nc2cc(F)c(F)cc2n1CC1CCCCC1
Reactant: BrCC1CCCCC1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CC(C)=O
Product: Fc1cc2nc(-c3ccc(Cl)cc3OCC3CCCCC3)n(CC3CCCCC3)c2cc1F
Yield: 56 %

Procedure:
To the solution of 5-chloro-2-(1-cyclohexylmethyl-5,6-difluoro-1H-benzoimidazol-2-yl)-phenol (Example 19, intermediate a) (98 mg, 0.26 mmol) in acetone (10 ml) was added cesium carbonate (127 mg, 0.39 mmol) followed by bromomethyl-cyclohexane (42 mg, 0.31 mmol; CAS Reg. No. 2550-36-9) and the reaction was refluxed for 12 h. The reaction mixture was filtered, and the filtrate was concentrated under reduced pressure. The crude material was purified by column chromatography using silica gel (30-40% ethyl acetate/n-hexane) to afford the desired product as an off-white powder (56%). MS (Turbo Spray): m/z=473.0 (M+H).
Reaction SMILES: [CH2:1]([O:3][C:4]1[C:5]([F:11])=[C:6]([OH:10])[CH:7]=[CH:8][CH:9]=1)[CH3:2].[CH2:12]([O:14][C:15](=[O:19])[C:16]#[C:17][CH3:18])[CH3:13].N12CCCN=C1CCCCC2>O1CCCC1>[CH2:12]([O:14][C:15](=[O:19])/[CH:16]=[C:17](/[O:10][C:6]1[CH:7]=[CH:8][CH:9]=[C:4]([O:3][CH2:1][CH3:2])[C:5]=1[F:11])\[CH3:18])[CH3:13]
Reactant: CC#CC(=O)OCC
Reactant: CCOc1cccc(O)c1F
Solvent: C1CCC2=NCCCN2CC1
Solvent: C1CCOC1
Product: CCOC(=O)/C=C(\C)Oc1cccc(OCC)c1F

Procedure:
To a stirred mixture of 3-ethoxy-2-fluoro-phenol (6.00 g, 0.038 mol) and ethyl-2-butynoate (8.60 g, 0.077 mol) in tetrahydrofuran (50 mL) was added 1,8-diazabicyclo[5.4.0]undec-7-ene (5.80 g, 0.038 mol) slowly. After addition was complete the mixture was stirred at reflux for 7 h. Upon completion of the reaction the tetrahydrofuran was removed in vacuo and the residue was diluted in diethyl ether and washed first with 1N aqueous hydrochloric acid, then 10% aqueous sodium hydroxide solution, a saturated sodium chloride solution and dried over magnesium sulfate. The crude product, (E)-3-(3-ethoxy-2-fluoro-phenoxy)-but-2-enoic acid ethyl ester, was obtained as a brown oil (6.00 g, 58%) and used without further purification.