Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[CH:4][C:5]([F:17])=[C:6]([C@:8]2([CH3:16])[C@@H:13]([F:14])[CH2:12][O:11][C:10]([NH2:15])=[N:9]2)[CH:7]=1.[C:18]([C:20]1[CH:21]=[CH:22][C:23]([C:26](O)=[O:27])=[N:24][CH:25]=1)#[N:19]>>[NH2:15][C:10]1[O:11][CH2:12][C@H:13]([F:14])[C@:8]([C:6]2[CH:7]=[C:2]([NH:1][C:26]([C:23]3[CH:22]=[CH:21][C:20]([C:18]#[N:19])=[CH:25][N:24]=3)=[O:27])[CH:3]=[CH:4][C:5]=2[F:17])([CH3:16])[N:9]=1
Reactant: C[C@]1(c2cc(N)ccc2F)N=C(N)OC[C@@H]1F
Reactant: N#Cc1ccc(C(=O)O)nc1
Product: C[C@]1(c2cc(NC(=O)c3ccc(C#N)cn3)ccc2F)N=C(N)OC[C@@H]1F

Procedure:
The condensation of (4R,5R)-4-(5-amino-2-fluoro-phenyl)-5-fluoro-4-methyl-5,6-dihydro-4H-[1,3]oxazin-2-ylamine (intermediate A8.2) and 5-cyano-pyridine-2-carboxylic acid (CAS 53234-55-2) following procedure I yielded the title compound as a crystalline white solid. MS (ISP): m/z=372.2 [M+H]+.
Reaction SMILES: C(OC(N(C)[C@@H](C)C(N[C@@H](C(C)(C)C)C(N1[C@H](C(=O)N[C@H]2C3C(=CC=CC=3)CCC2)CC2C(=CC(C(O)=O)=CC=2)C1)=O)=O)=O)(C)(C)C.[C:48]([O:52][C:53]([N:55]1[C@H:59]([C:60](=[O:72])[NH:61][C@H:62]2[C:71]3[C:66](=[CH:67][CH:68]=[CH:69][CH:70]=3)[CH2:65][CH2:64][CH2:63]2)[CH2:58][C@H:57]([C:73]2[CH:82]=[C:81]3[C:76]([CH2:77][C@@H:78]([C:90]([O:92]C)=[O:91])[N:79]([C:83]([O:85][C:86]([CH3:89])([CH3:88])[CH3:87])=[O:84])[CH2:80]3)=[CH:75][CH:74]=2)[CH2:56]1)=[O:54])([CH3:51])([CH3:50])[CH3:49]>>[C:86]([O:85][C:83]([N:79]1[C@H:78]([C:90]([OH:92])=[O:91])[CH2:77][C:76]2[C:81](=[CH:82][C:73]([C@H:57]3[CH2:58][C@@H:59]([C:60](=[O:72])[NH:61][C@H:62]4[C:71]5[C:66](=[CH:67][CH:68]=[CH:69][CH:70]=5)[CH2:65][CH2:64][CH2:63]4)[N:55]([C:53]([O:52][C:48]([CH3:51])([CH3:50])[CH3:49])=[O:54])[CH2:56]3)=[CH:74][CH:75]=2)[CH2:80]1)=[O:84])([CH3:89])([CH3:88])[CH3:87]
Reactant: COC(=O)[C@@H]1Cc2ccc([C@H]3C[C@@H](C(=O)N[C@@H]4CCCc5ccccc54)N(C(=O)OC(C)(C)C)C3)cc2CN1C(=O)OC(C)(C)C
Agent: C[C@@H](C(=O)N[C@H](C(=O)N1Cc2cc(C(=O)O)ccc2C[C@H]1C(=O)N[C@@H]1CCCc2ccccc21)C(C)(C)C)N(C)C(=O)OC(C)(C)C
Product: CC(C)(C)OC(=O)N1Cc2cc([C@H]3C[C@@H](C(=O)N[C@@H]4CCCc5ccccc54)N(C(=O)OC(C)(C)C)C3)ccc2C[C@H]1C(=O)O
Yield: 93.8 %

Procedure:
Following a procedure analogous to that for the synthesis of Compound K of Example 1, (S)-2-tert-butyl 3-methyl 7-((3R,5S)-1-(tert-butoxycarbonyl)-5-(((R)-1,2,3,4-tetrahydronaphthalen-1-yl)carbamoyl)pyrrolidin-3-yl)-3,4-dihydroisoquinoline-2,3(1H)-dicarboxylate (650 mg, 1.03 mmol) was converted to the title compound (599 mg, 94%). MS (ESI+) m/z 620.5 (M+H)+.
Reaction SMILES: C1([O:7][C:8](=O)[NH:9][C:10]2[CH:15]=[CH:14][C:13]([O:16][C:17]3[C:26]4[C:21](=[CH:22][C:23]([O:29][CH3:30])=[C:24]([O:27][CH3:28])[CH:25]=4)[N:20]=[CH:19][CH:18]=3)=[CH:12][CH:11]=2)C=CC=CC=1.[NH2:32][C:33]1[S:34][CH:35]=[CH:36][N:37]=1.C(OCC)(=O)C.O>CS(C)=O.CO>[CH3:28][O:27][C:24]1[CH:25]=[C:26]2[C:21](=[CH:22][C:23]=1[O:29][CH3:30])[N:20]=[CH:19][CH:18]=[C:17]2[O:16][C:13]1[CH:14]=[CH:15][C:10]([NH:9][C:8]([NH:32][C:33]2[S:34][CH:35]=[CH:36][N:37]=2)=[O:7])=[CH:11][CH:12]=1
Reactant: Nc1nccs1
Reactant: COc1cc2nccc(Oc3ccc(NC(=O)Oc4ccccc4)cc3)c2cc1OC
Solvent: CO
Solvent: O
Solvent: CCOC(C)=O
Product: COc1cc2nccc(Oc3ccc(NC(=O)Nc4nccs4)cc3)c2cc1OC
Yield: 71 %

Procedure:
4-(6,7-Dimethoxyquinolin-4-yloxy)phenylcarbamic acid phenyl ester (208 mg, 0.500 mmol) and 2-aminothiazole (100 mg, 1.00 mmol) were heated and stirred in dimethylsulfoxide (1 ml) at 85° C. for 1 hour. The reaction solution was distributed between ethyl acetate and water, the organic layer was washed with 1N aqueous sodium hydroxide, water and saturated brine and dried over anhydrous magnesium sulfate, the drying agent was filtered off and the filtrate was distilled off under reduced pressure. The obtained crude product was subjected to silica gel column chromatography (eluent—ethyl acetate:methanol=20:1), the fraction containing the target substance was concentrated and suspended in ethyl acetate, the suspension was diluted with hexane and the crystals were filtered out, washed with hexane and blow-dried to obtain the title compound (150 mg, 0.355 mmol, 71%) as colorless crystals.
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4]2[C:9](=[C:10]([CH2:16][CH:17](Br)[CH2:18]Br)[C:11]=1[O:12]C(=O)C)[O:8][C:7](=[O:21])[CH:6]=[CH:5]2.[OH-].[K+].O1C2C(=CC=CC=2)C=CC1=O.[OH-].[K+].Cl>O>[CH3:18][C:17]1[O:12][C:11]2[C:10](=[C:9]3[O:8][C:7](=[O:21])[CH:6]=[CH:5][C:4]3=[CH:3][C:2]=2[CH3:1])[CH:16]=1
Reactant: CC(=O)Oc1c(C)cc2ccc(=O)oc2c1CC(Br)CBr
Agent: Cl
Agent: O=c1ccc2ccccc2o1
Agent: [K+]
Solvent: O
Product: Cc1cc2c(o1)c(C)cc1ccc(=O)oc12

Procedure:
To an ethanolic solution (100 ml) of 6-methyl-7-a-cetoxy-8-(2',3'-dibromopropyl) coumarin (XIII) (1.5 g) a volume of ethanolic 4% KOH solution was added, equivalent to a molar ratio coumarin/KOH 1:10. The mixture was refluxed for 80 min. in the dark, chilled, diluted with H2O (200 ml) and acidified with dil. HCl. The precipitate thus obtained was filtered, washed with H2O, dried and chromatographed on a silica gel column by eluting with CHCl3, yielding the 6,5'-dimethylangelicin (XVI), crystallized from MeOH (0.52 g; m.p. 175°-6° C.). ##STR21##
Reaction SMILES: [N:1]1[C:8](Cl)=[N:7][C:5](Cl)=[N:4][C:2]=1[Cl:3].[C:10]1([CH3:17])[CH:15]=[CH:14][CH:13]=[C:12]([CH3:16])[CH:11]=1.[Cl-].[Al+3].[Cl-].[Cl-].Cl>ClC1C=CC=CC=1>[Cl:3][C:2]1[N:4]=[C:5]([C:15]2[CH:14]=[CH:13][C:12]([CH3:16])=[CH:11][C:10]=2[CH3:17])[N:7]=[C:8]([C:15]2[CH:14]=[CH:13][C:12]([CH3:16])=[CH:11][C:10]=2[CH3:17])[N:1]=1
Reactant: Cc1cccc(C)c1
Reactant: Clc1nc(Cl)nc(Cl)n1
Agent: Cl
Agent: [Al+3]
Agent: [Cl-]
Solvent: Clc1ccccc1
Product: Cc1ccc(-c2nc(Cl)nc(-c3ccc(C)cc3C)n2)c(C)c1

Procedure:
2-Chloro-4,6-bis(2,4-dimethylphenyl)-1,3,5-triazine was prepared by allowing to react 1 eq of cyanuric chloride with 1.9 eq of m-xylene in the presence of 3 eq of aluminum chloride and concentrated HCl in chlorobenzene as discussed above.
Reaction SMILES: O=[C:2]1[CH:11]([CH2:12][C:13]([O:15]C)=O)[CH2:10][CH2:9][C:8]2[N:7]=[CH:6][CH:5]=[CH:4][C:3]1=2.N1C2CCCC(=O)C=2C=CC=1.[Cl:28][C:29]1[CH:34]=[CH:33][C:32]([NH:35][NH2:36])=[CH:31][CH:30]=1>>[Cl:28][C:29]1[CH:34]=[CH:33][C:32]([N:35]2[C:13](=[O:15])[CH2:12][CH:11]3[C:2]([C:3]4[CH:4]=[CH:5][CH:6]=[N:7][C:8]=4[CH2:9][CH2:10]3)=[N:36]2)=[CH:31][CH:30]=1
Reactant: NNc1ccc(Cl)cc1
Reactant: COC(=O)CC1CCc2ncccc2C1=O
Agent: O=C1CCCc2ncccc21
Product: O=C1CC2CCc3ncccc3C2=NN1c1ccc(Cl)cc1

Procedure:
Prepared according to the method described in Example 1 from methyl 5,6,7,8-tetrahydro-5-oxoquinoline-6-acetate (prepared from 7,8-dihydroquinoline-5(6H)-one (J. Med. Chem. (1991)34, 2736) according to the method of Wu et al supra) and 4-chlorophenylhydrazine.
Reaction SMILES: [O:1]=[C:2]1[NH:8][C:7]2[C:9]3[CH2:10][CH2:11][CH2:12][CH2:13][C:14]=3[CH:15]=[CH:16][C:6]=2[N:5]([C:17]2[CH:22]=[CH:21][C:20]([N:23]([CH3:36])S(C3C=CC=CC=3[N+]([O-])=O)(=O)=O)=[CH:19][CH:18]=2)[C:4](=[O:37])[CH2:3]1.C1(S)C=CC=CC=1.C(=O)([O-])[O-].[K+].[K+]>CN(C=O)C>[CH3:36][NH:23][C:20]1[CH:19]=[CH:18][C:17]([N:5]2[C:4](=[O:37])[CH2:3][C:2](=[O:1])[NH:8][C:7]3[C:9]4[CH2:10][CH2:11][CH2:12][CH2:13][C:14]=4[CH:15]=[CH:16][C:6]2=3)=[CH:22][CH:21]=1
Reactant: CN(c1ccc(N2C(=O)CC(=O)Nc3c2ccc2c3CCCC2)cc1)S(=O)(=O)c1ccccc1[N+](=O)[O-]
Agent: O=C([O-])[O-]
Agent: Sc1ccccc1
Agent: [K+]
Solvent: CN(C)C=O
Product: CNc1ccc(N2C(=O)CC(=O)Nc3c2ccc2c3CCCC2)cc1
Temperature: 25 °C
Reaction time: 16 h
Yield: 54.9 %

Procedure:
N-[4-(2,4-Dioxo-1,2,3,4,8,9,10,11-octahydro-naphtho[1,2-b][1,4]diazepin-5-yl)phenyl]-N-methyl-2-nitrobenzenesulfonamide (99 mg, 0.190 mmol) obtained in Example 152, thiophenol (23 μL, 0.228 mmol), potassium carbonate (79 mg, 0.570 mmol), and anhydrous DMF were mixed, and the mixture was stirred at room temperature for 16 hours. After the disappearance of the starting materials was confirmed, a post-treatment was performed in a conventional manner to give the title compound (35 mg, yield 55%).
Reaction SMILES: F[C:2]1[CH:3]=[C:4]([CH2:11][N:12]2[CH2:17][CH2:16][N:15]([CH3:18])[CH2:14][CH2:13]2)[CH:5]=[CH:6][C:7]=1[N+:8]([O-:10])=[O:9].[NH2:19][C:20]1[S:24][C:23]([C:25]([O:27][CH3:28])=[O:26])=[C:22]([O:29][C@@H:30]([C:32]2[CH:37]=[CH:36][CH:35]=[CH:34][C:33]=2[C:38]([F:41])([F:40])[F:39])[CH3:31])[CH:21]=1.[OH-].[K+]>C(#N)C>[CH3:18][N:15]1[CH2:16][CH2:17][N:12]([CH2:11][C:4]2[CH:5]=[CH:6][C:7]([N+:8]([O-:10])=[O:9])=[C:2]([NH:19][C:20]3[S:24][C:23]([C:25]([O:27][CH3:28])=[O:26])=[C:22]([O:29][C@@H:30]([C:32]4[CH:37]=[CH:36][CH:35]=[CH:34][C:33]=4[C:38]([F:41])([F:39])[F:40])[CH3:31])[CH:21]=3)[CH:3]=2)[CH2:13][CH2:14]1
Reactant: CN1CCN(Cc2ccc([N+](=O)[O-])c(F)c2)CC1
Reactant: COC(=O)c1sc(N)cc1O[C@H](C)c1ccccc1C(F)(F)F
Agent: [K+]
Agent: [OH-]
Solvent: CC#N
Product: COC(=O)c1sc(Nc2cc(CN3CCN(C)CC3)ccc2[N+](=O)[O-])cc1O[C@H](C)c1ccccc1C(F)(F)F
Temperature: 25 °C
Yield: 50.7 %

Procedure:
A solution of 1-[(3-fluoro-4-nitrophenyl)methyl]-4-methylpiperazine (0.733 g, 2.90 mmol) in acetonitrile (5 mL) was added dropwise to a mixture of methyl 5-amino-3-({(1R)-1-[2-(trifluoromethyl)phenyl]ethyl}oxy)-2-thiophenecarboxylate (1.00 g, 2.90 mmol) and KOH (0.325 g, 5.79 mmol) in acetonitrile (10 mL) at 0° C. The reaction mixture was allowed to warm to room temperature overnight and then heated to 40° C. for 1 h until analysis by HPLC showed complete consumption of starting materials. The reaction mixture was partitioned between EtOAc (50 mL) and H2O (50 mL). The organic layer was washed with saturated aqueous NaHCO3 (10 mL), concentrated under reduced pressure and then purified by flash column chromatography (DCM:MeOH 98:2 to 85:15, then EtOAC:MeOH 99:1 to 85:15) to give the title compound (0.85 g, 50%) as a red amorphous solid.
Reaction SMILES: [Cl:1][C:2]1[N:7]=[C:6]([N+:8]([O-])=O)[C:5]([NH2:11])=[CH:4][CH:3]=1>[Ni].CO>[Cl:1][C:2]1[N:7]=[C:6]([NH2:8])[C:5]([NH2:11])=[CH:4][CH:3]=1
Reactant: Nc1ccc(Cl)nc1[N+](=O)[O-]
Agent: [Ni]
Solvent: CO
Product: Nc1ccc(Cl)nc1N
Temperature: 25 °C
Reaction time: 24 h
Yield: 95.6 %

Procedure:
A mixture of 6-chloro-2-nitropyridin-3-amine (E-23) (8.8 g, 51 mmol, 1.0 eq) and Raney nickel (0.88 g) in Methanol (100 mL) was stirred under hydrogen at RT for 24 h, then filtered and the filtrate was concentrated in vacuo to afford the desired product 6-chloropyridine-2,3-diamine (E-24) (7 g, 95.6% yield) as a pale solid. ESI-MS m/z: 144.05[M+H]+.
Reaction SMILES: ClC(Cl)(Cl)[C:3]([C:5]1[N:14]2[C:8]([CH2:9][N:10]([C:19]([C:21]3[CH:26]=[CH:25][C:24]([C:27]4[CH:32]=[CH:31][CH:30]=[CH:29][C:28]=4[O:33][CH3:34])=[CH:23][CH:22]=3)=[O:20])[C:11]3[CH:18]=[CH:17][CH:16]=[CH:15][C:12]=3[CH2:13]2)=[CH:7][CH:6]=1)=[O:4].[Br:37][C:38]1[CH:39]=[C:40]([CH2:44][NH2:45])[CH:41]=[N:42][CH:43]=1.C(N(CC)CC)C.CS(C)=O>C(#N)C>[Br:37][C:38]1[CH:39]=[C:40]([CH2:44][NH:45][C:3]([C:5]2[N:14]3[C:8]([CH2:9][N:10]([C:19]([C:21]4[CH:22]=[CH:23][C:24]([C:27]5[CH:32]=[CH:31][CH:30]=[CH:29][C:28]=5[O:33][CH3:34])=[CH:25][CH:26]=4)=[O:20])[C:11]4[CH:18]=[CH:17][CH:16]=[CH:15][C:12]=4[CH2:13]3)=[CH:7][CH:6]=2)=[O:4])[CH:41]=[N:42][CH:43]=1
Reactant: COc1ccccc1-c1ccc(C(=O)N2Cc3ccc(C(=O)C(Cl)(Cl)Cl)n3Cc3ccccc32)cc1
Reactant: NCc1cncc(Br)c1
Solvent: CCN(CC)CC
Solvent: CS(C)=O
Solvent: CC#N
Product: COc1ccccc1-c1ccc(C(=O)N2Cc3ccc(C(=O)NCc4cncc(Br)c4)n3Cc3ccccc32)cc1
Yield: 44.7 %

Procedure:
A solution of 2,2,2-trichloro-1-{10-[(2′-methoxy-1,1′-biphenyl-4-yl)carbonyl]-10,11-dihydro-5H-pyrrolo[2,1-c][1,4]benzodiazepin-3-yl}ethanone (0.288 g, 0.534 mmol), (5-bromopyridin-3-yl)methylamine of Step C (0.20 g, 1.07 mmol), triethylamine (0.043 g, 0.588 mmol), dimethylsulfoxide (0.190 mL, 2.67 mmol), and acetonitrile (5 mL) was heated for 17 hours at an oil bath temperature of 81° C. The solvent was removed under reduced pressure and the resulting residue taken up in dichloromethane. The organics were washed with water and brine, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure to a yellow solid. The solid was triturated with hexane, diethyl ether, and ethyl acetate, collected by filtration, and dried under reduced pressure to give the title compound (0.145 g) as an off white solid, m.p 180-184° C.
Reaction SMILES: [NH2:1][CH:2]1[CH2:7][C:6]([CH3:9])([CH3:8])[NH:5][C:4]([CH3:11])([CH3:10])[CH2:3]1.[O:12]1[CH2:36][CH:13]1[CH2:14][O:15][C:16]1[CH:21]=[CH:20][C:19]([C:22]([C:25]2[CH:30]=[CH:29][C:28]([O:31][CH2:32][CH:33]3[O:35][CH2:34]3)=[CH:27][CH:26]=2)([CH3:24])[CH3:23])=[CH:18][CH:17]=1>CO>[OH:12][CH:13]([CH2:36][NH:1][CH:2]1[CH2:3][C:4]([CH3:11])([CH3:10])[NH:5][C:6]([CH3:9])([CH3:8])[CH2:7]1)[CH2:14][O:15][C:16]1[CH:17]=[CH:18][C:19]([C:22]([C:25]2[CH:30]=[CH:29][C:28]([O:31][CH2:32][CH:33]([OH:35])[CH2:34][NH:1][CH:2]3[CH2:3][C:4]([CH3:11])([CH3:10])[NH:5][C:6]([CH3:9])([CH3:8])[CH2:7]3)=[CH:27][CH:26]=2)([CH3:23])[CH3:24])=[CH:20][CH:21]=1
Reactant: CC1(C)CC(N)CC(C)(C)N1
Reactant: CC(C)(c1ccc(OCC2CO2)cc1)c1ccc(OCC2CO2)cc1
Solvent: CO
Product: CC1(C)CC(NCC(O)COc2ccc(C(C)(C)c3ccc(OCC(O)CNC4CC(C)(C)NC(C)(C)C4)cc3)cc2)CC(C)(C)N1

Procedure:
To 100 ml of methanol were added 7.8 g of 4-amino-2,2,6,6-tetramethylpiperidine and 8.5 g of 2,2-bis[p-(2,3-epoxypropoxy)phenyl]propane; the mixture was then reacted in a similar manner to that described in Example 1, giving the desired compound in the form of a white powder. The compound had an Rf value of 0.28 on thin layer chromatography on silica gel developed with a 1:3:1 by volume mixture of methanol, ethyl acetate and triethylamine.
Reaction SMILES: C([N:8]1[C:17]2[C:16]3[CH:18]=[CH:19][CH:20]=[CH:21][C:15]=3[N:14]([C:22]([C:24]3[CH:45]=[CH:44][C:27]([CH2:28][NH:29][C:30]([CH:32]4[CH2:37][CH2:36][N:35]([CH2:38][CH2:39][C:40]([CH3:43])([CH3:42])[CH3:41])[CH2:34][CH2:33]4)=[O:31])=[C:26]([CH3:46])[CH:25]=3)=[O:23])[CH2:13][CH2:12][C:11]=2[N:10]=[C:9]1[CH3:47])C1C=CC=CC=1.C1CCCCC=1>C(O)C.[Pd]>[CH3:46][C:26]1[CH:25]=[C:24]([C:22]([N:14]2[CH2:13][CH2:12][C:11]3[N:10]=[C:9]([CH3:47])[NH:8][C:17]=3[C:16]3[CH:18]=[CH:19][CH:20]=[CH:21][C:15]2=3)=[O:23])[CH:45]=[CH:44][C:27]=1[CH2:28][NH:29][C:30]([CH:32]1[CH2:33][CH2:34][N:35]([CH2:38][CH2:39][C:40]([CH3:43])([CH3:42])[CH3:41])[CH2:36][CH2:37]1)=[O:31]
Reactant: Cc1cc(C(=O)N2CCc3nc(C)n(Cc4ccccc4)c3-c3ccccc32)ccc1CNC(=O)C1CCN(CCC(C)(C)C)CC1
Agent: [Pd]
Solvent: CCO
Solvent: C1=CCCCC1
Product: Cc1nc2c([nH]1)-c1ccccc1N(C(=O)c1ccc(CNC(=O)C3CCN(CCC(C)(C)C)CC3)c(C)c1)CC2
Temperature: 60 °C
Yield: 48 %

Procedure:
1-(3,3-Dimethyl-butyl)-piperidine-4-carboxylic acid 4-(1-benzyl-2-methyl-4,5-dihydro-1H-1,3,6-triaza-benzo[e]azulene-6-carbonyl)-2-methyl-benzylamide from Example E121 (110 mg, 0.17 mmol) was dissolved in absolute ethanol (5 ml) and placed under an inert atmosphere. 10% Palladium on carbon (110 mg) and cyclo-hexene (0.176 ml, 1.7 mmol) were added and the mixture was heated at 60° C. for 3 h. The catalyst was filtered off through Celite® filter agent and the filtrate was concentrated in vacuo. The residue was purified by preparative HPLC (eluant; 0.5% 35% ammonia:9.5% methanol:90% dichloromethane) to give a white powder identified as the title compound (45 mg, 48%).
Reaction SMILES: [H-].[Na+].[CH2:3]([O:5][C:6](=[O:17])[CH2:7][CH2:8][CH2:9][N:10]1[C:14](=[O:15])[CH2:13][NH:12][C:11]1=[S:16])[CH3:4].[Cl:18][C:19]1[CH:24]=[CH:23][C:22]([C:25]2[O:29][C:28]([CH:30]=O)=[C:27]([C:32](OCC)=[O:33])[CH:26]=2)=[CH:21][CH:20]=1.C(OCC)(=O)C>C1COCC1.CCCCCC>[CH2:3]([O:5][C:6](=[O:17])[CH2:7][CH2:8][CH2:9][N:10]1[C:14](=[O:15])[C:13]2[N:12]([C:32](=[O:33])[C:27]3[CH:26]=[C:25]([C:22]4[CH:23]=[CH:24][C:19]([Cl:18])=[CH:20][CH:21]=4)[O:29][C:28]=3[CH:30]=2)[C:11]1=[S:16])[CH3:4]
Reactant: CCOC(=O)CCCN1C(=O)CNC1=S
Reactant: CCOC(=O)c1cc(-c2ccc(Cl)cc2)oc1C=O
Agent: [H-]
Agent: [Na+]
Solvent: CCCCCC
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: CCOC(=O)CCCN1C(=O)c2cc3oc(-c4ccc(Cl)cc4)cc3c(=O)n2C1=S
Temperature: 0 °C
Reaction time: 0.33 h

Procedure:
As further depicted in Scheme 40 below, NaH (88 mg of 60% oil dispersion, 53 mg, 2.2 mmol) is added in four portions over 10 minutes under a nitrogen atmosphere to a solution of 4-(5-oxo-2-thioxo-imidazolidin-1-yl)-butyric acid ethyl ester (230 mg, 1 mmol) and ethyl 5-(4-chlorophenyl)-2-formyl-3-furoate (293 mg, 1.05 mmol obtained from Maybridge Ltd.; Cat. No. SP 00067) in anhydrous THF (20 ml). After the ensuing mildly exothermic reaction is completed, the reaction mixture is refluxed for 8-10 hours while monitoring the reaction progress by TLC analysis using an ethyl acetate:hexane mixture as eluent. Thereafter the solvent is removed under reduced pressure, and 6 M HCl (50 ml) is added to the residue while cooling the reaction vessel. Ether (50 ml) is added and the resulting heterogeneous mixture is stirred vigorously at 0° C. for 20 minutes, filtered, washed with ether and water and the solvents are removed under heat at 50° C. overnight to give Compound 48.
Reaction SMILES: [CH:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[C:3]([C:11]([NH:13][C:14]2[NH:18][C:17]3[CH:19]=[CH:20][C:21]([O:26][CH3:27])=[C:22]([C:23]([OH:25])=O)[C:16]=3[N:15]=2)=[O:12])[N:2]=1.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.S(O)(O)(=O)=O.[NH2:66][C:67]1[NH:68][CH:69]=[CH:70][N:71]=1>CN(C=O)C.[Cl-].[Na+].O>[NH:68]1[CH:69]=[CH:70][N:71]=[C:67]1[NH:66][C:23]([C:22]1[C:16]2[NH:15][C:14]([NH:13][C:11]([C:3]3[N:2]=[CH:1][C:10]4[C:5]([CH:4]=3)=[CH:6][CH:7]=[CH:8][CH:9]=4)=[O:12])=[N:18][C:17]=2[CH:19]=[CH:20][C:21]=1[O:26][CH3:27])=[O:25]
Reactant: COc1ccc2[nH]c(NC(=O)c3cc4ccccc4cn3)nc2c1C(=O)O
Reactant: Nc1ncc[nH]1
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Agent: O=S(=O)(O)O
Solvent: CN(C)C=O
Solvent: O
Solvent: CCN(C(C)C)C(C)C
Product: COc1ccc2nc(NC(=O)c3cc4ccccc4cn3)[nH]c2c1C(=O)Nc1ncc[nH]1
Yield: 33.8 %

Procedure:
66 mg (0.18 mmol) of 2-[(isoquinoline-3-carbonyl)-amino]-5-methoxy-1H-benzoimidazole-4-carboxylic acid and 200 mg (0.53 mmol) of HBTU were dissolved in 1.0 mL of DMF and 0.5 mL of DIEA was treated with 132 mg (1.0 mmol) of 2-aminoimidazole sulfate as described in general procedure A. Upon completion, the reaction was diluted with brine. The resulting solid was filtered, washed with water and EtOAc, and dried under vacuum to produce 26 mg (34%) of isoquinoline-3-carboxylic acid [7-(1H-imidazol-2-ylcarbamoyl)-6-methoxy-1H-benzoimidazol-2-yl]-amide. LCMS: 428 (M+1)+.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([NH:17][C:18]2[N:27]=[CH:26]C3C(=CC=C(C=O)C=3)N=2)[CH:5]=[CH:6][C:7]=1[O:8][CH2:9][C:10]1[CH:15]=[CH:14][CH:13]=[C:12]([F:16])[CH:11]=1.C[Mg]Br.O.C([O:37][CH2:38][CH3:39])(=O)C>O1CCCC1>[Cl:1][C:2]1[CH:3]=[C:4]([NH:17][C:18]2[C:5]3[C:4](=[CH:3][CH:2]=[C:7]([CH:38]([OH:37])[CH3:39])[CH:6]=3)[N:17]=[CH:26][N:27]=2)[CH:5]=[CH:6][C:7]=1[O:8][CH2:9][C:10]1[CH:15]=[CH:14][CH:13]=[C:12]([F:16])[CH:11]=1
Reactant: O=Cc1ccc2nc(Nc3ccc(OCc4cccc(F)c4)c(Cl)c3)ncc2c1
Reactant: CCOC(C)=O
Agent: C[Mg]Br
Solvent: C1CCOC1
Solvent: O
Product: CC(O)c1ccc2ncnc(Nc3ccc(OCc4cccc(F)c4)c(Cl)c3)c2c1

Procedure:
In 30 mL of tetrahydrofuran was dissolved 620 mg of 4 (3-chloro-4-(3-fluorobenzyloxy)phenylamino)-6-formylquinazoline (IV-1), the solution was cooled to 0° C. under the nitrogen atmosphere, and 4.9 mL of methylmagnesium bromide (0.93M tetrahydrofuran solution) was added dropwise. After the reaction at 0° C. for 1 hour under the nitrogen atmosphere, water and ethyl acetate were added to separate the layers. The organic layer was washed sequentially with water and aqueous saturated sodium chloride solution, and dried over magnesium sulfate. After concentration, the resulting crystal was washed with chloroform to obtain 330 mg of 4-(3-chloro-4-(3-fluorobenzyloxy)phenylamino)-6-(1-hydroxyethan-1-yl)quinazoline (VI-1).
Reaction SMILES: [Cl:1][C:2]1[C:7]([C:8]2[CH:13]=[CH:12][C:11](Cl)=[CH:10][CH:9]=2)=[N:6][CH:5]=[CH:4][N:3]=1.[CH3:15][O:16]C1C=CC(B(O)O)=CC=1>>[Cl:1][C:2]1[C:7]([C:8]2[CH:13]=[CH:12][C:11]([O:16][CH3:15])=[CH:10][CH:9]=2)=[N:6][CH:5]=[CH:4][N:3]=1
Reactant: Clc1ccc(-c2nccnc2Cl)cc1
Reactant: COc1ccc(B(O)O)cc1
Product: COc1ccc(-c2nccnc2Cl)cc1
Yield: 54 %

Procedure:
Use the method used to make 2-chloro-3-(4-chlorophenyl)-pyrazine, using 4-methoxyphenylboronic acid to obtain 2-chloro-3-(4-methoxyphenyl)-pyrazine (54% yield).
Reaction SMILES: [O:1]=[C:2]1[NH:8][C:7]2[CH:9]=[CH:10][CH:11]=[CH:12][C:6]=2[NH:5][CH2:4][CH:3]1[NH:13][C:14]([O:16][C:17]([CH3:20])([CH3:19])[CH3:18])=[O:15].C(=O)([O-])O.[Na+].Br[CH:27]1[CH2:32][CH2:31][CH2:30][CH:29]=[CH:28]1>CN(C)C=O>[O:1]=[C:2]1[NH:8][C:7]2[CH:9]=[CH:10][CH:11]=[CH:12][C:6]=2[N:5]([CH:32]2[CH2:31][CH2:30][CH2:29][CH:28]=[CH:27]2)[CH2:4][CH:3]1[NH:13][C:14]([O:16][C:17]([CH3:20])([CH3:19])[CH3:18])=[O:15]
Reactant: BrC1C=CCCC1
Reactant: CC(C)(C)OC(=O)NC1CNc2ccccc2NC1=O
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)NC1CN(C2C=CCCC2)c2ccccc2NC1=O
Temperature: 50 °C
Reaction time: 1 h
Yield: 81.7 %

Procedure:
To a solution of (±)-2-oxo-3-tert-butoxycarbonylamino-1,3,4,5-tetrahydro-2H-1,5-benzodiazepine (28.6 g) in N,N-dimethylformamide (50 mL), sodium hydrogencarbonate (17.3 g) and 3-bromocyclohexene (33.2 g) were added, followed by LZ stirring at 50° C. for 1 hour. The reaction mixture was allowed to cool down. Subsequent to addition of ice water, the reaction mixture was extracted with methylene chloride. The organic layer was washed with brine and then dried over anhydrous sodium sulfate. The solvent was evaporated under reduced pressure. Diisopropyl ether was added to the residue for crystallization. Crystals so precipitated were then collected by filtration. The crystals were washed with ethanol and then dried, whereby the title compound (30.1 g) was obtained. Yield: 82%.
Reaction SMILES: [CH:1](/O)=[CH:2]/[CH:3]=[CH:4]\[CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH3:11].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.CCCCCC.C(Cl)(Cl)(Cl)[Cl:39]>>[Cl:39][CH2:1]/[CH:2]=[CH:3]\[CH2:4]/[CH:5]=[CH:6]\[CH2:7][CH2:8][CH2:9][CH2:10][CH3:11]
Reactant: CCCCCCC/C=C\C=C/O
Reactant: ClC(Cl)(Cl)Cl
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CCCCCC
Product: CCCCC/C=C\C/C=C\CCl
Temperature: 23 °C
Reaction time: 9 h
Yield: 92 %

Procedure:
A mixture of (Z,Z)-undecadien-1-ol (3.42 g, 20.4 mmol) and triphenylphosphine (7.5 g, 28.6 mmol) in dry CCl4 (25 ml) was refluxed with stirring for 9 h. The reaction mixture was allowed to cool to 23° C., hexane (60 ml) was added, and stirring was continued for an additional 10 minutes. The precipitate of triphenylphosphine oxide was filtered and washed with hexane. The solvent was removed from the combined filtrate at 40° C./~30 mmHg. Evaporative distillation of the resulting residue at 125°-130° C./0.3 mmHg gave 3.5 g (92%) of (Z,Z)-1-chloro-2,5-undecadiene as a colorless liquid.
Reaction SMILES: [NH2:1][C@@H:2]([CH2:5][C@@H:6]([O:9][C:10]1[CH:15]=[CH:14][CH:13]=[C:12]([O:16][CH2:17][C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)[CH:11]=1)[CH2:7][CH3:8])[CH2:3][OH:4].C([O-])(=O)C.[Na+].[N:29]#[C:30]Br>CO.[OH-].[Na+]>[CH2:17]([O:16][C:12]1[CH:11]=[C:10]([CH:15]=[CH:14][CH:13]=1)[O:9][C@@H:6]([CH2:7][CH3:8])[CH2:5][C@H:2]1[CH2:3][O:4][C:30]([NH2:29])=[N:1]1)[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1
Reactant: N#CBr
Reactant: CC[C@@H](C[C@H](N)CO)Oc1cccc(OCc2ccccc2)c1
Agent: CC(=O)[O-]
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: CC[C@@H](C[C@H]1COC(N)=N1)Oc1cccc(OCc2ccccc2)c1
Reaction time: 18 h
Yield: 71 %

Procedure:
To a stirred mixture of (2S,4S)-2-amino-4-(3-benzyloxy-phenoxy)-hexan-1-ol (90 mg) and sodium acetate (46 mg) in methanol (2 ml) under an argon atmosphere was added a solution of cyanogen bromide (37 mg) in methanol (1 ml). The mixture was stirred for 18 hours then diluted with 1 N aqueous sodium hydroxide solution. The mixture was extracted twice with dichloromethane and the combined organic phases were dried over sodium sulphate and concentrated in vacuo. The crude product was purified by column chromatography (column: Isolute® Flash-NH2 from Separtis; gradient: dichloromethane/MeOH 100:0→95:5) to afford (S)-4-[(S)-2-(3-benzyloxy-phenoxy)-butyl]-4,5-dihydro-oxazol-2-ylamine (69 mg, 71%) as a light yellow gum. MS (ISP): 341.1 ([M+H]+).