Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C([N:4]1[C:8]2=[N:9][CH:10]=[C:11]([F:14])[C:12](I)=[C:7]2[CH:6]=[CH:5]1)(=O)C.[CH2:15]([N:17]1[CH:21]=[C:20](B2OC(C)(C)C(C)(C)O2)[C:19]([C:31]2[CH:36]=[CH:35][C:34]([N+:37]([O-:39])=[O:38])=[CH:33][CH:32]=2)=[N:18]1)[CH3:16].C(=O)(O)[O-].[Na+].O>C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.CN(C)C=O>[CH2:15]([N:17]1[CH:21]=[C:20]([C:12]2[C:11]([F:14])=[CH:10][N:9]=[C:8]3[NH:4][CH:5]=[CH:6][C:7]=23)[C:19]([C:31]2[CH:36]=[CH:35][C:34]([N+:37]([O-:39])=[O:38])=[CH:33][CH:32]=2)=[N:18]1)[CH3:16]
Reactant: CCn1cc(B2OC(C)(C)C(C)(C)O2)c(-c2ccc([N+](=O)[O-])cc2)n1
Reactant: CC(=O)n1ccc2c(I)c(F)cnc21
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: CCn1cc(-c2c(F)cnc3[nH]ccc23)c(-c2ccc([N+](=O)[O-])cc2)n1
Temperature: 100 °C
Yield: 80 %

Procedure:
A mixture of 1-acetyl-5-fluoro-4-iodo-1H-pyrrolo[2,3-b]pyridine (0.822 mmol), 1-ethyl-3-(4-nitrophenyl)-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole (1.15 mmol), tetrakis(triphenylphosphine)palladium(0) (0.041 mmol), sodium bicarbonate (2.47 mmol), water (2 mL) and N,N-dimethylformamide (6 mL) were heated to 100° C. in a sealed tube for 16 h. The reaction mixture was quenched with water (5 mL) and extracted with ethyl acetate (3×10 mL). The combined extracts were dried over sodium sulfate filtered and concentrated under reduced pressure. The residue was purified by silica gel chromatography (50% ethyl acetate/hexanes) to give the title compound as a yellow solid (80%). ESMS [M+H]+: 352.2
Reaction SMILES: [Cl:1][C:2]1[CH:14]=[CH:13][C:5]([O:6][C:7]([CH3:12])([CH3:11])[C:8]([OH:10])=[O:9])=[CH:4][CH:3]=1.[Si:15]([O:22][C@H:23]1[CH2:32][C@H:31](O)[C@H:30]2[C:25]([CH:26]=[CH:27][C@H:28]([CH3:51])[C@@H:29]2[CH2:34][CH2:35][C@H:36]2[O:41][C:40](=[O:42])[CH2:39][C@H:38]([O:43][Si:44]([C:47]([CH3:50])([CH3:49])[CH3:48])([CH3:46])[CH3:45])[CH2:37]2)=[CH:24]1)([C:18]([CH3:21])([CH3:20])[CH3:19])([CH3:17])[CH3:16]>>[Si:15]([O:22][C@H:23]1[CH2:32][C@H:31]([O:9][C:8](=[O:10])[C:7]([O:6][C:5]2[CH:4]=[CH:3][C:2]([Cl:1])=[CH:14][CH:13]=2)([CH3:12])[CH3:11])[C@H:30]2[C:25]([CH:26]=[CH:27][C@H:28]([CH3:51])[C@@H:29]2[CH2:34][CH2:35][C@H:36]2[O:41][C:40](=[O:42])[CH2:39][C@H:38]([O:43][Si:44]([C:47]([CH3:50])([CH3:49])[CH3:48])([CH3:45])[CH3:46])[CH2:37]2)=[CH:24]1)([C:18]([CH3:19])([CH3:20])[CH3:21])([CH3:17])[CH3:16]
Reactant: C[C@H]1C=CC2=C[C@@H](O[Si](C)(C)C(C)(C)C)C[C@H](O)[C@@H]2[C@H]1CC[C@@H]1C[C@@H](O[Si](C)(C)C(C)(C)C)CC(=O)O1
Reactant: CC(C)(Oc1ccc(Cl)cc1)C(=O)O
Product: C[C@H]1C=CC2=C[C@@H](O[Si](C)(C)C(C)(C)C)C[C@H](OC(=O)C(C)(C)Oc3ccc(Cl)cc3)[C@@H]2[C@H]1CC[C@@H]1C[C@@H](O[Si](C)(C)C(C)(C)C)CC(=O)O1

Procedure:
A procedure similar to that described in Example 10, above, was followed, but using 0.78 g of 2-(4-chlorophenoxy)-2-methylpropionic acid and 1.0 g of (4R,6R)-6-{(1S,2S,6S,8S,8aR)-2-[1,2,6,7,8,8a-hexahydro-6-t-butyldimethylsilyloxy-8-hydroxy-2-methyl-1-naphthyl}ethyl)tetrahydro-4-t-butyldimethylsilyloxy-2H-pyran-2-one [prepared as described in Example B, above], to give1.08 g of the title compound as a colorless foam.
Reaction SMILES: C(Cl)(=O)C.Cl[C:6]1[CH:11]=[C:10]([C:12]2[CH:17]=[CH:16][CH:15]=[C:14]([O:18][C:19]([F:22])([F:21])[F:20])[CH:13]=2)[CH:9]=[CH:8][N:7]=1.[I-:23].[Na+].C(=O)([O-])[O-].[Na+].[Na+].S(S([O-])=O)([O-])(=O)=O.[Na+].[Na+]>CC#N.CCOC(C)=O.O>[I:23][C:6]1[CH:11]=[C:10]([C:12]2[CH:17]=[CH:16][CH:15]=[C:14]([O:18][C:19]([F:22])([F:21])[F:20])[CH:13]=2)[CH:9]=[CH:8][N:7]=1
Reactant: [I-]
Reactant: FC(F)(F)Oc1cccc(-c2ccnc(Cl)c2)c1
Agent: O=C([O-])[O-]
Agent: O=S([O-])S(=O)(=O)[O-]
Agent: [Na+]
Solvent: O
Solvent: CCOC(C)=O
Solvent: CC(=O)Cl
Product: FC(F)(F)Oc1cccc(-c2ccnc(I)c2)c1
Temperature: 80 °C
Reaction time: 3 h
Yield: 107 %

Procedure:
Acetyl chloride (4.45 mL, 62.6 mmol) was added to a solution of 2-chloro-4-[3-(trifluoromethoxy)phenyl]-pyridine [CAS 1261856-64-7] (11.42 g, 41.73 mmol) and sodium iodide (31.28 g, 208.67 mmol) in MeCN (200 mL) under N2, and the resulting suspension was heated at 80° C. for 18 hrs. Additional sodium iodide was added (20 mol %) and stirring was continued for 3 hrs. The reaction was cooled and the mixture was treated with aqueous sodium carbonate. After 5 minutes, solid sodium metabisulphite was added until decolourisation achieved. Water was added to redissolve a precipitate which had formed. The mixture was diluted with EtOAc and the layers separated. The aqueous layer was washed with EtOAc (2×), the combined organics were dried (MgSO4) and the solvent evaporated to afford the crude 2-iodo-4-[3-(trifluoromethoxy)phenyl]pyridine (D9) (16.3 g) as a amber oil containing about ˜5% of reduced 2-H material and ˜8% of unreacted chloride starting material;
Reaction SMILES: [C:1]([CH:3]([N:10]([CH3:18])[C:11](=[O:17])[O:12][C:13]([CH3:16])([CH3:15])[CH3:14])[CH2:4][CH2:5][CH2:6][CH:7]([OH:9])[CH3:8])#[N:2].C(O)(C)(C)C.[NH2:24][OH:25]>CO>[NH2:2]/[C:1](=[N:24]\[OH:25])/[CH:3]([N:10]([CH3:18])[C:11](=[O:17])[O:12][C:13]([CH3:14])([CH3:16])[CH3:15])[CH2:4][CH2:5][CH2:6][CH:7]([OH:9])[CH3:8]
Reactant: CC(O)CCCC(C#N)N(C)C(=O)OC(C)(C)C
Reactant: NO
Solvent: CC(C)(C)O
Solvent: CO
Product: CC(O)CCCC(/C(N)=N/O)N(C)C(=O)OC(C)(C)C
Temperature: 60 °C

Procedure:
The tert-butyl (1-cyano-5-hydroxyhexyl)methylcarbamate (129 g) which contained an undetermined amount of t-butanol was dissolved in methanol (250 mL) and treated with 50% aqueous hydroxylamine (33 mL). The mixture was then heated to 60° C. for 3 hours. The reaction mixture was then cooled and the solvents removed in vacuo. The residue was azeotropically dried twice with toluene (200 mL each time) and dried in vacuo at 50° C. to give the product as a very thick clear oil which was contaminated by t-butanol: ES MS M+1=290.0.
Reaction SMILES: C([O:3][C:4]([CH2:6][N:7]([C:12]1[CH:17]=[CH:16][C:15]([N+:18]([O-:20])=[O:19])=[CH:14][CH:13]=1)[S:8]([CH3:11])(=[O:10])=[O:9])=[O:5])C.[OH-].[Na+].Cl>C(O)C>[C:4]([CH2:6][N:7]([C:12]1[CH:17]=[CH:16][C:15]([N+:18]([O-:20])=[O:19])=[CH:14][CH:13]=1)[S:8]([CH3:11])(=[O:9])=[O:10])([OH:5])=[O:3]
Reactant: CCOC(=O)CN(c1ccc([N+](=O)[O-])cc1)S(C)(=O)=O
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: CS(=O)(=O)N(CC(=O)O)c1ccc([N+](=O)[O-])cc1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
26.8 g (88.6 mmol) of 4-(N-ethoxycarbonylmethyl-N-methylsulphonyl-amino)-nitrobenzene are suspended in 320 ml of ethanol and combined with 268 ml of 1 N sodium hydroxide solution. The mixture is stirred for one hour at ambient temperature and then 268 ml of 1 N hydrochloric acid are added. The precipitate formed is suction filtered, washed with a little ethanol and ether, and dried in vacuo.
Reaction SMILES: [C:1]([C:3]1[CH:4]=[C:5]([N:9]([CH:19]2[CH2:25][CH2:24][CH2:23][CH2:22][CH2:21][CH2:20]2)[C:10]([NH:12][CH:13]2[CH2:18][CH2:17][NH:16][CH2:15][CH2:14]2)=[O:11])[CH:6]=[CH:7][CH:8]=1)#[N:2].CC1C=C(C)[N:29]([C:33](N)=[NH:34])N=1>N1C=CC=CC=1>[C:1]([C:3]1[CH:4]=[C:5]([N:9]([CH:19]2[CH2:25][CH2:24][CH2:23][CH2:22][CH2:21][CH2:20]2)[C:10]([NH:12][CH:13]2[CH2:18][CH2:17][N:16]([C:33](=[NH:29])[NH2:34])[CH2:15][CH2:14]2)=[O:11])[CH:6]=[CH:7][CH:8]=1)#[N:2]
Reactant: N#Cc1cccc(N(C(=O)NC2CCNCC2)C2CCCCCC2)c1
Reactant: Cc1cc(C)n(C(=N)N)n1
Solvent: c1ccncc1
Product: N#Cc1cccc(N(C(=O)NC2CCN(C(=N)N)CC2)C2CCCCCC2)c1
Temperature: 110 °C

Procedure:
N-(3-Cyanophenyl)-N′-(piperidin-4-yl)cycloheptylurea (0.05 g, 0.126 mmol) was dissolved in pyridine (2 ml) and 3,5-dimethylpyrazole-1-carboxamidine (0.037 g, 0.188 mmol) was added under a nitrogen atmosphere. The reaction was heated to 110° C. for 6 h, then was allowed to cool and was concentrated to give a viscous amber oil. The product was purfied by HPLC on a Vydec® C-18 column eluting with solvent mixture A (acetonitrile:water:TFA 80:20:0.3) and solvent mixture B (water:TFA 99.7:0.3) using a gradient starting with A:B at 3:97 and changing to A:B at 70:30 over 15 min. The product eluted at 13.8 minutes was concentrated to give N-(3-cyanophenyl)-N′-(1-amidinopiperidin-4-yl)cycloeptylurea as an amorphous solid (0.036 g); LRMS (M+H)+ m/z 341.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][N:3]=1.CCCCCC.C([Li])CCC.[CH:19]([C@@H:21]1[CH2:26][C@H:25]([N:27]([C:32]([C:34]2[N:38]([CH2:39][CH2:40][CH2:41][CH2:42][O:43][CH3:44])[C:37]3[CH:45]=[CH:46][CH:47]=[CH:48][C:36]=3[N:35]=2)=[O:33])[CH2:28][CH:29]([CH3:31])[CH3:30])[CH2:24][N:23]([C:49]([O:51][C:52]([CH3:55])([CH3:54])[CH3:53])=[O:50])[CH2:22]1)=[O:20].[Cl-].[NH4+]>C1COCC1>[OH:20][CH:19]([C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][N:3]=1)[C@@H:21]1[CH2:26][C@H:25]([N:27]([C:32]([C:34]2[N:38]([CH2:39][CH2:40][CH2:41][CH2:42][O:43][CH3:44])[C:37]3[CH:45]=[CH:46][CH:47]=[CH:48][C:36]=3[N:35]=2)=[O:33])[CH2:28][CH:29]([CH3:30])[CH3:31])[CH2:24][N:23]([C:49]([O:51][C:52]([CH3:53])([CH3:55])[CH3:54])=[O:50])[CH2:22]1
Reactant: COCCCCn1c(C(=O)N(CC(C)C)[C@H]2C[C@@H](C=O)CN(C(=O)OC(C)(C)C)C2)nc2ccccc21
Reactant: Brc1ccccn1
Agent: [Cl-]
Agent: [Li]CCCC
Agent: [NH4+]
Solvent: C1CCOC1
Solvent: CCCCCC
Product: COCCCCn1c(C(=O)N(CC(C)C)[C@H]2C[C@@H](C(O)c3ccccn3)CN(C(=O)OC(C)(C)C)C2)nc2ccccc21
Reaction time: 0.5 h

Procedure:
To a solution of bromopyridine (0.058 ml) cooled to −78° C. in THF (5 ml) was added 1.6M-butyllithium hexane solution (0.33 ml) and the mixture was stirred for 30 min. A solution of tert-butyl (3R,5S)-3-formyl-5-[{[1-(4-methoxybutyl)-1H-benzimidazol-2-yl]carbonyl}(2-methylpropyl)amino]piperidine-1-carboxylate (257 mg) in THF (5 ml) was added and the mixture was stirred at −20° C. for 2 hr. The reaction mixture was poured into saturated aqueous ammonium chloride solution, and the mixture was extracted with ethyl acetate. The extract was washed with saturated brine, and dried over anhydrous sodium sulfate. The solvent was evaporated under reduced pressure. The residue was subjected to silica gel column chromatography, and a fraction eluted with ethyl acetate-hexane (1:1-1:0) was concentrated under reduced pressure to give the object product (100 mg).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:14]([C:24]2[CH:29]=[CH:28][C:27]([F:30])=[CH:26][CH:25]=2)[NH:15][C@H:16]([C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)[CH3:17])[CH:6]=[C:7]([N+:11]([O-])=O)[C:8]=1[O:9][CH3:10].[BH4-].[Na+]>O.O.O.O.O.O.[Ni](Cl)Cl>[CH3:10][O:9][C:8]1[C:3]([O:2][CH3:1])=[CH:4][C:5]([CH:14]([C:24]2[CH:25]=[CH:26][C:27]([F:30])=[CH:28][CH:29]=2)[NH:15][C@H:16]([C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)[CH3:17])=[CH:6][C:7]=1[NH2:11]
Reactant: COc1cc(C(N[C@@H](C)c2ccccc2)c2ccc(F)cc2)cc([N+](=O)[O-])c1OC
Agent: Cl[Ni]Cl
Agent: [BH4-]
Agent: [Na+]
Solvent: O
Product: COc1cc(C(N[C@@H](C)c2ccccc2)c2ccc(F)cc2)cc(N)c1OC

Procedure:
In a similar manner to that described in Example (15b), N-[(3,4-dimethoxy-5-nitrophenyl)-(4-fluorophenyl)methyl]-N-[(S)-1-phenylethyl]amine (2.73 g) [prepared as described in step (a) above], nickel chloride hexahydrate (3.19 g) and sodium borohydride (1.01 g) were reacted, and the reaction mixture was purified, to afford isomer A (895 mg) as a yellow oil and isomer B (319 mg) as a pale yellow oil of the title compound.
Reaction SMILES: C(OC([N:8]([C:16]1[C:21]([NH:22][C:23]([O:25][CH2:26][C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=2)=[O:24])=[CH:20][CH:19]=[C:18]([C:33]2[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=2)[N:17]=1)C(OC(C)(C)C)=O)=O)(C)(C)C.C(O)(C(F)(F)F)=O>C(Cl)Cl>[CH2:26]([O:25][C:23](=[O:24])[NH:22][C:21]1[C:16]([NH2:8])=[N:17][C:18]([C:33]2[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=2)=[CH:19][CH:20]=1)[C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1
Reactant: CC(C)(C)OC(=O)N(C(=O)OC(C)(C)C)c1nc(-c2ccccc2)ccc1NC(=O)OCc1ccccc1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: Nc1nc(-c2ccccc2)ccc1NC(=O)OCc1ccccc1
Reaction time: 3 h

Procedure:
A solution of di-tert-butyl(3-{[(benzyloxy)carbonyl]amino}-6-phenylpyridin-2-yl)imidodicarbonate (359 mg, 0.691 mmol) and methylene chloride (2.76 mL) was treated with TFA (0.691 mL) in one portion. The reaction was stirred for 3 h, then concentrated via rotovap slowly to afford a residue purified via MPLC, silica cartridge, 0-5% MeOH in methylene chloride to afford the product as a light orange solid. 1H NMR (DMSO-d6, 600 MHz, rotamers present) δ 9.04 (br s, 1H), 7.86 (d, J=7.3 Hz, 1H), 7.47-7.30 (m, 5H), 7.15 (d, J=8.2 Hz, 1H), 6.40 (br s, 2H), 5.16 (s, 2H); MS cal'd 320 (M+H)+, exp 320 (M+H)+.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][CH:5]=[C:6]2[C:10]=1[N:9]([CH:11]([C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1)[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1)[C:8](=[O:24])[CH:7]2[C:25]1[C:26]([OH:34])=[CH:27][C:28]2[O:32][CH2:31][CH2:30][C:29]=2[CH:33]=1.[C:35]1(C(C2C=CC=CC=2)N2C3C(=CC=CC=3)C(C3C=C(C)C(OC)=CC=3O)C2=O)C=CC=CC=1>>[Cl:1][C:2]1[CH:3]=[CH:4][CH:5]=[C:6]2[C:10]=1[N:9]([CH:11]([C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1)[C:18]1[CH:19]=[CH:20][CH:21]=[CH:22][CH:23]=1)[C:8](=[O:24])[C:7]12[CH2:35][O:34][C:26]2[CH:27]=[C:28]3[C:29](=[CH:33][C:25]1=2)[CH2:30][CH2:31][O:32]3
Reactant: O=C1C(c2cc3c(cc2O)OCC3)c2cccc(Cl)c2N1C(c1ccccc1)c1ccccc1
Reactant: COc1cc(O)c(C2C(=O)N(C(c3ccccc3)c3ccccc3)c3ccccc32)cc1C
Product: O=C1N(C(c2ccccc2)c2ccccc2)c2c(Cl)cccc2C12COc1cc3c(cc12)CCO3

Procedure:
Following the procedure as described in EXAMPLE 2 and making non-critical variations using 7-chloro-1-(diphenylmethyl)-3-(6-hydroxy-2,3-dihydro-1-benzofuran-5-yl)-1,3-dihydro-2H-indol-2-one to replace 1-(diphenylmethyl)-3-(2-hydroxy-4-methoxy-5-methylphenyl)-1,3-dihydro-2H-indol-2-one, 7′-chloro-1′-(diphenylmethyl)-5,6-dihydrospiro[benzo[1,2-b:5,4-b′]difuran-3,3′-indol]-2′(1′H)-one was obtained (80%) as a colorless solid: 1H NMR (300 MHz, DMSO-d6) δ7.45-7.06 (m, 14H), 6.38-6.32 (m, 2H), 4.75 (s, 2H), 4.48 (t, J=8.7 Hz, 2H), 2.94 (t, J=8.7 Hz, 2H).
Reaction SMILES: Br[CH2:2][C:3]([C:5]1[CH:10]=[CH:9][C:8]([C:11]([F:14])([F:13])[F:12])=[CH:7][CH:6]=1)=O.[C:15]([CH2:17][C:18]([NH2:20])=[S:19])#[N:16]>>[F:12][C:11]([F:14])([F:13])[C:8]1[CH:9]=[CH:10][C:5]([C:3]2[N:20]=[C:18]([CH2:17][C:15]#[N:16])[S:19][CH:2]=2)=[CH:6][CH:7]=1
Reactant: O=C(CBr)c1ccc(C(F)(F)F)cc1
Reactant: N#CCC(N)=S
Product: N#CCc1nc(-c2ccc(C(F)(F)F)cc2)cs1
Yield: 48 %

Procedure:
This compound was synthesized from 2-bromo-1-(4-(trifluoromethyl)phenyl)ethanone and 2-cyanothioacetamide as described in example 1 step 1 (2.4 g, 48% yield), and it was carried through without further purification. MS (ESI) m/z: Calculated for C12H7F3N2S: 268.03. found: 269.0 (M+H)+.
Reaction SMILES: [OH-].[K+].[OH:3][C:4]1[CH:13]=[CH:12][CH:11]=[C:10]2[C:5]=1[CH2:6][CH2:7][C:8](=[O:14])[NH:9]2.Br[CH2:16][CH2:17][Cl:18].[OH-].[Na+]>C(O)CC>[Cl:18][CH2:17][CH2:16][O:3][C:4]1[CH:13]=[CH:12][CH:11]=[C:10]2[C:5]=1[CH2:6][CH2:7][C:8](=[O:14])[NH:9]2
Reactant: O=C1CCc2c(O)cccc2N1
Reactant: ClCCBr
Agent: [K+]
Agent: [Na+]
Agent: [OH-]
Solvent: CCCO
Product: O=C1CCc2c(cccc2OCCCl)N1
Yield: 69 %

Procedure:
Potassium hydroxide (20 g) was added to a solution of 3,4-dihydro-5-hydroxycarbostyril (32.5 g) in propanol (250 mL), and stirred at 50°-60° C. until complete dissolution. 1-bromo-2-chloroethane (30 g) was then added, and the mixture heated at reflux temperature for 15 hours. After cooling, the reaction mixture was poured into aqueous sodium hydroxide (2N, 500 mL). The crude product thus formed was isolated by filtration, then recrystallized from diisopropyl ether to yield 31 g of pure 5-(2-chloroethoxy)-3,4-dihydrocarbostyril.
Reaction SMILES: C[O:2][C:3]([C:5]1[CH:6]=[C:7]([NH:11][C:12]2[N:17]=[C:16]([C:18]3[CH:23]=[CH:22][N:21]=[C:20]([NH:24][CH2:25][CH2:26][CH2:27][OH:28])[CH:19]=3)[CH:15]=[CH:14][N:13]=2)[CH:8]=[CH:9][CH:10]=1)=O.[NH2:29][CH2:30][CH2:31][CH2:32][NH2:33]>C(OCC)(=O)C>[NH2:29][CH2:30][CH2:31][CH2:32][NH:33][C:3]([C:5]1[CH:6]=[C:7]([NH:11][C:12]2[N:17]=[C:16]([C:18]3[CH:23]=[CH:22][N:21]=[C:20]([NH:24][CH2:25][CH2:26][CH2:27][OH:28])[CH:19]=3)[CH:15]=[CH:14][N:13]=2)[CH:8]=[CH:9][CH:10]=1)=[O:2]
Reactant: COC(=O)c1cccc(Nc2nccc(-c3ccnc(NCCCO)c3)n2)c1
Reactant: NCCCN
Solvent: CCOC(C)=O
Product: NCCCNC(=O)c1cccc(Nc2nccc(-c3ccnc(NCCCO)c3)n2)c1

Procedure:
100 mg (0.26 mmol) of N-[3-methoxycarbonyl-phenyl]-4-[2-(3-hydroxy-propyl-amino)-4-pyridyl]-2-pyrimidineamine and 0.5 ml of 1,3-diamino-propane are stirred for 24 h at 90° and then diluted with 20 ml of ethyl acetate and extracted with 2×10 ml of sodium chloride solution. The organic phase is dried, concentrated and crystallised from methylene chloride/diethyl ether to give N-[3-{N-(3-amino-propyl)-aminocarbonyl}-phenyl]-4-[2-(3-hydroxy-propyl-amino)-4-pyridyl]-2-pyrimidineamine;
Reaction SMILES: FC(F)(F)C(O)=O.C[O:9][C:10](=O)[C:11]1[CH:16]=[C:15]([C:17]2[CH:22]=[C:21]([S:23][CH2:24][CH2:25][NH:26][C:27](=[O:40])[CH2:28][CH2:29][CH2:30][NH:31][CH2:32]C(OC(C)(C)C)=O)[N:20]=[C:19]([NH2:41])[N:18]=2)[C:14]([CH3:42])=[CH:13][C:12]=1[O:43][CH3:44].[OH-].[Li+].Cl.C(OCC)(=O)C.ON1C2C=CC=CC=2N=N1.C(N(C(C)C)CC)(C)C.Cl.C(N=C=NCCCN(C)C)C>ClCCl>[NH2:41][C:19]1[N:20]=[C:21]2[CH:22]=[C:17]([C:15]3[CH:16]=[C:11]([C:10](=[O:9])[N:31]([CH3:32])[CH2:30][CH2:29][CH2:28][C:27](=[O:40])[NH:26][CH2:25][CH2:24][S:23]2)[C:12]([O:43][CH3:44])=[CH:13][C:14]=3[CH3:42])[N:18]=1
Reactant: COC(=O)c1cc(-c2cc(SCCNC(=O)CCCNCC(=O)OC(C)(C)C)nc(N)n2)c(C)cc1OC
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CCOC(C)=O
Solvent: CCN(C(C)C)C(C)C
Solvent: O=C(O)C(F)(F)F
Product: COc1cc(C)c2cc1C(=O)N(C)CCCC(=O)NCCSc1cc-2nc(N)n1
Reaction time: 3 h
Yield: 9.9 %

Procedure:
Trifluoroacetic acid (1.0 ml) was added to a dichloromethane (3.0 ml) solution of 5-(2-amino-6-{2-[4-(tert-butoxycarbonylmethylamino)butyrylamino]ethylsulfanyl}pyrimidin-4-yl)-2-methoxy-4-methylbenzoic acid methyl ester (95 mg, 0.17 mmol) obtained in Step 1 above. The reaction solution was stirred for 3 hours while gradually warming from 0° C. to room temperature. The reaction solution was concentrated under reduced pressure, and then benzene (1.5 ml) was added to the resulting residue. The solution was again concentrated under reduced pressure. After this treatment was repeated three times, the obtained colorless syrup-like material was dissolved in tetrahydrofuran (1.5 ml), methanol (1.5 ml), and water (1.0 ml). Lithium hydroxide (74 mg, 1.75 mmol) was added to the mixture. The reaction solution was stirred at room temperature for 12 hours, and then acidified by adding 4N hydrochloric acid-ethyl acetate solution (1.32 ml). The solvent was distilled off under reduced pressure. N,N-Dimethylformamide (44 ml) and tetrahydrofuran (44 ml) were added to the obtained white solid material. N-Hydroxybenzotriazole (118 mg, 0.87 mmol), diisopropylethylamine (0.38 ml, 1.7 mmol), and 1-ethyl-3-(3′-dimethylaminopropyl)carbodiimide hydrochloride (335 mg, 1.7 mmol) were sequentially added to the mixture. The resulting reaction solution was stirred at room temperature for 2.5 hours. The solution was concentrated under reduced pressure. The resulting residue was diluted with ethyl acetate (100 ml), and then sequentially washed twice with water (50 ml), and with a saturated aqueous sodium bicarbonate solution (50 ml), water (50 ml), and a saturated aqueous sodium chloride solution (50 ml). The washed ethyl acetate solution was dried over anhydrous sodium sulfate (10 g). After filtration, the filtrate was concentrated under reduced pressure. The resulting crude product was purified by silica gel column chromatography with diol-silica gel (developing solvent: ethyl acetate to ethyl acetate:methanol=15:1) and amino-silica gel (developing solvent: ethyl acetate to ethyl acetate:methanol=15:1) to yield 4-amino-18-methoxy-15,20-dimethyl-7-thia-3,5,10,15-tetraazatricyclo[15.3.1.12,6]docosa-1(20),2(22),3,5,17(21),18-hexaene-11,16-dione (Compound 10) (7 mg) as a white solid material.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2([CH3:35])[CH:12]([C:13]3[CH:18]=[CH:17][C:16]([Cl:19])=[CH:15][CH:14]=3)[N:11]([C:20](Cl)=[O:21])[C:10]([C:23]3[CH:28]=[CH:27][C:26]([O:29][CH3:30])=[CH:25][C:24]=3[O:31][CH:32]([CH3:34])[CH3:33])=[N:9]2)=[CH:4][CH:3]=1.Cl.Cl.[CH3:38][S:39]([CH2:42][CH2:43][CH2:44][N:45]1[CH2:50][CH2:49][NH:48][CH2:47][CH2:46]1)(=[O:41])=[O:40]>>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C@@:8]2([CH3:35])[C@@H:12]([C:13]3[CH:18]=[CH:17][C:16]([Cl:19])=[CH:15][CH:14]=3)[N:11]([C:20]([N:48]3[CH2:47][CH2:46][N:45]([CH2:44][CH2:43][CH2:42][S:39]([CH3:38])(=[O:40])=[O:41])[CH2:50][CH2:49]3)=[O:21])[C:10]([C:23]3[CH:28]=[CH:27][C:26]([O:29][CH3:30])=[CH:25][C:24]=3[O:31][CH:32]([CH3:34])[CH3:33])=[N:9]2)=[CH:4][CH:3]=1
Reactant: COc1ccc(C2=NC(C)(c3ccc(Cl)cc3)C(c3ccc(Cl)cc3)N2C(=O)Cl)c(OC(C)C)c1
Reactant: CS(=O)(=O)CCCN1CCNCC1
Agent: Cl
Product: COc1ccc(C2=N[C@@](C)(c3ccc(Cl)cc3)[C@@H](c3ccc(Cl)cc3)N2C(=O)N2CCN(CCCS(C)(=O)=O)CC2)c(OC(C)C)c1

Procedure:
In a manner analogous to the method described in example 5, rac-(4S*,5R*)-4,5-bis-(4-chloro-phenyl)-2-(2-isopropoxy-4-methoxy-phenyl)-4-methyl-4,5-dihydro-imidazole-1-carbonyl chloride was reacted with 1-(3-methanesulfonyl-propyl)-piperazine dihydrochloride (prepared as described in Fotouhi, N. et al. WO 2005110996) to give the title compound. LC-MS: 701.2 [(M+H)+]
Reaction SMILES: [CH:1]([C:4]([CH3:22])([N:7]1[C:11](=[O:12])[C:10]2[CH:13]=[CH:14][C:15]3[CH:19]=[CH:18][N:17]([CH3:20])[C:16]=3[C:9]=2[C:8]1=[O:21])[C:5]#[N:6])([CH3:3])[CH3:2].S(=O)(=O)(O)[OH:24]>C(Cl)Cl>[CH:1]([C:4]([CH3:22])([N:7]1[C:11](=[O:12])[C:10]2[CH:13]=[CH:14][C:15]3[CH:19]=[CH:18][N:17]([CH3:20])[C:16]=3[C:9]=2[C:8]1=[O:21])[C:5]([NH2:6])=[O:24])([CH3:3])[CH3:2]
Reactant: CC(C)C(C)(C#N)N1C(=O)c2ccc3ccn(C)c3c2C1=O
Reactant: O=S(=O)(O)O
Solvent: ClCCl
Product: CC(C)C(C)(C(N)=O)N1C(=O)c2ccc3ccn(C)c3c2C1=O
Reaction time: 8 h
Yield: 23.2 %

Procedure:
A solution of 6,8-dihydro-a-isopropyl-a,1-dimethyl-6,8-dioxobenzo[2,1-b:3,4-c']dipyrrole-7(1H)-acetonitrile (5.30 g, 18.0 mmol) in methylene chloride is added dropwise to concentrated sulfuric acid at 5°-10° C. with rapid stirring. The ice bath is removed and the reaction mixture is stirred overnight at ambient temperatures, poured over crushed ice, diluted with methylene chloride, treated with 50% sodium hydroxide solution with ice bath cooling to pH 3-4 and separated. The aqueous layer is extracted with methylene chloride. The combined organic layers are dried (MgSO4) and concentrated in vacuo to give an orange foam residue, which is recrystallized from methylene chloride to afford the title product as yellow crystals (1.30 g, 23.2%), mp 184°-189° C.
Reaction SMILES: [NH2:1][C:2]1[C:7]([O:8][CH2:9][C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)=[CH:6][CH:5]=[CH:4][N:3]=1.Cl.[F:17][C:18]1[CH:23]=[CH:22][C:21]([CH2:24][C:25](=[NH:29])OCC)=[CH:20][CH:19]=1>C(O)C>[CH2:9]([O:8][C:7]1[C:2]([NH:1][C:25](=[NH:29])[CH2:24][C:21]2[CH:22]=[CH:23][C:18]([F:17])=[CH:19][CH:20]=2)=[N:3][CH:4]=[CH:5][CH:6]=1)[C:10]1[CH:11]=[CH:12][CH:13]=[CH:14][CH:15]=1
Reactant: Nc1ncccc1OCc1ccccc1
Reactant: CCOC(=N)Cc1ccc(F)cc1
Agent: Cl
Solvent: CCO
Product: N=C(Cc1ccc(F)cc1)Nc1ncccc1OCc1ccccc1
Yield: 6 %

Procedure:
A mixture of 2-amino-3-benzyloxypyridine (4.84 g, 24.2 mmol) and ethyl 4-fluorophenylacetimidate hydrochloride (5.8 g, 26.7 mmol) in ethanol (80 ml) was heated under reflux for 2 hours. Evaporation of the solvent gave an oil which was converted to the free base and purified by flash chromatography (chloroform/methanol) to obtain the product (0.49 g), m.p. 86°-93° C.