Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:12]([C:13]3[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=3)[C:11]3[CH:19]=[CH:20][CH:21]=[CH:22][C:10]=3[N:9]=2)=[CH:4][CH:3]=1.C([Li])CCC.[C:28]1([C:34]2[CH:47]=[C:46]([C:48]3[CH:53]=[CH:52][CH:51]=[CH:50][CH:49]=3)[C:45]3[C:36](=[C:37]4[C:42](=[CH:43][CH:44]=3)[C:41]([C:54]3[CH:59]=[CH:58][CH:57]=[CH:56][CH:55]=3)=[CH:40][CH:39]=[N:38]4)[N:35]=2)[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1.O>C1COCC1>[C:28]1([C:34]2[CH:47]=[C:46]([C:48]3[CH:53]=[CH:52][CH:51]=[CH:50][CH:49]=3)[C:45]3[C:36](=[C:37]4[C:42](=[CH:43][CH:44]=3)[C:41]([C:54]3[CH:55]=[CH:56][CH:57]=[CH:58][CH:59]=3)=[CH:40][C:39]([C:2]3[CH:7]=[CH:6][C:5]([C:8]5[N:12]([C:13]6[CH:14]=[CH:15][CH:16]=[CH:17][CH:18]=6)[C:11]6[CH:19]=[CH:20][CH:21]=[CH:22][C:10]=6[N:9]=5)=[CH:4][CH:3]=3)=[N:38]4)[N:35]=2)[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1
Reactant: Brc1ccc(-c2nc3ccccc3n2-c2ccccc2)cc1
Reactant: c1ccc(-c2cc(-c3ccccc3)c3ccc4c(-c5ccccc5)ccnc4c3n2)cc1
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: O
Product: c1ccc(-c2cc(-c3ccccc3)c3ccc4c(-c5ccccc5)cc(-c5ccc(-c6nc7ccccc7n6-c6ccccc6)cc5)nc4c3n2)cc1
Temperature: -78 °C
Yield: 47 %

Procedure:
To a three-necked flask of 250 ml, 3.84 g (11 mmol) of 2-(4-bromophenyl)-1-phenyl-1H-benzo[d]imidazole and 70 ml of THF were charged, then 6.9 ml (11 mmol) n-butyllithium (1.6M in Hexane solution) was dropped under stirring at −78° C. in a nitrogen atmosphere. The mixture was stirred for one hour at −78° C., and a solution of 2.29 g (5.6 mmol) 2,4,7-triphenyl-1,10-phenanthroline in 30 ml THF was dropped. Then the mixture was stirred at room temperature for overnight and was added with water. The organic layer was extracted with Dichloromethane and dried with anhydrous magnesium sulfate, the solvent was removed by rotary evaporation. The product was purified by column chromatography on alumina using Dichloromethane/Hexane as eluent and dried in vacuo, obtaining white powder compound 1.78 g (yield of 47.12%). MS (m/z, FAB+) 676.8(100%).
Reaction SMILES: [F:1][C:2]1[CH:19]=[CH:18][C:5]([CH2:6][O:7][C:8]2[N:13]=[CH:12][C:11]([C:14](=O)[CH3:15])=[CH:10][C:9]=2[CH3:17])=[CH:4][CH:3]=1.[CH3:20][C:21]([S@:24]([NH2:26])=[O:25])([CH3:23])[CH3:22]>>[F:1][C:2]1[CH:19]=[CH:18][C:5]([CH2:6][O:7][C:8]2[N:13]=[CH:12][C:11]([CH:14]([NH:26][S@@:24]([C:21]([CH3:23])([CH3:22])[CH3:20])=[O:25])[CH3:15])=[CH:10][C:9]=2[CH3:17])=[CH:4][CH:3]=1
Reactant: CC(=O)c1cnc(OCc2ccc(F)cc2)c(C)c1
Reactant: CC(C)(C)[S@](N)=O
Product: Cc1cc(C(C)N[S@](=O)C(C)(C)C)cnc1OCc1ccc(F)cc1
Yield: 79 %

Procedure:
The title compound is prepared in 79% yield (2.15 g, white solid) from 1-(6-((4-fluorobenzyl)oxy)-5-methylpyridin-3-yl)ethanone (1.94 g, 7.48 mmol, Step-3) and (R)-2-methylpropane-2-sulfinamide (1.36 g, 11.2 mmol) in a similar manner to Step-4 of Amine-1.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][CH:6]=[C:5]2[CH2:11][CH2:12][NH:13][C:14](=[O:22])[C:15]1[CH:20]=[CH:19][CH:18]=[C:17](I)[CH:16]=1.[CH3:23][O:24][C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][C:26]=1B(O)O.C(=O)([O-])[O-].[Na+].[Na+]>C(COC)OC.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>[Cl:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][CH:6]=[C:5]2[CH2:11][CH2:12][NH:13][C:14]([C:15]1[CH:16]=[C:17]([C:26]2[CH:27]=[CH:28][CH:29]=[CH:30][C:25]=2[O:24][CH3:23])[CH:18]=[CH:19][CH:20]=1)=[O:22]
Reactant: COc1ccccc1B(O)O
Reactant: O=C(NCCc1c[nH]c2ccc(Cl)cc12)c1cccc(I)c1
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: COCCOC
Solvent: O
Product: COc1ccccc1-c1cccc(C(=O)NCCc2c[nH]c3ccc(Cl)cc23)c1
Yield: 78.6 %

Procedure:
N-(2-(5-chloro-1H-indol-3-yl)ethyl)-2′-methoxybiphenyl-3-carboxamide was prepared according to method B with N-(2-(5-chloro-1H-indol-3-yl)ethyl)-3-iodobenzamide (0.075 g; 0.176 mmol), 2-methoxyphenylboronic acid (0.028 g; 0.180 mmol), tetrakis(triphenylphosphine)palladium (0.010 g; 0.009 mmol), sodium carbonate (0.037 g; 0.353 mmol), in dimethoxyethane (3 mL) and water (1 mL), irradiated in a microwave oven at 130° C. for 15 minutes. Flash chromatography on silica gel (eluent 1 to 20% ethyl acetate in dichloromethane) furnished 0.056 g (78%) of N-(2-(5-chloro-1H-indol-3-yl)ethyl)-2′-methoxybiphenyl-3-carboxamide as a white solid.
Reaction SMILES: [F:1][C:2]([F:40])([F:39])[C:3]1[CH:4]=[C:5]([CH:32]=[C:33]([C:35]([F:38])([F:37])[F:36])[CH:34]=1)[CH2:6][N:7]1[CH2:14][CH2:13][CH2:12][N:11]([CH3:15])[C:10]2[N:16]=[C:17](S(C)(=O)=O)[N:18]=[C:19]([C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][C:21]=3[CH3:26])[C:9]=2[C:8]1=[O:31].[NH:41]1[CH2:46][CH2:45][O:44][CH2:43][CH2:42]1>>[F:1][C:2]([F:40])([F:39])[C:3]1[CH:4]=[C:5]([CH:32]=[C:33]([C:35]([F:38])([F:37])[F:36])[CH:34]=1)[CH2:6][N:7]1[CH2:14][CH2:13][CH2:12][N:11]([CH3:15])[C:10]2[N:16]=[C:17]([N:41]3[CH2:46][CH2:45][O:44][CH2:43][CH2:42]3)[N:18]=[C:19]([C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][C:21]=3[CH3:26])[C:9]=2[C:8]1=[O:31]
Reactant: C1COCCN1
Reactant: Cc1ccccc1-c1nc(S(C)(=O)=O)nc2c1C(=O)N(Cc1cc(C(F)(F)F)cc(C(F)(F)F)c1)CCCN2C
Product: Cc1ccccc1-c1nc(N2CCOCC2)nc2c1C(=O)N(Cc1cc(C(F)(F)F)cc(C(F)(F)F)c1)CCCN2C
Yield: 91.9 %

Procedure:
In a similar manner to Example 1, 6-[3,5-bis(trifluoromethyl)benzyl]-5,6,7,8,9,10-hexahydro-10-methyl-4-(2-methylphenyl)-2-(methylsulfonyl)-5-oxopyrimido[4,5-b][1,5]diazocine (Compound of Reference Example 21; 88.0 mg) was reacted with morpholine (15.7 mg) to obtain 6-[3,5-bis(trifluoromethyl)benzyl]-5,6,7,8,9,10-hexahydro-10-methyl-4-(2-methylphenyl)-2-(morpholine-4-yl)-5-oxopyrimido(4,5-b][1,5]diazocine (81.8 mg, 92%).
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:9]=[C:10]([N:22]3[CH2:27][CH2:26][O:25][CH2:24][C@@H:23]3[CH3:28])[C:11]3[CH2:16][N:15]([C:17]([O:19][CH2:20][CH3:21])=[O:18])[CH2:14][C:12]=3[N:13]=2)=[C:4]([F:29])[CH:3]=1.[N:30]([CH:33]1[CH2:35][CH2:34]1)=[C:31]=[O:32]>>[CH:33]1([NH:30][C:31](=[O:32])[NH:1][C:2]2[CH:7]=[CH:6][C:5]([C:8]3[N:9]=[C:10]([N:22]4[CH2:27][CH2:26][O:25][CH2:24][C@@H:23]4[CH3:28])[C:11]4[CH2:16][N:15]([C:17]([O:19][CH2:20][CH3:21])=[O:18])[CH2:14][C:12]=4[N:13]=3)=[C:4]([F:29])[CH:3]=2)[CH2:35][CH2:34]1
Reactant: CCOC(=O)N1Cc2nc(-c3ccc(N)cc3F)nc(N3CCOC[C@@H]3C)c2C1
Reactant: O=C=NC1CC1
Product: CCOC(=O)N1Cc2nc(-c3ccc(NC(=O)NC4CC4)cc3F)nc(N3CCOC[C@@H]3C)c2C1
Yield: 47 %

Procedure:
Method as example 113 step 2 using (S)-ethyl 2-(4-amino-2-fluorophenyl)-4-(3-methylmorpholino)-5H-pyrrolo[3,4-d]pyrimidine-6(7H)-carboxylate and isocyanatocyclopropane as starting materials. The solvent was removed in vacuo and the residue purified by prep HPLC (low pH) yielding the final compound (17 mg, 0.04 mmol, 47%).
Reaction SMILES: [NH:1]1[CH:5]=[C:4]([C:6]2[C:7]([C:12]3[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=3)=[N:8][O:9][C:10]=2[CH3:11])[N:3]=[CH:2]1.[CH2:18]([O:20][C:21](=[O:29])[C:22]1[CH:27]=[CH:26][C:25](F)=[CH:24][CH:23]=1)[CH3:19]>>[CH2:18]([O:20][C:21](=[O:29])[C:22]1[CH:27]=[CH:26][C:25]([N:1]2[CH:5]=[C:4]([C:6]3[C:7]([C:12]4[CH:13]=[CH:14][CH:15]=[CH:16][CH:17]=4)=[N:8][O:9][C:10]=3[CH3:11])[N:3]=[CH:2]2)=[CH:24][CH:23]=1)[CH3:19]
Reactant: CCOC(=O)c1ccc(F)cc1
Reactant: Cc1onc(-c2ccccc2)c1-c1c[nH]cn1
Product: CCOC(=O)c1ccc(-n2cnc(-c3c(-c4ccccc4)noc3C)c2)cc1
Yield: 71.8 %

Procedure:
As described for Example 1, 4-(1H-imidazol-4-yl)-5-methyl-3-phenyl-isoxazole (2.25 g, 10.0 mmol) was converted, using 4-fluorobenzoic acid ethyl ester (1.54 g, 10.0 mmol) instead of 4-fluoroacetophenone, to the title compound (2.68 g, 72%) which was obtained as brown oil. MS: m/e=374.1 [M+H]+.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:24])[C:5]1[CH:10]=[CH:9][CH:8]=[C:7]([S:11][C:12]2[C:20]3[C:15](=[CH:16][C:17]([Cl:21])=[CH:18][CH:19]=3)[NH:14][C:13]=2[CH3:22])[C:6]=1[CH3:23])[CH3:2].Br[C:26]1[CH:27]=[N:28][N:29]([CH3:31])[CH:30]=1>>[CH2:1]([O:3][C:4](=[O:24])[C:5]1[CH:10]=[CH:9][CH:8]=[C:7]([S:11][C:12]2[C:20]3[C:15](=[CH:16][C:17]([Cl:21])=[CH:18][CH:19]=3)[N:14]([C:26]3[CH:27]=[N:28][N:29]([CH3:31])[CH:30]=3)[C:13]=2[CH3:22])[C:6]=1[CH3:23])[CH3:2]
Reactant: CCOC(=O)c1cccc(Sc2c(C)[nH]c3cc(Cl)ccc23)c1C
Reactant: Cn1cc(Br)cn1
Product: CCOC(=O)c1cccc(Sc2c(C)n(-c3cnn(C)c3)c3cc(Cl)ccc23)c1C

Procedure:
Prepared according to the procedure described in Example 42, Step 4, using the following starting materials: 3-(6-chloro-2-methyl-1H-indol-3-ylsulfanyl)-2-methyl-benzoic acid ethyl ester and 4-bromo-1-methylpyrazole.
Reaction SMILES: F[C:2]1[CH:7]=[CH:6][C:5]([N+:8]([O-:10])=[O:9])=[CH:4][C:3]=1[C:11]([N:13]1[CH2:18][CH2:17][N:16]([C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][C:20]=2[F:25])[CH2:15][CH2:14]1)=[O:12].[NH:26]1[CH2:31][CH2:30][O:29][CH2:28][CH2:27]1>>[F:25][C:20]1[CH:21]=[CH:22][CH:23]=[CH:24][C:19]=1[N:16]1[CH2:17][CH2:18][N:13]([C:11]([C:3]2[CH:4]=[C:5]([N+:8]([O-:10])=[O:9])[CH:6]=[CH:7][C:2]=2[N:26]2[CH2:31][CH2:30][O:29][CH2:28][CH2:27]2)=[O:12])[CH2:14][CH2:15]1
Reactant: O=C(c1cc([N+](=O)[O-])ccc1F)N1CCN(c2ccccc2F)CC1
Reactant: C1COCCN1
Product: O=C(c1cc([N+](=O)[O-])ccc1N1CCOCC1)N1CCN(c2ccccc2F)CC1

Procedure:
The title compound was prepared according to the procedure described for example 1 from (2-Fluoro-5-nitro-phenyl)-[4-(2-fluoro-phenyl)-piperazin-1-yl]-methanone and morpholine (87%, yellow solid, MS (m/e): 415.2 (M+H, 100%)
Reaction SMILES: [CH3:1][O:2][CH:3]([O:7][CH3:8])[CH2:4][NH:5][CH3:6].C1C=CC=CC=1.[CH3:15][C:16]1[CH:17]=[C:18]([CH:30]=[CH:31][CH:32]=1)[O:19][CH:20]([C:22]1[S:26][C:25]([N:27]=[C:28]=[O:29])=[N:24][N:23]=1)[CH3:21]>CCCCCC>[CH3:15][C:16]1[CH:17]=[C:18]([CH:30]=[CH:31][CH:32]=1)[O:19][CH:20]([C:22]1[S:26][C:25]([NH:27][C:28](=[O:29])[N:5]([CH3:6])[CH2:4][CH:3]([O:7][CH3:8])[O:2][CH3:1])=[N:24][N:23]=1)[CH3:21]
Reactant: CNCC(OC)OC
Reactant: Cc1cccc(OC(C)c2nnc(N=C=O)s2)c1
Solvent: c1ccccc1
Solvent: CCCCCC
Product: COC(CN(C)C(=O)Nc1nnc(C(C)Oc2cccc(C)c2)s1)OC

Procedure:
Methylaminoacetaldehyde dimethylacetal (3.7 grams, 0.031 mole) was added to a 50 milliliter benzene solution containing 3.7 grams (0.031 equivalent) of the 5-[1-(3-methylphenoxy)ethyl]-1,3,4-thiadiazol-2-yl isocyanate dimer (prepared above) and the resulting solution was refluxed for 15 minutes and then cooled. Hexane (100 milliliters) was added and the resulting solution formed crystals which were filtered off, and dried in a vacuum oven at 80° C. to 9.0 grams of white crystals of [5-[1-(3-methylphenoxy)ethyl]-1,3,4thiadiazol-2-yl]-1-methyl-1-(2,2-dimethoxyethyl)urea (melting point 122°-125° C.).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]2[C:16]3[C:11](=[CH:12][C:13]([OH:17])=[CH:14][CH:15]=3)[C:10](=[O:18])[CH2:9]2)=[CH:4][CH:3]=1.[OH:19][C:20]1C=C2C(C(C3C=CC=CC=3)CC2=O)=C[CH:21]=1>>[C:20]([O:17][C:13]1[CH:12]=[C:11]2[C:16](=[CH:15][CH:14]=1)[CH:8]([C:5]1[CH:4]=[CH:3][C:2]([Cl:1])=[CH:7][CH:6]=1)[CH2:9][C:10]2=[O:18])(=[O:19])[CH3:21]
Reactant: O=C1CC(c2ccc(Cl)cc2)c2ccc(O)cc21
Reactant: O=C1CC(c2ccccc2)c2ccc(O)cc21
Product: CC(=O)Oc1ccc2c(c1)C(=O)CC2c1ccc(Cl)cc1
Reaction time: 1.5 h
Yield: 99 %

Procedure:
The procedure of Step 3 of Example 1 was repeated except for using 3-(4-chlorophenyl)-2,3-dihydro-6-hydroxyinden-1-one obtained in Step 2 as a starting material instead of 2,3-dihydro-6-hydroxy-3-phenylinden-1-one and being stirred for 1.5 h to obtain the title compound (99%).
Reaction SMILES: S(Cl)([Cl:3])=O.[CH3:5][C:6]1[N:14]=[C:13]([C:15]([F:18])([F:17])[F:16])[CH:12]=[CH:11][C:7]=1[C:8](O)=[O:9]>C1(C)C=CC=CC=1>[CH3:5][C:6]1[C:7]([C:8]([Cl:3])=[O:9])=[CH:11][CH:12]=[C:13]([C:15]([F:18])([F:17])[F:16])[N:14]=1
Reactant: Cc1nc(C(F)(F)F)ccc1C(=O)O
Reactant: O=S(Cl)Cl
Solvent: Cc1ccccc1
Product: Cc1nc(C(F)(F)F)ccc1C(=O)Cl
Temperature: 25 °C

Procedure:
Thionyl chloride (4.35 g, 36.5 mmol) was added to a mixture of 2-methyl-6-trifluoromethyl nicotinic acid (5.00 g, 24.4 mmol) in 75 mL of toluene and the mixture was heated at reflux for 3 hours. The reaction was cooled to room temperature and the solvent was removed under reduced pressure. Excess thionyl chloride was removed by azeotrope with toluene. The resultant acid chloride was used as is in Example 4, Step B.
Reaction SMILES: [F:1][C:2]1[CH:3]=[CH:4][CH:5]=[C:6]2[C:14]=1[N:13]([CH3:15])[C:12]1[CH2:11][CH2:10][CH2:9][C:8](=O)[C:7]2=1.Cl.[NH2:18][OH:19]>N1C=CC=CC=1>[F:1][C:2]1[CH:3]=[CH:4][CH:5]=[C:6]2[C:14]=1[N:13]([CH3:15])[C:12]1[CH2:11][CH2:10][CH2:9][C:8](=[N:18][OH:19])[C:7]2=1
Reactant: Cn1c2c(c3cccc(F)c31)C(=O)CCC2
Reactant: NO
Agent: Cl
Solvent: c1ccncc1
Product: Cn1c2c(c3cccc(F)c31)C(=NO)CCC2
Yield: 56.1 %

Procedure:
A mixture of 8-fluoro-1,2,3,9-tetrahydro-9-methyl-4H-carbazol-4-one (3.0 g) and hydroxylamine hydrochloride (2.92 g) in pyridine (ca. 35 ml) was heated at 60° for 3 h. The solution was concentrated in vacuo then azeotropically dried with toluene (2×10 ml). The residue was treated with 8% sodium bicarbonate solution (125 ml) and extracted with ethyl acetate (3×100 ml). The combined extracts were filtered and concentrated in vacuo to give the title compound (1.8 g) as a solid, t.l.c. (System A, 100:8:1) Rf 0.66.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[NH:16][C:15]2[CH:14]=[N:13][CH:12]=[N:11][C:10]=2[CH:9]=1.[Br:17]N1C(=O)CCC1=O>CC(C)=O.CCOC(C)=O>[Br:17][C:9]1[C:10]2[N:11]=[CH:12][N:13]=[CH:14][C:15]=2[NH:16][C:8]=1[C:3]1[CH:4]=[CH:5][CH:6]=[CH:7][C:2]=1[F:1]
Reactant: Fc1ccccc1-c1cc2ncncc2[nH]1
Reactant: O=C1CCC(=O)N1Br
Solvent: CCOC(C)=O
Solvent: CC(C)=O
Product: Fc1ccccc1-c1[nH]c2cncnc2c1Br
Temperature: 25 °C
Reaction time: 2 h
Yield: 60 %

Procedure:
To a slurry of 6-(2-fluorophenyl)-5H-pyrrolo[3,2-d]pyrimidine (1.0 g) in acetone (50 mL) was added N-bromosuccinimide (1.0 g). The reaction was stirred at rt for 2 h, until complete conversion was observed by LC-MS. The reaction mixture was diluted with EtOAc (150 mL) and the solid was collected via filtration and washed with EtOAc yielding 820 mg of desired (60% yield). LCMS calculated for C12H7BrFN3 292.1, found 292.23: [M+].
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][N:5]=[C:4]([CH2:8][CH2:9][CH2:10][CH2:11][CH3:12])[CH:3]=1.Cl[C:14]1C=C(CC)C=CN=1>>[CH2:1]([C:2]1[CH:7]=[CH:6][N:5]=[C:4]([CH2:8][CH2:9][CH2:10][CH2:11][CH3:12])[CH:3]=1)[CH3:14]
Reactant: CCc1ccnc(Cl)c1
Reactant: CCCCCc1cc(C)ccn1
Product: CCCCCc1cc(CC)ccn1

Procedure:
This compound was obtained using the same experimental procedure as per 4-methyl-2-pentyl-pyridine (see above), using 2-chloro-4-ethyl pyridine instead of 2-bromo-4-methyl pyridine. The product was obtained with similar yield and purified in the same way.
Reaction SMILES: [CH3:1][N:2]([C:4]1[CH:9]=[CH:8][C:7]([N:10]=[N:11][C:12]2[CH:17]=[CH:16][C:15]([S:18](Cl)(=[O:20])=[O:19])=[CH:14][CH:13]=2)=[CH:6][CH:5]=1)[CH3:3].[NH2:22][CH2:23][CH2:24][CH2:25][CH2:26][N:27]1[C:35]2[CH:34]=[C:33]([CH3:36])[N:32]=[C:31]([NH2:37])[C:30]=2[N:29]=[C:28]1[CH2:38][O:39][CH2:40][CH3:41]>>[NH2:37][C:31]1[C:30]2[N:29]=[C:28]([CH2:38][O:39][CH2:40][CH3:41])[N:27]([CH2:26][CH2:25][CH2:24][CH2:23][NH:22][S:18]([C:15]3[CH:16]=[CH:17][C:12](/[N:11]=[N:10]/[C:7]4[CH:8]=[CH:9][C:4]([N:2]([CH3:3])[CH3:1])=[CH:5][CH:6]=4)=[CH:13][CH:14]=3)(=[O:20])=[O:19])[C:35]=2[CH:34]=[C:33]([CH3:36])[N:32]=1
Reactant: CCOCc1nc2c(N)nc(C)cc2n1CCCCN
Reactant: CN(C)c1ccc(N=Nc2ccc(S(=O)(=O)Cl)cc2)cc1
Product: CCOCc1nc2c(N)nc(C)cc2n1CCCCNS(=O)(=O)c1ccc(/N=N/c2ccc(N(C)C)cc2)cc1

Procedure:
Using the method of Examples 32-46, 4-dimethylaminoazobenzene-4′-sulfonyl chloride was reacted with 1-(4-aminobutyl)-2-ethoxymethyl-6-methyl-1H-imidazo[4,5-c]pyridin-4-amine to provide the desired product. The observed accurate mass was 565.2720.
Reaction SMILES: O.[OH-].[Li+].C([O:6][C:7]([C:9]1[CH2:10][S:11][C:12]2[CH:13]=[N:14][C:15]3[C:20]([C:21]=2[CH:22]=1)=[CH:19][C:18]([O:23][CH3:24])=[CH:17][CH:16]=3)=[O:8])C.Cl>O1CCCC1.O>[CH3:24][O:23][C:18]1[CH:19]=[C:20]2[C:15](=[CH:16][CH:17]=1)[N:14]=[CH:13][C:12]1[S:11][CH2:10][C:9]([C:7]([OH:8])=[O:6])=[CH:22][C:21]2=1
Reactant: CCOC(=O)C1=Cc2c(cnc3ccc(OC)cc23)SC1
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Product: COc1ccc2ncc3c(c2c1)C=C(C(=O)O)CS3
Temperature: 25 °C
Reaction time: 2 h
Yield: 88.3 %

Procedure:
Lithium hydroxide monohydrate (731 mg, 17.42 mmol, 15.0 eq) is added at room temperature to a stirred solution of 6-methoxy-2H-1-thia-9-aza-phenanthrene-3-carboxylic acid ethyl ester (350 mg, 1.16 mmol, 1.0 eq) in tetrahydrofuran (5 mL) and water (5 mL). After 2 hours stirring at room temperature, the reaction mixture is acidified until pH=6 with a 1N hydrochloric acid aqueous solution and the resulting precipitate is collected by filtration, dried under vacuum to afford 6-methoxy-2H-1-thia-9-aza-phenanthrene-3-carboxylic acid as a yellow solid (280 mg, 88% yield).
Reaction SMILES: [NH2:1][C:2]1[C:3]([F:16])=[CH:4][C:5]2[O:10][CH2:9][C:8](=[O:11])[N:7]([CH2:12][C:13]#[N:14])[C:6]=2[CH:15]=1.[C:17]1(=O)[O:22][C:20](=[O:21])[CH:19]2[CH2:23][CH2:24][CH:25]=[CH:26][CH:18]12.C(O)(=O)C>O>[C:13]([CH2:12][N:7]1[C:6]2[CH:15]=[C:2]([N:1]3[C:20](=[O:21])[C:19]4[CH2:23][CH2:24][CH2:25][CH2:26][C:18]=4[C:17]3=[O:22])[C:3]([F:16])=[CH:4][C:5]=2[O:10][CH2:9][C:8]1=[O:11])#[N:14]
Reactant: O=C1OC(=O)C2CCC=CC12
Reactant: N#CCN1C(=O)COc2cc(F)c(N)cc21
Solvent: CC(=O)O
Solvent: O
Product: N#CCN1C(=O)COc2cc(F)c(N3C(=O)C4=C(CCCC4)C3=O)cc21
Yield: 73.5 %

Procedure:
6-amino-4-cyanomethyl-7-fluoro-2H-1,4-benzoxazin-3(4H)-one (0.5 g), tetrahydrophthalic anhydride (0.38 g) and acetic acid (10 ml) were mixed with each other, then the mixture was refluxed under heating for 3 hours. After the liquor was allowed to cool, it was added to water (40 ml), and separating crystals were collected by filtration, and then the crystals were dissolved in dichloromethane (30 ml). The dichloromethane solution was washed with a saturated solution of sodium bicarbonate, and water, in that order, and then dehydrated with anhydrous sodium sulfate, and subsequently concentrated. Separated crystals were washed with a small amount of ether to give the desired 2-[4-cyanomethyl-7-fluoro-2H-1,4-benzoxazin-3(4H)-on 6-yl]-4,5,6,7-tetrahydro-2H-isoindole-1,3-dione (0.59 g). mp. 227°-229° C.
Reaction SMILES: [F:1][C:2]1[CH:9]=[C:8]([OH:10])[C:7]([O:11][CH3:12])=[CH:6][C:3]=1[CH:4]=[O:5].CN(C)C=O.[H-].[Na+].[NH:20]1[C:24]2[CH:25]=[CH:26][CH:27]=[CH:28][C:23]=2[N:22]=[C:21]1[CH2:29]OC1C(Cl)=CC(C=O)=C(F)C=1>O>[NH:20]1[C:24]2[CH:25]=[CH:26][CH:27]=[CH:28][C:23]=2[N:22]=[C:21]1[CH2:29][O:10][C:8]1[C:7]([O:11][CH3:12])=[CH:6][C:3]([CH:4]=[O:5])=[C:2]([F:1])[CH:9]=1
Reactant: COc1cc(C=O)c(F)cc1O
Reactant: O=Cc1cc(Cl)c(OCc2nc3ccccc3[nH]2)cc1F
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: COc1cc(C=O)c(F)cc1OCc1nc2ccccc2[nH]1
Temperature: 25 °C
Reaction time: 0.33 h
Yield: 45.6 %

Procedure:
2-Fluoro-4-hydroxy-5-methoxy-benzaldehyde (39, 0.290 g, 1.7 mmol, prepared as described in Scheme 12 of Example 15) was dissolved in N,N-dimethylformamide (20 mL, 200 mmol). Sodium hydride (60% dispersion in oil, 0.852 g, 2.13 mmol) was added to the solution and after the mixture was stirred for 20 minutes at room temperature, 2-chloromethyl-1H-benzoimidazole (106, 0.28 g, 1.7 mmol) was added to the reaction. The obtained mixture was heated to 80° C. and stirred overnight. After cooling to room temperature, the reaction was poured into water and extracted with ethyl acetate. The organic portion was dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated and purified by silica gel column chromatography eluting with a gradient of ethyl acetate (40 to 100%) in hexane to give the desired compound (142, 0.233 g, 45%).
Reaction SMILES: [CH3:1][C@H:2]1[CH2:7][N:6]([CH2:8][C:9]2[CH:18]=[N:17][C:16]3[NH:15][C:14](=[O:19])[N:13]4[N:20]=[CH:21][N:22]=[C:12]4[C:11]=3[CH:10]=2)[CH2:5][C@@H:4]([CH3:23])[O:3]1.[F:24][C:25]([F:36])([F:35])[O:26][C:27]1[CH:34]=[CH:33][C:30]([CH2:31]Br)=[CH:29][CH:28]=1.C(=O)([O-])[O-].[K+].[K+]>CN(C)C=O>[CH3:1][C@H:2]1[CH2:7][N:6]([CH2:8][C:9]2[CH:18]=[N:17][C:16]3[N:15]([CH2:31][C:30]4[CH:33]=[CH:34][C:27]([O:26][C:25]([F:24])([F:35])[F:36])=[CH:28][CH:29]=4)[C:14](=[O:19])[N:13]4[N:20]=[CH:21][N:22]=[C:12]4[C:11]=3[CH:10]=2)[CH2:5][C@@H:4]([CH3:23])[O:3]1
Reactant: FC(F)(F)Oc1ccc(CBr)cc1
Reactant: C[C@@H]1CN(Cc2cnc3[nH]c(=O)n4ncnc4c3c2)C[C@H](C)O1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: C[C@@H]1CN(Cc2cnc3c(c2)c2ncnn2c(=O)n3Cc2ccc(OC(F)(F)F)cc2)C[C@H](C)O1
Temperature: 55 °C
Yield: 74.2 %

Procedure:
To a mixture of 9-(((2S,6R)-2,6-dimethylmorpholino)methyl)pyrido[3,2-e][1,2,4]triazolo[1,5-c]pyrimidin-5(6H)-one (50 mg, 0.16 mmol) and 4-(trifluoromethoxy)benzyl bromide (49 mg, 0.19 mmol) in N,N-dimethylformamide (2 ml) was added potassium carbonate (44 mg, 0.32 mmol). The resulting mixture was heated at 55° C. overnight. The crude mixture was filtered then purified directly via reverse phase HPLC to yield 273 (58 mg, 61%) as a white solid.
Reaction SMILES: [NH2:1][C:2]1[C:3]([O:17][CH3:18])=[C:4]([NH:12][S:13]([CH3:16])(=[O:15])=[O:14])[CH:5]=[C:6]([C:8]([CH3:11])([CH3:10])[CH3:9])[CH:7]=1.C([O-])(O)=O.[Na+].C1COCC1.Cl[C:30]([O:32][C:33]1[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=1)=[O:31]>C(Cl)Cl>[C:8]([C:6]1[CH:5]=[C:4]([NH:12][S:13]([CH3:16])(=[O:15])=[O:14])[C:3]([O:17][CH3:18])=[C:2]([NH:1][C:30](=[O:31])[O:32][C:33]2[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=2)[CH:7]=1)([CH3:10])([CH3:11])[CH3:9]
Reactant: O=C(Cl)Oc1ccccc1
Reactant: COc1c(N)cc(C(C)(C)C)cc1NS(C)(=O)=O
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Solvent: C1CCOC1
Product: COc1c(NC(=O)Oc2ccccc2)cc(C(C)(C)C)cc1NS(C)(=O)=O
Temperature: 25 °C
Reaction time: 4 h

Procedure:
Under N2 was charged the product of step (ix) above (167.0 g, 613 mmol), NaHCO3 (77.3 g, 920 mmol), THF (870 mL) and DCM (1440 mL). Phenyl chloroformate (82.6 mL, 659 mmol) was added dropwise, while maintaining the temperature below 20° C., and the reaction was stirred at room temperature for 4 h. HPLC analysis of the reaction mixture indicated 98.6% product and 0.03% starting material. The reaction mixture was filtered and the cake was washed with THF (˜50 mL). The filtrate was concentrated to ˜900 mL and cyclohexane (2400 mL) was added, then the mixture was left to stir overnight. The resulting solid was collected via vacuum filtration and washed with cyclohexane (500 mL). The pale pink solid produced was dried, under vacuum, at 40° C. for 4 h. Yield=232.6 g (96.7%). HPLC purity 94.5%. 1H NMR purity >95%.
Reaction SMILES: C([NH:8][C@H:9]1[CH2:14][CH2:13][C@@H:12]([C:15]2[CH:20]=[CH:19][C:18]([O:21][Si:22]([C:25]([CH3:28])([CH3:27])[CH3:26])([CH3:24])[CH3:23])=[CH:17][C:16]=2[O:29][Si:30]([C:33]([CH3:36])([CH3:35])[CH3:34])([CH3:32])[CH3:31])[CH2:11][CH2:10]1)C1C=CC=CC=1>C(O)C.[Pd]>[Si:30]([O:29][C:16]1[CH:17]=[C:18]([O:21][Si:22]([C:25]([CH3:26])([CH3:27])[CH3:28])([CH3:24])[CH3:23])[CH:19]=[CH:20][C:15]=1[C@@H:12]1[CH2:11][CH2:10][C@H:9]([NH2:8])[CH2:14][CH2:13]1)([C:33]([CH3:34])([CH3:35])[CH3:36])([CH3:32])[CH3:31]
Reactant: CC(C)(C)[Si](C)(C)Oc1ccc([C@H]2CC[C@@H](NCc3ccccc3)CC2)c(O[Si](C)(C)C(C)(C)C)c1
Agent: [Pd]
Solvent: CCO
Product: CC(C)(C)[Si](C)(C)Oc1ccc([C@H]2CC[C@@H](N)CC2)c(O[Si](C)(C)C(C)(C)C)c1
Reaction time: 18 h

Procedure:
To a round bottom flask equipped with magnetic stirrer was added cis-N-benzyl-N-[4-(2,4-bis{[tert-butyl(dimethyl)silyl]oxy}phenyl)cyclohexyl]amine (700 mg) and ethanol (30 ml). To the stirred solution was added palladium (10% w/w on activated carbon, 283 mg) as a slurry in ethanol (5 ml). The reaction vessel was evacuated then placed under hydrogen (10 cycles). The reaction mixture was stirred vigorously under an atmosphere of hydrogen for 18 hr then filtered through a celite plug, washing with methanol (100 ml). The solvent was removed in vacuo affording the title compound (561 mg, 97%) as a colourless oil. δH(CDCl3) 0.01 (6H, s), 0.04 (6H, s), 0.78 (9H, s), 0.83 (9H, s), 1.21-1.55 (10H, m), 2.64 (1H, m), 3.05 (1H, m), 6.11 (1H, d), 6.22 (1H, dd), 6.84 (1H, d).