Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][C@:2]([CH2:8][O:9][CH2:10][CH2:11][Si:12]([CH3:15])([CH3:14])[CH3:13])([CH:6]=[CH2:7])[C:3]([OH:5])=[O:4].Br[C:17]1[CH:26]=[C:25]2[C:20]([CH:21]=[CH:22][C:23]([C@H:27]([O:29][C:30](=[O:32])[CH3:31])[CH3:28])=[N:24]2)=[CH:19][CH:18]=1.C1(C)C=CC=CC=1P(C1C=CC=CC=1C)C1C=CC=CC=1C.C1(CNCC2CCCCC2)CCCCC1>O1CCOCC1.C([O-])(=O)C.[Pd+2].C([O-])(=O)C>[C:30]([O:29][C@@H:27]([C:23]1[CH:22]=[CH:21][C:20]2[C:25](=[CH:26][C:17](/[CH:7]=[CH:6]/[C@:2]([CH3:1])([CH2:8][O:9][CH2:10][CH2:11][Si:12]([CH3:15])([CH3:13])[CH3:14])[C:3]([OH:5])=[O:4])=[CH:18][CH:19]=2)[N:24]=1)[CH3:28])(=[O:32])[CH3:31]
Reactant: CC(=O)O[C@H](C)c1ccc2ccc(Br)cc2n1
Reactant: C=C[C@](C)(COCC[Si](C)(C)C)C(=O)O
Agent: [Pd+2]
Agent: C1CCC(CNCC2CCCCC2)CC1
Agent: CC(=O)[O-]
Solvent: C1COCCO1
Product: CC(=O)O[C@H](C)c1ccc2ccc(/C=C/[C@](C)(COCC[Si](C)(C)C)C(=O)O)cc2n1
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 85.3 %

Procedure:
A solution of (R)-2-methyl-2-(2-trimethylsilanyl-ethoxymethyl)-but-3-enoic acid (214.1 0.728 mmol), acetic acid (R)-1-(7-bromo-quinolin-2-yl)-ethyl ester (167.7 mg, 0.728 mmol), palladium(II)acetate (33.0 mg, 0.146 mmol), tri(o-tolyl)phosphine (44.4 mg, 0.146 mmol) and N,N-dicyclohexylmethylamine (390 μL, 1.820 mmol) in anhydrous 1,4-dioxane (10 mL) was heated at reflux for 3 h, after which palladium(II)acetate (33.0 mg, 0.146 mmol) and tri(o-tolyl)phosphine (44.4 mg, 0.146 mmol) were added. After 1.5 h, the heating was stopped and the reaction was allowed to stand at room temperature overnight. The mixture was then treated with palladium(II)acetate (33.0 mg, 0.146 mmol) and tri(o-tolyl)phosphine (44.4 mg, 0.146 mmol). After stirring at reflux for 3 h, the mixture was cooled to room temperature, quenched with hydrochloric acid (1 M, 10 mL). The aqueous layer was extracted with ethyl acetate (2×). The organics were combined, dried over anhydrous sodium sulfate, filtered and the volatiles were removed in vacuo. The residue was purified by silica gel chromatography using a 25 g Isolute cartridge eluted with a continuous gradient of iso-hexanes/ethyl acetate 1:0 to 1:1 to afford the title compound (275.5 mg, 85%) as a yellow oil. 1H NMR (300 MHz, CDCl3) δ 0.04 (s, 9H), 1.02 (dd, J=9.1, 7.3 Hz, 2H), 1.50 (s, 3H), 1.69 (d, J=6.7 Hz, 3H), 2.18 (s, 3H), 3.59-3.76 (m, 4H), 6.07 (q, J=6.7 Hz, 1H), 6.67 (ABq, ΔδAB=0.15, JAB=16.3 Hz, 2H), 7.44 (d, J=8.2 1H), 7.62 (dd, J=8.5, 1.3 Hz, 1H), 7.75 (d, J=8.5 Hz, 1H), 8.05 (s, 1H), 8.12 (d, J=8.5 Hz, 1H). LCMS (m/z) 444.1 [M+H], Tr=3.29 min.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)=[O:9])=[CH:4][C:3]=1[NH2:16].[CH3:17][O:18][C:19]([N:21]=[C:22]=[S:23])=[O:20]>CC(C)=O>[CH3:17][O:18][C:19]([NH:21][C:22](=[S:23])[NH:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)=[O:9])=[CH:4][C:3]=1[NH:16][C:22]([NH:21][C:19]([O:18][CH3:17])=[O:20])=[S:23])=[O:20]
Reactant: COC(=O)N=C=S
Reactant: Nc1ccc(S(=O)c2ccccc2)cc1N
Solvent: CC(C)=O
Product: COC(=O)NC(=S)Nc1ccc(S(=O)c2ccccc2)cc1NC(=S)NC(=O)OC

Procedure:
2.1 G. 1,2-diamino-4-phenylsulfinylbenzene in 150 ml. acetone is treated with 6 g. methoxy carbonyl isothiocyanate overnight at 20°-25° C. The reaction mixture is stripped and the residue triturated with ether. Recrystallization from methanol yields pure 1,2-bis-(3-methoxycarbonyl-2-thioureido)- 4-phenylsulfinylbenzene.
Reaction SMILES: [CH2:1]([C:5]1[CH:6]=[C:7]([OH:12])[C:8](=[CH:10][CH:11]=1)[OH:9])[CH2:2][CH2:3][CH3:4].[CH3:13][C:14]([CH3:16])=O.O.C1(C)C=CC(S(O)(=O)=O)=CC=1>C1C=CC=CC=1>[CH2:1]([C:5]1[CH:11]=[CH:10][C:8]2[O:9][C:14]([CH3:16])([CH3:13])[O:12][C:7]=2[CH:6]=1)[CH2:2][CH2:3][CH3:4]
Reactant: CC(C)=O
Reactant: CCCCc1ccc(O)c(O)c1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: O
Solvent: c1ccccc1
Product: CCCCc1ccc2c(c1)OC(C)(C)O2

Procedure:
The same procedures as described in Example were carried out by using 4.16 g (25 mM) of.4-n-butylcatechol, 15 ml of acetone, 30 mg of p-toluenesulfonic acid monohydrate and 7 ml of benzene. 5-n-Butyl-2,2-dimethyl 1,3 benzodioxol was obtained in the yield of 4.74 g (23 mM) as colorless transparent liquid having a boiling point of 74°-75° C./1 mmHg.
Reaction SMILES: Br[C:2]1[C:3]([C:23]2[CH:28]=[CH:27][C:26]([Cl:29])=[CH:25][CH:24]=2)=[CH:4][C:5]2[N:6]([C:8]([CH2:11][C:12]3[C:13]([CH3:22])=[N:14][C:15]([C:18]([F:21])([F:20])[F:19])=[CH:16][CH:17]=3)=[N:9][N:10]=2)[CH:7]=1.[F:30][C:31]1[CH:36]=[CH:35][CH:34]=[CH:33][C:32]=1B(O)O.C([O-])([O-])=O.[K+].[K+].ClC1C=CC(C2C(C3C=CC(Cl)=CC=3Cl)=CN3C(CC4C=NC(C(F)(F)F)=CC=4)=NN=C3C=2)=CC=1>O1CCOCC1.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:29][C:26]1[CH:27]=[CH:28][C:23]([C:3]2[C:2]([C:32]3[CH:33]=[CH:34][CH:35]=[CH:36][C:31]=3[F:30])=[CH:7][N:6]3[C:8]([CH2:11][C:12]4[C:13]([CH3:22])=[N:14][C:15]([C:18]([F:20])([F:21])[F:19])=[CH:16][CH:17]=4)=[N:9][N:10]=[C:5]3[CH:4]=2)=[CH:24][CH:25]=1
Reactant: Cc1nc(C(F)(F)F)ccc1Cc1nnc2cc(-c3ccc(Cl)cc3)c(Br)cn12
Reactant: OB(O)c1ccccc1F
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: FC(F)(F)c1ccc(Cc2nnc3cc(-c4ccc(Cl)cc4)c(-c4ccc(Cl)cc4Cl)cn23)cn1
Agent: O=C([O-])[O-]
Solvent: C1COCCO1
Solvent: O
Product: Cc1nc(C(F)(F)F)ccc1Cc1nnc2cc(-c3ccc(Cl)cc3)c(-c3ccccc3F)cn12
Yield: 55.3 %

Procedure:
The title compound (5.5 mg, 55%) as a white powder was prepared from 6-bromo-7-(4-chlorophenyl)-3-((2-methyl-6-(trifluoromethyl)pyridin-3-yl)methyl)-[1,2,4]triazolo[4,3-a]pyridine (9.5 mg, 0.020 mmol), 2-fluorophenylboronic acid (5.5 mg, 0.039 mmol), K2CO3 (8.2 mg, 0.059 mmol) and Pd(PPh3)4 (2.8 mg, 0.002 mmol) in 1,4-dioxane (0.28 mL) and H2O (0.09 mL) by the procedures analogous to those described for 7-(4-chlorophenyl)-6-(2,4-dichlorophenyl)-3-((6-(trifluoromethyl)pyridin-3-yl)methyl)-[1,2,4]triazolo[4,3-a]pyridine (Example 56E). LC/MS (method B): retention time=Time: 1.86, [M+H]+=497.3.
Reaction SMILES: O[C:2]1[CH:17]=[C:16]([OH:18])[CH:15]=[CH:14][C:3]=1[C:4]([C:6]1[CH:11]=[CH:10][C:9]([OH:12])=[CH:8][C:7]=1[OH:13])=O.C([O-])(=O)C.[Na+].C(O)(=O)C(O)=O.[CH2:30]([NH:32][NH2:33])[CH3:31]>O>[CH2:30]([N:32]1[C:2]2[C:3](=[CH:14][CH:15]=[C:16]([OH:18])[CH:17]=2)[C:4]([C:6]2[CH:11]=[CH:10][C:9]([OH:12])=[CH:8][C:7]=2[OH:13])=[N:33]1)[CH3:31]
Reactant: O=C(c1ccc(O)cc1O)c1ccc(O)cc1O
Reactant: CCNN
Agent: CC(=O)[O-]
Agent: O=C(O)C(=O)O
Agent: [Na+]
Solvent: O
Product: CCn1nc(-c2ccc(O)cc2O)c2ccc(O)cc21
Temperature: 90 °C
Yield: 18.5 %

Procedure:
A mixture of 2,2′,4,4′-tetrahydroxybenzophenone (0.123 g, 0.5 mmol), sodium acetate (0.164 g, 2.0 mmol) and ethylhydrazine oxalate (0.30 g, 2.0 mmol) in 2 mL H2O was heated at 90° C. overnight. The cooled reaction mixture was partitioned with EtOAc and 1 N HCl. The organic layer was dried (Na2SO4) and concentrated in vacuo to give the crude product. The residue was purified by HPLC chromatography using a silica gel column 150×12 mm (Biotage) at 10 mL/min with methyl-t-butyl ether/hexane (1:3, v/v) to give 0.025 g of product as an off-white solid.
Reaction SMILES: COC1C=CC(C[N:8]2[C:12]3[N:13]=[C:14]([C:25]4[CH:30]=[CH:29][C:28]([O:31]C)=[CH:27][CH:26]=4)[C:15]4[CH2:16][NH:17][C:18]5[CH:24]=[CH:23][CH:22]=[CH:21][C:19]=5[C:20]=4[C:11]=3[C:10]([CH3:33])=[N:9]2)=CC=1>FC(F)(F)C(O)=O>[CH3:33][C:10]1[C:11]2[C:20]3[C:19]4[CH:21]=[CH:22][CH:23]=[CH:24][C:18]=4[N:17]=[CH:16][C:15]=3[C:14]([C:25]3[CH:30]=[CH:29][C:28]([OH:31])=[CH:27][CH:26]=3)=[N:13][C:12]=2[NH:8][N:9]=1
Reactant: COc1ccc(Cn2nc(C)c3c4c(c(-c5ccc(OC)cc5)nc32)CNc2ccccc2-4)cc1
Solvent: O=C(O)C(F)(F)F
Product: Cc1n[nH]c2nc(-c3ccc(O)cc3)c3cnc4ccccc4c3c12
Temperature: 25 °C
Reaction time: 4 h
Yield: 13.1 %

Procedure:
A solution of 350 mg (0.75 mmol) of 3-(4-methoxybenzyl)-5-(4-methoxyphenyl)-1-methyl-6,7-dihydro-3H-benzo[f]pyrazolo[3,4-c][2,7]naphthyridine dissolved in 15 ml of trifluoroacetic acid is carried at 70° C. for 4 hours and then cooled to room temperature. The solvents are evaporated and then water is added. The product is extracted with ethyl acetate; the organic phases are dried on magnesium sulfate and concentrated. The residue is triturated in acetonitrile. The solid is filtered and then dissolved in 20 ml of anhydrous dichloroethane. The reaction medium is cooled to 0° C. before the slow addition of 7 ml (7 mmol) of a 1 M solution of boron tribromide in dichloromethane. The reaction medium is carried at reflux for 7 hours and then cooled again to 0° C. Methanol is added until the reaction medium is completely homogenized. The solvents are evaporated and then the residue is purified several times by silica gel chromatography (eluent: 95:5 DCM/MeOH) to yield 32 mg (15%) of 4-(1-methyl-3H-benzo[f]pyrazolo[3,4-c][2,7]naphthyridin-5-yl)phenol in the form of a brown solid.
Reaction SMILES: [CH2:1]([N:3]1[CH:7]=[C:6](B2OC(C)(C)C(C)(C)O2)[CH:5]=[N:4]1)[CH3:2].[NH2:17][CH:18]1[CH2:24][CH2:23][CH2:22][CH2:21][N:20](C(OC(C)(C)C)=O)[CH2:19]1>>[CH2:1]([N:3]1[CH:7]=[C:6]([C:21]2[N:20]=[CH:19][C:6]3[CH:5]=[N:4][N:3]([C:1]4[N:17]=[C:18]([NH:17][CH:18]5[CH2:24][CH2:23][CH2:22][CH2:21][NH:20][CH2:19]5)[CH:24]=[CH:23][CH:2]=4)[C:7]=3[CH:22]=2)[CH:5]=[N:4]1)[CH3:2]
Reactant: CC(C)(C)OC(=O)N1CCCCC(N)C1
Reactant: CCn1cc(B2OC(C)(C)C(C)(C)O2)cn1
Product: CCn1cc(-c2cc3c(cn2)cnn3-c2cccc(NC3CCCCNC3)n2)cn1
Yield: 2.8 %

Procedure:
Following the procedures as described in EXAMPLE 8 and starting with 1-ethyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole and tert-butyl 3-aminoazepane-1-carboxylate, 143 was obtained as an off-white solid (3.6 mg, 2.8%) over 2 steps. MS (ESI) m/z: 403.2 [M+H]+
Reaction SMILES: C(N(CC)CC)C.Cl[C:9](Cl)([O:11]C(=O)OC(Cl)(Cl)Cl)Cl.[CH2:20]([C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][C:23]=1[O:28][C:29]1[N:34]=[CH:33][C:32]([NH:35][C:36](=[O:41])[C:37]([CH3:40])([CH3:39])[NH2:38])=[CH:31][CH:30]=1)[CH3:21]>ClCCl.CN(C)C1C=CN=CC=1>[CH2:20]([C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][C:23]=1[O:28][C:29]1[N:34]=[CH:33][C:32]([N:35]2[C:36](=[O:41])[C:37]([CH3:40])([CH3:39])[NH:38][C:9]2=[O:11])=[CH:31][CH:30]=1)[CH3:21]
Reactant: O=C(OC(Cl)(Cl)Cl)OC(Cl)(Cl)Cl
Reactant: CCc1ccccc1Oc1ccc(NC(=O)C(C)(C)N)cn1
Agent: CN(C)c1ccncc1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CCc1ccccc1Oc1ccc(N2C(=O)NC(C)(C)C2=O)cn1
Temperature: 0 °C
Reaction time: 0.33 h
Yield: 171.7 %

Procedure:
In a 50 mL round-bottomed flask N1-{6-[(2-ethylphenyl)oxy]-3-pyridinyl}-2-methylalaninamide (Intermediate 78, 67.1 mg) was dissolved in dichloromethane (5 mL) to give a pale yellow solution. The reaction mixture was cooled at 0° C. N,N-dimethyl-4-pyridinamine (13.28 mg, 0.109 mmol), triethylamine (0.076 mL, 0.544 mmol) and triphosgene (32.3 mg, 0.109 mmol) were added. The reaction mixture was stirred at 0° C. After 20 minutes, the reaction mixture was evaporated under vacuum to afford a yellow solid which was purified by silica gel chromatography (Biotage system, 10 g SNAP column) eluting with a gradient Cyclohexane/EtOAc from 2:1 to 1:3 in 20 CV; then 1:3 for 5 CV. The collected fractions afforded the title compound as a white solid (60.9 mg).
Reaction SMILES: [O:1]1[CH2:15][CH:2]1[CH2:3][O:4][C:5]1[CH:6]=[CH:7][CH:8]=[C:9]2[C:14]=1[S:13][CH2:12][CH2:11][CH2:10]2.[CH3:16][O:17][C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=1[N:24]1[CH2:29][CH2:28][NH:27][CH2:26][CH2:25]1>O1CCCC1>[CH3:16][O:17][C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=1[N:24]1[CH2:29][CH2:28][N:27]([CH2:15][CH:2]([OH:1])[CH2:3][O:4][C:5]2[CH:6]=[CH:7][CH:8]=[C:9]3[C:14]=2[S:13][CH2:12][CH2:11][CH2:10]3)[CH2:26][CH2:25]1
Reactant: c1cc2c(c(OCC3CO3)c1)SCCC2
Reactant: COc1ccccc1N1CCNCC1
Solvent: C1CCOC1
Product: COc1ccccc1N1CCN(CC(O)COc2cccc3c2SCCC3)CC1

Procedure:
140 mg (0.63 mmol) of the compound obtained in Step A are dissolved in 1.5 cm3 of anhydrous tetrahydrofuran. 600 mg (3.15 mmol) of 1-(2-methoxyphenyl)piperazine, diluted in 1.5 cm3 of anhydrous tetrahydrofuran, are added.
Reaction SMILES: [CH2:1]([NH2:5])[CH2:2][CH2:3][CH3:4].C([O:8][C:9]([C:11]1[N:12]=[C:13]2[CH:18]=[CH:17][C:16]([N:19]3[CH2:24][CH2:23][N:22]([C:25](=[O:36])[C:26]4[CH:31]=[CH:30][CH:29]=[CH:28][C:27]=4[C:32]([F:35])([F:34])[F:33])[CH2:21][CH2:20]3)=[N:15][N:14]2[CH:37]=1)=O)C>>[CH2:1]([NH:5][C:9]([C:11]1[N:12]=[C:13]2[CH:18]=[CH:17][C:16]([N:19]3[CH2:20][CH2:21][N:22]([C:25](=[O:36])[C:26]4[CH:31]=[CH:30][CH:29]=[CH:28][C:27]=4[C:32]([F:33])([F:35])[F:34])[CH2:23][CH2:24]3)=[N:15][N:14]2[CH:37]=1)=[O:8])[CH2:2][CH2:3][CH3:4]
Reactant: CCCCN
Reactant: CCOC(=O)c1cn2nc(N3CCN(C(=O)c4ccccc4C(F)(F)F)CC3)ccc2n1
Product: CCCCNC(=O)c1cn2nc(N3CCN(C(=O)c4ccccc4C(F)(F)F)CC3)ccc2n1
Yield: 72 %

Procedure:
Following the procedure as described in Example 1, making variations only as required to use n-butylamine in place of isoamylamine to react with 6-[4-(2-trifluoromethylbenzoyl)piperazin-1-yl]imidazo[1,2-b]pyridazine-2-carboxylic acid ethyl ester, the title compound was obtained as a white solid in 72% yield (0.077 g). m.p. 187-189° C. 1H NMR (300 MHz, CDCl3) δ 8.1 (s, 1H), 7.75-7.66 (m, 2H), 7.65-7.5 (m, 2H), 7.48-7.38 (m, 1H), 7.37-7.3 (m, 1H), 6.92 (d, J=9.6 Hz, 1H), 4.05-3.94 (m, 1H), 3.93-3.82 (m, 1H), 3.69-3.54 (m, 2H), 3.5-3.38 (m, 4H), 3.35-3.28 (m, 2H), 1.65-1.53 (m 2H), 1.47-1.33 (m, 2H), 0.92 (t, J=7.5 Hz, 3H). 13C NMR (75 MHz, CDCl3) δ 167.5, 161.9, 154.9, 137.7, 135.3, 134.2, 132.4, 129.5, 127.2, 126.8, 126.7, 126.2, 125.4, 121.8, 118.3, 112.3, 46.2, 46.1, 45.6, 41.1, 38.9, 31.7, 20.1, 13.8. MS (ES+) m/z 475.2 (M+1).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][C:11]=1[O:12][CH3:13])[O:8][C:7](=[O:14])[C:6]([C:15]1[CH:20]=[CH:19][C:18]([C:21]([F:24])([F:23])[F:22])=[CH:17][CH:16]=1)=[C:5]2[CH2:25][C:26]1[CH:31]=[CH:30][C:29]([OH:32])=[CH:28][CH:27]=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.O[CH2:53][CH2:54][N:55]1[CH2:59][CH2:58][CH2:57][CH2:56]1.N(C(OC(C)C)=O)=NC(OC(C)C)=O>C1COCC1.O>[Br:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][C:11]=1[O:12][CH3:13])[O:8][C:7](=[O:14])[C:6]([C:15]1[CH:16]=[CH:17][C:18]([C:21]([F:23])([F:22])[F:24])=[CH:19][CH:20]=1)=[C:5]2[CH2:25][C:26]1[CH:27]=[CH:28][C:29]([O:32][CH2:53][CH2:54][N:55]2[CH2:59][CH2:58][CH2:57][CH2:56]2)=[CH:30][CH:31]=1
Reactant: COc1cc2oc(=O)c(-c3ccc(C(F)(F)F)cc3)c(Cc3ccc(O)cc3)c2cc1Br
Reactant: OCCN1CCCC1
Agent: CC(C)OC(=O)N=NC(=O)OC(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: O
Solvent: C1CCOC1
Product: COc1cc2oc(=O)c(-c3ccc(C(F)(F)F)cc3)c(Cc3ccc(OCCN4CCCC4)cc3)c2cc1Br
Temperature: 25 °C
Reaction time: 8 h
Yield: 52.2 %

Procedure:
To a solution of 6-bromo-4-(4-hydroxy-benzyl)-7-methoxy-3-(4-trifluoromethyl-phenyl)-chromen-2-one (0.70 g, 1.4 mmol) and triphenylphosphine (0.73 g, 2.8 mmol) in THF (40 mL) were sequentially added 1-(2-hydroxylethyl)pyrrolidine (0.65 mL, 5.6 mmol) and diisoproyl azodicaroxylate (0.55 mL, 2.8 mmol). The reaction mixture was allowed to stir at room temperature overnight. The reaction mixture was poured into water and extracted with EtOAc. Organic extracts were combined and washed with water and saturated sodium chloride in succession, dried over magnesium sulfate, filtered and concentrated under reduced pressure. Purification using silica gel flash column chromatography (10% methanol in CH2Cl2) provided the title compound as a solid (0.44 g, 53%). MS (ESI) m/z 602.3 (M+1)+, 604.3 (M+1+2)+.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:14][CH2:13][C:12]2[C:15]([S:20][CH2:21][CH2:22][CH2:23][C:24]([O:26]C)=O)=[C:16]([Cl:19])[CH:17]=[CH:18][C:11]=2[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[OH-].[Li+].[Cl-].[NH4+].C(Cl)CCl.ON1C2C=CC=CC=2N=N1.[CH2:46]([N:48](CC)[CH2:49]C)C.CNC>O1CCOCC1.O.[Cl-].[Na+].O.O>[C:1]([O:5][C:6]([N:8]1[CH2:14][CH2:13][C:12]2[C:15]([S:20][CH2:21][CH2:22][CH2:23][C:24](=[O:26])[N:48]([CH3:49])[CH3:46])=[C:16]([Cl:19])[CH:17]=[CH:18][C:11]=2[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: CCN(CC)CC
Reactant: COC(=O)CCCSc1c(Cl)ccc2c1CCN(C(=O)OC(C)(C)C)CC2
Agent: CNC
Agent: On1nnc2ccccc21
Agent: [Cl-]
Solvent: ClCCCl
Solvent: O
Solvent: C1COCCO1
Product: CN(C)C(=O)CCCSc1c(Cl)ccc2c1CCN(C(=O)OC(C)(C)C)CC2
Temperature: 25 °C
Reaction time: 8 h

Procedure:
Treat a solution of 3-tert-butoxycarbonyl-7-chloro-6-(3-methoxycarbonyl-propylthio)-2,3,4,5-tetrahydro-1H-benzo[d]azepine (385 mg, 0.90 mmol) in dioxane/water (1:1, 3.5 mL) with lithium hydroxide (43.0 mg, 1.01 mmol) at 80° C. for 1.5 h. Cool to ambient temperature, add aqueous saturated ammonium chloride and brine, extract three times with ethyl ether, dry over anhydrous MgSO4, and concentrate in vacuo. Dissolve the residue in DCM (3.5 mL) and add EDC (162 mg, 0.84 mmol), 1-hydroxybenzotriazole (91.0 mg, 0.67 mmol), triethylamine (0.20 mL, 1.35 mmol), and dimethylamine (0.700 mL, 1.35 mmol). Stir overnight at ambient temperature. Dilute with water, extract with ethyl ether, dry over anhydrous MgSO4; and concentrate in vacuo. Purify by chromatography on silica gel eluting with hexane/EtOAc/methanol 60:40:1 to give 3-tert-butoxycarbonyl-7-chloro-6-(3-dimethylcarbamoyl-propylthio)-2,3,4,5-tetrahydro-1H-benzo[d]azepine.
Reaction SMILES: C(OCC(C)C[N:8]1[CH2:11][C@H:10]([NH:12][C:13]([O:15][CH2:16][C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)=[O:14])[C:9]1=[O:23])(=O)C.C(=O)([O-])[O-].[K+].[K+].[BH4-].[Na+].Cl>CO.O>[O:23]=[C:9]1[C@@H:10]([NH:12][C:13](=[O:14])[O:15][CH2:16][C:17]2[CH:18]=[CH:19][CH:20]=[CH:21][CH:22]=2)[CH2:11][NH:8]1
Reactant: CC(=O)OCC(C)CN1C[C@H](NC(=O)OCc2ccccc2)C1=O
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [BH4-]
Solvent: CO
Solvent: O
Product: O=C(N[C@H]1CNC1=O)OCc1ccccc1
Yield: 160.6 %

Procedure:
A solution of 3.12 g of 1-[(acetyloxy)-2-methyl(propyl)]-2-oxo-(3S)-[[(phenylmethoxy)-carbonyl]amino]azetidine in 70 ml of methanol and 7 ml of water was cooled to -15° C. and 1.33 g of potassium carbonate and 349 mg of sodium borohydride was added. The reaction mixture was stirred at -15° C. -0° C. After the reaction was complete (about 2 hours), the mixture was neutralized to pH 7 with 2N HCl and concentrated in vacuo. The concentrate was adjusted to pH 5.8, saturated with salt and extracted with ethyl acetate (3 times). The organic layer was dried and evaporated in vacuo. The residue was combined with material from a similar experiment and triturated with ether to give 3.30 g of the title compound.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[N:8]=[C:9]=[S:10].[CH:11]([NH:13][NH2:14])=[O:12]>O1CCCC1>[CH:11]([NH:13][NH:14][C:9]([NH:8][C:3]1[CH:4]=[CH:5][CH:6]=[CH:7][C:2]=1[F:1])=[S:10])=[O:12]
Reactant: Fc1ccccc1N=C=S
Reactant: NNC=O
Solvent: C1CCOC1
Product: O=CNNC(=S)Nc1ccccc1F

Procedure:
Fifty grams (0.33 mole) of 2-fluorophenylisothiocyanate and 20 g. (0.33 mole) of formylhydrazine were refluxed for 7 hours in 500 ml. of tetrahydrofuran (THF). The reaction mixture was allowed to cool and the insoluble product was collected by filtration. The crude product was washed with water, filtered and dried. The yield was 10 g. of 1-formyl-4-(2-fluorophenyl)-3-thiosemicarbazide, mp. about 148°-149° C.
Reaction SMILES: [CH2:1]([Sn](CCCC)(CCCC)C(C)=C)[CH2:2][CH2:3]C.Br[C:18]1[CH:25]=[C:22]([CH:23]=[O:24])[C:21]([O:26][CH3:27])=[CH:20][CH:19]=1.CCOCC.[F-].[K+]>C1(C)C=CC=CC=1>[C:2]([C:18]1[CH:25]=[C:22]([CH:23]=[O:24])[C:21]([O:26][CH3:27])=[CH:20][CH:19]=1)([CH3:3])=[CH2:1]
Reactant: COc1ccc(Br)cc1C=O
Reactant: C=C(C)[Sn](CCCC)(CCCC)CCCC
Agent: [F-]
Agent: [K+]
Solvent: Cc1ccccc1
Solvent: CCOCC
Product: C=C(C)c1ccc(OC)c(C=O)c1
Reaction time: 3 h

Procedure:
Tri-n-butyl-isopropenyltin (12.1 g, 36.6 mmol) dissolved in toluene (10 ml) was added to a mixture of 5-bromo-o-anisaldehyde (6.00 g, 27.9 mmol), tetrakis (triphenylphosphine)palladium (1.21 g, 1.05 mmol), and 2,6-t-butyl4-methylphenol (10 mg) in toluene (50 ml) under nitrogen at room temperature. This mixture was heated at reflux for 7 hr. Ether and aq. KF solution (80 ml) were added to the reaction mixture, and the resulting solution was stirred for 3 hr. Insoluble materials were removed by filtration through Celite. The filtrate was extracted with ether, and the organic phase was washed with 1N-NaHSO4 aq. NaHCO3 and brine. The extracts were dried over Na2SO4, and concentrated by evaporation. The residual oil was purified by chromatography (SiO2, 140 g, 5%-EtOAc/hexane) to afford 5-isopropenyl-o-anis-aldehyde, as a yellow oil (2.49 g, 51%).
Reaction SMILES: I[C:2]1[N:3]=[CH:4][N:5]([C:7]2[N:12]=[C:11]([C:13]([F:16])([F:15])[F:14])[CH:10]=[C:9]([C:17]3[CH:18]=[N:19][C:20]([C:23]([F:26])([F:25])[F:24])=[CH:21][CH:22]=3)[N:8]=2)[CH:6]=1.[NH2:27][C:28]1[CH:33]=[CH:32][C:31](B2OC(C)(C)C(C)(C)O2)=[CH:30][N:29]=1>>[F:14][C:13]([F:16])([F:15])[C:11]1[CH:10]=[C:9]([C:17]2[CH:18]=[N:19][C:20]([C:23]([F:26])([F:25])[F:24])=[CH:21][CH:22]=2)[N:8]=[C:7]([N:5]2[CH:6]=[C:2]([C:31]3[CH:32]=[CH:33][C:28]([NH2:27])=[N:29][CH:30]=3)[N:3]=[CH:4]2)[N:12]=1
Reactant: CC1(C)OB(c2ccc(N)nc2)OC1(C)C
Reactant: FC(F)(F)c1ccc(-c2cc(C(F)(F)F)nc(-n3cnc(I)c3)n2)cn1
Product: Nc1ccc(-c2cn(-c3nc(-c4ccc(C(F)(F)F)nc4)cc(C(F)(F)F)n3)cn2)cn1

Procedure:
The title compound was prepared from 2-(4-iodo-imidazol-1-yl)-4-trifluoromethyl-6-(6-trifluoromethyl-pyridin-3-yl)-pyrimidine (example B.5) (0.485 g, 1.0 mmol) and commercially available 2-amino-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridine (0.264 g, 1.2 mmol) according to the general procedure III. Obtained as a yellow solid (0.03 g, 7%). MS (ISP) 452.1 [(M+H)+]; mp 259° C.
Reaction SMILES: [CH:1]1([CH2:4][O:5][C:6]2[CH:11]=[C:10]([F:12])[C:9]([CH3:13])=[CH:8][C:7]=2[C:14]2[C:15]3[N:22]([CH2:23][O:24][CH2:25][CH2:26][Si:27]([CH3:30])([CH3:29])[CH3:28])[C:21]([CH3:31])=[C:20]([C:32]([OH:34])=O)[C:16]=3[N:17]=[CH:18][N:19]=2)[CH2:3][CH2:2]1.[NH2:35][C@@H:36]1[CH2:41][CH2:40][C@H:39]([NH:42][C:43](=[O:49])[O:44][C:45]([CH3:48])([CH3:47])[CH3:46])[CH2:38][CH2:37]1>>[CH:1]1([CH2:4][O:5][C:6]2[CH:11]=[C:10]([F:12])[C:9]([CH3:13])=[CH:8][C:7]=2[C:14]2[C:15]3[N:22]([CH2:23][O:24][CH2:25][CH2:26][Si:27]([CH3:28])([CH3:30])[CH3:29])[C:21]([CH3:31])=[C:20]([C:32]([NH:35][C@@H:36]4[CH2:41][CH2:40][C@H:39]([NH:42][C:43](=[O:49])[O:44][C:45]([CH3:47])([CH3:46])[CH3:48])[CH2:38][CH2:37]4)=[O:34])[C:16]=3[N:17]=[CH:18][N:19]=2)[CH2:3][CH2:2]1
Reactant: Cc1cc(-c2ncnc3c(C(=O)O)c(C)n(COCC[Si](C)(C)C)c23)c(OCC2CC2)cc1F
Reactant: CC(C)(C)OC(=O)N[C@H]1CC[C@@H](N)CC1
Product: Cc1cc(-c2ncnc3c(C(=O)N[C@H]4CC[C@@H](NC(=O)OC(C)(C)C)CC4)c(C)n(COCC[Si](C)(C)C)c23)c(OCC2CC2)cc1F

Procedure:
Starting from 4-[2-(cyclopropylmethoxy)-4-fluoro-5-methylphenyl]-6-methyl-5-{[2-(trimethylsilyl)ethoxy]methyl}-5H-pyrrolo[3,2-d]pyrimidine-7-carboxylic acid (example D.c11) and commercially available tert-butyl cis-(4-amino-cyclohexyl)-carbamate the title compound is obtained as pale yellow foam.
Reaction SMILES: Cl[C:2]1[CH:3]=[CH:4][C:5](=[O:9])[N:6]([CH3:8])[N:7]=1.[NH:10]1[CH2:15][CH2:14][CH:13]([OH:16])[CH2:12][CH2:11]1>CCN(C(C)C)C(C)C.O>[OH:16][CH:13]1[CH2:14][CH2:15][N:10]([C:2]2[CH:3]=[CH:4][C:5](=[O:9])[N:6]([CH3:8])[N:7]=2)[CH2:11][CH2:12]1
Reactant: Cn1nc(Cl)ccc1=O
Reactant: OC1CCNCC1
Solvent: CCN(C(C)C)C(C)C
Solvent: O
Product: Cn1nc(N2CCC(O)CC2)ccc1=O
Temperature: 120 °C
Reaction time: 8 h
Yield: 82.6 %

Procedure:
To a slurry of 6-chloro-2-methylpyridazin-3(2H)-one (1 g, 6.94 mmol) in DIPEA (20 mL) was added piperidin-4-ol (0.84 g, 8.33 mmol) and the reaction mixture was stirred at 120° C. overnight. The resulting mixture was diluted with water (30 mL) and extracted with DCM (3×30 mL) to remove impurities. The aqueous phase was concentrated to dryness to afford the title compound as a yellow solid (1.2 g, 83%). [LCMS: Rt=1.07 min, m/z 210.1 (M+H)+].