Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C:2]1[C:3]2[C:10]([C:11]3[CH:12]=[N:13][C:14]4[C:19]([CH:20]=3)=[CH:18][CH:17]=[CH:16][CH:15]=4)=[C:9](Br)[N:8]([CH2:22][C@@H:23]([NH:27][C:28](=[O:34])[O:29][C:30]([CH3:33])([CH3:32])[CH3:31])[CH2:24][CH:25]=[CH2:26])[C:4]=2[N:5]=[CH:6][N:7]=1.NC1C2C(C3C=NC4C(C=3)=CC=CC=4)=C3N(C=2N=CN=1)C[C@@H](NC(=O)OC(C)(C)C)CC3>>[NH2:1][C:2]1[C:3]2[C:10]([C:11]3[CH:12]=[N:13][C:14]4[C:19]([CH:20]=3)=[CH:18][CH:17]=[CH:16][CH:15]=4)=[C:9]3[CH2:26][CH2:25][CH2:24][C@H:23]([NH:27][C:28](=[O:34])[O:29][C:30]([CH3:33])([CH3:32])[CH3:31])[CH2:22][N:8]3[C:4]=2[N:5]=[CH:6][N:7]=1
Reactant: C=CC[C@@H](Cn1c(Br)c(-c2cnc3ccccc3c2)c2c(N)ncnc21)NC(=O)OC(C)(C)C
Agent: CC(C)(C)OC(=O)N[C@H]1CCc2c(-c3cnc4ccccc4c3)c3c(N)ncnc3n2C1
Product: CC(C)(C)OC(=O)N[C@H]1CCCc2c(-c3cnc4ccccc4c3)c3c(N)ncnc3n2C1
Yield: 91.8 %

Procedure:
In accordance with Example 10, except that the (S)-tert-butyl (1-(4-amino-6-bromo-5-(quinolin-3-yl)-7H-pyrrolo[2,3-d]pyrimidin-7-yl)penta-4-en-2-yl)carbamate (2.0 g) obtained in Reference Example 8 was used in place of the (S)-tert-butyl (1-(4-amino-6-bromo-5-(quinolin-3-yl)-7H-pyrrolo[2,3-d]pyrimidin-7-yl)but-3-en-2-yl)carbamate obtained in Example 10, the title compound (1.56 g) (yield: 92%) was obtained as a light-yellow solid.
Reaction SMILES: [F:1][C:2]1[C:7]([F:8])=[C:6]([NH:9][C:10]2[CH:15]=[CH:14][C:13]([I:16])=[CH:12][C:11]=2[F:17])[C:5]([NH2:18])=[CH:4][CH:3]=1.[CH2:19]([S:23](Cl)(=[O:25])=[O:24])[CH2:20][CH2:21][CH3:22]>>[F:8][C:7]1[C:6]([NH:9][C:10]2[CH:15]=[CH:14][C:13]([I:16])=[CH:12][C:11]=2[F:17])=[C:5]([NH:18][S:23]([CH2:19][CH2:20][CH2:21][CH3:22])(=[O:25])=[O:24])[CH:4]=[CH:3][C:2]=1[F:1]
Reactant: Nc1ccc(F)c(F)c1Nc1ccc(I)cc1F
Reactant: CCCCS(=O)(=O)Cl
Product: CCCCS(=O)(=O)Nc1ccc(F)c(F)c1Nc1ccc(I)cc1F
Yield: 55 %

Procedure:
According to the general procedure A, 5,6-difluoro-N1-(2-fluoro-4-iodophenyl)benzene-1,2-diamine was reacted with n-butylsulfonyl chloride to obtain the desired product. Yield: 55%. 1H-NMR (500 MHz, CDCl3): δ=7.50-7.43 (m, 1H), 7.35-7.34 (m, 1H), 7.27-7.26 (m, 1H), 7.15-7.09 (q, 1H, J=1.6 Hz), 6.62 (s, 1H, br), 6.22-6.18 (q, 1H, J=1.5 Hz)5 5.65 (s, 1H, br), 3.06-3.031 (t, 2H, J=1.4 Hz), 1.75-1.71 (m, 2H), 1.38-1.36 (m, 2H), 0.87-0.86 (t, 3H, J=1.3 Hz); m/z 483 [M−1]−.
Reaction SMILES: [N:1]([CH2:4][C@@H:5]1[CH2:9][C@@H:8]([OH:10])[CH2:7][N:6]1[C:11]([O:13][C:14]([CH3:17])([CH3:16])[CH3:15])=[O:12])=[N+:2]=[N-:3].CC(C)([O-])C.[K+].Br[C:25]1[CH:30]=[N:29][C:28]([CH:31]2[CH2:33][CH2:32]2)=[CH:27][N:26]=1>O1CCCC1.O>[N:1]([CH2:4][C@@H:5]1[CH2:9][C@@H:8]([O:10][C:25]2[CH:30]=[N:29][C:28]([CH:31]3[CH2:33][CH2:32]3)=[CH:27][N:26]=2)[CH2:7][N:6]1[C:11]([O:13][C:14]([CH3:17])([CH3:16])[CH3:15])=[O:12])=[N+:2]=[N-:3]
Reactant: CC(C)(C)OC(=O)N1C[C@H](O)C[C@H]1CN=[N+]=[N-]
Reactant: Brc1cnc(C2CC2)cn1
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: O
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)N1C[C@H](Oc2cnc(C3CC3)cn2)C[C@H]1CN=[N+]=[N-]
Temperature: 25 °C
Reaction time: 24 h
Yield: 59.8 %

Procedure:
To a solution of the product from Example 174B (98 mg, 0.404 mmol) in tetrahydrofuran (1 mL) was added potassium-t-butoxide (63.5 mg, 0.566 mmol) followed by addition of 2-bromo-5-cyclopropylpyrazine (Combi-Phos Inc; 89 mg, 0.445 mmol). After stirring at room temperature for 24 hours, the mixture was diluted with water and extracted with ethyl acetate (2×20 mL). The combined ethyl acetate extracts were dried over Na2SO4, filtered, and concentrated under a stream of nitrogen. The residue was purified by flash chromatography on a 12 g silica gel column, eluting with 5% ethyl acetate/hexanes for 3 minutes then a gradient to 100% ethyl acetate over 20 minutes to afford the title compound as a colorless oil (87 mg, 59.7%). 1H NMR (400 MHz, DMSO-d6) δ ppm 8.09 (d, J=1.3 Hz, 1H), 8.06 (d, J=1.3 Hz, 1H), 5.44-5.39 (m, 1H), 4.12-4.04 (m, 1H), 3.71 (dd, J=12.4, 5.3 Hz, 1H), 3.64 (d, J=12.3 Hz, 1H), 3.57 (dd, J=12.4, 4.6 Hz, 1H), 3.39 (dd, J=12.4, 3.2 Hz, 1H), 2.30-2.06 (m, 3H), 1.41 (s, 9H), 0.97-0.90 (m, 2H), 0.87-0.81 (m, 2H).
Reaction SMILES: Br[C:2]1[N:3]=[CH:4][C:5]([N:8]([CH3:31])[C@@H:9]2[CH2:13][CH2:12][N:11]([C:14]3[C:15]4[CH:22]=[CH:21][N:20]([CH2:23][O:24][CH2:25][CH2:26][Si:27]([CH3:30])([CH3:29])[CH3:28])[C:16]=4[N:17]=[CH:18][N:19]=3)[CH2:10]2)=[N:6][CH:7]=1.[NH:32]1[CH:36]=[C:35](B2OC(C)(C)C(C)(C)O2)[CH:34]=[N:33]1.C([O-])([O-])=O.[Cs+].[Cs+]>O1CCOCC1.CCOC(C)=O.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>[CH3:31][N:8]([C@@H:9]1[CH2:13][CH2:12][N:11]([C:14]2[C:15]3[CH:22]=[CH:21][N:20]([CH2:23][O:24][CH2:25][CH2:26][Si:27]([CH3:30])([CH3:29])[CH3:28])[C:16]=3[N:17]=[CH:18][N:19]=2)[CH2:10]1)[C:5]1[CH:4]=[N:3][C:2]([C:35]2[CH:36]=[N:32][NH:33][CH:34]=2)=[CH:7][N:6]=1
Reactant: CN(c1cnc(Br)cn1)[C@@H]1CCN(c2ncnc3c2ccn3COCC[Si](C)(C)C)C1
Reactant: CC1(C)OB(c2cn[nH]c2)OC1(C)C
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: [Cs+]
Solvent: C1COCCO1
Solvent: O
Solvent: CCOC(C)=O
Product: CN(c1cnc(-c2cn[nH]c2)cn1)[C@@H]1CCN(c2ncnc3c2ccn3COCC[Si](C)(C)C)C1
Temperature: 25 °C

Procedure:
Under N2, a mixture of (R)-5-bromo-N-methyl-N-(1-(7-((2-(trimethylsilyl)ethoxy)methyl)-7H-pyrrolo[2,3-d]pyrimidin-4-yl)pyrrolidin-3-yl)pyrazin-2-amine (64 mg, 0.127 mmol), 4-pyrazoleboronic acid pinacol ester (37 mg, 0.19 mmol), Pd(PPh3)4 (29 mg, 0.0254 mmol), Cs2CO3 (124 mg, 0.381 mmol) in 1,4-Dioxane (3 mL)/water (0.3 mL) was stirred at reflux for 14 h. It was then cooled to ambient temperature, diluted with EtOAc and H2O, and extracted with EtOAc. The combined extracts was washed with brine (50 mL), dried over Na2SO4, concentrated in vacuo, and purified by flash chromatography to give the title compound.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][N:5]=[C:4](Cl)[CH:3]=1.[C:9]1([C:15]2([NH2:19])[CH2:18][CH2:17][CH2:16]2)[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1.CN1C(=O)CCC1>O.C(OCC)(=O)C>[Br:1][C:2]1[CH:7]=[CH:6][N:5]=[C:4]([NH:19][C:15]2([C:9]3[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=3)[CH2:16][CH2:17][CH2:18]2)[CH:3]=1
Reactant: Clc1cc(Br)ccn1
Reactant: NC1(c2ccccc2)CCC1
Solvent: CCOC(C)=O
Solvent: O
Solvent: CN1CCCC1=O
Product: Brc1ccnc(NC2(c3ccccc3)CCC2)c1
Temperature: 120 °C
Reaction time: 72 h
Yield: 9.2 %

Procedure:
To a 20 dram vial was added 4-bromo-2-chloropyridine (250 mg, 5.0 mmol, 1.0 equiv), 1-phenylcyclobutanamine (1.0 g, 7 mmol, 1.4 equiv), and NMP (1 mL). The reaction was heated to 120° C., stirred for 72 h, and then diluted with water (20 mL) and ethyl acetate (50 mL). After transferring to a separatory funnel and shaking, the organic layer was separated from the aqueous layer. The organic layer was then dried over Na2SO4, filtered, and concentrated to give a crude solid that was purified by silica gel column chromatography, affording 139 mg (9%) of 4-bromo-N-(1-phenylcyclobutyl)pyridin-2-amine as an orange solid.
Reaction SMILES: [CH3:1][C:2]1[N:6]=[C:5]([C:7]2[CH:15]=[CH:14][C:10]([C:11]([OH:13])=O)=[CH:9][CH:8]=2)[O:4][N:3]=1.C(Cl)CCl.C1C=CC2N(O)N=NC=2C=1.C(N(CC)CC)C.[CH3:37][O:38][C:39]([C:41]1([C:47]2[CH:52]=[CH:51][CH:50]=[CH:49][CH:48]=2)[CH2:46][CH2:45][NH:44][CH2:43][CH2:42]1)=[O:40]>C(Cl)Cl.C(OCC)(=O)C.CCCCCCC>[CH3:37][O:38][C:39]([C:41]1([C:47]2[CH:52]=[CH:51][CH:50]=[CH:49][CH:48]=2)[CH2:42][CH2:43][N:44]([C:11](=[O:13])[C:10]2[CH:9]=[CH:8][C:7]([C:5]3[O:4][N:3]=[C:2]([CH3:1])[N:6]=3)=[CH:15][CH:14]=2)[CH2:45][CH2:46]1)=[O:40]
Reactant: Cc1noc(-c2ccc(C(=O)O)cc2)n1
Reactant: COC(=O)C1(c2ccccc2)CCNCC1
Agent: On1nnc2ccccc21
Solvent: ClCCCl
Solvent: CCOC(C)=O
Solvent: CCN(CC)CC
Product: COC(=O)C1(c2ccccc2)CCN(C(=O)c2ccc(-c3nc(C)no3)cc2)CC1
Temperature: 25 °C
Reaction time: 12 h
Yield: 85.1 %

Procedure:
To a mixture of 4-(3-methyl-1,2,4-oxadiazol-5-yl)benzoic acid (408 mg, 2.0 mmol) (commercially available), EDC (614 mg, 3.2 mmol), HOBT (490 mg, 3.2 mmol) and triethylamine (1031 μL, 7.4 mmol) in DCM (6 ml) at room temperature was added slowly a solution of 4-phenyl-piperidine-4-carboxylic acid methyl ester (439 mg, 2.0 mmol) in DCM (3 mL). The reaction mixture was stirred at room temperature for 12 h. The reaction mixture was subjected to flash chromatography with n-heptane and ethyl acetate over a 70 g silica gel column to give 690 mg 1-[4-(3-methyl-[1,2,4]oxadiazol-5-yl)-benzoyl]-4-phenyl-piperidine-4-carboxylic acid methyl ester. MS ISP (m/e): 406.3 [(M+H)+].
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[N+:8]([O-:10])=[O:9].[Cl:11][C:12]1[CH:17]=[CH:16][C:15](B(O)O)=[CH:14][CH:13]=1.P([O-])([O-])([O-])=O.[K+].[K+].[K+].CN(C)C=O>[Br-].C([N+](CCCC)(CCCC)CCCC)CCC.C([O-])(=O)C.[Pd+2].C([O-])(=O)C.O>[Cl:11][C:12]1[CH:17]=[CH:16][C:15]([C:2]2[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=2[N+:8]([O-:10])=[O:9])=[CH:14][CH:13]=1
Reactant: OB(O)c1ccc(Cl)cc1
Reactant: O=[N+]([O-])c1ccccc1Br
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Solvent: O
Solvent: CN(C)C=O
Product: O=[N+]([O-])c1ccccc1-c1ccc(Cl)cc1
Temperature: 130 °C
Reaction time: 3 h
Yield: 74.4 %

Procedure:
A mixed solution of 10 g of 2-bromonitrobenzene, 8.5 g of 4-chlorophenylboronic acid, 25.4 g of tripotassium phosphate, 3.9 g of tetrabutylammonium bromide, 270 mg of palladium acetate and 150 ml of dimethylformamide was heated and stirred under a nitrogen gas stream at 130° C. for 3 hours. The solution was cooled to room temperature and 100 ml of water was poured into the solution, followed by extraction with 150 ml of ethyl acetate. The organic layer was washed twice with 100 ml of water, dried over magnesium sulfate and then evaporated. The concentrate was purified by silica gel column chromatography and then vacuum-dried to obtain 8.6 g of 2-(4-chlorophenyl)nitrobenzene.
Reaction SMILES: [Cl:1]C1C=C(C=C(I)C=1)C(N)=N.FC1C=CC(I)=CC=1C(N)=N.IC1C=C(C=CC=1)C(N)=N.Cl[C:34]1[CH:35]=[C:36]([C:41]2[N:50]=[CH:49][C:48]3[CH2:47][CH2:46][C:45]4[N:51]=[C:52]([NH:54][C:55](=[O:57])[CH3:56])[S:53][C:44]=4[C:43]=3[N:42]=2)[CH:37]=[C:38]([I:40])[CH:39]=1.FC1C=CC(I)=CC=1C1N=CC2CCC3N=C(NC(=O)C)SC=3C=2N=1.IC1C=C(C2N=CC3CCC4N=C(NC(=O)C)SC=4C=3N=2)C=CC=1>>[Cl:1][C:35]1[CH:34]=[CH:39][C:38]([I:40])=[CH:37][C:36]=1[C:41]1[N:50]=[CH:49][C:48]2[CH2:47][CH2:46][C:45]3[N:51]=[C:52]([NH:54][C:55](=[O:57])[CH3:56])[S:53][C:44]=3[C:43]=2[N:42]=1
Reactant: CC(=O)Nc1nc2c(s1)-c1nc(-c3cc(Cl)cc(I)c3)ncc1CC2
Reactant: N=C(N)c1cc(Cl)cc(I)c1
Agent: CC(=O)Nc1nc2c(s1)-c1nc(-c3cc(I)ccc3F)ncc1CC2
Agent: CC(=O)Nc1nc2c(s1)-c1nc(-c3cccc(I)c3)ncc1CC2
Agent: N=C(N)c1cc(I)ccc1F
Product: CC(=O)Nc1nc2c(s1)-c1nc(-c3cc(I)ccc3Cl)ncc1CC2

Procedure:
The following intermediates may be prepared analogously starting from 3-chloro-5-iodo-benzamidine, 2-fluoro-5-iodo-benzamidine and 3-iodo-benzamidine: N-[8-(3-chloro-5-iodo-phenyl)-4,5-dihydro-thiazolo[4,5-h]quinazolin-2-yl]-acetamide; N-[8-(2-fluoro-5-iodo-phenyl)-4,5-dihydro-thiazolo[4,5-h]quinazolin-2-yl]-acetamide; N-[8-(3-iodo-phenyl)-4,5-dihydro-thiazolo[4,5-h]quinazolin-2-yl]-acetamide
Reaction SMILES: [CH3:1]/[CH:2]=[C:3](/[C:5]([O:7][C@@H:8]1[C@:16]23[C@H:20]([C@@:21]([C@:25]45[O:30][C@@:29]4([CH3:31])[C@@H:28]4[C@:32]6([OH:38])[C@H:36]([O:37][C@H:26]5[CH2:27]4)[O:35][CH:34]=[CH:33]6)([CH3:24])[C@H:22]([OH:23])[C@H:14]4[C@H:15]2[C@:11]([C:44]([O:46][CH3:47])=[O:45])([CH2:12][O:13]4)[C@H:10]([O:48]C(C)=O)[CH2:9]1)[C@@:19]([OH:43])([C:39]([O:41][CH3:42])=[O:40])[O:18][CH2:17]3)=[O:6])\[CH3:4].C[O-].[Na+]>>[CH3:1]/[CH:2]=[C:3](/[C:5]([O:7][C@@H:8]1[C@:16]23[C@H:20]([C@@:21]([C@:25]45[O:30][C@@:29]4([CH3:31])[C@@H:28]4[C@:32]6([OH:38])[C@H:36]([O:37][C@H:26]5[CH2:27]4)[O:35][CH:34]=[CH:33]6)([CH3:24])[C@H:22]([OH:23])[C@H:14]4[C@H:15]2[C@:11]([C:44]([O:46][CH3:47])=[O:45])([CH2:12][O:13]4)[C@H:10]([OH:48])[CH2:9]1)[C@@:19]([OH:43])([C:39]([O:41][CH3:42])=[O:40])[O:18][CH2:17]3)=[O:6])\[CH3:4]
Reactant: C/C=C(\C)C(=O)O[C@H]1C[C@@H](OC(C)=O)[C@@]2(C(=O)OC)CO[C@H]3[C@@H](O)[C@@](C)([C@]45O[C@@]4(C)[C@H]4C[C@@H]5O[C@@H]5OC=C[C@@]54O)[C@H]4[C@]1(CO[C@]4(O)C(=O)OC)[C@@H]32
Agent: C[O-]
Agent: [Na+]
Product: C/C=C(\C)C(=O)O[C@H]1C[C@@H](O)[C@@]2(C(=O)OC)CO[C@H]3[C@@H](O)[C@@](C)([C@]45O[C@@]4(C)[C@H]4C[C@@H]5O[C@@H]5OC=C[C@@]54O)[C@H]4[C@]1(CO[C@]4(O)C(=O)OC)[C@@H]32

Procedure:
Referring to the numbered compounds of Table 1, transesterification of azadirachtin (1) with sodium methoxide gave 3-deacetylazadirachtin (2). Heating a solution of azadirachtin (1) and acetic anhydride at reflux gave a monoacetylated product, 13O-acetylazadirachtin (4).
Reaction SMILES: FC(F)(F)S(O[C:7]1[CH2:8][CH2:9][CH2:10][N:11]([C:13]([O:15][C:16]([CH3:19])([CH3:18])[CH3:17])=[O:14])[CH:12]=1)(=O)=O.[CH3:22][N:23]1[C:27](B(O)O)=[CH:26][CH:25]=[N:24]1.C([O-])([O-])=O.[Na+].[Na+]>O1CCOCC1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.Cl[Pd]Cl.[Fe+2]>[CH3:22][N:23]1[C:27]([C:7]2[CH2:8][CH2:9][CH2:10][N:11]([C:13]([O:15][C:16]([CH3:19])([CH3:18])[CH3:17])=[O:14])[CH:12]=2)=[CH:26][CH:25]=[N:24]1
Reactant: Cn1nccc1B(O)O
Reactant: CC(C)(C)OC(=O)N1C=C(OS(=O)(=O)C(F)(F)F)CCC1
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: O=C([O-])[O-]
Solvent: C1COCCO1
Product: Cn1nccc1C1=CN(C(=O)OC(C)(C)C)CCC1
Temperature: 80 °C
Reaction time: 18 h
Yield: 50.6 %

Procedure:
To a solution of tert-butyl 5-(trifluoromethylsulfonyloxy)-3,4-dihydropyridine-1(2H)-carboxylate (2.0 g, 6.0 mmol) in dioxane (40 mL) was added 1-methyl-1H-pyrazol-5-ylboronic acid (0.83 g, 6.60 mmol), Na2CO3 (1.90 g, 18.1 mmol), and Pd(dppf)Cl2 (370 mg, 0.600 mmol). The resulting mixture was stirred at 80° C. for 18 h. After concentration, the residue was purified by silica gel chromatography eluting with a 0-25% gradient of EtOAc in petroleum ether to give tert-butyl 5-(1-methyl-1H-pyrazol-5-yl)-3,4-dihydropyridine-1(2H)-carboxylate (0.80 g, 58% yield) as pale yellow oil. LCMS (ESI) m/z: 263.2 [M+H+].
Reaction SMILES: NC1C(C2C=CC(Cl)=C(Cl)C=2)CN(C(C2CCN(C(C3(C)CC3)=O)CC2)=O)C1.[F:29][C:30]1[CH:35]=[CH:34][C:33]([O:36][C:37](=[O:68])[N:38]([C@H:41]2[C@H:45]([C:46]3[CH:51]=[CH:50][C:49]([Cl:52])=[C:48](Cl)[CH:47]=3)[CH2:44][N:43](C(C3CCN(C(C4(C)CC4)=O)CC3)=O)[CH2:42]2)[CH2:39][CH3:40])=[CH:32][CH:31]=1>>[F:29][C:30]1[CH:35]=[CH:34][C:33]([O:36][C:37](=[O:68])[N:38]([C@H:41]2[C@H:45]([C:46]3[CH:47]=[CH:48][C:49]([Cl:52])=[CH:50][CH:51]=3)[CH2:44][NH:43][CH2:42]2)[CH2:39][CH3:40])=[CH:32][CH:31]=1
Reactant: CCN(C(=O)Oc1ccc(F)cc1)[C@@H]1CN(C(=O)C2CCN(C(=O)C3(C)CC3)CC2)C[C@H]1c1ccc(Cl)c(Cl)c1
Agent: CC1(C(=O)N2CCC(C(=O)N3CC(N)C(c4ccc(Cl)c(Cl)c4)C3)CC2)CC1
Product: CCN(C(=O)Oc1ccc(F)cc1)[C@@H]1CNC[C@H]1c1ccc(Cl)cc1

Procedure:
In analogy to the procedure described for rac-(3S,4R)-[3-Amino-4-(3,4-dichloro-phenyl)-pyrrolidin-1-yl]-[1-(1-methyl-cyclopropanecarbonyl)-piperidin-4-yl]-methanone (example 1, f) the Boc protecting group was removed. The liberated amine was reacted to the respective carbamate in analogy to the procedure described for the synthesis of rac-{(3S,4R)-4-(3,4-Dichloro-phenyl)-1-[1-(1-methyl-cyclopropanecarbonyl)-piperidine-4-carbonyl]-pyrrolidin-3-yl}-ethyl-carbamic acid 4-fluoro-phenyl ester (example 1, h). The benzyl protecting group was removed in analogy to the procedure described for rac-(3S,4R)-[4-(3,4-Dichloro-phenyl)-pyrrolidin-3-yl]-carbamic acid tert-butyl ester (example 1, d) to yield the title compound as amorphous crude brown foam. MS m/e: 363.3 [M+H]+.
Reaction SMILES: [Si:1]([O:8][CH2:9][C:10]1[N:15]=[CH:14][C:13]2[N:16]([C:19]3[S:23][C:22]([C:24]([O:26][CH3:27])=[O:25])=[C:21]([OH:28])[CH:20]=3)[CH:17]=[N:18][C:12]=2[CH:11]=1)([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2].[F:29][C:30]([F:41])([F:40])[C:31]1[CH:36]=[CH:35][CH:34]=[CH:33][C:32]=1[CH:37](O)[CH3:38].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.N(C(OC(C)(C)C)=O)=NC(OC(C)(C)C)=O>ClCCl>[Si:1]([O:8][CH2:9][C:10]1[N:15]=[CH:14][C:13]2[N:16]([C:19]3[S:23][C:22]([C:24]([O:26][CH3:27])=[O:25])=[C:21]([O:28][CH:37]([C:32]4[CH:33]=[CH:34][CH:35]=[CH:36][C:31]=4[C:30]([F:29])([F:40])[F:41])[CH3:38])[CH:20]=3)[CH:17]=[N:18][C:12]=2[CH:11]=1)([C:4]([CH3:5])([CH3:6])[CH3:7])([CH3:2])[CH3:3]
Reactant: CC(O)c1ccccc1C(F)(F)F
Reactant: COC(=O)c1sc(-n2cnc3cc(CO[Si](C)(C)C(C)(C)C)ncc32)cc1O
Agent: CC(C)(C)OC(=O)N=NC(=O)OC(C)(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: ClCCl
Product: COC(=O)c1sc(-n2cnc3cc(CO[Si](C)(C)C(C)(C)C)ncc32)cc1OC(C)c1ccccc1C(F)(F)F

Procedure:
In a similar manner as described for example B31, 10.0 g of methyl 5-[6-({[tert-butyl(dimethyl)silyl]oxy}methyl)-3H-imidazo[4,5-c]pyridin-3-yl]-3-hydroxythiophene-2-carboxylate, 6.8 g of 1-[2-(trifluoromethyl)phenyl]ethanol, 12.5 g of triphenylphosphine (polymer bound, ˜3 mmol/g) and 11.0 g of di-tert-butyl azodicarboxylate in 300 ml anhydrous dichloromethane yield the title compound.
Reaction SMILES: [NH2:1][C:2]1[C:6]([C:7]#[N:8])=[CH:5][N:4]([C:9]2[CH:14]=[CH:13][CH:12]=[C:11]([N:15]3[N:24]=[CH:23][C:22]4[C:17](=[CH:18][CH:19]=[C:20]([C:25]([CH3:28])([CH3:27])[CH3:26])[CH:21]=4)[C:16]3=[O:29])[C:10]=2[CH2:30][OH:31])[N:3]=1.Br[C:33]1[CH:38]=[CH:37][C:36]([C:39](=[O:41])[CH3:40])=[CH:35][CH:34]=1.CC(C1C=C(C(C)C)C(C2C(P(C3CCCCC3)C3CCCCC3)=C(OC)C=CC=2OC)=C(C(C)C)C=1)C.C(=O)([O-])[O-].[Cs+].[Cs+]>C(O)(C)(C)C.CCOC(C)=O.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd]>[C:39]([C:36]1[CH:37]=[CH:38][C:33]([NH:1][C:2]2[C:6]([C:7]#[N:8])=[CH:5][N:4]([C:9]3[CH:14]=[CH:13][CH:12]=[C:11]([N:15]4[N:24]=[CH:23][C:22]5[C:17](=[CH:18][CH:19]=[C:20]([C:25]([CH3:26])([CH3:27])[CH3:28])[CH:21]=5)[C:16]4=[O:29])[C:10]=3[CH2:30][OH:31])[N:3]=2)=[CH:34][CH:35]=1)(=[O:41])[CH3:40]
Reactant: CC(C)(C)c1ccc2c(=O)n(-c3cccc(-n4cc(C#N)c(N)n4)c3CO)ncc2c1
Reactant: CC(=O)c1ccc(Br)cc1
Agent: [Pd]
Agent: COc1ccc(OC)c(P(C2CCCCC2)C2CCCCC2)c1-c1c(C(C)C)cc(C(C)C)cc1C(C)C
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Solvent: CC(C)(C)O
Solvent: CCOC(C)=O
Product: CC(=O)c1ccc(Nc2nn(-c3cccc(-n4ncc5cc(C(C)(C)C)ccc5c4=O)c3CO)cc2C#N)cc1
Temperature: 25 °C
Reaction time: 0.08 h
Yield: 62.1 %

Procedure:
To a 5 mL microwave reaction vial were introduced 3-amino-1-(3-(6-tert-butyl-1-oxophthalazin-2(1H)-yl)-2-(hydroxymethyl)phenyl)-1H-pyrazole-4-carbonitrile (50 mg, 0.121 mmol), 1-(4-bromophenyl)ethanone (29 mg, 0.145 mmol), Pd2(dba)3 (7.7 mg, 0.008 mmol), 2-(DICYCLOHEXYLPHOSPHINO)-3,6-DIMETHOXY-2′-4′-6′-TRI-I-PROPYL-1,1′-BIPHENYL (Brett-Phos) (9.1 mg, 0.017 mmol), cesium carbonate (59 mg, 0.181 mmol) and suspended in t-butanol (1.5 mL). The reaction vessel was inerted three times by alternating vacuum and an Ar purge, then stirred at room temperature for 5 minutes to give a heterogeneous mixture that turned color from purplish-red to reddish-orange. The reaction was heat to 100° C. (external), during which the color of the reaction mixture changed to orange after ˜2 minutes of heating. After 1.5 hr, the reaction was judged complete by TLC. The mixture was diluted with EtOAc, filtered through a pad of diatomaceous earth and bound to silica gel. The crude product was purified over silica gel using a 12 g silica gel cartridge eluting the column with a 30%-100% EtOAc/hexanes gradient to give 3-(4-Acetyl-phenylamino)-1-[3-(6-tert-butyl-1-oxo-1H-phthalazin-2-yl)-2-hydroxymethyl-phenyl]-1H-pyrazole-4-carbonitrile (40 mg, 62%) as a white powder.
Reaction SMILES: C(#N)C.[NH2:4][C:5]1[CH:10]=[CH:9][C:8]([CH3:11])=[CH:7][CH:6]=1.N1C=CC=CC=1.[C:18]1([S:24](Cl)(=[O:26])=[O:25])[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1>O>[C:18]1([S:24]([NH:4][C:5]2[CH:10]=[CH:9][C:8]([CH3:11])=[CH:7][CH:6]=2)(=[O:26])=[O:25])[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1
Reactant: O=S(=O)(Cl)c1ccccc1
Reactant: Cc1ccc(N)cc1
Solvent: CC#N
Solvent: O
Solvent: c1ccncc1
Product: Cc1ccc(NS(=O)(=O)c2ccccc2)cc1
Yield: 100 %

Procedure:
200 ml of an acetonitrile solution containing 32.1 g (0.3 mol) of p-toluidine and 26 ml (0.32 mol) of pyridine was stirred while maintaining it at a temperature of less than 25° C., and 54.7 g (0.31 mol) of benzenesulfonyl chloride was added dropwise thereto. After the addition was completed, the mixture was further stirred for 1 hour and then the reaction solution was added to 1 liter of water. The precipitate formed was extracted with ethyl acetate and then the extract was separated. The ethyl acetate phase was washed with a saline solution and dried over sodium sulfate. The ethyl acetate was distilled off under reduced pressure to yield 74.3 g (0.3 mol) of the desired compound. This compound was used in the subsequent step without purification.
Reaction SMILES: C(OC([N:11]1[CH2:18][C@@H:17]2[C@@:13]([NH:19][C:20]([O:22][C:23]([CH3:26])([CH3:25])[CH3:24])=[O:21])([CH:14]=[CH:15][CH2:16]2)[CH2:12]1)=O)C1C=CC=CC=1.[Na].N.[OH-].[Na+]>O1CCCC1.[Cl-].[NH4+]>[C:23]([O:22][C:20]([NH:19][C@@:13]12[CH:14]=[CH:15][CH2:16][C@@H:17]1[CH2:18][NH:11][CH2:12]2)=[O:21])([CH3:26])([CH3:24])[CH3:25]
Reactant: CC(C)(C)OC(=O)N[C@@]12C=CC[C@@H]1CN(C(=O)OCc1ccccc1)C2
Agent: N
Agent: [Cl-]
Agent: [NH4+]
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)N[C@@]12C=CC[C@@H]1CNC2
Reaction time: 1 h
Yield: 98.3 %

Procedure:
[(1S,5R)-1-tert-Butoxycarbonylamino-3-azabicyclo[3.3.0]oct-7-en-3-yl]carboxylic acid benzyl ester (85.0 mg, 0.24 mmol) was dissolved in tetrahydrofuran (20 mL). After bubbling with liquid ammonia (20 mL) at −78° C., sodium (17.1 mg, 0.71 mmol) was added, and the mixture was stirred for one hour. A saturated ammonium chloride solution (6 drops) were added, and then ammonia was vaporized in an ice water bath. A 1N sodium hydroxide solution was added, followed by extraction with chloroform twice. The organic layers were combined, dried over anhydrous sodium sulfate, and filtered. Then, the filtrate was concentrated under reduced pressure to give 52.9 mg of the title compound as a colorless solid.
Reaction SMILES: [CH3:1][C:2]1([CH3:17])[C@@H:4](/[CH:5]=[CH:6]\[C:7](=[O:13])[O:8][CH2:9][CH:10]([Cl:12])[Cl:11])[C@H:3]1[C:14]([OH:16])=[O:15].[C:18]([C@@H:20](O)[C:21]1[CH:26]=[CH:25][CH:24]=[C:23]([O:27][C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=2)[CH:22]=1)#[N:19]>>[CH3:1][C:2]1([CH3:17])[C@@H:4](/[CH:5]=[CH:6]\[C:7](=[O:13])[O:8][CH2:9][CH:10]([Cl:11])[Cl:12])[C@H:3]1[C:14]([O:16][C@H:20]([C:18]#[N:19])[C:21]1[CH:26]=[CH:25][CH:24]=[C:23]([O:27][C:28]2[CH:29]=[CH:30][CH:31]=[CH:32][CH:33]=2)[CH:22]=1)=[O:15]
Reactant: CC1(C)[C@H](C(=O)O)[C@@H]1/C=C\C(=O)OCC(Cl)Cl
Reactant: N#C[C@@H](O)c1cccc(Oc2ccccc2)c1
Product: CC1(C)[C@H](C(=O)O[C@H](C#N)c2cccc(Oc3ccccc3)c2)[C@@H]1/C=C\C(=O)OCC(Cl)Cl

Procedure:
Using the procedure of Step F of Example 9, 3 g of the product of Step B and 2.25 g of (S)α-cyano-3-phenoxy-benzyl alcohol were reacted to obtain after elution with 8-3 and 9-1 mixtures of cyclohexane-ethyl acetate 1.6 of (S)α-cyano-3-phenoxy-benzyl (1R,cis) 2,2-dimethyl-3-[(Z) 3-oxo-3-(2,2-dichloroethoxy(-1-propenyl]-cyclopropane-carboxylate with a specific rotation of [α]D20 =+54°±2° (c=1% in benzene).
Reaction SMILES: O1CCCCC1[N:7]1[C:15]2[C:10](=[CH:11][C:12]([C:16]3[N:20]=[CH:19][N:18](C(C4C=CC=CC=4)(C4C=CC=CC=4)C4C=CC=CC=4)[N:17]=3)=[CH:13][CH:14]=2)[C:9]([C:40]2[CH:41]=[C:42]([NH:46][C:47](=[O:56])[CH2:48][CH2:49]C3C=CC=CC=3)[CH:43]=[CH:44][CH:45]=2)=[N:8]1>Cl.O1CCOCC1>[NH:18]1[CH:19]=[N:20][C:16]([C:12]2[CH:11]=[C:10]3[C:15](=[CH:14][CH:13]=2)[NH:7][N:8]=[C:9]3[C:40]2[CH:41]=[C:42]([NH:46][C:47](=[O:56])[CH2:48][CH3:49])[CH:43]=[CH:44][CH:45]=2)=[N:17]1
Reactant: O=C(CCc1ccccc1)Nc1cccc(-c2nn(C3CCCCO3)c3ccc(-c4ncn(C(c5ccccc5)(c5ccccc5)c5ccccc5)n4)cc23)c1
Agent: Cl
Solvent: C1COCCO1
Product: CCC(=O)Nc1cccc(-c2n[nH]c3ccc(-c4nc[nH]n4)cc23)c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 48 %

Procedure:
N-(3-{1-Perhydro-2H-pyran-2-yl-5-[1-(triphenylmethyl)(1,2,4-triazol-3-yl)](1H-indazol-3-yl)}phenyl)-3-phenylpropanamide was dissolved in 4 mL of 4.0 N HCl in 1,4-dioxane and the reaction was stirred at room temperature overnight. After neutralization with aqueous NaHCO3, the crude product was extracted in ethyl acetate and purified by preparative HPLC (0.049 g, 48% yield over 2 steps): 1H NMR (CD3OD) δ 8.73 (s, 1H), 8.40 (br s, 2H), 8.16 (s, 1H), 8.10 (d, 1H), 7.77–7.67 (m, 3H), 7.50 (t, 1H), 7.28 (d, 4H), 7.18 (sextet, 1H); ES-MS (m/z) 409.