Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [H-].[Na+].[Br:3][C:4]1[CH:5]=[C:6]([C:12]2[N:16]=[C:15]([C:17]([O:19][CH2:20][CH3:21])=[O:18])[O:14][N:13]=2)[CH:7]=[C:8]([Br:11])[C:9]=1[OH:10].[CH3:22][O:23][C:24]1[CH:31]=[CH:30][C:27]([CH2:28]Cl)=[CH:26][CH:25]=1.O>CN(C)C=O>[Br:3][C:4]1[CH:5]=[C:6]([C:12]2[N:16]=[C:15]([C:17]([O:19][CH2:20][CH3:21])=[O:18])[O:14][N:13]=2)[CH:7]=[C:8]([Br:11])[C:9]=1[O:10][CH2:28][C:27]1[CH:30]=[CH:31][C:24]([O:23][CH3:22])=[CH:25][CH:26]=1
Reactant: COc1ccc(CCl)cc1
Reactant: CCOC(=O)c1nc(-c2cc(Br)c(O)c(Br)c2)no1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: CCOC(=O)c1nc(-c2cc(Br)c(OCc3ccc(OC)cc3)c(Br)c2)no1
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 65.6 %

Procedure:
Sodium hydride (100 mg of a 60% suspension in oil, 2.5 mmol) was added to a stirred solution of ethyl 3-(3,5-dibromo-4-hydroxyphenyl)-1,2,4-oxadiazole-5-carboxylate (980 mg, 2.5 mmol) in dry dimethylformamide (5 mL) under nitrogen and the mixture was stirred at room temperature for 15 minutes. 4-Methoxybenzyl chloride (470 mg, 3.0 mmol) was added and the resulting solution was stirred at 50° C. for 20 h. The cooled mixture was treated with water (10 mL) to give a colourless solid that was filtered, washed with water and dried. Crystallization from di-isopropyl ether gave the title compound (840 mg, 65%) as a colourless powder. 1H NMR δ (ppm) (DMSO-d6): 1.41 (3 H, t), 3.52 (3 H, s), 4.49 (2 H, t), 5.06 (2 H, s), 7.01 (2 H, d), 7.53 (2H, d), 8.30 (2H, s).
Reaction SMILES: [Cl:1][C:2]1[N:7]=[C:6]([N:8]([CH3:28])[C:9]2[CH:27]=[CH:26][C:12]3[N:13]([CH3:25])[C:14]([NH:16][CH2:17][C:18]4[CH:23]=[CH:22][CH:21]=[C:20]([F:24])[CH:19]=4)=[N:15][C:11]=3[CH:10]=2)[CH:5]=[CH:4][N:3]=1.[NH2:29][C:30]1[CH:35]=[CH:34][C:33]([CH2:36][S:37]([NH2:40])(=[O:39])=[O:38])=[CH:32][CH:31]=1>>[ClH:1].[F:24][C:20]1[CH:19]=[C:18]([CH:23]=[CH:22][CH:21]=1)[CH2:17][NH:16][C:14]1[N:13]([CH3:25])[C:12]2[CH:26]=[CH:27][C:9]([N:8]([CH3:28])[C:6]3[CH:5]=[CH:4][N:3]=[C:2]([NH:29][C:30]4[CH:35]=[CH:34][C:33]([CH2:36][S:37]([NH2:40])(=[O:38])=[O:39])=[CH:32][CH:31]=4)[N:7]=3)=[CH:10][C:11]=2[N:15]=1
Reactant: CN(c1ccc2c(c1)nc(NCc1cccc(F)c1)n2C)c1ccnc(Cl)n1
Reactant: Nc1ccc(CS(N)(=O)=O)cc1
Product: CN(c1ccc2c(c1)nc(NCc1cccc(F)c1)n2C)c1ccnc(Nc2ccc(CS(N)(=O)=O)cc2)n1
Product: Cl

Procedure:
The title compound was prepared following the procedure of example one with N5-(2-chloro-pyrimidin-4-yl)-N2-(3-fluoro-benzyl)-1,N5-dimethyl-1H-benzoimidazole-2,5-diamine (99 mg, 0.25 mmol) and (4-amino-phenyl)-methanesulfonamide (46 mg, 0.25 mmol) as a white solid (111 mg, 76%). 1H NMR (300 MHz, dG-DMSO+NaHCO3) δ 10.03 (br s, 2H), 9.37 (br s, 1H), 7.87 (d, J=6.6 Hz, 1H), 7.54-7.64 (m, 2H), 7.32-7.44 (m, 3H), 7.19-7.24 (M, 3H), 7.08-7.14 (M, 1H), 6.81 (s, 2H), 5.82 (d, J=6.0 Hz, 1H), 4.76 (d, J=5.7 Hz, 2H), 4.18 (s, 2H), 3.72 (s, 3H), 3.47 (s, 3H). MS (ESI) m/z=547 [M+H].
Reaction SMILES: Br[CH2:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1/[C:9](=[CH:14]\[O:15][CH3:16])/[C:10]([O:12][CH3:13])=[O:11].[CH2:17]([O:20]/[N:21]=[C:22](/[C:24]1[CH:29]=[C:28]([CH3:30])[C:27]([OH:31])=[CH:26][C:25]=1[CH3:32])\[CH3:23])[CH2:18][CH3:19].C(=O)([O-])[O-].[Cs+].[Cs+]>C(#N)C>[CH3:30][C:28]1[CH:29]=[C:24](/[C:22](=[N:21]/[O:20][CH2:17][CH2:18][CH3:19])/[CH3:23])[C:25]([CH3:32])=[CH:26][C:27]=1[O:31][CH2:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1/[C:9](=[CH:14]\[O:15][CH3:16])/[C:10]([O:12][CH3:13])=[O:11]
Reactant: CO/C=C(/C(=O)OC)c1ccccc1CBr
Reactant: CCCO/N=C(\C)c1cc(C)c(O)cc1C
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CC#N
Product: CCCO/N=C(\C)c1cc(C)c(OCc2ccccc2/C(=C\OC)C(=O)OC)cc1C
Temperature: 25 °C
Reaction time: 3 h
Yield: 59.1 %

Procedure:
To a solution of (E)-methyl 2-(2-(bromomethyl)phenyl)-3-methoxyacrylate (1.0 g, 3.5 mmol) and (E)-1-(4-hydroxy-2,5-dimethylphenyl)ethanone propyloxime (0.6 g, 4.2 mmol) obtained in Step 5 in 20 mL of acetonitrile (CH3CN) was added cesium carbonate (1.7 g, 5.2 mmol), followed by stirring at room temperature for 3 hours. The reaction solvent was removed by concentration in a vacuum. The residue was stirred in water (20 mL) and the aqueous layer was extracted twice with 20 mL of dichloromethane. The organic layer was dried over anhydrous magnesium sulfate, filtered and concentrated in a vacuum to remove the solvent. The concentrate was purified through silica gel chromatography to afford (E)-methyl 2-(2-((2,5-dimethyl-4-((E)-1-(propoxyimino)ethyl)phenoxy)methyl)phenyl)-3-methoxyacrylate as a white oil (0.88 g, yield 71%).
Reaction SMILES: [NH:1]1[CH2:5][CH2:4][CH2:3][C@H:2]1[CH2:6][OH:7].[Cl:8][C:9]1[N:14]=[C:13]([C:15]2[N:20]=[CH:19][C:18]3[CH:21]=[N:22][N:23]([C:24]4[N:29]=[C:28]([N:30]5[CH2:35][CH2:34][N:33](C(OC(C)(C)C)=O)[CH2:32][CH2:31]5)[CH:27]=[CH:26][CH:25]=4)[C:17]=3[CH:16]=2)[CH:12]=[N:11][CH:10]=1.[F-].[Cs+].O>CS(C)=O>[ClH:8].[ClH:8].[N:30]1([C:28]2[N:29]=[C:24]([N:23]3[C:17]4[CH:16]=[C:15]([C:13]5[N:14]=[C:9]([N:1]6[CH2:5][CH2:4][CH2:3][C@H:2]6[CH2:6][OH:7])[CH:10]=[N:11][CH:12]=5)[N:20]=[CH:19][C:18]=4[CH:21]=[N:22]3)[CH:25]=[CH:26][CH:27]=2)[CH2:31][CH2:32][NH:33][CH2:34][CH2:35]1
Reactant: CC(C)(C)OC(=O)N1CCN(c2cccc(-n3ncc4cnc(-c5cncc(Cl)n5)cc43)n2)CC1
Reactant: OC[C@@H]1CCCN1
Agent: [Cs+]
Agent: [F-]
Solvent: O
Solvent: CS(C)=O
Product: Cl
Product: OC[C@@H]1CCCN1c1cncc(-c2cc3c(cn2)cnn3-c2cccc(N3CCNCC3)n2)n1
Temperature: 105 °C

Procedure:
A mixture of 3-5 eq. of (S)-pyrrolidin-2-ylmethanol, 1 eq. of tert-butyl 4-(6-(6-(6-chloropyrazin-2-yl)-1H-pyrazolo[4,3-c]pyridin-1-yl)pyridin-2-yl)piperazine-1-carboxylate, 6-10 eq of cesium fluoride in DMSO was heated at 105° C. for 12-24 hours. The mixture was mixed with water and extracted with ethyl acetate. The organic extracts were washed with water, brine, dried over sodium sulfate and concentrated in vacuum. The crude products were purified on a silica gel column eluting with gradient of ethyl acetate in heptane or DCM. The Boc group was deprotected with 4 M HCl in dioxane in methanol. The crude product was collected by filtration, dissolved in water and lyophilized to give 280. 1H NMR (400 MHz, DMSO-d6) δ 9.37 (s, 1H), 9.31-9.19 (m, 2H), 9.10 (s, 1H), 8.80 (s, 1H), 8.73 (s, 1H), 8.19 (s, 1H), 7.89 (t, J=8.1 Hz, 1H), 7.35 (d, J=7.8 Hz, 1H), 6.97 (d, J=8.5 Hz, 1H), 4.21 (d, J=6.0 Hz, 1H), 3.93 (t, J=5.3 Hz, 4H), 3.58 (m, 1H), 3.49 (m, 2H), 3.22 (d, J=5.4 Hz, 4H), 2.06 (m, 4H). MS (ESI) m/z: 458.3.
Reaction SMILES: Br[C:2]1[C:10]2[C:9]([NH2:11])=[N:8][CH:7]=[N:6][C:5]=2[N:4]([CH:12]2[CH2:15][N:14]([CH3:16])[CH2:13]2)[CH:3]=1.CC1(C)C(C)(C)OB([C:25]2[CH:26]=[C:27]3[C:31](=[CH:32][CH:33]=2)[N:30]([C:34](=[O:46])[CH2:35][C:36]2[CH:41]=[CH:40][CH:39]=[C:38]([C:42]([F:45])([F:44])[F:43])[CH:37]=2)[CH2:29][CH2:28]3)O1.O1CCOCC1.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>[CH3:16][N:14]1[CH2:15][CH:12]([N:4]2[C:5]3[N:6]=[CH:7][N:8]=[C:9]([NH2:11])[C:10]=3[C:2]([C:25]3[CH:26]=[C:27]4[C:31](=[CH:32][CH:33]=3)[N:30]([C:34](=[O:46])[CH2:35][C:36]3[CH:41]=[CH:40][CH:39]=[C:38]([C:42]([F:45])([F:43])[F:44])[CH:37]=3)[CH2:29][CH2:28]4)=[CH:3]2)[CH2:13]1
Reactant: CC1(C)OB(c2ccc3c(c2)CCN3C(=O)Cc2cccc(C(F)(F)F)c2)OC1(C)C
Reactant: CN1CC(n2cc(Br)c3c(N)ncnc32)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: O
Solvent: C1COCCO1
Product: CN1CC(n2cc(-c3ccc4c(c3)CCN4C(=O)Cc3cccc(C(F)(F)F)c3)c3c(N)ncnc32)C1
Temperature: 100 °C
Yield: 13.2 %

Procedure:
To 5-bromo-7-(1-methyl-3-azetidinyl)-7H-pyrrolo[2,3-d]pyrimidin-4-amine (64 mg, 0.227 mmol) and 5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1-{[3-(trifluoromethyl)phenyl]acetyl}-2,3-dihydro-1H-indole (137 mg, 0.318 mmol) were added 1,4-Dioxane (2 mL) and saturated NaHCO3 (1 mL) in a 5 ml sealable vessel. The mixture was then bubbled with N2 gas for 5 minutes and Pd(Ph3P)4 (26.2 mg, 0.023 mmol) was added and the vessel was capped. The reaction was then heated at 100° C. overnight. The reaction was then diluted with water (2 ml) then extracted with EtOAc (3×3 ml). The organics were then combined and washed with brine, dried over MgSO4, filtered and concentrated. The crude product was then dissolved in 3 mL of DMSO and purified by HPLC: (HPLC condition: Gilson using Trilution software with a Sunfire 5u C18(2) 100A. 50×30.00 mm 5 micron. 7.3-minute run (47 ml/min, 20% ACN/H2O, 0.1% TFA to 45% ACN/H2O, 0.1% TFA) with UV detection at 254 nm). Product fractions were combined and the volume was reduced to remove most of the MeCN. To the water left behind was added saturated NaHCO3 and then the mixture was extracted with EtOAc (3×15 mL). The organics were combined and washed with saturated NaCl solution, dried over MgSO4, filtered and concentrated. Then the product was transferred to a 40 mL vial with MeCN then water was added and the solution was freeze-dried to give 7-(1-methyl-3-azetidinyl)-5-(1-{[3-(trifluoromethyl)phenyl]acetyl}-2,3-dihydro-1H-indol-5-yl)-7H-pyrrolo[2,3-d]pyrimidin-4-amine (15 mg, 0.030 mmol, 13.06% yield) as a white solid. LC/MS (ES) m/z=507.5 [M+H]+. 1H NMR (400 MHz, DMSO-d6) δ 8.16 (s, 1H), 8.14 (d, J=8.08 Hz, 1H), 7.69 (s, 1H), 7.57-7.67 (m, 4H), 7.38 (s, 1H), 7.27 (d, J=8.08 Hz, 1H), 6.16 (br. s., 2H), 5.41 (quin, J=7.20 Hz, 1H), 4.28 (t, J=8.34 Hz, 2H), 4.06-4.13 (m, 2H), 4.04 (s, 2H), 3.90-3.99 (m, 2H), 3.24-3.29 (m, 2H), 2.65 (br. s., 3H).
Reaction SMILES: [F:1][C:2]1[CH:3]=[CH:4][C:5]([O:8][CH:9]([CH3:20])[C:10]([O:12][CH2:13][C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)=[O:11])=[N:6][CH:7]=1.CI.[CH3:23][Si](C)(C)[N-][Si](C)(C)C.[K+]>C1COCC1>[F:1][C:2]1[CH:3]=[CH:4][C:5]([O:8][C:9]([CH3:23])([CH3:20])[C:10]([O:12][CH2:13][C:14]2[CH:15]=[CH:16][CH:17]=[CH:18][CH:19]=2)=[O:11])=[N:6][CH:7]=1
Reactant: CC(Oc1ccc(F)cn1)C(=O)OCc1ccccc1
Reactant: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [K+]
Solvent: CI
Solvent: C1CCOC1
Product: CC(C)(Oc1ccc(F)cn1)C(=O)OCc1ccccc1
Temperature: 25 °C

Procedure:
To a solution of benzyl 2-(5-fluoro-2-pyridyloxy)propionate (2.9 g, 10 mmol) and methyl iodide (3.3 mL, 53 mmol) in 40 mL of anhydrous THF at −78° C. was added potassium hexamethyldisilazide (0.5 M in toluene, 32 mL, 16 mmol). The reaction was allowed to warm to room temperature over 3 h and was partitioned between saturated ammonium chloride (150 mL) and EtOAc (150 mL). The organic layer was separated and the aqueous layer extracted with EtOAc (2×50 mL). The combined organic extracts were dried over anhydrous sodium sulfate, filtered, and concentrated to dryness, and the residue was purified by flash column chromatography on silica gel eluted with 0 to 20% EtOAc in hexane to give the title compound. 1H NMR (500 MHz, CD3OD): δ 7.63 (d, 1H), 7.44 (ddd, 1H), 7.27 (m, 3H), 7.18 (m, 2H), 6.74 (dd, 1H), 5.09 (s, 2H) 1.64 (s, 6H). LC-MS: m/e 290 (M+H)+ (3.7 min).
Reaction SMILES: [N:1]1[CH:6]=[CH:5][C:4]([NH2:7])=[CH:3][N:2]=1.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.C(N(C(C)C)CC)(C)C.[Br:41][C:42]1[CH:43]=[CH:44][C:45]([O:51][CH2:52][C:53]2[CH:58]=[CH:57][C:56]([F:59])=[C:55]([F:60])[CH:54]=2)=[C:46]([CH:50]=1)[C:47](O)=[O:48]>CN(C)C=O.C(OCC)(=O)C>[Br:41][C:42]1[CH:43]=[CH:44][C:45]([O:51][CH2:52][C:53]2[CH:58]=[CH:57][C:56]([F:59])=[C:55]([F:60])[CH:54]=2)=[C:46]([CH:50]=1)[C:47]([NH:7][C:4]1[CH:5]=[CH:6][N:1]=[N:2][CH:3]=1)=[O:48]
Reactant: O=C(O)c1cc(Br)ccc1OCc1ccc(F)c(F)c1
Reactant: Nc1ccnnc1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: O=C(Nc1ccnnc1)c1cc(Br)ccc1OCc1ccc(F)c(F)c1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
4-Pyridazinamine (0.42 g, 4.37 mmol), HATU (2.22 g, 5.83 mmol) and diisopropylethylamine (1.53 ml, 8.74 mmol) were added to a solution of 5-bromo-2-{[(3,4-difluorophenyl)methyl]oxy}benzoic acid (may be prepared by Description 89; 1 g, 2.91 mmol) in N,N-dimethylformamide (25 ml). The mixture was stirred at room temperature for 2 hours. The mixture was diluted with ethyl acetate (200 ml), shaken and allowed to stand for 5 min. The precipitate was filtered, washed with water (25 ml) and ethyl acetate (50 ml), and dried under vacuum to yield the title compound as a white solid. No further purification was carried out. 900 mg.
Reaction SMILES: ClC1N=[C:4]([NH:11][C:12]2[CH:13]=[C:14]3[C:18](=[CH:19][CH:20]=2)[NH:17][N:16]=[CH:15]3)[C:5]2[S:10][CH:9]=[CH:8][C:6]=2N=1.C([O-])([O-])=O.[Na+].[Na+].[N:27]1[CH:32]=[CH:31][CH:30]=[CH:29][C:28]=1[NH:33][CH2:34][C:35]1[CH:40]=[CH:39][C:38](B(O)O)=[CH:37][CH:36]=1.[CH2:44](O)[CH2:45][CH2:46]C.C1(C)C=CC=CC=1>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>[NH:17]1[C:18]2[C:14](=[CH:13][C:12]([NH:11][C:4]3[C:5]4[S:10][CH:9]=[CH:8][C:6]=4[CH:46]=[C:45]([C:38]4[CH:39]=[CH:40][C:35]([CH2:34][NH:33][C:28]5[CH:29]=[CH:30][CH:31]=[CH:32][N:27]=5)=[CH:36][CH:37]=4)[CH:44]=3)=[CH:20][CH:19]=2)[CH:15]=[N:16]1
Reactant: Clc1nc(Nc2ccc3[nH]ncc3c2)c2sccc2n1
Reactant: OB(O)c1ccc(CNc2ccccn2)cc1
Reactant: CCCCO
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: Cc1ccccc1
Product: c1ccc(NCc2ccc(-c3cc(Nc4ccc5[nH]ncc5c4)c4sccc4c3)cc2)nc1

Procedure:
To a mixture of N-(2-chlorothieno[3,2-d]pyrimidin-4-yl)-N-(1H-indazol-5-yl)amine (50 mg, 0.16 mmol), Na2CO3(aq) (2 M, 1.0 mL) in butanol/toluene (1:1, 4 mL) a stream of argon was bubbled through for 15 min. To the mixture was added 4-[(2-pyridinylamino)methyl]phenylboronic acid (0.15 g, 0.66 mmol) and tetrakis(triphenylphosphine)palladium(0) (0.06 g, 0.08 mmol) in a single portion. The resulting reaction mixture was heated to reflux for 24 h. On cooling, the solution was concentrated, taken up in EtOAc and washed with water. The organic layers were dried over anhyd sodium sulfate and concentrated in vacuo. The crude product was purified by silica gel column chromatography (gradient from 20% to 80% EtOAc/hexane) to give the product (25 mg). HPLC/MS: (M+H)+ 450.1 m/z. Retention time (LC-MS)=min. 1H NMR (CD3OD): 8.31 (2H, d); 8.11 (1H, s); 8.05 (1H, s); 7.96(1H, d); 7.91 (1H, d); 7.71(1H, d); 7.58 (1H, d); 7.47(4H, m); 6.61(2H, m); 4.55 (2H, s).
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:10]=[C:11]([CH:13]=[CH:14][CH:15]=1)[NH2:12])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[N:16]([O-])=O.[Na+].[Sn](Cl)[Cl:21].[OH-].[Na+]>O.Cl>[ClH:21].[CH2:1]([O:8][C:9]1[CH:10]=[C:11]([NH:12][NH2:16])[CH:13]=[CH:14][CH:15]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: Cl[Sn]Cl
Reactant: Nc1cccc(OCc2ccccc2)c1
Reactant: O=N[O-]
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: NNc1cccc(OCc2ccccc2)c1
Reaction time: 1 h
Yield: 83 %

Procedure:
3-(benzyloxy)aniline (5 g, 25.09 mmol) was added dropwise to 6M HCl (100 mL) at 4° C. A solution of sodium nitrite (3.46 g, 50.19 mmol) in water (50 mL) was added dropwise over 10 minutes and the reaction was stirred for 1 hour. A solution of tin (II) chloride (17.53 g, 77.7 mmol) in 6M HCl (150 mL) was added dropwise over 20 minutes, maintaining the internal temperature below 7° C. The suspension was stirred for 2 hours before neutralising then basifying the reaction to pH>12 using sodium hydroxide. The aqueous layer was extracted with diethyl ether (3×150 mL), the combined organic layers were dried over sodium sulfate and concentrated in vacuo. The yellow oil was dissolved in HCl in methanol and concentrated in vacuo. The resulting solid was triturated with diethylether, filtered and dried in vacuo to afford the title compound as purple solid (5.22 g, 83%).
Reaction SMILES: Br[C:2]1[CH:11]=[C:10]2[C:5]([CH:6]=[CH:7][CH:8]=[N:9]2)=[C:4]([O:12][C@@H:13]([C@H:15]2[CH2:19][NH:18][C:17](=[O:20])[CH2:16]2)[CH3:14])[CH:3]=1.CNCCNC.[I-:27].[Na+]>O1CCOCC1.C(Cl)Cl.[Cu]I>[I:27][C:2]1[CH:11]=[C:10]2[C:5]([CH:6]=[CH:7][CH:8]=[N:9]2)=[C:4]([O:12][C@@H:13]([C@H:15]2[CH2:19][NH:18][C:17](=[O:20])[CH2:16]2)[CH3:14])[CH:3]=1
Reactant: [I-]
Reactant: C[C@@H](Oc1cc(Br)cc2ncccc12)[C@H]1CNC(=O)C1
Agent: [Cu]I
Agent: CNCCNC
Agent: [Na+]
Solvent: C1COCCO1
Solvent: ClCCl
Product: C[C@@H](Oc1cc(I)cc2ncccc12)[C@H]1CNC(=O)C1
Temperature: 110 °C
Yield: 26.3 %

Procedure:
50 mg of Example 27 and 9 mg of copper (I) iodide were suspended in 300 μL dioxane under argon. 9.6 μL N,N′dimethylethylendiamine and 45 mg of sodium iodide were added and the mixture heated to 110° C. over weekend. The mixture was diluted with DCM and extracted with aqueous ammonia and water, the organic phase was subsequently concentrated in vacuo and the residual purified with HPLC (XbridgeC18; MeOH/water, TFA) to yield 15 mg yellow solid as Example 37.
Reaction SMILES: [CH:1]1([C:4](OC)=O)C[CH2:2]1.[Br:8][C:9]1[CH:16]=[CH:15][CH:14]=[CH:13][C:10]=1[CH:11]=O.[NH2:17][C:18]1[CH:22]=[CH:21][NH:20][N:19]=1>>[Br:8][C:9]1[CH:16]=[CH:15][CH:14]=[CH:13][C:10]=1[CH:11]1[C:22]([C:18]#[N:17])=[C:21]([CH:4]2[CH2:1][CH2:2]2)[NH:17][C:18]2=[N:19][NH:20][CH:21]=[C:22]12
Reactant: COC(=O)C1CC1
Reactant: Nc1cc[nH]n1
Reactant: O=Cc1ccccc1Br
Product: N#CC1=C(C2CC2)Nc2n[nH]cc2C1c1ccccc1Br

Procedure:
The title compound was prepared from methyl cyclopropanecarboxylate, 2-bromobenzaldehyde and 3-aminopyrazole in the same manner as in Example 94.
Reaction SMILES: Br[CH2:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1/[CH:9]=[CH:10]/[C:11]([O:13][CH2:14][CH3:15])=[O:12].[Cl:16][C:17]1[CH:18]=[C:19](B(O)O)[CH:20]=[CH:21][C:22]=1[Cl:23]>>[Cl:16][C:17]1[CH:18]=[C:19]([CH:20]=[CH:21][C:22]=1[Cl:23])[CH2:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1/[CH:9]=[CH:10]/[C:11]([O:13][CH2:14][CH3:15])=[O:12]
Reactant: OB(O)c1ccc(Cl)c(Cl)c1
Reactant: CCOC(=O)/C=C/c1ccccc1CBr
Product: CCOC(=O)/C=C/c1ccccc1Cc1ccc(Cl)c(Cl)c1

Procedure:
The benzyl bromide (500 mg) of example 1, step 2 was treated with 3,4-dichlorobenzeneboronic acid according to the same procedure described in step 3 of example 1 to yield 410 mg of the title compound.
Reaction SMILES: [CH:1]1([C:4]2[N:8]([CH2:9][C:10]3[CH:15]=[CH:14][C:13]([C:16]4[C:17]([C:22]([O:24]C(C)(C)C)=[O:23])=[CH:18][CH:19]=[CH:20][CH:21]=4)=[CH:12][CH:11]=3)[C:7]3[CH:29]=[C:30]([C:34]4[N:35]=[CH:36][N:37]([CH2:39][CH2:40][O:41][CH3:42])[CH:38]=4)[CH:31]=[C:32]([CH3:33])[C:6]=3[N:5]=2)[CH2:3][CH2:2]1.FC(F)(F)C(O)=O>C(Cl)Cl>[CH:1]1([C:4]2[N:8]([CH2:9][C:10]3[CH:15]=[CH:14][C:13]([C:16]4[C:17]([C:22]([OH:24])=[O:23])=[CH:18][CH:19]=[CH:20][CH:21]=4)=[CH:12][CH:11]=3)[C:7]3[CH:29]=[C:30]([C:34]4[N:35]=[CH:36][N:37]([CH2:39][CH2:40][O:41][CH3:42])[CH:38]=4)[CH:31]=[C:32]([CH3:33])[C:6]=3[N:5]=2)[CH2:3][CH2:2]1
Reactant: COCCn1cnc(-c2cc(C)c3nc(C4CC4)n(Cc4ccc(-c5ccccc5C(=O)OC(C)(C)C)cc4)c3c2)c1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: COCCn1cnc(-c2cc(C)c3nc(C4CC4)n(Cc4ccc(-c5ccccc5C(=O)O)cc4)c3c2)c1

Procedure:
Prepared analogously to Example 88 from tert.butyl 4'-[(2-cyclopropyl-4-methyl-6-(1-(2-methoxyethyl)-imidazol-4-yl)-benzimidazol-1-yl)-methyl]-biphenyl-2-carboxylate and trifluoroacetic acid in methylene chloride.
Reaction SMILES: Cl.[NH2:2][C@@H:3]1[CH2:8][CH2:7][C@H:6]([NH:9][C:10]([C:12]2[C:16]3[N:17]=[CH:18][N:19]=[C:20]([C:21]4[CH:26]=[C:25]([F:27])[C:24]([O:28][CH3:29])=[CH:23][C:22]=4[O:30][CH2:31][CH:32]4[CH2:34][CH2:33]4)[C:15]=3[NH:14][C:13]=2[CH3:35])=[O:11])[CH2:5][CH2:4]1.Cl[C:37]([O:39][CH2:40][CH3:41])=[O:38]>>[CH:32]1([CH2:31][O:30][C:22]2[CH:23]=[C:24]([O:28][CH3:29])[C:25]([F:27])=[CH:26][C:21]=2[C:20]2[C:15]3[NH:14][C:13]([CH3:35])=[C:12]([C:10]([NH:9][C@@H:6]4[CH2:7][CH2:8][C@H:3]([NH:2][C:37](=[O:38])[O:39][CH2:40][CH3:41])[CH2:4][CH2:5]4)=[O:11])[C:16]=3[N:17]=[CH:18][N:19]=2)[CH2:34][CH2:33]1
Reactant: COc1cc(OCC2CC2)c(-c2ncnc3c(C(=O)N[C@H]4CC[C@@H](N)CC4)c(C)[nH]c23)cc1F
Reactant: CCOC(=O)Cl
Agent: Cl
Product: CCOC(=O)N[C@H]1CC[C@@H](NC(=O)c2c(C)[nH]c3c(-c4cc(F)c(OC)cc4OCC4CC4)ncnc23)CC1

Procedure:
Starting from N-(cis-4-aminocyclohexyl)-4-[2-(cyclopropylmethoxy)-5-fluoro-4-methoxyphenyl]-6-methyl-5H-pyrrolo[3,2-d]pyrimidine-7-carboxamide hydrochloride (example D.f46) and commercially available ethyl chloroformate the title compound is obtained as colorless solid.
Reaction SMILES: [C:1](O)(=O)C.C=O.O.[C:8]([BH3-])#[N:9].[Na+].C1COCC1.[NH2:17][C:18]([C:20]1[N:24]([C@@H:25]2[CH2:56][C@:29]34[C:33]5[C@H:42]([CH2:43][CH2:44][C@H:28]3[C@@:27]([CH3:57])([CH2:32][O:31][CH2:30]4)[C@H:26]2[O:58][CH2:59][C@@:60](N)([CH3:64])[CH:61]([CH3:63])[CH3:62])[C@:41]2([CH3:45])[C@:36]([CH3:55])([C@H:37]([C:52]([OH:54])=[O:53])[C@:38]([C@H:47]([CH3:51])[CH:48]([CH3:50])[CH3:49])([CH3:46])[CH2:39][CH2:40]2)[CH2:35][CH:34]=5)[N:23]=[CH:22][N:21]=1)=[O:19]>CO>[NH2:17][C:18]([C:20]1[N:24]([C@@H:25]2[CH2:56][C@:29]34[C:33]5[C@H:42]([CH2:43][CH2:44][C@H:28]3[C@@:27]([CH3:57])([CH2:32][O:31][CH2:30]4)[C@H:26]2[O:58][CH2:59][C@@:60]([N:9]([CH3:8])[CH3:1])([CH3:64])[CH:61]([CH3:63])[CH3:62])[C@:41]2([CH3:45])[C@:36]([CH3:55])([C@H:37]([C:52]([OH:54])=[O:53])[C@:38]([C@H:47]([CH3:51])[CH:48]([CH3:50])[CH3:49])([CH3:46])[CH2:39][CH2:40]2)[CH2:35][CH:34]=5)[N:23]=[CH:22][N:21]=1)=[O:19]
Reactant: CC(=O)O
Reactant: CC(C)[C@@H](C)[C@@]1(C)CC[C@]2(C)[C@H]3CC[C@@H]4[C@@]5(COC[C@@]4(C)[C@@H](OC[C@](C)(N)C(C)C)[C@H](n4ncnc4C(N)=O)C5)C3=CC[C@@]2(C)[C@@H]1C(=O)O
Reactant: [BH3-]C#N
Agent: C=O
Agent: [Na+]
Solvent: CO
Solvent: O
Solvent: C1CCOC1
Product: CC(C)[C@@H](C)[C@@]1(C)CC[C@]2(C)[C@H]3CC[C@@H]4[C@@]5(COC[C@@]4(C)[C@@H](OC[C@@](C)(C(C)C)N(C)C)[C@H](n4ncnc4C(N)=O)C5)C3=CC[C@@]2(C)[C@@H]1C(=O)O
Reaction time: 6 h

Procedure:
Acetic acid (2 μl, 0.035 mmol), formaldehyde 37% in water (5.4 μl, 0.073 mmol), and sodium cyanoborohydride 1.0 M in THF (67 μl, 0.067 mmol) were added to a stirred hazy solution of (1S,4aR,6aS,7R,8R,10aR,10bR,12aR,14R,15R)-14-[5-(aminocarbonyl)-1H-1,2,4-triazol-1-yl]-15-[[(2R)-2-amino-2,3-dimethylbutyl]oxy]-8-[(1R)-1,2-dimethylpropyl]-1,6,6a,7,8,9,10,10a,10b,11,12,12a-dodecahydro-1,6a,8,10a-tetramethyl-4H-1,4a-propano-2H-phenanthro[1,2-c]pyran-7-carboxylic acid (Example 41, 13.3 mg, 0.017 mmol) in methanol (0.33 ml). The reaction mixture was a hazy solution. After 6 hr, LCMS showed complete consumption of starting material. The reaction mixture was diluted with methanol, the solvent was evaporated under reduced pressure, and the resulting residue was placed under high vacuum. The residue was dissolved in methanol and purified using a single HPLC run on a 19×150 mm Sunfire Prep C18 OBD 10 μm column by eluting with acetonitrile/water+0.1% TFA. The total flow rate was 15 ml/min and the HPLC method employed a 12 minute 20%-100% acetonitrile/water gradient followed by a 7 minute acetonitrile flush. The product HPLC fractions were combined and the solvent was evaporated under reduced pressure to give the title compound as a colorless residue.
Reaction SMILES: [OH:1][CH:2](P(=O)(OC)OC)[C:3]1[CH:8]=[CH:7][C:6]([C:9]([CH3:12])([CH3:11])[CH3:10])=[CH:5][CH:4]=1.O>C1(C)C=CC=CC=1>[C:9]([C:6]1[CH:5]=[CH:4][C:3]([CH:2]=[O:1])=[CH:8][CH:7]=1)([CH3:12])([CH3:10])[CH3:11]
Reactant: COP(=O)(OC)C(O)c1ccc(C(C)(C)C)cc1
Solvent: Cc1ccccc1
Solvent: O
Product: CC(C)(C)c1ccc(C=O)cc1
Yield: 85.1 %

Procedure:
27.2 g (0.1 mol) of dimethyl α-hydroxy-4-tert.-butylbenzylphosphonate were dissolved in 25 ml of toluene and were added dropwise, from a dropping funnel, into a distillation apparatus which had been preheated to 180° C. and had a small Vigreux column to which a water pump vacuum was applied. The distillate was fractionally distilled in a high vacuum. 13.8 g (81.5% of theory) of 4-tert.-butylbenzaldehyde of boiling point 72° C./0.15 mbars were obtained.