Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][CH2:2][C@@H:3]([OH:20])[CH2:4][N:5]1[CH2:10][CH2:9][CH:8]([O:11][C:12]2[CH:17]=[CH:16][C:15]([Cl:18])=[C:14]([Cl:19])[CH:13]=2)[CH2:7][CH2:6]1.[C:21]([C:23]1[CH:24]=[C:25]([CH:29]=[CH:30][CH:31]=1)[C:26](O)=[O:27])#[N:22]>>[C:21]([C:23]1[CH:24]=[C:25]([CH:29]=[CH:30][CH:31]=1)[C:26]([NH:1][CH2:2][C@@H:3]([OH:20])[CH2:4][N:5]1[CH2:10][CH2:9][CH:8]([O:11][C:12]2[CH:17]=[CH:16][C:15]([Cl:18])=[C:14]([Cl:19])[CH:13]=2)[CH2:7][CH2:6]1)=[O:27])#[N:22]
Reactant: N#Cc1cccc(C(=O)O)c1
Reactant: NC[C@@H](O)CN1CCC(Oc2ccc(Cl)c(Cl)c2)CC1
Product: N#Cc1cccc(C(=O)NC[C@@H](O)CN2CCC(Oc3ccc(Cl)c(Cl)c3)CC2)c1

Procedure:
Prepared as described in Example 1 from (2R)-1-amino-3-[4-(3,4-dichlorophenoxy)piperidin-1-yl]propan-2-ol (0.2 g) and 3-cyanobenzoic acid (0.092 g). Title compound obtained as white solid (0.050 g).
Reaction SMILES: [F:1][C:2]1[C:7]([F:8])=[CH:6][CH:5]=[CH:4][C:3]=1[C:9]1([OH:14])[CH2:13][CH2:12][NH:11][CH2:10]1.C(=O)([O-])[O-].[K+].[K+].[CH:21]1([CH2:24]Br)[CH2:23][CH2:22]1>C(#N)C>[CH:21]1([CH2:24][N:11]2[CH2:12][CH2:13][C:9]([C:3]3[CH:4]=[CH:5][CH:6]=[C:7]([F:8])[C:2]=3[F:1])([OH:14])[CH2:10]2)[CH2:23][CH2:22]1
Reactant: BrCC1CC1
Reactant: OC1(c2cccc(F)c2F)CCNC1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: OC1(c2cccc(F)c2F)CCN(CC2CC2)C1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
Preparation according to Example 43: Enantiomer E2 of 3-(2,3-difluorophenyl)-pyrrolidin-3-ol (0.58 g, 2.9 mmol), acetonitrile (20 mL), potassium carbonate (0.69 g, 5 mmol), cyclopropylmethyl bromide (0.308 mL, 3.18 mmol). Stirred 2 h at ambient temperature and 2×5 min at 40° C.; Purification by flash chromatography on silica gel (ethyl acetate/methanol, 4:1) Yield: 0.28 g. [α]D=−14.3° (methanol). The amine was converted to the oxalic acid salt and recrystallized from ethanol/diethyl ether: M.p. 172.8° C.; MS m/z (relative intensity, 70 eV) 253 (M+, 4) 55 (50), 141 (18), 127 (14), 96 (bp).
Reaction SMILES: [NH2:1][C:2]1[CH:11]=[CH:10][CH:9]=[C:8]2[C:3]=1[CH:4]=[CH:5][N:6]([C@H:13]([CH3:20])[C:14]([NH:16][CH:17]1[CH2:19][CH2:18]1)=[O:15])[C:7]2=[O:12].[Cl:21][C:22]1[CH:27]=[CH:26][C:25]([C@H:28]([CH3:32])[C:29](O)=[O:30])=[CH:24][CH:23]=1.F[P-](F)(F)(F)(F)F.C[N+](C)=C(N(C)C)ON1C2N=CC=CC=2N=N1.C(N(CC)C(C)C)(C)C.CN(C)C=O>C(Cl)Cl>[Cl:21][C:22]1[CH:23]=[CH:24][C:25]([C@H:28]([CH3:32])[C:29]([NH:1][C:2]2[CH:11]=[CH:10][CH:9]=[C:8]3[C:3]=2[CH:4]=[CH:5][N:6]([C@H:13]([CH3:20])[C:14]([NH:16][CH:17]2[CH2:19][CH2:18]2)=[O:15])[C:7]3=[O:12])=[O:30])=[CH:26][CH:27]=1
Reactant: C[C@H](C(=O)NC1CC1)n1ccc2c(N)cccc2c1=O
Reactant: C[C@H](C(=O)O)c1ccc(Cl)cc1
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: ClCCl
Solvent: CN(C)C=O
Product: C[C@H](C(=O)Nc1cccc2c(=O)n([C@H](C)C(=O)NC3CC3)ccc12)c1ccc(Cl)cc1

Procedure:
(R)-2-(5-Amino-1-oxoisoquinolin-2(1H)-yl)-N-cyclopropylpropanamide (0.2 g, 0.0007 mol), (S)-2-(4-chlorophenyl)propanoic acid (0.16 g, 0.00088 mol), N,N,N′,N′-tetramethyl-O-(7-azabenzotriazol-1-yl)uronium hexafluorophosphate (0.33 g, 0.00088 mol), N,N-diisopropylethylamine (0.4 g, 0.003 mol) were stirred in N,N-dimethylformamide (3 mL, 0.04 mol) at room temperature over a weekend. The reaction mixture was diluted with CH2Cl2 (100 mL), washed with NaHCO3 (20 mL×3), dried over Na2SO4, purified via flash chromatography (12 g of silica gel, 0-90% EtOAc/Hexane) and then prep. HPLC gave a white solid. 1H NMR δ (CDCl3) δ: 8.23 (d, J=8.5 Hz, 1H), 7.95 (d, J=7.9 Hz, 1H), 7.52-7.39 (m, 5H), 7.22 (d, J=7.6 Hz, 1H), 7.09 (br, 1H), 6.44 (br, 1H), 6.06-6.03 (m, 1H), 5.58 (q, J=7.0 Hz, 1H), 3.83 (q, J=6.7 Hz, 1H), 2.63 (br, 1H), 1.64 (d, J=7.2 Hz, 3H), 1.56 (d, J=5.2 Hz, 3H), 0.78-0.67 (m, 2H), 0.51-0.40 (m, 2H). MS m/z 438.3 (M+H)+.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][CH2:9][C:10]([O:12][CH3:13])=[O:11])=[CH:4][CH:3]=1.[CH3:14][S:15](Cl)(=[O:17])=[O:16]>C(Cl)Cl.N1C=CC=CC=1>[CH3:14][S:15]([NH:1][C:2]1[CH:3]=[CH:4][C:5]([CH2:8][CH2:9][C:10]([O:12][CH3:13])=[O:11])=[CH:6][CH:7]=1)(=[O:17])=[O:16]
Reactant: CS(=O)(=O)Cl
Reactant: COC(=O)CCc1ccc(N)cc1
Solvent: c1ccncc1
Solvent: ClCCl
Product: COC(=O)CCc1ccc(NS(C)(=O)=O)cc1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
Methyl 3-(4-aminophenyl)propanoate (250 mg, 1.39 mmol) was dissolved in DCM (2 ml) and pyridine (500 μl), then methanesulfonyl chloride was added (191 mg, 1.67 mmol), and the mixture was stirred at RT for 2 hours. The reaction was diluted with DCM, and the organic phase was washed with HCl 1N (2×) and brine, dried over Na2SO4 and evaporated under vacuum to give 250 mg of the desired product.
Reaction SMILES: [CH2:1]1[O:12][C:11]2[CH:10]=[CH:9][C:5]([CH2:6][CH2:7][NH2:8])=[CH:4][C:3]=2[O:2]1.Cl[C:14]1[C:15]2[CH:27]=[C:26]([N+:28]([O-:30])=[O:29])[S:25][C:16]=2[N:17]=[C:18]([C:20]2[O:24][N:23]=[CH:22][CH:21]=2)[N:19]=1>>[O:24]1[C:20]([C:18]2[N:19]=[C:14]([NH:8][CH2:7][CH2:6][C:5]3[CH:9]=[CH:10][C:11]4[O:12][CH2:1][O:2][C:3]=4[CH:4]=3)[C:15]3[CH:27]=[C:26]([N+:28]([O-:30])=[O:29])[S:25][C:16]=3[N:17]=2)=[CH:21][CH:22]=[N:23]1
Reactant: NCCc1ccc2c(c1)OCO2
Reactant: O=[N+]([O-])c1cc2c(Cl)nc(-c3ccno3)nc2s1
Product: O=[N+]([O-])c1cc2c(NCCc3ccc4c(c3)OCO4)nc(-c3ccno3)nc2s1

Procedure:
With the procedure of Example 1, the reaction of 3,4-methylenedioxyphenethylamine with 4-chloro-2-(isoxazol-5-yl)-6-nitro-thieno-[2,3-d]-pyrimidine yields 2-(isoxazol-5-yl)-4-(3,4-methylenedioxyphenethylamino)-6-nitro-thieno-[2,3-d]-pyrimidine.
Reaction SMILES: Br[C:2]1[CH:23]=[C:22]([C:24]([F:27])([F:26])[F:25])[CH:21]=[C:20]([Cl:28])[C:3]=1[CH2:4][NH:5][C:6]1[CH:11]=[CH:10][C:9]([C:12]2[CH:17]=[CH:16][C:15]([Cl:18])=[CH:14][C:13]=2[Cl:19])=[CH:8][CH:7]=1.CC1(C)C(C)(C)OB([C:37]2[CH:38]=[CH:39][C:40]([C:43]([NH:45][CH2:46][CH2:47][C:48]([O:50][CH2:51][CH3:52])=[O:49])=[O:44])=[N:41][CH:42]=2)O1.C([O-])([O-])=O.[K+].[K+]>O1CCOCC1.CCOC(C)=O.[Na+].[Cl-].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]>[Cl:28][C:20]1[C:3]([CH2:4][NH:5][C:6]2[CH:7]=[CH:8][C:9]([C:12]3[CH:17]=[CH:16][C:15]([Cl:18])=[CH:14][C:13]=3[Cl:19])=[CH:10][CH:11]=2)=[C:2]([C:37]2[CH:38]=[CH:39][C:40]([C:43]([NH:45][CH2:46][CH2:47][C:48]([O:50][CH2:51][CH3:52])=[O:49])=[O:44])=[N:41][CH:42]=2)[CH:23]=[C:22]([C:24]([F:27])([F:25])[F:26])[CH:21]=1
Reactant: CCOC(=O)CCNC(=O)c1ccc(B2OC(C)(C)C(C)(C)O2)cn1
Reactant: FC(F)(F)c1cc(Cl)c(CNc2ccc(-c3ccc(Cl)cc3Cl)cc2)c(Br)c1
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: O=C([O-])[O-]
Solvent: CCOC(C)=O
Solvent: C1COCCO1
Product: CCOC(=O)CCNC(=O)c1ccc(-c2cc(C(F)(F)F)cc(Cl)c2CNc2ccc(-c3ccc(Cl)cc3Cl)cc2)cn1
Temperature: 80 °C

Procedure:
N-(2-bromo-6-chloro-4-(trifluoromethyl)benzyl)-2′,4′-dichloro-[1,1′-biphenyl]-4-amine (4.5 g, 8.8 mmol) and ethyl 3-(5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)picolinamido)propanoate (3.1 g, 8.8 mmol), Pd(dppf)Cl2 (321 mg, 0.4 mmol), and 2 M K2CO3 (aq) (8.8 mL, 17.6 mmol) were dissolved in 1,4-dioxane (35 mL) and heated to 80° C. After 1 h the reaction was cooled to room temperature diluted with EtOAc and 4M aqueous NaCl, and the layers were separated. The aqueous layer was extracted with EtOAc and the combined organics were dried (Na2SO4), concentrated, and purified via column chromatography to yield the title compound.
Reaction SMILES: [Cl:1][C:2]1[C:3]([F:31])=[C:4]([CH:8]2[C:12]([C:15]3[CH:20]=[CH:19][C:18]([Cl:21])=[CH:17][C:16]=3[F:22])([C:13]#[N:14])[CH:11]([CH2:23][C:24]([CH3:27])([CH3:26])[CH3:25])[NH:10][CH:9]2[C:28]([OH:30])=O)[CH:5]=[CH:6][CH:7]=1.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C.[N:65]1([C:71](=[O:79])[CH2:72][N:73]2[CH2:78][CH2:77][NH:76][CH2:75][CH2:74]2)[CH2:70][CH2:69][O:68][CH2:67][CH2:66]1>C(Cl)Cl>[Cl:1][C:2]1[C:3]([F:31])=[C:4]([CH:8]2[CH:9]([C:28]([N:76]3[CH2:77][CH2:78][N:73]([CH2:72][C:71]([N:65]4[CH2:66][CH2:67][O:68][CH2:69][CH2:70]4)=[O:79])[CH2:74][CH2:75]3)=[O:30])[NH:10][CH:11]([CH2:23][C:24]([CH3:26])([CH3:25])[CH3:27])[C:12]2([C:15]2[CH:20]=[CH:19][C:18]([Cl:21])=[CH:17][C:16]=2[F:22])[C:13]#[N:14])[CH:5]=[CH:6][CH:7]=1
Reactant: CC(C)(C)CC1NC(C(=O)O)C(c2cccc(Cl)c2F)C1(C#N)c1ccc(Cl)cc1F
Reactant: O=C(CN1CCNCC1)N1CCOCC1
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: ClCCl
Product: CC(C)(C)CC1NC(C(=O)N2CCN(CC(=O)N3CCOCC3)CC2)C(c2cccc(Cl)c2F)C1(C#N)c1ccc(Cl)cc1F
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a stirred solution of rac (2R,3S,4R,5S)-3-(3-Chloro-2-fluoro-phenyl)-4-(4-chloro-2-fluoro-phenyl)-4-cyano-5-(2,2-dimethyl-propyl)-pyrrolidine-2-carboxylic acid (80 mg, 0.138 mmol) in methylene chloride (5 mL), HATU (Aldrich, 79 mg, 0.21 mmol) was added followed by the addition of DIPEA (0.145 mL, 0.83 mmol) and 1-morpholin-4-yl-2-piperazin-1-yl-ethanone (Oakwood, 44 mg, 0.21 mmol). The mixture was stirred at rt for overnight. The reaction was quenched with addition of water. The mixture was extracted with methylene chloride (2×10 mL) and the extracts were dried with magnesium sulfate. The solvent was removed and the residue was purified on a ISCO machine (12 g column, eluent, 20% EtOAc/methylene chloride) to give a white solid. 63 mg.
Reaction SMILES: [N+](=[CH:3][CH3:4])=[N-].CCOCC.[OH:10][CH:11]1[CH2:16][CH2:15][C:14](=[O:17])[CH2:13][CH2:12]1>C(O)C.C(O)(=O)C>[OH:17][CH:14]1[CH2:13][CH2:12][C:11](=[O:10])[CH:3]([CH3:4])[CH2:16][CH2:15]1
Reactant: CC=[N+]=[N-]
Reactant: O=C1CCC(O)CC1
Solvent: CCOCC
Solvent: CC(=O)O
Solvent: CCO
Product: CC1CCC(O)CCC1=O

Procedure:
To a freshly prepared solution of diazoethane in ether (~550 ml of 0.297 M =163 mmol) cooled to -10° C. and well stirred with a magnetic stirrer in an open 1 liter Erlenmeyer flask is added slowly a solution of 4-hydroxycyclohexanone (14.8 g, 13 mmol) in ethanol (150 ml) over a period of 15 minutes. The cooling bath is removed and the stirred reaction mixture is allowed to come to room temperature and stirred overnight. The excess diazoethane is discharged by adding a few drops of 10% aq. acetic acid and then the solvent is removed in vacuo. The residue is dissolved in ether, washed with a satd. aq. NaHCO3 solution, dried (Na2SO4) and the ether is removed in vacuo. Distillation of the residue in vacuo affords (±) 5-hydroxy-2-methylcycloheptanone which exists as an equilibrium mixture with its tautomeric bicyclic hemiacetal form (bp, 1.4 mm, 97°-99°, 17.51 g, 95%). IR (neat)μ: 2.93 (OH), 5.90 (C=O), NMR (CDCl3)δ: 0.91 (d, J=7 Hz, 2-CH of 2-y), 0.8 (d, J=7 Hz, 2-CH3), 3.4-4.5 (m, ##STR3## and ##STR4## GC-MS: RGC shows two components (~60:40) both of which show M+ 142 and identical fragmentations. MOX derivatization gave a single peak in RGC with M+ 171.
Reaction SMILES: C([O-])(=O)C.[Na+].[CH2:6]([NH:10][C:11]1[CH:16]=[CH:15][N:14]2[N:17]=[CH:18][CH:19]=[C:13]2[N:12]=1)[CH2:7][CH2:8][CH3:9].[Br:20]Br.C(=O)(O)[O-].[Na+]>C(O)(=O)C.O>[Br:20][C:19]1[CH:18]=[N:17][N:14]2[CH:15]=[CH:16][C:11]([NH:10][CH2:6][CH2:7][CH2:8][CH3:9])=[N:12][C:13]=12
Reactant: CCCCNc1ccn2nccc2n1
Reactant: BrBr
Agent: CC(=O)[O-]
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CC(=O)O
Solvent: O
Product: CCCCNc1ccn2ncc(Br)c2n1
Temperature: 25 °C

Procedure:
Sodium acetate [127-09-3] (0.7 g, 8.9 mmol) was added to a solution of butyl-pyrazolo[1,5-a]pyrimidin-5-yl-amine (1.1 g, 5.9 mmol) in glacial acetic acid (100 mL) and allowed to stir at ambient temperature until all of the solid had dissolved. Bromine [7726-95-6] (0.3 mL, 6.4 mmol) was added drop by drop into the ambient temperature, buffered, acetic acid reaction solution over 5 minutes. Upon completion of the bromine addition, the suspension was allowed to stir for a further 15 minutes then was slowly poured into 500 mL of stirred water. Saturated aqueous sodium bicarbonate was added to the stirred suspension until pH of the supernatant was determined to be approximately 8 by pH paper, then the suspension was extracted with ethyl acetate. The extract was dried (MgSO4) and flash chromatographed (silica gel eluted with 60% (v/v) ethyl acetate/heptane) to provide 1.2 g of off white solid, mp. 94-95° C. 1 H NMR (400 MHz, DMSO-d6) δ ppm 0.93 (t, J=7.33 Hz, 3 H) 1.31-1.44 (m, 2 H) 1.56 (quin, J=7.20 Hz, 2 H) 3.31-3.38 (m, 2 H) 6.28 (d, J=7.58 Hz, 1 H) 7.61 (t, J=5.05 Hz, 1 H) 7.85 (s, 1 H) 8.42 (d, J=7.58 Hz, 1H). 13C NMR (100 MHz, DMSO-d6) δ ppm 13.67, 19.64, 30.53, 76.99, 100.87, 135.14, 143.03, 145.13, 156.09. LRMS (ESI) m/z 269.0/271.0 [(M+H)]+, calc'd for C10H13BrN4: 269.15.
Reaction SMILES: Cl.C(OC([N:9]1[CH2:13][CH2:12][C:11]([CH2:25][C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=2)([C:14]([C:16]2[CH:17]=[C:18]3[C:22](=[CH:23][CH:24]=2)[NH:21][CH:20]=[CH:19]3)=[O:15])[CH2:10]1)=O)(C)(C)C>CO>[CH2:25]([C:11]1([C:14]([C:16]2[CH:17]=[C:18]3[C:22](=[CH:23][CH:24]=2)[NH:21][CH:20]=[CH:19]3)=[O:15])[CH2:12][CH2:13][NH:9][CH2:10]1)[C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1
Reactant: CC(C)(C)OC(=O)N1CCC(Cc2ccccc2)(C(=O)c2ccc3[nH]ccc3c2)C1
Agent: Cl
Solvent: CO
Product: O=C(c1ccc2[nH]ccc2c1)C1(Cc2ccccc2)CCNC1
Temperature: 25 °C
Reaction time: 6 h
Yield: 93 %

Procedure:
A solution of HCl (1.0 M in MeOH, 12 mL) was added to a solution of 3-benzyl-3-(1H-indole-5-carbonyl)-pyrrolidine-1-carboxylic acid tert-butyl ester enantiomer A (257 mg, 0.635 mmol) in MeOH (5 mL). The resulting pale yellow solution was stirred at room temperature for 6 hours, then cooled to 0° C. and quenched by addition of aqueous NaOH (1.0 M). The mixture was diluted with water and extracted with DCM. The combined organic layers were dried over MgSO4, filtered and evaporated under reduced pressure. The residue was purified by flash chromatography (5% to 10% of MeOH in DCM with 0.5% of NH4OH) to give 179 mg (93% yield) of (3-Benzyl-pyrrolidin-3-yl)-(1H-indol-5-yl)-methanone, which was dissolved in a mixture of DCM/MeOH. A solution of HCl (1 M in Et2O) was added, and the resulting mixture was evaporated under reduced pressure and the residue was triturated with Et2O to give 173 mg of (3-benzyl-pyrrolidin-3-yl)-(1H-indol-5-yl)-methanone hydrochloride enantiomer A as a white powder. MS=305 [M+H]+; [α]D=−26.3° (5.40 mg/1.0 mL of MeOH).
Reaction SMILES: [C:1]1([CH2:7][NH:8][C@H:9]([CH2:12][CH3:13])[CH2:10][OH:11])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH2:14]([C@@H:16]1[O:18][CH2:17]1)Cl.Cl([O-])(=O)(=O)=O.[Li+].[O-]CC.[Na+].[NH4+].[Cl-]>ClCCCl>[CH2:12]([C@H:9]1[N:8]([CH2:7][C:1]2[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=2)[CH2:14][C@@H:16]([CH2:17][OH:18])[O:11][CH2:10]1)[CH3:13]
Reactant: CC[C@H](CO)NCc1ccccc1
Reactant: ClC[C@H]1CO1
Agent: CC[O-]
Agent: [Cl-]
Agent: [Li+]
Solvent: ClCCCl
Product: CC[C@@H]1CO[C@H](CO)CN1Cc1ccccc1
Temperature: 25 °C
Reaction time: 48 h
Yield: 122.7 %

Procedure:
To a solution of (2R)-2-[(phenylmethyl)amino]-1-butanol (10.06 g, 56.1 mmol) in 1,2-dichloroethane (DCE) (250 mL) was added (R)-(−)-epichlorohydrin (6.75 g, 72.9 mmol) followed by lithium perchlorate (5.97 g, 56.1 mmol) under nitrogen. The reaction was stirred for 2 days at room temperature, then sodium ethoxide (52.4 mL, 140 mmol) was added and the reaction continued to stir for 3 days. Saturated NH4Cl was added, and the product was extracted with EtOAc. The organic layers were combined, dried over Na2SO4, and concentrated to afford the title compound (16.2 g) as a colorless oil. LC-MS (ES) m/z=236 [M+H]+.
Reaction SMILES: [CH:1]1([CH:4]([C:11]2[CH:16]=[CH:15][CH:14]=[C:13]([CH2:17][O:18][C:19]3[CH:24]=[CH:23][C:22]([C:25]4[CH:30]=[C:29]([O:31][CH3:32])[CH:28]=[CH:27][C:26]=4[F:33])=[C:21]([OH:34])[CH:20]=3)[CH:12]=2)[CH2:5][C:6]([O:8][CH2:9][CH3:10])=[O:7])[CH2:3][CH2:2]1.[CH3:35][C:36]([CH3:40])([CH3:39])[CH2:37]O.C(C=P(CCCC)(CCCC)CCCC)#N.O>C1(C)C=CC=CC=1>[CH:1]1([CH:4]([C:11]2[CH:16]=[CH:15][CH:14]=[C:13]([CH2:17][O:18][C:19]3[CH:24]=[CH:23][C:22]([C:25]4[CH:30]=[C:29]([O:31][CH3:32])[CH:28]=[CH:27][C:26]=4[F:33])=[C:21]([O:34][CH2:35][C:36]([CH3:40])([CH3:39])[CH3:37])[CH:20]=3)[CH:12]=2)[CH2:5][C:6]([O:8][CH2:9][CH3:10])=[O:7])[CH2:3][CH2:2]1
Reactant: CC(C)(C)CO
Reactant: CCOC(=O)CC(c1cccc(COc2ccc(-c3cc(OC)ccc3F)c(O)c2)c1)C1CC1
Agent: CCCCP(=CC#N)(CCCC)CCCC
Solvent: O
Solvent: Cc1ccccc1
Product: CCOC(=O)CC(c1cccc(COc2ccc(-c3cc(OC)ccc3F)c(OCC(C)(C)C)c2)c1)C1CC1
Temperature: 100 °C
Reaction time: 2 h
Yield: 52.1 %

Procedure:
Under a nitrogen atmosphere, to a solution of ethyl 3-cyclopropyl-3-(3-(((2′-fluoro-2-hydroxy-5′-methoxybiphenyl-4-yl)oxy)methyl)phenyl)propanoate (195 mg), 2,2-dimethyl-1-propanol (79 mg) in toluene (5.0 mL) was added cyanomethylenetributylphosphorane (0.25 mL), and the mixture was stirred at 100° C. for 2 hr. Water was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The extract was washed with saturated brine, and dried over anhydrous sodium sulfate. The solvent was evaporated under reduced pressure, and the residue was purified by silica gel column chromatography (ethyl acetate/hexane) to give the title compound (117 mg) as a colorless oil.
Reaction SMILES: Cl.FC1C=C(C=CC=1)CN1C=C(C2C3C(=NC=C(C4C=CC(C5CCNCC5)=CC=4)C=3)N(S(C3C=CC(C)=CC=3)(=O)=O)C=2)C=N1.[F:46][C:47]1[CH:48]=[C:49]([C:60]2[CH:61]=[C:62]3[C:68]([C:69]4[CH:70]=[N:71][N:72]([CH2:74][C:75]5[CH:80]=[CH:79][CH:78]=[C:77]([F:81])[CH:76]=5)[CH:73]=4)=[CH:67][N:66](S(C4C=CC(C)=CC=4)(=O)=O)[C:63]3=[N:64][CH:65]=2)[CH:50]=[N:51][C:52]=1[N:53]1[CH2:58][CH2:57][N:56]([CH3:59])[CH2:55][CH2:54]1.[OH-].[Li+]>C1COCC1.CO.O>[F:46][C:47]1[CH:48]=[C:49]([C:60]2[CH:61]=[C:62]3[C:68]([C:69]4[CH:70]=[N:71][N:72]([CH2:74][C:75]5[CH:80]=[CH:79][CH:78]=[C:77]([F:81])[CH:76]=5)[CH:73]=4)=[CH:67][NH:66][C:63]3=[N:64][CH:65]=2)[CH:50]=[N:51][C:52]=1[N:53]1[CH2:54][CH2:55][N:56]([CH3:59])[CH2:57][CH2:58]1
Reactant: Cc1ccc(S(=O)(=O)n2cc(-c3cnn(Cc4cccc(F)c4)c3)c3cc(-c4cnc(N5CCN(C)CC5)c(F)c4)cnc32)cc1
Agent: Cc1ccc(S(=O)(=O)n2cc(-c3cnn(Cc4cccc(F)c4)c3)c3cc(-c4ccc(C5CCNCC5)cc4)cnc32)cc1
Agent: Cl
Agent: [Li+]
Solvent: CO
Solvent: O
Solvent: C1CCOC1
Product: CN1CCN(c2ncc(-c3cnc4[nH]cc(-c5cnn(Cc6cccc(F)c6)c5)c4c3)cc2F)CC1
Yield: 30 %

Procedure:
Using similar reaction conditions as described in step-iii of example-1, 5-(5-fluoro-6-(4-methylpiperazin-1-yl)pyridin-3-yl)-3-(1-(3-fluorobenzyl)-1H-pyrazol-4-yl)-1-tosyl-1H-pyrrolo[2,3-b]pyridine (150 mg, 0.234 mmol) was hydrolyzed with lithium hydroxide (98 mg, 2.34 mmol) in THF/methanol/water (12/4/4 mL) to yield 34 mg (30% yield) after purification by prep TLC using 8% methanol in chloroform as eluent. 1H NMR (CD3OD, 300 MHz): δ 8.459-8.452 (d, 1H), 8.36-8.34 (m, 2H), 8.24 (s, 1H), 7.94 (s, 1H), 7.85-7.79 (dd, 1H), 7.65 (s, 1H), 7.41-7.33 (q, 1H), 7.12-7.00 (m, 3H), 5.43 (s, 2H), 3.57-3.54 (t, 4H), 2.65-2.62 (m, 4H), 2.37 (s, 3H). MS: m/z=486.2 (M+1), HPLC: 98.03% in method A.
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:10]=[C:11]([S:15](Cl)(=[O:17])=[O:16])[CH:12]=[CH:13][CH:14]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(N(CC)C(C)C)(C)C.[C:28]([O:32][C:33]([NH:35][C@@H:36]1[CH2:40][CH2:39][NH:38][CH2:37]1)=[O:34])([CH3:31])([CH3:30])[CH3:29]>C(Cl)Cl>[CH2:1]([O:8][C:9]1[CH:10]=[C:11]([S:15]([N:38]2[CH2:39][CH2:40][C@@H:36]([NH:35][C:33]([O:32][C:28]([CH3:31])([CH3:30])[CH3:29])=[O:34])[CH2:37]2)(=[O:17])=[O:16])[CH:12]=[CH:13][CH:14]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=S(=O)(Cl)c1cccc(OCc2ccccc2)c1
Reactant: CC(C)(C)OC(=O)N[C@@H]1CCNC1
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: CC(C)(C)OC(=O)N[C@@H]1CCN(S(=O)(=O)c2cccc(OCc3ccccc3)c2)C1
Temperature: 25 °C
Reaction time: 4 h

Procedure:
To a stirred solution of 3-benzyloxyphenylsulfonyl chloride, as described above in Step C, (1.8 g, 7.2 mmol) in CH2Cl2 (50 mL) was added N,N-diisopropylethylamine (1.8 mL, 10.3 mmol) followed by (R)-3-(tert-butoxycarbonylamino)pyrrolidine (1.77 g, 9.5 mmol) and the reaction mixture was stirred at ambient temperature for 4 hours. The mixture was washed with 10% aqueous citric acid (75 mL), then water (50 mL), then saturated aqueous NaHCO3 (50 mL). The organic layer was dried over MgSO4, filtered, and concentrated in vacuo. The crude product was purified by flash column chromatography on silica, eluting with hexane—20% EtOAc to yield the desired product as a white solid.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([NH:11][C:12]2[CH:17]=[C:16](Cl)[N:15]=[C:14]([NH2:19])[N:13]=2)(=[O:10])=[O:9])=[CH:4][CH:3]=1.[CH3:20][OH:21]>[Na]>[NH2:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([NH:11][C:12]2[CH:17]=[C:16]([O:21][CH3:20])[N:15]=[C:14]([NH2:19])[N:13]=2)(=[O:10])=[O:9])=[CH:4][CH:3]=1
Reactant: Nc1ccc(S(=O)(=O)Nc2cc(Cl)nc(N)n2)cc1
Reactant: CO
Agent: [Na]
Product: COc1cc(NS(=O)(=O)c2ccc(N)cc2)nc(N)n1
Temperature: 150 °C
Reaction time: 9 h
Yield: 94 %

Procedure:
0.27 g (0.0009 mol) of 4-amino-N-(2-amino-6-chloro-pyrimidin-4-yl)-benzenesulfonamide was dissolved in a solution of 0.23 g of sodium in 20 ml of methanol and stirred in an autoclave at 150° C. for 9 hours. The solvent was distilled off, the residue was added to water and the pH value was adjusted to 4-5 with 1N HCl. The precipitate which thereby separated was filtered off under suction, washed with water and dried. The crystals obtained were triturated in 20 ml of methanol, again filtered off and dried in a high vacuum. There was obtained 0.25 g (94%) of 4-amino-N-(2-amino-6-methoxy-pyrimidin-4-yl)-benzenesulfonamide as beige crystals; m.p.: >250° C. (dec.).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([CH:8]=[C:9]([I:11])[CH:10]=1)[C:5]([OH:7])=[O:6].Cl.CN(C)CCCN=C=NCC.[C:24](O)([CH3:27])([CH3:26])[CH3:25]>C(Cl)Cl.CN(C1C=CN=CC=1)C>[C:24]([O:6][C:5](=[O:7])[C:4]1[CH:8]=[C:9]([I:11])[CH:10]=[C:2]([Br:1])[CH:3]=1)([CH3:27])([CH3:26])[CH3:25]
Reactant: CC(C)(C)O
Reactant: O=C(O)c1cc(Br)cc(I)c1
Agent: CCN=C=NCCCN(C)C
Agent: CN(C)c1ccncc1
Agent: Cl
Solvent: ClCCl
Product: CC(C)(C)OC(=O)c1cc(Br)cc(I)c1
Temperature: 25 °C
Reaction time: 48 h
Yield: 86.3 %

Procedure:
To a solution of 3-bromo-5-iodo-benzoic acid (D7) (50 g, 153 mmol, 1 equiv) in CH2Cl2 (500 ml) was added 1-(3-dimethylaminopropyl)-3-ethyl-carbodiimide hydrochloride (30.8 g, 160 mmol, 1.05 equiv), DMAP (14 g, 114 mmol, 0.75 equiv) and tert-butanol (90 ml, 917 mmol, 6 equiv). The resulting mixture was stirred at room temperature for 48 h then DMAP (4.67 g, 38 mmol, 0.25 equiv) was added, and the solution was stirred for another 24 h then concentrated in vacuo. The residue was diluted with AcOEt and washed sequentially with 2N aqueous HCl solution, 1N aqueous NaOH solution and brine, dried over MgSO4 and concentrated in vacuo to give 3-bromo-5-iodo-benzoic acid tert-butyl ester (D8b) (50.6 g, 86%) as a brown solid.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:12]=1[O:13][CH3:14])[N:9]=[C:8]([C:15]1[CH:20]=[C:19]([O:21][CH3:22])[C:18]([O:23][CH3:24])=[C:17]([O:25][CH3:26])[CH:16]=1)[N:7]=[C:6]2[C:27]([OH:29])=O.Cl.[F:31][C:32]1[CH:33]=[C:34]2[C:39](=[CH:40][CH:41]=1)[CH2:38][NH:37][CH2:36][CH2:35]2>>[CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:12]=1[O:13][CH3:14])[N:9]=[C:8]([C:15]1[CH:16]=[C:17]([O:25][CH3:26])[C:18]([O:23][CH3:24])=[C:19]([O:21][CH3:22])[CH:20]=1)[N:7]=[C:6]2[C:27]([N:37]1[CH2:36][CH2:35][C:34]2[C:39](=[CH:40][CH:41]=[C:32]([F:31])[CH:33]=2)[CH2:38]1)=[O:29]
Reactant: Fc1ccc2c(c1)CCNC2
Reactant: COc1cc2nc(-c3cc(OC)c(OC)c(OC)c3)nc(C(=O)O)c2cc1OC
Agent: Cl
Product: COc1cc2nc(-c3cc(OC)c(OC)c(OC)c3)nc(C(=O)N3CCc4cc(F)ccc4C3)c2cc1OC
Yield: 56.2 %

Procedure:
Reaction of 6,7-dimethoxy-2-(3,4,5-trimethoxyphenyl)quinazoline-4-carboxylic acid with 6-fluoro-1,2,3,4-tetrahydroisoquinoline hydrochloride gave compound 120 (56.2% yield). 1H NMR (300 MHz, DMSO-d6) δ 2.93 and 3.09 (2t, 2H), 3.51-4.05 (m, 17H), 4.47 and 4.98 (2s, 2H), 6.91-7.42 (m, 4H), 7.48 and 7.51 (2s, 1H), 7.78 and 7.83 (2s, 2H); MS (ESI) m/z 534 ([M+H]+).