Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [OH:1][CH2:2][C:3]1[CH:4]=[CH:5][C:6]2[O:11][C:10]([CH3:13])([CH3:12])[C:9](=[O:14])[NH:8][C:7]=2[CH:15]=1.Cl[CH2:17][CH2:18][CH2:19][O:20][CH3:21].[F-].[K+].[I-].[K+]>C(#N)C>[OH:1][CH2:2][C:3]1[CH:4]=[CH:5][C:6]2[O:11][C:10]([CH3:13])([CH3:12])[C:9](=[O:14])[N:8]([CH2:17][CH2:18][CH2:19][O:20][CH3:21])[C:7]=2[CH:15]=1
Reactant: COCCCCl
Reactant: CC1(C)Oc2ccc(CO)cc2NC1=O
Agent: [F-]
Agent: [I-]
Agent: [K+]
Solvent: CC#N
Product: COCCCN1C(=O)C(C)(C)Oc2ccc(CO)cc21

Procedure:
A suspension of 2.270 g of 6-hydroxymethyl-2,2-dimethyl-4H-benz[1,4]oxazin-3-one in 180 ml of acetonitrile is admixed with 2.410 ml of 1-chloro-3-methoxypropane, 9.844 g of potassium fluoride on alumina and 0.036 g of potassium Iodide. The reaction mixture is heated to reflux over 30 hours and filtered through Hyflo, and the filtrate is concentrated. The title compound is obtained as a beige solid from the residue by means of flash chromatography (SiO2 60F). Rf=0.20 (3:1 EtOAc-heptane); Rt=3.25.
Reaction SMILES: C1(O[C:8](=[O:30])[NH:9][C:10]2[S:14][N:13]=[C:12]([O:15][CH2:16][C:17]3[C:22]([F:23])=[CH:21][C:20]([CH3:24])=[C:19]([F:25])[C:18]=3[F:26])[C:11]=2[C:27](=[O:29])[NH2:28])C=CC=CC=1.[N:31]1([CH2:36][CH2:37][CH2:38][CH2:39][NH2:40])[CH2:35][CH2:34][CH2:33][CH2:32]1>>[N:31]1([CH2:36][CH2:37][CH2:38][CH2:39][NH:40][C:8](=[O:30])[NH:9][C:10]2[S:14][N:13]=[C:12]([O:15][CH2:16][C:17]3[C:22]([F:23])=[CH:21][C:20]([CH3:24])=[C:19]([F:25])[C:18]=3[F:26])[C:11]=2[C:27]([NH2:28])=[O:29])[CH2:35][CH2:34][CH2:33][CH2:32]1
Reactant: NCCCCN1CCCC1
Reactant: Cc1cc(F)c(COc2nsc(NC(=O)Oc3ccccc3)c2C(N)=O)c(F)c1F
Product: Cc1cc(F)c(COc2nsc(NC(=O)NCCCCN3CCCC3)c2C(N)=O)c(F)c1F

Procedure:
The title compound was prepared from [4-carbamoyl-3-(2,3,6-trifluoro-4-methyl-benzyloxy)-isothiazol-5-yl]-carbamic acid phenyl ester and 4-pyrrolidin-1-yl-butylamine by the procedure analogous to Example 1. MS (APCI, m/z): 486 [M+H]+.
Reaction SMILES: [CH3:1][S:2][C:3](=[N:5][N+:6]([O-:8])=[O:7])[NH2:4].[H-].[Na+].[Cl:11][C:12]1[CH:17]=[CH:16][C:15]([CH2:18]Cl)=[CH:14][N:13]=1>CS(C)=O>[Cl:11][C:12]1[CH:17]=[CH:16][C:15]([CH2:18][NH:4][C:3](=[N:5][N+:6]([O-:8])=[O:7])[S:2][CH3:1])=[CH:14][N:13]=1
Reactant: CSC(N)=N[N+](=O)[O-]
Reactant: ClCc1ccc(Cl)nc1
Agent: [H-]
Agent: [Na+]
Solvent: CS(C)=O
Product: CSC(=N[N+](=O)[O-])NCc1ccc(Cl)nc1
Reaction time: 1 h
Yield: 6.9 %

Procedure:
To a solution of 2-methyl-3-nitroisothiourea (15.0 g) in dimethylsulfoxide (100 ml) was gradually added sodium hydride (oil free 2.9 g) at 5° C., while being stirred for one hour. Thereafter, 2-chloro-5-chloromethyl pyridine (18.0 g) was added to the solution at a temperature in the range of from 5° to 10° C., followed by overnight stirring thereofat room temperature. After the dimethylsulfoxide in the solution was distilled off under reduced pressure, the resulting residue was purified on a chromatographic column (the eluent was a mixture of ethanol and chloroform), so as to obtain the desired 1-(2-chloro-5-pyridylmethyl)-2-methyl-3-nitroisothiourea (2.0 g) having a melting point in the range of from 141° to 143° C.
Reaction SMILES: [NH:1]([C:18]([O:20]C(C)(C)C)=O)[C@H:2]([C:8]([O:10][CH2:11][C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1)=[O:9])[CH2:3][C:4]([CH3:7])([CH3:6])[CH3:5].CN1CCOCC1.C(OC(=O)[C@@H:41]([N:57]=[N+:58]=[N-:59])[C:42]1([C:47]([O:49][CH2:50][C:51]2[CH:56]=[CH:55][CH:54]=[CH:53][CH:52]=2)=[O:48])[CH2:46][CH2:45][CH2:44][CH2:43]1)C1C=CC=CC=1.F[P-](F)(F)(F)(F)F.N1(O[P+](N(C)C)(N(C)C)N(C)C)C2C=CC=CC=2N=N1>C(O)(C(F)(F)F)=O.C(Cl)Cl>[CH2:11]([O:10][C:8](=[O:9])[C@@H:2]([NH:1][C:18](=[O:20])[C@@H:41]([N:57]=[N+:58]=[N-:59])[C:42]1([C:47]([O:49][CH2:50][C:51]2[CH:56]=[CH:55][CH:54]=[CH:53][CH:52]=2)=[O:48])[CH2:46][CH2:45][CH2:44][CH2:43]1)[CH2:3][C:4]([CH3:5])([CH3:6])[CH3:7])[C:12]1[CH:13]=[CH:14][CH:15]=[CH:16][CH:17]=1
Reactant: CC(C)(C)C[C@H](NC(=O)OC(C)(C)C)C(=O)OCc1ccccc1
Reactant: [N-]=[N+]=N[C@H](C(=O)OCc1ccccc1)C1(C(=O)OCc2ccccc2)CCCC1
Agent: CN(C)[P+](On1nnc2ccccc21)(N(C)C)N(C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Solvent: CN1CCOCC1
Product: CC(C)(C)C[C@H](NC(=O)[C@@H](N=[N+]=[N-])C1(C(=O)OCc2ccccc2)CCCC1)C(=O)OCc1ccccc1
Temperature: 25 °C
Reaction time: 18 h
Yield: 94.9 %

Procedure:
A solution of Boc-γMeLeu-OBzl (0.272 g, 0.81 mmol) in 30% TFA in CH2Cl2 was stirred at 0° for 1 h. The solvent was evaporated and the residue was dried under vacuum. The resulting TFA salt was dissolved in acetonitrile (20 mL). NMM (0.53 mL, 4.86 mmol) was added to the solution, followed by the addition of (S)-α-azido-1-[(phenylmethoxy)carbonyllcyclo-pentaneacetic acid (0.269 g, 0.89 mmol, described in example 7) and BOP (0.464 g, 1.05 mmol). The mixture was stirred at room temperature for 18h. The solvent was evaporated. The residue was dissolved in EtOAc (50 mL). The solution was washed with 10% aqueous HCl (2×25 mL), a sainted aqueous solution of Na2CO3 (2×25 mL) and brine (25 mL). Evaporation of the organic phase gave N-{(S)-α-azido-1-[(phenylmethoxy)-carbonyl]cyclopentaneacetyl}-2(S)-amino-4,4-dimethylpentanoic acid benzyl ester as a yellow oil (0.400 g, 96% yield).
Reaction SMILES: [CH2:1]([C:5]1([CH2:32][CH2:33][CH2:34][CH3:35])[C:17]2[CH:16]=[C:15]([N:18]([C:25]3[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=3)[C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=3)[CH:14]=[CH:13][C:12]=2[C:11]2[C:6]1=[CH:7][C:8](Br)=[CH:9][CH:10]=2)[CH2:2][CH2:3][CH3:4].C([Li])CCC.[B:41](OC)([O:44]C)[O:42]C.Cl>O.C1COCC1>[CH2:1]([C:5]1([CH2:32][CH2:33][CH2:34][CH3:35])[C:17]2[CH:16]=[C:15]([N:18]([C:25]3[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=3)[C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=3)[CH:14]=[CH:13][C:12]=2[C:11]2[C:6]1=[CH:7][C:8]([B:41]([OH:44])[OH:42])=[CH:9][CH:10]=2)[CH2:2][CH2:3][CH3:4]
Reactant: CCCCC1(CCCC)c2cc(Br)ccc2-c2ccc(N(c3ccccc3)c3ccccc3)cc21
Reactant: COB(OC)OC
Agent: Cl
Agent: [Li]CCCC
Solvent: O
Solvent: C1CCOC1
Product: CCCCC1(CCCC)c2cc(B(O)O)ccc2-c2ccc(N(c3ccccc3)c3ccccc3)cc21
Temperature: -30 °C
Reaction time: 1 h
Yield: 79.4 %

Procedure:
To a dry 100 mL two-neck flask containing 1.3 g (2.47 mmol) of compound 2 and 30 mL of dry THF was dropwise added 2.3 mL (3.71 mmol) of 1.6 M of n-butyl lithium under N2 at −78° C. while maintaining a good stirring. After stirring for 1 h, trimethyl borate (0.4 mL, 3.71 mmol) was added in one portion. The reaction mixture was then stirred for 1 h at −78° C. When the mixture was naturally warmed to −30° C., water and HCl (3 M) were added. Then the solution mixture was poured into water wad extracted with ethyl acetate (3×50 mL). The combined organic phase was dried over anhydrous sodium sulfate, filtered and evaporated to dryness under 35° C. The crude product was purified by silica gel column chromatography using dichloromethane and petroleum ether/ethyl acetate as eluent affording a light-yellow solid (0.96 g, 79%). 1H NMR (400 MHz, DMSO-d6, δ) 8.02 (s, 2H), 7.80 (s, 1H), 7.77 (d, J=7.6 Hz, 1H), 7.71 (d, J=8.4 Hz, 1H), 7.27 (t, J=7.6 Hz, 1H), 7.08 (d, J=1.6 Hz, 1H), 6.93-7.01 (m, 6H), 6.91 (d, J=2.0 Hz, 1H), 1.79-1.88 (m, 4H), 0.95-1.04 (m, 4H), 0.65 (t, J=7.4 Hz, 6H), 0.50-0.58 (m, 4H). 13C NMR (100 MHz, DMSO-d6, δ) 152.1, 148.9, 147.4, 146, 8, 142.1, 136.1, 133.1, 129.4, 129.3, 128.2, 123, 3, 122.7, 121.1, 119.1, 118.3, 54.3, 39.2, 25.8, 22.4, 13.8. MS (FAB) m/z 489.7 (M+).
Reaction SMILES: [F:1][C:2]1[CH:10]=[C:9]2[C:5]([CH:6]=[N:7][N:8]2[CH3:11])=[CH:4][C:3]=1[CH:12]([C:14]1[N:18]2[N:19]=[C:20]([C:23](=O)[CH3:24])[CH:21]=[CH:22][C:17]2=[N:16][CH:15]=1)[CH3:13].Cl.[NH:27]([C:29]([NH2:31])=[O:30])[NH2:28]>CO>[F:1][C:2]1[CH:10]=[C:9]2[C:5]([CH:6]=[N:7][N:8]2[CH3:11])=[CH:4][C:3]=1[CH:12]([C:14]1[N:18]2[N:19]=[C:20](/[C:23](=[N:28]/[NH:27][C:29]([NH2:31])=[O:30])/[CH3:24])[CH:21]=[CH:22][C:17]2=[N:16][CH:15]=1)[CH3:13]
Reactant: NNC(N)=O
Reactant: CC(=O)c1ccc2ncc(C(C)c3cc4cnn(C)c4cc3F)n2n1
Agent: Cl
Solvent: CO
Product: C/C(=N\NC(N)=O)c1ccc2ncc(C(C)c3cc4cnn(C)c4cc3F)n2n1
Temperature: 35 °C
Reaction time: 5 h
Yield: 34.1 %

Procedure:
To a solution of 1-(3-(1-(6-fluoro-1-methyl-1H-indazol-5-yl)ethyl)imidazo[1,2-b]pyridazin-6-yl)ethanone (35 mg, 0.104 mmol) in MeOH (4 mL), was added hydrazinecarboxamide hydrochloride (28.9 mg, 0.259 mmol). The reaction mixture was heated to 35° C. After stirring for 5 h, the solvent was removed and DCM was added to dilute the residue. The resulting mixture was then washed with brine, dried over Na2SO4, and concentrated in vacuo to give (E)-2-(1-(3-(1-(6-fluoro-1-methyl-1H-indazol-5-yl)ethyl)imidazo[1,2-b]pyridazin-6-yl)ethylidene)hydrazinecarboxamide (14 mg, 33%) as a white solid. 1H-NMR (400 MHz, DMSO-d6) δ ppm 9.64 (s, 1H), 8.14 (d, 1H), 7.93 (m, 2H), 7.74 (s, 1H), 7.51 (m, 2H), 4.93 (m, 1H), 3.96 (s, 3H), 2.13 (s, 3H), 1.76 (d, 3H). LCMS (method B): [MH]+=395, tR=2.32 min.
Reaction SMILES: [CH3:1][C:2]1[CH:11]=[C:10]([N:12]2[CH2:16][CH2:15][CH:14]([C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=3)[CH2:13]2)[C:9]2[C:4](=[CH:5][CH:6]=[C:7]([N+:23]([O-])=O)[CH:8]=2)[N:3]=1>[Pd].C(O)C.ClCCl>[CH3:1][C:2]1[CH:11]=[C:10]([N:12]2[CH2:16][CH2:15][CH:14]([C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=3)[CH2:13]2)[C:9]2[C:4](=[CH:5][CH:6]=[C:7]([NH2:23])[CH:8]=2)[N:3]=1
Reactant: Cc1cc(N2CCC(c3ccccc3)C2)c2cc([N+](=O)[O-])ccc2n1
Agent: [Pd]
Solvent: CCO
Solvent: ClCCl
Product: Cc1cc(N2CCC(c3ccccc3)C2)c2cc(N)ccc2n1

Procedure:
2-Methyl-6-nitro-4-(3-phenylpyrrolidin-1-yl)quinoline (0.29 g; see Preparation 7 above) and palladium on carbon (10%, 0.2 g) in ethanol (10 mL) and dichloromethane (4 mL) was stirred under a hydrogen atmosphere for 3 hours. The reaction mixture was filtered and concentrated to give the title compound as a thick yellow oil, which was used without further purification.
Reaction SMILES: [CH3:1][S:2]([CH2:5][C:6]([NH:14][C:15]([C:17]1[CH:22]=[C:21]([O:23][CH2:24][C:25]([F:28])([F:27])[F:26])[C:20](Br)=[CH:19][N:18]=1)=[O:16])([CH3:13])[C:7]1[N:11]=[C:10]([CH3:12])[O:9][N:8]=1)(=[O:4])=[O:3].[Br-].[CH:31]1([Zn+])[CH2:33][CH2:32]1>C1COCC1>[CH3:1][S:2]([CH2:5][C:6]([NH:14][C:15]([C:17]1[CH:22]=[C:21]([O:23][CH2:24][C:25]([F:28])([F:27])[F:26])[C:20]([CH:31]2[CH2:33][CH2:32]2)=[CH:19][N:18]=1)=[O:16])([CH3:13])[C:7]1[N:11]=[C:10]([CH3:12])[O:9][N:8]=1)(=[O:4])=[O:3]
Reactant: [Zn+]C1CC1
Reactant: Cc1nc(C(C)(CS(C)(=O)=O)NC(=O)c2cc(OCC(F)(F)F)c(Br)cn2)no1
Agent: [Br-]
Solvent: C1CCOC1
Product: Cc1nc(C(C)(CS(C)(=O)=O)NC(=O)c2cc(OCC(F)(F)F)c(C3CC3)cn2)no1
Temperature: 100 °C
Reaction time: 1.5 h
Yield: 11 %

Procedure:
To a solution of 5-Bromo-4-(2,2,2-trifluoro-ethoxy)-pyridine-2-carboxylic acid [2-methanesulfonyl-1-methyl-1-(5-methyl-[1,2,4]oxadiazol-3-yl)-ethyl]-amide (Example 84c, 60 mg, 120 μmol) in dry THF (0.5 ml) under an argon atmosphere was added tetrakis(tripehylphosphine) palladium(0) (13.8 mg, 12.0 μmol) followed by cyclopropylzinc(II) bromide solution 0.5M in THF (527 μl, 263 μmol). The reaction mixture was then stirred at 100° C. under microwave radiation for 90 min. The reaction mixture was concentrated in vacuo. The residue was dissolved in ethylacetate and solution was extracted with an 1.0M aqueous solution of sodium bicarbonate. The organic phase was dried over sodium sulfate and evaporated down to dryness. The crude material was purified by preparative HPLC to yield the title compound (5.9 mg, 11%) as white solid. MS (ESI, m/z): 463.4 (M+H+).
Reaction SMILES: [O:1]1[C:5]2[CH:6]=[CH:7][C:8]([N:10]3[C:14]4[C:15]5[CH:16]=[C:17]([N+:23]([O-])=O)[CH:18]=[CH:19][C:20]=5[O:21][CH2:22][C:13]=4[C:12]([C:26]([O:28][CH2:29][CH3:30])=[O:27])=[N:11]3)=[CH:9][C:4]=2[O:3][CH2:2]1>[Ni].CN(C=O)C>[NH2:23][C:17]1[CH:18]=[CH:19][C:20]2[O:21][CH2:22][C:13]3[C:12]([C:26]([O:28][CH2:29][CH3:30])=[O:27])=[N:11][N:10]([C:8]4[CH:7]=[CH:6][C:5]5[O:1][CH2:2][O:3][C:4]=5[CH:9]=4)[C:14]=3[C:15]=2[CH:16]=1
Reactant: CCOC(=O)c1nn(-c2ccc3c(c2)OCO3)c2c1COc1ccc([N+](=O)[O-])cc1-2
Agent: [Ni]
Solvent: CN(C)C=O
Product: CCOC(=O)c1nn(-c2ccc3c(c2)OCO3)c2c1COc1ccc(N)cc1-2
Yield: 78.2 %

Procedure:
The title material from step 3 (17 g, 0.0416 mol) was treated with Raney nickel in DMF under 25 psi at RT for 17 h. The reaction mixture was filtrated and washed with DMF. The combined filtrate and washes were concentrated under reduced pressure. The resulting residue was diluted with MeOH, sonicated at 40° C., the solid was collected by filtration, to give ethyl 8-amino-1-[1,3-benzodioxol-5-yl]-1,4-dihydrochromeno[4,3-c]pyrazole-3-carboxylate (12.3415 g, 78.3%). The product was characterized by 1H NMR, LC/MS (MH+ 380), and HPLC (98% purity).
Reaction SMILES: [Na+].[C:2]([CH2:4][C@@H:5]([OH:10])[CH2:6][C:7]([O-:9])=[O:8])#[N:3].S(=O)(=O)(O)O>C(O)C>[C:2]([CH2:4][C@@H:5]([OH:10])[CH2:6][C:7]([OH:9])=[O:8])#[N:3]
Reactant: N#CC[C@@H](O)CC(=O)[O-]
Agent: O=S(=O)(O)O
Agent: [Na+]
Solvent: CCO
Product: N#CC[C@@H](O)CC(=O)O

Procedure:
The reaction mixture containing (R)-4-cyano-3-hydroxybutyric acid sodium salt was acidified to pH 1 with concentrated sulfuric acid. The reaction mixture was condensed, dissolved in ethanol and filtered. The filtrate was concentrated to give (R)-4-cyano-3-hydroxybutyric acid which was used for esterification without further purification.
Reaction SMILES: C(OC(=O)[NH:7][C@@H:8]([CH2:45][CH:46]([CH3:48])[CH3:47])[CH2:9][O:10][C:11]1[CH:12]=[CH:13][C:14]2[C:24]3[C:19](=[CH:20][N:21]=[C:22]([N:25](CC4C=CC(OC)=CC=4)CC4C=CC(OC)=CC=4)[CH:23]=3)[CH:18]([CH3:44])[O:17][C:15]=2[CH:16]=1)(C)(C)C.C(O)(C(F)(F)F)=O>ClCCl>[NH2:7][C@@H:8]([CH2:45][CH:46]([CH3:48])[CH3:47])[CH2:9][O:10][C:11]1[CH:12]=[CH:13][C:14]2[C:24]3[C:19](=[CH:20][N:21]=[C:22]([NH2:25])[CH:23]=3)[CH:18]([CH3:44])[O:17][C:15]=2[CH:16]=1
Reactant: COc1ccc(CN(Cc2ccc(OC)cc2)c2cc3c(cn2)C(C)Oc2cc(OC[C@H](CC(C)C)NC(=O)OC(C)(C)C)ccc2-3)cc1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CC(C)C[C@H](N)COc1ccc2c(c1)OC(C)c1cnc(N)cc1-2
Temperature: 25 °C
Reaction time: 8 h
Yield: 41.8 %

Procedure:
To a stirred solution of tert-butyl((2S)-1-((2-(bis(4-methoxybenzyl)amino)-5-methyl-5H-chromeno[3,4-c]pyridin-8-yl)oxy)-4-methylpentan-2-yl)carbamate (110 mg, 0.165 mmol) in dichloromethane (10 mL) was added TFA (0.254 mL, 3.29 mmol) and the reaction was stirred at room temperature overnight. The volatiles were evaporated and the crude material was purified by preparative HPLC (0.1% TFA in MeOH) to afford 8-(((S)-2-amino-4-methylpentyl)oxy)-5-methyl-5H-chromeno[3,4-c]pyridin-2-amine (25 mg, 0.069 mmol, 42% yield) as a yellow solid. 1H NMR (400 MHz, MeOD) δ 7.74 (m, 2 H), 6.84 (s, 1 H), 6.75 (dd, J=2.4 Hz, J=8.4 Hz, 1 H), 6.63 (d, J=2.4 Hz, 1 H), 5.18 (m, 1 H), 4.32 (m, 1 H), 4.15 (m, 1 H), 3.65 (m, 1 H), 1.83 (m, 1 H), 1.65 (m, 5 H), 1.04 (m, 6 H); LCMS (ESI) m/e 328.2 [(M+H)+, calcd for C19H26N3O2 328.2]; LC/MS retention time (Method D): tR=1.24 min; HPLC retention time (method A): tR=8.42 min.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([C:8]([C:10]2[C:11](Cl)=[N:12][C:13]([Cl:16])=[N:14][CH:15]=2)=O)[CH:5]=[CH:6][CH:7]=1.[NH2:18][NH2:19]>C1COCC1>[Br:1][C:2]1[CH:3]=[C:4]([C:8]2[C:10]3[C:11](=[N:12][C:13]([Cl:16])=[N:14][CH:15]=3)[NH:19][N:18]=2)[CH:5]=[CH:6][CH:7]=1
Reactant: O=C(c1cccc(Br)c1)c1cnc(Cl)nc1Cl
Reactant: NN
Solvent: C1CCOC1
Product: Clc1ncc2c(-c3cccc(Br)c3)n[nH]c2n1
Temperature: 25 °C
Reaction time: 0.33 h

Procedure:
To a solution of crude (3-bromo-phenyl)-(2,4-dichloro-pyrimidin-5-yl)-methanone (from Example 37 supra) (1 g, 3.0 mmol) in THF (70 mL), 85% hydrazine (0.45 g, 7.64 mmol) was added dropwise at room temperature. The mixture was stirred for additional 20 minutes at room temperature and then heated at 50° C. for another 20 minutes. The solvent was removed under reduced pressure, and the residue was washed with water (5 mL), petroleum ether (10 mL) and dried to give 3-(3-bromo-phenyl)-6-chloro-1H-pyrazolo[3,4-d]pyrimidine as yellow solid. (Yield 0.848 g, 91.3%).
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][CH2:9][NH:10][C:11](=[O:21])[C@@H:12]([NH:16][S:17]([CH3:20])(=[O:19])=[O:18])[CH:13]([CH3:15])[CH3:14])=[CH:4][C:3]=1[O:22][CH3:23].[C:24]1([C:30]#[C:31][CH2:32]OS(C2C=CC(C)=CC=2)(=O)=O)[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1.C[O-].[Na+].[I-].[K+].[Cl-].[Na+]>CO>[CH3:23][O:22][C:3]1[CH:4]=[C:5]([CH2:8][CH2:9][NH:10][C:11](=[O:21])[C@@H:12]([NH:16][S:17]([CH3:20])(=[O:19])=[O:18])[CH:13]([CH3:15])[CH3:14])[CH:6]=[CH:7][C:2]=1[O:1][CH2:32][C:31]#[C:30][C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1
Reactant: Cc1ccc(S(=O)(=O)OCC#Cc2ccccc2)cc1
Reactant: COc1cc(CCNC(=O)[C@@H](NS(C)(=O)=O)C(C)C)ccc1O
Agent: C[O-]
Agent: [Cl-]
Agent: [I-]
Solvent: CO
Product: COc1cc(CCNC(=O)[C@@H](NS(C)(=O)=O)C(C)C)ccc1OCC#Cc1ccccc1

Procedure:
2.5 g of (S)-2-(methylsulfonyl-amino)-3-methyl-butyric acid N-[2-(4-hydroxy-3-methoxy-phenyl)-ethyl]-amide and 2.7 g of toluene-4-sulfonic acid (3-phenyl-2-propyn-1-yl) ester are heated at reflux for 3 hours together with 12 ml of 1M sodium methanolate solution with the addition of 20 mg of potassium iodide in 50 ml of methanol. The reaction mixture is cooled and introduced into 200 ml of saturated sodium chloride solution. Extraction is carried out twice using 200 ml of ethyl acetate each time. The organic phases are combined, dried over magnesium sulfate and concentrated. The residue is subjected to flash chromatography on silica gel with ethyl acetate/n-hexane (2:1), yielding (S)-2-(methylsulfonyl-amino)-3-methyl-butyric acid N-{2-[3-methoxy-4-(3-phenyl-2-propyn-1-yloxy)-phenyl]-ethyl}-amide, which is recrystallised from ethyl acetate/n-hexane, m.p. 130-132° C.
Reaction SMILES: [C:1]([N:9]1[CH2:14][CH2:13][N:12]([C:15]2[CH:23]=[CH:22][C:18]([C:19]([OH:21])=[O:20])=[C:17]([N+:24]([O-])=O)[CH:16]=2)[CH2:11][CH2:10]1)(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1>C(O)C.C1COCC1.[Pt]=O>[NH2:24][C:17]1[CH:16]=[C:15]([N:12]2[CH2:11][CH2:10][N:9]([C:1](=[O:8])[C:2]3[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=3)[CH2:14][CH2:13]2)[CH:23]=[CH:22][C:18]=1[C:19]([OH:21])=[O:20]
Reactant: O=C(O)c1ccc(N2CCN(C(=O)c3ccccc3)CC2)cc1[N+](=O)[O-]
Agent: O=[Pt]
Solvent: CCO
Solvent: C1CCOC1
Product: Nc1cc(N2CCN(C(=O)c3ccccc3)CC2)ccc1C(=O)O
Reaction time: 16 h
Yield: 65.5 %

Procedure:
The obtained 4-(4-benzoylpiperazin-1-yl)-2-nitrobenzoic acid (0.40 g, 93%) was dissolved in 30 ml ethanol and 10 ml THF, followed by the addition of platinum oxide (20 mg, 5%) and stirred under hydrogen gas for 16 hours. The reaction was filtered with the aid of celite. 2-amino-4-(4-bezoylpiperazin-1-yl)benzoic acid (0.24 g, 70%) was obtained after removing of solvents. To a solution of 2-amino-4-(4-bezoylpiperazin-1-yl)benzoic acid (0.2 g, 0.6 mmol) and benzaldehyde (0.14 ml, 1.3 mmol) added sodium triacetoxyborohydride (0.4 g, 1.8 mmol) and stirred under argon atmosphere overnight. The reaction was quenched with 10 ml water and extracted with ethyl acetate (3×20 ml), followed by drying it over anhydrous sodium sulfate. 2-(benzylamino)-4-(4-benzoylpiperazin-1-yl)benzoic acid (0.11 g, 40%) was obtained after concentration. 1H NMR (500 MHz, CDCl3) δ (ppm) 3.25-3.88 (m, br, 8H), 4.48 (s, 2H), 6.20 (d, J=2.3 Hz, 1H), 6.22 (dd, J=2.3, 9.1 Hz, 1H), 7.30-7.45 (m, 10H), 7.48 (d, J=9.1 Hz, 1H), 8.25 (s, 1H), 10.65 (s, 1H).
Reaction SMILES: C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.O[CH2:21][CH2:22][NH:23][C:24](=[O:30])[O:25][C:26]([CH3:29])([CH3:28])[CH3:27].[Br:31]N1C(=O)CCC1=O>ClCCl>[Br:31][CH2:21][CH2:22][NH:23][C:24](=[O:30])[O:25][C:26]([CH3:29])([CH3:28])[CH3:27]
Reactant: O=C1CCC(=O)N1Br
Reactant: CC(C)(C)OC(=O)NCCO
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: ClCCl
Product: CC(C)(C)OC(=O)NCCBr
Temperature: 12.5 °C
Reaction time: 16 h
Yield: 38 %

Procedure:
At 0-10° C. and under an atmosphere of nitrogen, a solution of triphenylphosphine (33.7 g, 128.53 mmol, 1.29 equiv.) in dichloromethane (80 mL) was added dropwise to a stirred solution of tert-butyl 2-hydroxyethylcarbamate (20.1 g, 99.75 mmol, 1.00 equiv.) and N-bromosuccinimide (23.6 g, 132.58 mmol, 1.33 equiv.) in dichloromethane (80 mL). The resulting solution was stirred at 10-15° C. for about 16 hours. The reaction mixture was washed with water (2×100 mL), the organic phase was dried over anhydrous sodium sulfate, and then concentrated in vacuo. The resulting residue was purified by silica gel column chromatography (ethyl acetate/petroleum ether (60:1)) to give the title product as a light-yellow oil (8.5 g; yield=36%). 1H NMR (300 MHz, CDCl3) δ: 4.98 (b, 1H), 3.45-3.55 (m, 4H), 1.41 (s, 9H).
Reaction SMILES: C([NH:18][CH2:19][CH2:20][C:21]([OH:23])=[O:22])(OCC1C2C(=CC=CC=2)C2C1=CC=CC=2)=O.N1CCCCC1.[CH:30]([C:32]1[CH:40]=[CH:39][C:35]([C:36]([OH:38])=O)=[CH:34][CH:33]=1)=[O:31].C(N(C(C)C)CC)(C)C.C1CN([P+](Br)(N2CCCC2)N2CCCC2)CC1.F[P-](F)(F)(F)(F)F>CN(C=O)C>[CH:30]([C:32]1[CH:33]=[CH:34][C:35]([C:36]([NH:18][CH2:19][CH2:20][C:21]([OH:23])=[O:22])=[O:38])=[CH:39][CH:40]=1)=[O:31]
Reactant: O=Cc1ccc(C(=O)O)cc1
Reactant: O=C(O)CCNC(=O)OCC1c2ccccc2-c2ccccc21
Agent: Br[P+](N1CCCC1)(N1CCCC1)N1CCCC1
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Solvent: C1CCNCC1
Product: O=Cc1ccc(C(=O)NCCC(=O)O)cc1
Reaction time: 0.5 h

Procedure:
To the above resin bound Fmoc β-alanine was added 1000 μL of a 20% solution of piperidine in DMF. Upon shaking for 30 min, the resin was drained and washed with 1 mL DMF containing 1-hydroxybenzotriazole (50 mg/mL) and DMF (2×1 mL). Then 200 μmol 4-formylbenzoic acid (30 mg) and diisopropylethylamine (70 μL) were dissolved in DMF (430 μL) and added to the resin followed by 200 μmol PyBrOP dissolved in DMF (500 μL). The mixture was shaken for 4 hours at 25° C. followed by filtration and washing of the resin with DMF (3×1 mL) and trimethylorthoformate (1×1 mL).
Reaction SMILES: [CH2:1]([O:4][C:5]1([CH3:51])[CH2:10][CH2:9][N:8]([C:11]2[N:16]3[CH:17]=[C:18]([C:20]4[CH:21]=[C:22]([C:26]5[CH:31]=[C:30]([F:32])[C:29]([CH3:33])=[CH:28][C:27]=5[O:34][C@H:35]([CH2:37][CH:38]=[CH2:39])[CH3:36])[CH:23]=[CH:24][CH:25]=4)[N:19]=[C:15]3[CH:14]=[C:13]([CH3:40])[C:12]=2[C@H:41]([O:46][C:47]([CH3:50])([CH3:49])[CH3:48])[C:42]([O:44][CH3:45])=[O:43])[CH2:7][CH2:6]1)C=C.C(O[C@@H](C1C(C)=CC2=NC3=CN2C=1N1CCC(C)(OCC=CC[C@H](C)OC2C=C(F)C=CC=2C2C=C3C=CC=2)CC1)C(OCC)=O)(C)(C)C>>[C:47]([O:46][C@@H:41]([C:12]1[C:13]([CH3:40])=[CH:14][C:15]2=[N:19][C:18]3=[CH:17][N:16]2[C:11]=1[N:8]1[CH2:7][CH2:6][C:5]([CH3:51])([O:4][CH2:1][CH:39]=[CH:38][CH2:37][C@H:35]([CH3:36])[O:34][C:27]2[CH:28]=[C:29]([CH3:33])[C:30]([F:32])=[CH:31][C:26]=2[C:22]2[CH:21]=[C:20]3[CH:25]=[CH:24][CH:23]=2)[CH2:10][CH2:9]1)[C:42]([O:44][CH3:45])=[O:43])([CH3:48])([CH3:49])[CH3:50]
Reactant: C=CCOC1(C)CCN(c2c([C@H](OC(C)(C)C)C(=O)OC)c(C)cc3nc(-c4cccc(-c5cc(F)c(C)cc5O[C@@H](C)CC=C)c4)cn23)CC1
Agent: CCOC(=O)[C@@H](OC(C)(C)C)c1c(C)cc2nc3cn2c1N1CCC(C)(CC1)OCC=CC[C@H](C)Oc1cc(F)ccc1-c1cccc-3c1
Product: COC(=O)[C@@H](OC(C)(C)C)c1c(C)cc2nc3cn2c1N1CCC(C)(CC1)OCC=CC[C@H](C)Oc1cc(C)c(F)cc1-c1cccc-3c1
Yield: 82 %

Procedure:
Prepared in 82% yield from (S)-methyl 2-(5-(4-(allyloxy)-4-methylpiperidin-1-yl)-2-(5′-fluoro-4′-methyl-2′-((S)-pent-4-en-2-yloxy)-[1,1′-biphenyl]-3-yl)-7-methylimidazo[1,2-a]pyridin-6-yl)-2-(tert-butoxy)acetate following the procedure for ethyl(2S)-2-(tert-butoxy)-2-[(22S)-18-fluoro-4,22,28-trimethyl-21,27-dioxa-1,7,34-triazahexacyclo[26.2.2.16,9.110,14.02,7.015,20]tetratriaconta-2,4,6(34),8,10(33),11,13,15(20),16,18,24-undecaen-3-yl]acetate. 1H NMR (400 MHz, CDCl3) δ 8.16 (d, J=7.8 Hz, 1H), 8.08 (s, 1H), 8.04 (s, 1H), 7.54-7.49 (m, 1H), 7.32 (s, 1H), 7.29 (d, J=1.3 Hz, 1H), 7.03 (d, J=10.3 Hz, 1H), 6.83 (d, J=6.5 Hz, 1H), 6.25-6.14 (m, 1H), 6.05 (br. s., 1H), 5.86-5.75 (m, 1H), 4.51-4.40 (m, 1H), 4.10-3.93 (m, 3H), 3.78 (t, J=10.9 Hz, 1H), 3.69 (s, 3H), 3.07 (d, J=7.8 Hz, 1H), 2.69 (d, J=7.5 Hz, 1H), 2.51-2.47 (m, 1H), 2.46 (s, 3H), 2.41-2.35 (m, 1H), 2.32 (d, J=1.5 Hz, 3H), 1.98 (t, J=12.8 Hz, 2H), 1.82-1.70 (m, 2H), 1.33 (s, 3H), 1.25 (s, 9H), 1.06 (d, J=6.0 Hz, 3H); LCMS (ESI, M+1): 670.25.