Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl.[N:2]1([C:8]([C:10]2[C:11]3[CH2:28][S:27](=[O:30])(=[O:29])[C:26]4[CH:25]=[CH:24][CH:23]=[CH:22][C:21]=4[C:12]=3[N:13]([CH:15]3[CH2:20][CH2:19][NH:18][CH2:17][CH2:16]3)[N:14]=2)=[O:9])[CH2:7][CH2:6][O:5][CH2:4][CH2:3]1.[Cl:31][CH2:32][CH:33]=O.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>ClCCCl.C(Cl)Cl>[Cl:31][CH2:32][CH2:33][N:18]1[CH2:19][CH2:20][CH:15]([N:13]2[C:12]3[C:21]4[CH:22]=[CH:23][CH:24]=[CH:25][C:26]=4[S:27](=[O:30])(=[O:29])[CH2:28][C:11]=3[C:10]([C:8]([N:2]3[CH2:3][CH2:4][O:5][CH2:6][CH2:7]3)=[O:9])=[N:14]2)[CH2:16][CH2:17]1
Reactant: O=C(c1nn(C2CCNCC2)c2c1CS(=O)(=O)c1ccccc1-2)N1CCOCC1
Reactant: O=CCCl
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: Cl
Agent: [Na+]
Solvent: ClCCCl
Solvent: ClCCl
Product: O=C(c1nn(C2CCN(CCCl)CC2)c2c1CS(=O)(=O)c1ccccc1-2)N1CCOCC1
Temperature: 65 °C
Reaction time: 8 h

Procedure:
A suspension of 3-(morpholin-4-ylcarbonyl)-1-piperidin-4-yl-1,4-dihydrothiochromeno[4,3-c]pyrazole 5,5-dioxide hydrochloride (100 mg; 0.23 mmol; 1 eq.), chloroacetaldehyde (31.13 mg; 0.24 mmol; 1.1 eq.) in DCE (4.2 ml) is added sodium triacetoxyborohydride (229.27 mg; 1.08 mmol; 1.4 eq) and the reaction mixture is stirred at 65° C. overnight. The reaction mixture is diluted with DCM and the organic phase is washed with a saturated aqueous solution of NaHCO3 then dried on MgSO4 and concentrated. The residue is purified by flash chromatography eluting from 100% to 30% AcOEt and MeOH to afford after concentration of the desired fractions of the title compound as a brown oil. HPLC (max plot) 89.6%; Rt 2.33 min.
Reaction SMILES: C(OC(=O)N(C1CNC1)C[C@H](O)COC1C=CC(O)=CC=1)(C)(C)C.C(N(CC)CC)C.[CH2:32]([O:36][C:37]1[CH:42]=[CH:41][C:40]([S:43](Cl)(=[O:45])=[O:44])=[CH:39][CH:38]=1)[CH2:33][CH2:34][CH3:35].[C:47]([O:51][C:52](=[O:84])[N:53]([CH:66]1[CH2:69][N:68]([S:70]([C:73]2[CH:78]=[CH:77][C:76]([O:79][CH2:80][CH2:81][CH2:82][CH3:83])=[CH:75][CH:74]=2)(=[O:72])=[O:71])[CH2:67]1)[CH2:54][C@H:55]([OH:65])[CH2:56][O:57][C:58]1[CH:63]=[CH:62][C:61]([OH:64])=[CH:60][CH:59]=1)([CH3:50])([CH3:49])[CH3:48].C(OC1C=CC(S(O)(=O)=O)=CC=1)CCC>C(Cl)(Cl)Cl>[CH2:80]([O:79][C:76]1[CH:77]=[CH:78][C:73]([S:70]([N:68]2[CH2:69][CH:66]([N:53]([C:52]([O:51][C:47]([CH3:50])([CH3:49])[CH3:48])=[O:84])[CH2:54][CH:55]([OH:65])[CH2:56][O:57][C:58]3[CH:59]=[CH:60][C:61]([O:64][S:43]([C:40]4[CH:39]=[CH:38][C:37]([O:36][CH2:32][CH2:33][CH2:34][CH3:35])=[CH:42][CH:41]=4)(=[O:45])=[O:44])=[CH:62][CH:63]=3)[CH2:67]2)(=[O:72])=[O:71])=[CH:74][CH:75]=1)[CH2:81][CH2:82][CH3:83]
Reactant: CCCCOc1ccc(S(=O)(=O)Cl)cc1
Reactant: CCCCOc1ccc(S(=O)(=O)N2CC(N(C[C@H](O)COc3ccc(O)cc3)C(=O)OC(C)(C)C)C2)cc1
Agent: CC(C)(C)OC(=O)N(C[C@H](O)COc1ccc(O)cc1)C1CNC1
Agent: CCCCOc1ccc(S(=O)(=O)O)cc1
Solvent: ClC(Cl)Cl
Solvent: CCN(CC)CC
Product: CCCCOc1ccc(S(=O)(=O)Oc2ccc(OCC(O)CN(C(=O)OC(C)(C)C)C3CN(S(=O)(=O)c4ccc(OCCCC)cc4)C3)cc2)cc1

Procedure:
To a solution of Azetidin-3-yl-[(2S)-2-hydroxy-3-(4-hydroxy-phenoxy)-propyl]-carbamicacid tert-butyl ester (0.28 g, 0.8 mmol) in chloroform (4 ml) was added triethylamine (0.2 g, 2 mmol), and 4-butoxybenzenesulfonyl chloride (0.26 g, 1.0 mmol). The mixture was stirred at reflux for 5 h, and then quenched with 50% sodium bicarbonate solution. The chloroform was evaporated and the aqueous solution was removed. The residue was chromatographed (silica gel, ethyl acetate-hexanes/2:1) to give: (1) 0.13 g of [1-(4-Butoxy-benzenesulfonyl)-azetidin-3-yl]-[(2S)-2-hydroxy-3-(4-hydroxy-phenoxy)-propyl]-carbamic acid tert-butyl ester as a colorless foam; MS (ES) m/z 551.1 (MH+); HRMS (El) Calcd. for C27H38N2O8S (M+): 550.2349, Found: 550.2353, and (2) 0.17 g of 4-Butoxy-benzenesulfonic acid 4-(3-{[(1-(4-butoxy-benzenesulfonyl)-azetidin-3-yl]-tert-butoxycarbonyl-amino}-2-hydroxy-propoxy)-phenylester as a colorless foam; MS (ES) m/z 763.3 (MH+); HRMS (ES) Calcd. for C37H51N2O11S2 (MH+): 763.2934, Found: 763.2899.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:58])[CH2:4][CH2:5][C:6]1[CH:11]=[C:10]([C:12](=[O:26])[C:13]2[CH:18]=[CH:17][C:16]([O:19][CH:20]3[CH2:24][CH2:23][CH2:22][CH2:21]3)=[CH:15][C:14]=2[OH:25])[CH:9]=[CH:8][C:7]=1[O:27][CH2:28][C:29]1[CH:57]=[CH:56][C:32]2[C:33](=[O:55])[N:34](C(C3C=CC=CC=3)(C3C=CC=CC=3)C3C=CC=CC=3)[O:35][C:31]=2[CH:30]=1.C(C(C)=O)C(C)C.S(=O)(=O)(O)O.[OH-].[Na+]>O.CO>[CH3:1][O:2][C:3](=[O:58])[CH2:4][CH2:5][C:6]1[CH:11]=[C:10]([C:12](=[O:26])[C:13]2[CH:18]=[CH:17][C:16]([O:19][CH:20]3[CH2:24][CH2:23][CH2:22][CH2:21]3)=[CH:15][C:14]=2[OH:25])[CH:9]=[CH:8][C:7]=1[O:27][CH2:28][C:29]1[CH:57]=[CH:56][C:32]2[C:33]([OH:55])=[N:34][O:35][C:31]=2[CH:30]=1
Reactant: COC(=O)CCc1cc(C(=O)c2ccc(OC3CCCC3)cc2O)ccc1OCc1ccc2c(=O)n(C(c3ccccc3)(c3ccccc3)c3ccccc3)oc2c1
Agent: O=S(=O)(O)O
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CC(=O)CC(C)C
Solvent: CO
Product: COC(=O)CCc1cc(C(=O)c2ccc(OC3CCCC3)cc2O)ccc1OCc1ccc2c(O)noc2c1
Reaction time: 1 h
Yield: 81 %

Procedure:
300 g of 3-{5-[4-(cyclopentyloxy)-2-hydroxybenzoyl]-2-[(3-oxo-2-triphenylmethyl-2,3-dihydro-1,2-benzisoxazol-6-yl)methoxy]phenyl}propionic acid methyl ester was added to a mixture of 1200 mL of methyl isobutyl ketone and 600 mL of methanol. 43.5 mL of sulfuric acid was added dropwise under ice-cooling. This was stirred for 1 hour under water-cooled, and then stirred for 1 hour 30 minutes at room temperature. After adding 1200 mL of water and 200 mL of 20% sodium hydroxide aqueous solution, the result was stirred at room temperature for 30 minutes and solids were filtered to obtain 167 g of 3-{5-[4-(cyclopentyloxy)-2-hydroxybenzoyl]-2-[(3-hydroxy-1,2-benzisoxazol-6-yl)methoxy]phenyl}propionic acid methyl ester in the form of a pale yellowish-white solid.
Reaction SMILES: [Mg].Br[C:3]1[CH:4]=[C:5]([O:11][CH3:12])[C:6]([O:9][CH3:10])=[CH:7][CH:8]=1.CO[C:15]1[CH:20]=[C:19]([O:21][CH3:22])[C:18]([O:23][CH3:24])=[CH:17][C:16]=1[C:25]1[O:26][CH2:27][C:28]([CH3:31])([CH3:30])[N:29]=1.[Cl-].[NH4+]>O1CCCC1>[CH3:12][O:11][C:5]1[CH:4]=[C:3]([C:15]2[CH:20]=[C:19]([O:21][CH3:22])[C:18]([O:23][CH3:24])=[CH:17][C:16]=2[C:25]2[O:26][CH2:27][C:28]([CH3:31])([CH3:30])[N:29]=2)[CH:8]=[CH:7][C:6]=1[O:9][CH3:10]
Reactant: COc1ccc(Br)cc1OC
Reactant: COc1cc(OC)c(C2=NC(C)(C)CO2)cc1OC
Agent: [Cl-]
Agent: [Mg]
Agent: [NH4+]
Solvent: C1CCOC1
Product: COc1ccc(-c2cc(OC)c(OC)cc2C2=NC(C)(C)CO2)cc1OC
Temperature: 25 °C
Reaction time: 48 h
Yield: 92.8 %

Procedure:
In tetrahydrofuran (100 ml), magnesium (1.3 g) was reacted with 4-bromoveratrole (13 g) to prepare a Grignard reagent. While cooling in an ice-water bath, a solution of 2-(2,4,5-trimethoxyphenyl)-4,4-dimethyl-2-oxazoline (7.7 g) in tetrahydrofuran (100 ml) was added thereto. After stirring at room temperature for 48 hours, an aqueous saturated ammonium chloride solution (150 ml) was added and stirred for 15 minutes. Then, the mixed solution was separated to extract the aqueous layer with tetrahydrofuran (150 ml). The organic layers were combined each other and concentrated by an evaporator. The residue was dissolved in 10% hydrochloric acid (100 ml), which was washed with diethyl ether. The aqueous layer was cooled in an ice-water bath, then neutralized by adding a 20% aqueous sodium hydroxide solution. It was extracted with ethyl acetate, washed with a saturated saline solution and then dried over sodium sulfate. The solvent was distilled off to give 10 g of 2-[2-(3,4-dimethoxyphenyl)-4,5-dimethoxyphenyl]-4,4-dimethyl-2-oxazoline as a pale brown oil.
Reaction SMILES: [CH2:1]([S:3](Cl)(=[O:5])=[O:4])[CH3:2].[S:7]1[C:11]2[CH:12]=[CH:13][CH:14]=[CH:15][C:10]=2[CH:9]=[C:8]1[C:16]1[C:17]([N:28](C(OC(C)(C)C)=O)C(=O)OC(C)(C)C)=[N:18][CH:19]=[C:20]([N:22]2[CH2:27][CH2:26][NH:25][CH2:24][CH2:23]2)[N:21]=1.C(N(CC)CC)C.Cl.O1CCOCC1>ClCCl>[S:7]1[C:8]([C:16]2[C:17]([NH2:28])=[N:18][CH:19]=[C:20]([N:22]3[CH2:27][CH2:26][N:25]([S:3]([CH2:1][CH3:2])(=[O:5])=[O:4])[CH2:24][CH2:23]3)[N:21]=2)=[CH:9][C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][C:11]1=2
Reactant: CC(C)(C)OC(=O)N(C(=O)OC(C)(C)C)c1ncc(N2CCNCC2)nc1-c1cc2ccccc2s1
Reactant: CCS(=O)(=O)Cl
Agent: Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Solvent: C1COCCO1
Product: CCS(=O)(=O)N1CCN(c2cnc(N)c(-c3cc4ccccc4s3)n2)CC1
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 19.8 %

Procedure:
Ethanesulfonyl chloride (25.43 mg, 18.74 μL, 0.1978 mmol) was added to a solution of tert-butyl N-[3-(benzothiophen-2-yl)-5-piperazin-1-yl-pyrazin-2-yl]-N-tert-butoxycarbonyl-carbamate (92 mg, 0.1798 mmol) and triethylamine (36.39 mg, 50.12 μL, 0.3596 mmol) in dichloromethane (3.965 mL) at 0° C. and the resulting solution stirred at room temperature for 1.5 hours. The reaction was then treated with HCl in dioxane (224.8 μL of 4 M, 0.8990 mmol) and allowed to stir at ambient temperature overnight. The mixture was concentrated in vacuo and the resultant residue was purified by reverse phase preparative HPLC [Waters Sunfire C18, 10 uM, 100A column, gradient 10%-95% B (solvent A: 0.05% TFA in water, solvent B: CH3CN) over 16 minutes at 25 mL/min]. The fractions were collected, passed through a sodium bicarbonate cartridge and freeze-dried to give the title compound as a yellow solid (14.4 mg, 20% Yield). 1H NMR (DMSO) d 1.24 (3H, t), 2.51 (2H, q), 3.30 masked signal, 3.52 (4H, m), 5.91 (2H, br s), 7.36-7.40 (2H, m), 7.84-7.86 (1H, m), 7.92 (1H, s), 7.95 (1H, m), 8.06 (1H, s) ppm; MS (ES+) 404.02
Reaction SMILES: C([O:4][CH2:5][C:6]([C:13]#[C:14][C:15]1[C:23]2[C:22]([Cl:24])=[N:21][C:20]([NH2:25])=[N:19][C:18]=2[N:17]([CH2:26][C:27]2[C:32]([CH3:33])=[C:31]([O:34][CH3:35])[C:30]([CH3:36])=[CH:29][N:28]=2)[CH:16]=1)([OH:12])[CH2:7][O:8]C(=O)C)(=O)C.CCN(CC)CC>C1COCC1.CO>[NH2:25][C:20]1[N:21]=[C:22]([Cl:24])[C:23]2[C:15]([C:14]#[C:13][C:6]([OH:12])([CH2:7][OH:8])[CH2:5][OH:4])=[CH:16][N:17]([CH2:26][C:27]3[C:32]([CH3:33])=[C:31]([O:34][CH3:35])[C:30]([CH3:36])=[CH:29][N:28]=3)[C:18]=2[N:19]=1
Reactant: COc1c(C)cnc(Cn2cc(C#CC(O)(COC(C)=O)COC(C)=O)c3c(Cl)nc(N)nc32)c1C
Solvent: CCN(CC)CC
Solvent: CO
Solvent: C1CCOC1
Product: COc1c(C)cnc(Cn2cc(C#CC(O)(CO)CO)c3c(Cl)nc(N)nc32)c1C

Procedure:
A solution of 2-((2-amino-4-chloro-7-((4-methoxy-3,5-dimethylpyridin-2-yl)methyl)-7H-pyrrolo[2,3-d]pyrimidin-5-yl)ethynyl)-2-hydroxypropane-1,3-diyl diacetate (see example 56) (60 mg) and Et3N (1 mL) in THF (1 mL) and MeOH (6 mL) was heated in a microwave oven to 150° C. for 20 min. Concentration and preparative HPLC gave the title compound, as a solid. HPLC Rt=3.90 min.
Reaction SMILES: [NH2:1][C:2]1[C:3]2[CH:14]=[C:13]([N+:15]([O-:17])=[O:16])[CH:12]=[CH:11][C:4]=2[S:5][C:6]=1C(OC)=O.O>CN1CCCC1=O.CN1CCNCC1>[NH2:1][C:2]1[C:3]2[CH:14]=[C:13]([N+:15]([O-:17])=[O:16])[CH:12]=[CH:11][C:4]=2[S:5][CH:6]=1
Reactant: COC(=O)c1sc2ccc([N+](=O)[O-])cc2c1N
Agent: CN1CCNCC1
Solvent: CN1CCCC1=O
Solvent: O
Product: Nc1csc2ccc([N+](=O)[O-])cc12
Temperature: 25 °C

Procedure:
A solution of 23.00 g (91.26 mmol) of methyl 3-amino-5-nitrobenzo[b]thiophene-2-carboxylate (J. Hetero. Chem., 34(4), 1163 (1997)) in 100 mL of 1-methyl-2-pyrrolidinone and 30 mL of 1-methylpiperazine is heated at 180° C. for 2 hours. The reaction is cooled to room temperature and poured into water. The resultant solid is collected by filtration and washed with water. The solid is dissolved in a mixture of ethyl acetate and diethyl ether and the solution is washed with water twice. The organic layer is dried over magnesium sulfate, filtered and concentrated in vacuo. Diethyl ether and hexane are added to the residue and the dark red solid is collected by filtration to provide 11.17 g (63%), mp 155-158° C.
Reaction SMILES: [CH3:1][N:2](C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.[Cl:25][C:26]1[N:27]=[CH:28][C:29]2[C:34]([CH:35]=1)=[CH:33][C:32]([C:36]([OH:38])=O)=[CH:31][CH:30]=2.CCN(C(C)C)C(C)C.Cl.CN>CN(C=O)C>[Cl:25][C:26]1[N:27]=[CH:28][C:29]2[C:34]([CH:35]=1)=[CH:33][C:32]([C:36]([NH:2][CH3:1])=[O:38])=[CH:31][CH:30]=2
Reactant: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Reactant: O=C(O)c1ccc2cnc(Cl)cc2c1
Agent: CN
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: CNC(=O)c1ccc2cnc(Cl)cc2c1
Reaction time: 18 h
Yield: 60.4 %

Procedure:
HATU (17.6 mg, 0.046 mmol) was added to a solution of 3-chloroisoquinoline-6-carboxylic acid (Preparation 54, 8 mg, 0.039 mmol), DIPEA (54 uL, 0.31 mmol) and methanamine hydrochloride (15.6 mg, 0.231 mmol) in DMF (4 mL) and the reaction was stirred for 18 hours. The reaction was partitioned between EtOAc and brine, the separated organic phase was washed with saturated NaHCO3 solution, citric acid and brine, dried over Na2SO4 and concentrated in vacuo to afford the title compound as yellow oil (5.2 mg, 61%).
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[C:3]([NH2:7])[CH:2]=1.[Br:8][C:9]1[CH:10]=[CH:11][C:12]([O:18][CH2:19][C:20]2[CH:25]=[CH:24][C:23]([F:26])=[CH:22][CH:21]=2)=[C:13]([CH:17]=1)[C:14](O)=[O:15].C(Cl)CCl.C1C=CC2N(O)N=NC=2C=1>CN(C=O)C.O>[Br:8][C:9]1[CH:10]=[CH:11][C:12]([O:18][CH2:19][C:20]2[CH:25]=[CH:24][C:23]([F:26])=[CH:22][CH:21]=2)=[C:13]([CH:17]=1)[C:14]([NH:7][C:3]1[CH:2]=[N:1][CH:6]=[CH:5][CH:4]=1)=[O:15]
Reactant: O=C(O)c1cc(Br)ccc1OCc1ccc(F)cc1
Reactant: Nc1cccnc1
Agent: On1nnc2ccccc21
Solvent: ClCCCl
Solvent: CN(C)C=O
Solvent: O
Product: O=C(Nc1cccnc1)c1cc(Br)ccc1OCc1ccc(F)cc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
Neat pyridin-3-amine (79 mg, 0.84 mmol) was added in one charge to a stirred solution of 5-bromo-2-{[(4-fluorophenyl)methyl]oxy}benzoic acid (may be prepared as described in Description 87; 200 mg, 0.56 mmol), EDC (213 mg, 1.11 mmol) and HOBT (170 mg, 1.11 mmol) in DMF (3 ml) at room temperature. The reaction mixture was stirred at 25° C. overnight. Water (25 ml) was added and the solid was filtered, washed with water (15 ml), and dried in vacuo. The residue was further purified with Prep-TLC (eluate: dichloromethane:methanol=25:1) to yield the title compound as a white solid. 76 mg.
Reaction SMILES: [CH2:1]([O:8][C:9]([N:11]1[CH2:15][CH2:14][CH:13]([NH:16]C(OC(C)(C)C)=O)[CH2:12]1)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(O)(C(F)(F)F)=O>ClCCl>[CH2:1]([O:8][C:9]([N:11]1[CH2:15][CH2:14][CH:13]([NH2:16])[CH2:12]1)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CC(C)(C)OC(=O)NC1CCN(C(=O)OCc2ccccc2)C1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: NC1CCN(C(=O)OCc2ccccc2)C1

Procedure:
To a solution of 3.21 g 3-tert-butoxycarbonylamino-pyrrolidine-1-carboxylic acid benzyl ester in 40 ml dichloromethane were added 13 ml TFA. After 16 h the solution was evaporated to give the crude hydrotrifluoroacetate. Yield: 3.20 g.
Reaction SMILES: C[O:2][C:3](=[O:35])[CH2:4][CH2:5][NH:6][C:7](=[O:34])[C:8]1[CH:13]=[CH:12][C:11]([CH:14]([CH:28]2[CH2:31][C:30]([CH3:33])([CH3:32])[CH2:29]2)[NH:15][C:16]2[C:25]([CH3:26])=[CH:24][C:23]3[C:18](=[CH:19][CH:20]=[C:21]([F:27])[CH:22]=3)[N:17]=2)=[CH:10][CH:9]=1.[OH-].[Na+]>CO.C1COCC1>[CH3:32][C:30]1([CH3:33])[CH2:31][CH:28]([CH:14]([NH:15][C:16]2[C:25]([CH3:26])=[CH:24][C:23]3[C:18](=[CH:19][CH:20]=[C:21]([F:27])[CH:22]=3)[N:17]=2)[C:11]2[CH:10]=[CH:9][C:8]([C:7]([NH:6][CH2:5][CH2:4][C:3]([OH:35])=[O:2])=[O:34])=[CH:13][CH:12]=2)[CH2:29]1
Reactant: COC(=O)CCNC(=O)c1ccc(C(Nc2nc3ccc(F)cc3cc2C)C2CC(C)(C)C2)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: C1CCOC1
Product: Cc1cc2cc(F)ccc2nc1NC(c1ccc(C(=O)NCCC(=O)O)cc1)C1CC(C)(C)C1

Procedure:
The title compound was prepared by treating 3-{4-[(3,3-Dimethyl-cyclobutyl)-(6-fluoro-3-methyl-quinolin-2-ylamino)-methyl]-benzoylamino}-propionic acid methyl ester, isomer 2, (intermediate 75) with 1N NaOH (2.5 eq.) in methanol/THF in a similar manner as described in Example 19 to provide the title compound. Analytical chiral SFC: (Chiralpak IC column, 4.6 mm×25 cm, 25% methanol/carbon dioxide eluent, 2.5 mL/min flow rate, 4.81 retention time); 1H NMR (400 MHz, DMSO-d6) δ 12.13 (s, 1H), 8.37 (t, J=5.5 Hz, 1H), 7.65-7.71 (m, 3H), 7.54 (d, J=8.3 Hz, 2H), 7.39-7.47 (m, 1H), 7.29-7.37 (m, 1H), 7.19-7.29 (m, 1H), 6.53 (d, J=8.1 Hz, 1H), 5.13-5.23 (m, 1H), 3.41 (dd, J=12.4, 6.8 Hz, 2H), 2.77-2.90 (m, 1H), 2.46 (t, J=7.1 Hz, 2H), 2.28 (s, 3H), 1.92-2.00 (m, 1H), 1.56-1.66 (m, 2H), 1.42-1.53 (m, 1H), 1.11 (s, 3H), 1.07 (s, 3H); MS (M+1): 464.2.
Reaction SMILES: Cl.[N+:2]([C:5]1[CH:11]=[CH:10][CH:9]=[CH:8][C:6]=1[NH2:7])([O-:4])=[O:3].[CH3:12][C:13]([C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)=[CH2:14].[OH-].[Na+]>[Cl-].[Zn+2].[Cl-].O>[C:13]([C:10]1[CH:9]=[CH:8][C:6]([NH2:7])=[C:5]([N+:2]([O-:4])=[O:3])[CH:11]=1)([C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)([CH3:14])[CH3:12]
Reactant: C=C(C)c1ccccc1
Reactant: Nc1ccccc1[N+](=O)[O-]
Agent: Cl
Agent: [Cl-]
Agent: [Na+]
Solvent: O
Product: CC(C)(c1ccccc1)c1ccc(N)c([N+](=O)[O-])c1

Procedure:
To 20.4 parts of 36% w/w hydrochloric acid in which had previously been dissolved 13.4 parts of anhydrous zinc chloride is added 27.6 parts of o-nitroaniline. This mixture is heated to reflux temperature and during the next hour 23.6 parts of α-methylstyrene are added dropwise with stirring. After completing the addition the reaction mixture is stirred and refluxed for further 2 hours before being poured whilst still hot into a solution of 50 parts sodium hydroxide in 100 parts of water. This mixture after stirring for 15 minutes is set aside to cool, whereupon the upper organic phase solidified. The solid cake is then broken up, filtered off, washed with water, dried, and crystallised from ethanol to give 4-cumyl-2-nitro-aniline as orange crystals m.p. 92°-4° C. with the following percentage composition by weight.
Reaction SMILES: [NH2:1][C:2]1[N:7]=[CH:6][N:5]=[C:4]2[N:8]([CH:12]([C:14]3[O:15][C:16]4[C:21]([C:22](=[O:30])[C:23]=3[C:24]3[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=3)=[CH:20][CH:19]=[CH:18][CH:17]=4)[CH3:13])[N:9]=[C:10](I)[C:3]=12.C([N:38]1[CH:42]=[C:41](B2OC(C)(C)C(C)(C)O2)[CH:40]=[N:39]1)(OC(C)(C)C)=O.C(=O)([O-])[O-].[Na+].[Na+].ClCCl>CN(C=O)C.C(O)C.O.[Pd]>[NH2:1][C:2]1[N:7]=[CH:6][N:5]=[C:4]2[N:8]([CH:12]([C:14]3[O:15][C:16]4[C:21]([C:22](=[O:30])[C:23]=3[C:24]3[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=3)=[CH:20][CH:19]=[CH:18][CH:17]=4)[CH3:13])[N:9]=[C:10]([C:41]3[CH:42]=[N:38][NH:39][CH:40]=3)[C:3]=12
Reactant: CC(C)(C)OC(=O)n1cc(B2OC(C)(C)C(C)(C)O2)cn1
Reactant: CC(c1oc2ccccc2c(=O)c1-c1ccccc1)n1nc(I)c2c(N)ncnc21
Agent: [Pd]
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CCO
Solvent: CN(C)C=O
Solvent: O
Product: CC(c1oc2ccccc2c(=O)c1-c1ccccc1)n1nc(-c2cn[nH]c2)c2c(N)ncnc21
Temperature: 80 °C
Reaction time: 12 h
Yield: 20 %

Procedure:
To a solution of Example 57b (0.400 g, 0.78 mmoles) in DMF (8 ml), ethanol (4 ml) and water (4 ml), N-Boc-pyrazole-4-boronic acid pinacol ester (0.344 g, 1.17 mmoles) and sodium carbonate (0.413 g, 3.9 mmoles) were added and the system is degassed for 30 min Tetrakis triphenylphosphine. Palladium (0.171 g, 0.148 mmoles) was added under nitrogen atmosphere and heated to 80° C. After 12 h, the reaction mixture was celite filtered, concentrated and extracted with ethyl acetate. The organic layer was dried over sodium sulphate and concentrated under reduced pressure. The crude product was purified by column chromatography with methanol:dichloromethane to afford the title compound as yellow solid (0.070 g, 19% yield). MP: 214-217° C. 1H-NMR (δ ppm, DMSO-d6, 400 MHz): δ 13.20 (s, 1H), 8.10 (s, 1H), 8.05 (s, 1H), 8.03 (dd, J=8.0, 1.6 Hz, 1H), 7.82 (m, 2H), 7.61 (d, J=8.0 Hz, 1H), 7.51 (dt, J=8.0, 0.9 Hz, 1H), (m, 3H), 7.31-6.87 (m, 5H), 5.92 (q, J=7.1 Hz, 1H), 1.87 (d, J=7.1 Hz, 3H). Mass: 449.852 (M+).
Reaction SMILES: [CH2:1]([C:3]1[CH:9]=[CH:8][CH:7]=[C:6]([CH2:10][CH3:11])[C:4]=1[NH2:5])[CH3:2].[Li]N([Si](C)(C)C)[Si](C)(C)C.[Br:22][C:23]1[CH:28]=[CH:27][C:26]([NH:29][C:30]2[N:35]=[C:34]3[C:36]4[N:43]([CH3:44])[N:42]=[C:41]([C:45](OCC)=[O:46])[C:37]=4[CH2:38][CH2:39][CH2:40][C:33]3=[CH:32][N:31]=2)=[C:25]([O:50][CH3:51])[CH:24]=1>C1COCC1>[Br:22][C:23]1[CH:28]=[CH:27][C:26]([NH:29][C:30]2[N:35]=[C:34]3[C:36]4[N:43]([CH3:44])[N:42]=[C:41]([C:45]([NH:5][C:4]5[C:6]([CH2:10][CH3:11])=[CH:7][CH:8]=[CH:9][C:3]=5[CH2:1][CH3:2])=[O:46])[C:37]=4[CH2:38][CH2:39][CH2:40][C:33]3=[CH:32][N:31]=2)=[C:25]([O:50][CH3:51])[CH:24]=1
Reactant: CCc1cccc(CC)c1N
Reactant: CCOC(=O)c1nn(C)c2c1CCCc1cnc(Nc3ccc(Br)cc3OC)nc1-2
Agent: [Li]N([Si](C)(C)C)[Si](C)(C)C
Solvent: C1CCOC1
Product: CCc1cccc(CC)c1NC(=O)c1nn(C)c2c1CCCc1cnc(Nc3ccc(Br)cc3OC)nc1-2
Temperature: 0 °C
Reaction time: 0.17 h
Yield: 90.8 %

Procedure:
To a solution of 2,6-diethylaniline (0.300 g, 2.01 mmol) in 10 mL of anhydrous THF under argon, 1M in THF solution of LiN(TMS)2 (4.02 mL, 4.02 mmol) at 0° C. were added dropwise. The mixture was stirred at 0° C. for 10 minutes then ethyl 9-[(4-bromo-2-methoxyphenyl)amino]-1-methyl-1,4,5,6-tetrahydropyrazolo[4′,3′:6,7]cyclohepta[1,2-d]pyrimidine-3-carboxylate (0.300 g, 0.67 mmol) in 10 mL of anhydrous THF at 0° C. were added dropwise. Ice bath was removed and the mixture was stirred at room temperature for 1 hour. Water (20 mL) was added and the mixture was extracted with AcOEt (2×30 mL). The organic layer was dried over anhydrous Na2SO4 and the solvent evaporated to dryness. The crude solid was purified by flash chromatography on silica gel (eluant: AcOEt/cyclohexane 1/1) to afford 0.350 g (95% yield) of the title compound as a white solid.
Reaction SMILES: [I-:1].[Cs+].II.N(OCCCCC)=O.[C:13]([O:17][C:18]([N:20]1[CH2:25][CH2:24][C:23]2[N:26](C)[C:27]([C:29]3[CH:34]=[CH:33][N:32]=[C:31](N)[N:30]=3)=[CH:28][C:22]=2[C:21]1=[O:37])=[O:19])([CH3:16])([CH3:15])[CH3:14]>COCCOC.[Cu](I)I.C(Cl)Cl>[C:13]([O:17][C:18]([N:20]1[CH2:25][CH2:24][C:23]2[NH:26][C:27]([C:29]3[CH:34]=[CH:33][N:32]=[C:31]([I:1])[N:30]=3)=[CH:28][C:22]=2[C:21]1=[O:37])=[O:19])([CH3:16])([CH3:15])[CH3:14]
Reactant: Cn1c(-c2ccnc(N)n2)cc2c1CCN(C(=O)OC(C)(C)C)C2=O
Reactant: [I-]
Agent: I[Cu]I
Agent: CCCCCON=O
Agent: II
Solvent: ClCCl
Solvent: COCCOC
Product: CC(C)(C)OC(=O)N1CCc2[nH]c(-c3ccnc(I)n3)cc2C1=O
Temperature: 80 °C
Reaction time: 4 h
Yield: 16.1 %

Procedure:
Cesium iodide (1.29 g, 4.97 mmol), iodine (0.63 g, 2.48 mmol), copper iodide (0.283 g, 1.48 mmol) and amyl nitrite (0.87 g, 7.45 mmol) were added under argon to a solution of 2-(2-amino-pyrimidin-4-yl)-1-methyl-4-oxo-1,4,6,7-tetrahydro-pyrrolo[3,2-c]-pyridine-5-carboxylic acid tert-butyl ester (synthesised as reported in Example 9) (1.137 g, 3.30 mmol) in DME (30.0 ml). The reaction mixture was stirred at 80° C. for 4 h. DCM was added to the solution (20 ml) and the organic layer was washed with a saturated solution of NaHCO3 (1×30 ml), with a saturated solution of Na2S2O3 (1×30 ml), with purite water (1×30 ml) and it was dried over Na2SO4. The filtrate was purified by flash chromatography, over silica gel, using DCM/MeOH (9.8:0.2) as eluent, to afford 2-(2-iodo-pyrimidin-4-yl)-4-oxo-1,4,6,7-tetrahydro-pyrrolo[3,2-c]pyridine-5-carboxylic acid tert-butyl ester (0.240 g, 0.53 mmol, 16%) as a yellow solid.
Reaction SMILES: Cl[C:2]1[CH:7]=[C:6]([CH2:8][O:9][Si:10]([C:13]([CH3:16])([CH3:15])[CH3:14])([CH3:12])[CH3:11])[CH:5]=[C:4]([O:17][CH3:18])[N:3]=1.N(C)(C1CCCCC1)C1CCCCC1.[C:33]([O:37][CH2:38][CH2:39][CH2:40][CH3:41])(=[O:36])[CH:34]=[CH2:35].O>O1CCOCC1.CC(C)([P](C(C)(C)C)([Pd][P](C(C)(C)C)(C(C)(C)C)C(C)(C)C)C(C)(C)C)C.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]>[CH3:14][C:13]([Si:10]([CH3:12])([CH3:11])[O:9][CH2:8][C:6]1[CH:5]=[C:4]([O:17][CH3:18])[N:3]=[C:2](/[CH:35]=[CH:34]/[C:33]([O:37][CH2:38][CH2:39][CH2:40][CH3:41])=[O:36])[CH:7]=1)([CH3:16])[CH3:15]
Reactant: COc1cc(CO[Si](C)(C)C(C)(C)C)cc(Cl)n1
Reactant: C=CC(=O)OCCCC
Agent: CC(C)(C)[P]([Pd][P](C(C)(C)C)(C(C)(C)C)C(C)(C)C)(C(C)(C)C)C(C)(C)C
Agent: [Pd]
Agent: CN(C1CCCCC1)C1CCCCC1
Solvent: C1COCCO1
Solvent: O
Product: CCCCOC(=O)/C=C/c1cc(CO[Si](C)(C)C(C)(C)C)cc(OC)n1
Temperature: 120 °C
Yield: 67.9 %

Procedure:
A solution of 2-chloro-4-({[(1,1-dimethylethyl)(dimethyl)silyl]oxy}methyl)-6-(methyloxy)pyridine (9.20 g, 32.01 mmol) in 1,4-dioxane (100 ml) was treated with Pd(Pt-Bu3)2 (327 mg, 0.64 mmol), Pd2(dba)3 (293 mg, 0.32 mmol), Cy2NMe (7.53 ml, 35.21 mmol) and n-butyl acrylate (5.96 ml, 41.62 mmol). The reaction was heated at 120° C. for 1 h and was then treated with water extracted 3× with diethyl ether, dried (magnesium sulphate), evaporated and chromatographed on silica gel (250 g), eluting with 1:4 ethyl acetate-hexane to give the desired product (8.25 g, 68%).