Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]([F:20])([F:19])[C:3]1[CH:8]=[CH:7][C:6]([C@:9]23[CH2:14][C@H:13]2[CH2:12][N:11]([CH2:15][CH2:16][CH2:17][OH:18])[CH2:10]3)=[CH:5][CH:4]=1.CS([C:25]1[N:30]=[C:29]([O:31][CH2:32][C:33]2[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=2)[CH:28]=[CH:27][N:26]=1)(=O)=O>CN(C=O)C>[C:33]1([CH2:32][O:31][C:29]2[CH:28]=[CH:27][N:26]=[C:25]([O:18][CH2:17][CH2:16][CH2:15][N:11]3[CH2:12][C@H:13]4[C@:9]([C:6]5[CH:5]=[CH:4][C:3]([C:2]([F:19])([F:1])[F:20])=[CH:8][CH:7]=5)([CH2:14]4)[CH2:10]3)[N:30]=2)[CH:34]=[CH:35][CH:36]=[CH:37][CH:38]=1
Reactant: OCCCN1C[C@@H]2C[C@]2(c2ccc(C(F)(F)F)cc2)C1
Reactant: CS(=O)(=O)c1nccc(OCc2ccccc2)n1
Solvent: CN(C)C=O
Product: FC(F)(F)c1ccc([C@]23C[C@H]2CN(CCCOc2nccc(OCc4ccccc4)n2)C3)cc1
Reaction time: 0.17 h
Yield: 72.2 %

Procedure:
To a solution of 3-{(1S,5R)-1-[4-(trifluoromethyl)phenyl]-3-azabicyclo[3.1.0]hex-3-yl}-1-propanol (P11, 144 mg) in dry DMF (1.8 mL) NaH (60% in mineral oil, 24 mg) was added at 0° C. The mixture was stirred at this temperature for 10 min, then at room temperature for 15 min. A solution of 2-(methylsulfonyl)-4-[(phenylmethyl)oxy]pyrimidine (135 mg) in dry DMF (1.1 mL) was then added. The reaction mixture was stirred at room temperature for 5 hours, then hydrolysed with water and extracted with ethyl acetate. The organic phase was washed with brine, dried over anhydrous Na2SO4 and concentrated under reduced pressure. The crude product was purified by a silica SPE cartridge (5 g) eluting with dichloromethane/methanol from 100/0 to 98/2 to give the title compound as a colourless oil (171 mg).
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([N:8]2[CH:12]=[CH:11][N:10]=[C:9]2[C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)[CH:5]=[CH:4][N:3]=1.[NH2:19][C:20]1[CH:21]=[N:22][CH:23]=[CH:24][CH:25]=1.CC([O-])(C)C.[Na+]>O.CC([O-])=O.CC([O-])=O.[Pd+2]>[C:13]1([C:9]2[N:8]([C:6]3[CH:5]=[CH:4][N:3]=[C:2]([NH:19][C:20]4[CH:21]=[N:22][CH:23]=[CH:24][CH:25]=4)[N:7]=3)[CH:12]=[CH:11][N:10]=2)[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1
Reactant: Clc1nccc(-n2ccnc2-c2ccccc2)n1
Reactant: Nc1cccnc1
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: CC(C)(C)[O-]
Solvent: O
Product: c1ccc(-c2nccn2-c2ccnc(Nc3cccnc3)n2)cc1

Procedure:
To a solution of 2-chloro-4-(2-phenyl-1H-imidazol-1-yl)pyrimidine (3-2, 50 mg, 0.2 mmol), 3-aminopyridine (22 mg, 0.23 mmol), NaOtBu (26 mg, 0.27 mmol), 2-biphenyl-di-tert-butylphosphine (5 mg, 0.02 mmol) was added Pd(OAc)2 (2 mg, 0.01 mmol) at room temperature. After 72 hours the mixture was diluted with H2O and extracted with EtOAc (3×). The combined organic layers were dried (MgSO4), filtered, and concentrated. Flash column chromatography (gradient, 3-10% MeOH/CH2Cl2) gave the title compound as an off-white solid after trituration with Et2O/hexanes. 1H-NMR (500 MHz, CDCl3) δ 8.62 (d, J=1.95 Hz, 1H), 8.33 (d, J=5.37 Hz, 1H), 8.29 (d, J=4.40 Hz, 1H), 7.91 (d, J=7.08 Hz, 1H), 7.61 (d, J=1.22 Hz, 1H), 7.50 (m, 2H), 7.41 (m, 3H), 7.21 (m, 2H), 6.40 (d, J=5.37 Hz, 1H).
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:27])[CH2:5][O:6][C:7]1[CH:12]=[CH:11][C:10]([N:13](C(OC(C)(C)C)=O)[CH3:14])=[CH:9][C:8]=1[CH2:22][CH2:23][CH2:24][O:25][CH3:26])[CH3:2].C(O)(C(F)(F)F)=O>C(Cl)Cl>[CH2:1]([O:3][C:4](=[O:27])[CH2:5][O:6][C:7]1[CH:12]=[CH:11][C:10]([NH:13][CH3:14])=[CH:9][C:8]=1[CH2:22][CH2:23][CH2:24][O:25][CH3:26])[CH3:2]
Reactant: CCOC(=O)COc1ccc(N(C)C(=O)OC(C)(C)C)cc1CCCOC
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CCOC(=O)COc1ccc(NC)cc1CCCOC
Reaction time: 0.5 h

Procedure:
1.55 g (4.06 mmol) of the above prepared [4-(tert-butoxycarbonyl-methyl-amino)-2-(3-methoxy-propyl)-phenoxy]-acetic acid ethyl ester was dissolved in 41 ml of CH2Cl2 and treated dropwise with 10 ml of TFA. After additional 30 min at RT, the bulk of the solvents was removed i. V. and the residue distributed between cold NaHCO3-solution and EtOAc. Washing with cold water and brine, drying over magnesium sulfate, and evaporation of the solvents left 1.15 g of the title compound as brownish oil which was used as such for the next step.
Reaction SMILES: [C:1]1(=[O:6])[CH2:5][CH2:4][CH:3]=[CH:2]1.[N+:7]([CH3:10])([O-:9])=[O:8].N12CCCC1=NCCC2>C(O)(C)C>[N+:7]([CH2:10][CH:3]1[CH2:4][CH2:5][C:1](=[O:6])[CH2:2]1)([O-:9])=[O:8]
Reactant: C[N+](=O)[O-]
Reactant: O=C1C=CCC1
Agent: C1CN=C2CCCN2C1
Solvent: CC(C)O
Product: O=C1CCC(C[N+](=O)[O-])C1
Reaction time: 5 h
Yield: 88 %

Procedure:
100 g of 2-cyclopentenone are dissolved together with 666 ml of nitromethane and 5 g of 1,5-diazabicyclo[4.3.0]non-5-ene (DBN) in 1.1 l of isopropanol, and the solution is left to stand at room temperature for 5 h. The isopropanol is then substantially distilled in vacuo, and the residue is dissolved in ethyl acetate and the solution is washed twice with 0.5 l of dilute sulphuric acid each time. The organic phase is dried with sodium sulphate and evaporated. In this way 154 g (88% of theory) of 3-(nitromethyl)cyclopentanone are obtained sufficiently pure for the next reaction.
Reaction SMILES: C([O:4][C:5]1[CH:14]=[C:13]([CH2:15]Br)[C:12]([C:17]([F:20])([F:19])[F:18])=[CH:11][C:6]=1[C:7]([O:9][CH3:10])=[O:8])(=O)C.C(N(CC)CC)C.[NH:28]1[CH2:33][CH2:32][O:31][CH2:30][CH2:29]1>CC(C)=O>[OH:4][C:5]1[CH:14]=[C:13]([CH2:15][N:28]2[CH2:33][CH2:32][O:31][CH2:30][CH2:29]2)[C:12]([C:17]([F:18])([F:19])[F:20])=[CH:11][C:6]=1[C:7]([O:9][CH3:10])=[O:8]
Reactant: C1COCCN1
Reactant: COC(=O)c1cc(C(F)(F)F)c(CBr)cc1OC(C)=O
Solvent: CC(C)=O
Solvent: CCN(CC)CC
Product: COC(=O)c1cc(C(F)(F)F)c(CN2CCOCC2)cc1O
Reaction time: 2 h

Procedure:
To a solution of methyl 2-(acetyloxy)-4-(bromomethyl)-5-(trifluoromethyl)benzoate (may be prepared as described in Description 47; 309 mg, 0.87 mmol) in acetone (5 ml) was added triethylamine (0.24 ml, 1.74 mmol) and morpholine (0.10 ml, 1.13 mmol) the solution was stirred for 2 hours. The solvent was removed in vacuo and the residue was dissolved in ethyl acetate (10 ml), washed with water (10 ml), dried (MgSO4) and the solvent removed in vacuo to give the title compound. 300 mg.
Reaction SMILES: [Cl:1][CH2:2][CH2:3][CH2:4][S:5]([N:8]1[CH2:13][CH2:12][CH:11]([C:14]2[C:22]3[C:17](=[C:18]([C:29]([NH2:31])=[O:30])[CH:19]=[C:20]([C:23]4[CH:28]=[CH:27][CH:26]=CC=4)[CH:21]=3)[NH:16][CH:15]=2)[CH2:10][CH2:9]1)(=[O:7])=[O:6].N1CCC(C2C3C(=C(C(N)=O)C=C(C4C=C[S:49]C=4)C=3)NC=2)CC1.C(N(CC)CC)C.ClCCCS(Cl)(=O)=O>>[Cl:1][CH2:2][CH2:3][CH2:4][S:5]([N:8]1[CH2:9][CH2:10][CH:11]([C:14]2[C:22]3[C:17](=[C:18]([C:29]([NH2:31])=[O:30])[CH:19]=[C:20]([C:23]4[S:49][CH:26]=[CH:27][CH:28]=4)[CH:21]=3)[NH:16][CH:15]=2)[CH2:12][CH2:13]1)(=[O:7])=[O:6]
Reactant: NC(=O)c1cc(-c2ccsc2)cc2c(C3CCNCC3)c[nH]c12
Reactant: NC(=O)c1cc(-c2ccccc2)cc2c(C3CCN(S(=O)(=O)CCCCl)CC3)c[nH]c12
Agent: O=S(=O)(Cl)CCCCl
Solvent: CCN(CC)CC
Product: NC(=O)c1cc(-c2cccs2)cc2c(C3CCN(S(=O)(=O)CCCCl)CC3)c[nH]c12
Yield: 64 %

Procedure:
The title compound was prepared according to the general procedure for intermediate 11. 3-(4-piperidinyl)-5-(3-thienyl)-1H-indole-7-carboxamide (275 mg, 0.84 mmol) was reacted with triethyl amine (0.35 mL, 2.52 mmol) and 3-chloropropylsulfonyl chloride (0.4 mL, 1.68 mmol) to give the title compound (250 mg, 64%)
Reaction SMILES: C[O:2][C:3](=[O:34])[CH2:4][CH2:5][NH:6][C:7](=[O:33])[C:8]1[CH:13]=[CH:12][C:11]([O:14][CH2:15][C:16]2[CH:21]=[CH:20][C:19]([C:22]3[CH:27]=[CH:26][C:25]([C:28]([F:31])([F:30])[F:29])=[CH:24][CH:23]=3)=[CH:18][C:17]=2[CH3:32])=[CH:10][CH:9]=1.[OH-].[Na+].Cl>C1COCC1>[CH3:32][C:17]1[CH:18]=[C:19]([C:22]2[CH:23]=[CH:24][C:25]([C:28]([F:29])([F:31])[F:30])=[CH:26][CH:27]=2)[CH:20]=[CH:21][C:16]=1[CH2:15][O:14][C:11]1[CH:12]=[CH:13][C:8]([C:7]([NH:6][CH2:5][CH2:4][C:3]([OH:34])=[O:2])=[O:33])=[CH:9][CH:10]=1
Reactant: COC(=O)CCNC(=O)c1ccc(OCc2ccc(-c3ccc(C(F)(F)F)cc3)cc2C)cc1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Product: Cc1cc(-c2ccc(C(F)(F)F)cc2)ccc1COc1ccc(C(=O)NCCC(=O)O)cc1
Temperature: 70 °C

Procedure:
A mixture of 3-[4-(3-methyl-4′-trifluoromethyl-biphenyl-4-ylmethoxy)-benzoylamino]-propionic acid methyl ester (0.11 g) and 5M NaOH (1.5 mL) in THF (3 mL) is heated to 70° C. for 12 h. The mixture is acidified with 5M HCl, and extracted with EtOAc. The organics are washed with water and brine, and dried with MgSO4 to yield the title compound. MS (ES): 458 (M+). The structure is also confirmed by 1H NMR.
Reaction SMILES: [C:1]1([C:7]#[CH:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C([Li])CCC.CCCCCC.[F:20][C:21]([F:28])([F:27])[C:22](OCC)=[O:23].[Cl-].[NH4+]>O.C1COCC1>[F:20][C:21]([F:28])([F:27])[C:22](=[O:23])[C:8]#[C:7][C:1]1[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: CCOC(=O)C(F)(F)F
Reactant: C#Cc1ccccc1
Agent: [Cl-]
Agent: [Li]CCCC
Agent: [NH4+]
Solvent: O
Solvent: C1CCOC1
Solvent: CCCCCC
Product: O=C(C#Cc1ccccc1)C(F)(F)F
Temperature: 0 °C
Reaction time: 2 h

Procedure:
Phenylacetylene (10.8 mL, 0.098 mole) was added into a 3-Neck round bottom flask under an atmosphere of Nitrogen. THF (100 mL) was added and the reaction was stirred and cooled to 0° C. 2.5 M n-butyllithium in hexane (36 mL, 0.089 mole) was added via syringe at 0° C. over 30 min. The reaction was stirred at 0° C. for 30 minutes. Ethyl trifluoroacetate (5.31 mL, 0.045 mole) was added via syringe at −60 to −50° C. over 10 minutes. The reaction was stirred at −70° C. for 1 h. Ammonium chloride 28% w/w in water (60 mL) was added and the mixture was extracted with Ether (2×50 mL). The organic phase was dried over magnesium sulfate, filtered and concentrated in vacuo, and then allowed to stand under high vacuum for 2 h to afford an orange oil. The oil was chromatographed on silica gel with 2:1 hexanes, methylene chloride to afford the title compound as a yellow oil; 1H NMR (CDCl3, 400 MHz) δ 7.44-7.48 (tt, 2H), 7.55-7.60 (tt, 1H), 7.67-7.70 (m, 2H); 19F NMR (CDCl3, 400 MHz) δ 77.54 (s).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C@H:8]([NH2:11])[CH2:9][CH3:10])=[C:4]([F:12])[C:3]=1[C:13]([C:15]1[CH:16]=[N:17][CH:18]=[CH:19][CH:20]=1)=[O:14].Br[CH2:22][CH2:23][C:24]([NH2:26])=[O:25]>>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C@H:8]([NH:11][CH2:22][CH2:23][C:24]([NH2:26])=[O:25])[CH2:9][CH3:10])=[C:4]([F:12])[C:3]=1[C:13]([C:15]1[CH:16]=[N:17][CH:18]=[CH:19][CH:20]=1)=[O:14]
Reactant: CC[C@@H](N)c1ccc(Cl)c(C(=O)c2cccnc2)c1F
Reactant: NC(=O)CCBr
Product: CC[C@@H](NCCC(N)=O)c1ccc(Cl)c(C(=O)c2cccnc2)c1F
Reaction time: 0.5 h
Yield: 0.8 %

Procedure:
(1R)-1-{4-chloro-2-fluoro-3-[(pyridin-3-yl)carbonyl]phenyl}propan-1-amine (0.1 g, 0.34 mmol) and 3-bromopropionamide (0.052 g, 0.34 mmol) heated in a microwave tube at 120° C., 150 W for 30 minutes. Reaction purified by Prep HPLC using Basic 0A3 system, followed by silica column (Biotage SP4) eluting 0-10% MeOH in EtOAc to give 3-{[(1R)-1-{4-chloro-2-fluoro-3-[(pyridin-3-yl)carbonyl]phenyl}propyl]amino}propanamide (0.001 g).
Reaction SMILES: [NH2:1][C@@H:2]([C:7]([CH3:10])([CH3:9])[CH3:8])[C:3]([O:5][CH3:6])=[O:4].CCN(C(C)C)C(C)C.F[C:21]([O:23][C:24]12[CH2:33][CH:28]3[CH2:29][CH:30]([CH2:32][CH:26]([CH2:27]3)[CH2:25]1)[CH2:31]2)=[O:22]>C(Cl)Cl>[CH3:6][O:5][C:3](=[O:4])[C@@H:2]([NH:1][C:21]([O:23][C:24]12[CH2:33][CH:28]3[CH2:27][CH:26]([CH2:32][CH:30]([CH2:29]3)[CH2:31]1)[CH2:25]2)=[O:22])[C:7]([CH3:10])([CH3:9])[CH3:8]
Reactant: COC(=O)[C@@H](N)C(C)(C)C
Reactant: O=C(F)OC12CC3CC(CC(C3)C1)C2
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: COC(=O)[C@@H](NC(=O)OC12CC3CC(CC(C3)C1)C2)C(C)(C)C
Temperature: 25 °C
Reaction time: 8 h
Yield: 80.4 %

Procedure:
To a mixture of (S)-methyl 2-amino-3,3-dimethylbutanoate (200 mg, 1.377 mmol) and DIEA (0.481 mL, 2.75 mmol) in DCM (2 mL) solution was add 1-adamantyl fluoroformate (334 mg, 1.515 mmol). The reaction mixture was stirred at rt overnight. The compound was purified by silica gel column chromatography (20% EtOAc/80% hexane) to give a colorless oil (358 mg, 68%) as product.
Reaction SMILES: [NH2:1][C:2]1[N:7]=[CH:6][N:5]=[C:4]2[N:8]([CH:20]([C:22]3[O:23][C:24]4[C:29]([C:30](=[O:39])[C:31]=3[C:32]3[CH:37]=[CH:36][CH:35]=[C:34]([F:38])[CH:33]=3)=[CH:28][CH:27]=[CH:26][CH:25]=4)[CH3:21])[N:9]=[C:10]([C:11]3[CH:16]=[CH:15][C:14]([F:17])=[CH:13][C:12]=3[O:18]C)[C:3]=12>ClCCl.B(Br)(Br)Br>[NH2:1][C:2]1[N:7]=[CH:6][N:5]=[C:4]2[N:8]([CH:20]([C:22]3[O:23][C:24]4[C:29]([C:30](=[O:39])[C:31]=3[C:32]3[CH:37]=[CH:36][CH:35]=[C:34]([F:38])[CH:33]=3)=[CH:28][CH:27]=[CH:26][CH:25]=4)[CH3:21])[N:9]=[C:10]([C:11]3[CH:16]=[CH:15][C:14]([F:17])=[CH:13][C:12]=3[OH:18])[C:3]=12
Reactant: COc1cc(F)ccc1-c1nn(C(C)c2oc3ccccc3c(=O)c2-c2cccc(F)c2)c2ncnc(N)c12
Agent: BrB(Br)Br
Solvent: ClCCl
Product: CC(c1oc2ccccc2c(=O)c1-c1cccc(F)c1)n1nc(-c2ccc(F)cc2O)c2c(N)ncnc21
Temperature: 25 °C
Reaction time: 12 h
Yield: 34.7 %

Procedure:
To a solution of Example 90 (0.080 g, 0.152 mmoles) in dichloromethane (4 ml), BBr3 (1M in dichloromethane, 0.8 ml) was added at 0° C. and the reaction mixture was warmed to RT and then stirred for 12 h. The reaction mixture was quenched with 1.5N HCl solution and extracted with dichloromethane. The organic layer was dried over sodium sulphate and concentrated. The crude product was purified by column chromatography with methanol: dichloromethane to afford the title compound as off-white solid (0.027 g, 35% yield). MP: 235-237° C. 1H-NMR (δ ppm, DMSO-D6, 400 MHz): δ 10.66(s,1H), 8.04(d, J=9.8 Hz, 1H), 8.02(s,1H),7.84(t, J=7.0Hz,1H), 7.66(d, J=8.3Hz, 1H), 7.52(t, J=7.9Hz, 1H), 7.35(t, J=7.2Hz, 2H), 7.10(t, J=8.4 Hz, 1H), 6.96(br s,2H), 6.79(m, 2H), 5.98(q, J=7.0 Hz, 1H),1.88(d, J=7.1Hz, 3H). Mass: 512.22(M++1).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][CH2:9][C:10]2[CH:15]=[CH:14][C:13]([CH3:16])=[CH:12][CH:11]=2)=[CH:4][CH:3]=1.[CH3:17][C:18]1([CH3:28])[O:22][C:21](=[O:23])/[C:20](=[CH:24]/[C:25](Cl)=[O:26])/[O:19]1>>[CH3:17][C:18]1([CH3:28])[O:19][C:20](=[CH:24][C:25]([N:8]([C:5]2[CH:4]=[CH:3][C:2]([F:1])=[CH:7][CH:6]=2)[CH2:9][C:10]2[CH:11]=[CH:12][C:13]([CH3:16])=[CH:14][CH:15]=2)=[O:26])[C:21](=[O:23])[O:22]1
Reactant: CC1(C)OC(=O)/C(=C/C(=O)Cl)O1
Reactant: Cc1ccc(CNc2ccc(F)cc2)cc1
Product: Cc1ccc(CN(C(=O)C=C2OC(C)(C)OC2=O)c2ccc(F)cc2)cc1

Procedure:
Acylation of (4-fluorophenyl)-(4-methylbenzyl)-amine (Pombrik, S. I. et al., Izv. Akad. Nauk. SSSR Ser. Khim., 10, 1981, 2406-2408) with (Z)-2,2-dimethyl-5-(chlorocarbonylmethylene)-1,3-dioxolan-4-one as described in the preparation of Intermediate 71A gave the title amide as a syrup. 1HNMR 400 MHz (CDCl3) δ (ppm): 1.72 (6H, s, CH3), 2.31 (3H, s, CH3) 4.87 (2H, s, NCH2), 5.63 (1H, s, CH), 6.93-7.11 (8H, m, aromatics). HRMS (MAB N2) calculated for C21H20FNO4 [M−]: 369.137637: found: 369.137900.
Reaction SMILES: [CH:1]1(Br)[CH2:4][CH2:3][CH2:2]1.[CH3:6][O:7][C:8]1[C:9]([OH:23])=[C:10]([C:15]([N+:20]([O-:22])=[O:21])=[CH:16][C:17]=1[O:18][CH3:19])[C:11]([O:13][CH3:14])=[O:12].C(=O)([O-])[O-].[K+].[K+].C(=O)([O-])[O-].[Na+].[Na+]>CN(C)C=O>[CH:1]1([O:23][C:9]2[C:8]([O:7][CH3:6])=[C:17]([O:18][CH3:19])[CH:16]=[C:15]([N+:20]([O-:22])=[O:21])[C:10]=2[C:11]([O:13][CH3:14])=[O:12])[CH2:4][CH2:3][CH2:2]1
Reactant: COC(=O)c1c([N+](=O)[O-])cc(OC)c(OC)c1O
Reactant: BrC1CCC1
Agent: O=C([O-])[O-]
Agent: [K+]
Agent: [Na+]
Solvent: CN(C)C=O
Product: COC(=O)c1c([N+](=O)[O-])cc(OC)c(OC)c1OC1CCC1
Temperature: 100 °C
Reaction time: 4 h
Yield: 42.1 %

Procedure:
Cyclobutyl bromide (0.44 ml, 0.0047 mol) was added to a suspension of methyl 3,4-dimethoxy-2-hydroxy-6-nitrobenzoate (1 g, 0.0039 mol) and potassium carbonate (1.2 g, 0.0086 mol) in dimethylformamide (10 ml) and the reaction stirred at 100° C. for 4 hours. On cooling, aqueous sodium carbonate solution was added and the mixture extracted with ethyl acetate (2×40 ml). The combined organic extracts were washed with water, dried (MgSO4), filtered and evaporated under reduced pressure. The crude product was purified on silica gel eluting with diethyl ether to give the subtitle compound as a colourless oil (511 mg, 42%). Rf 0.89 (diethyl ether). MS m/z 312 (MH)+. 1H-NMR (CDCl3): Γ=1.48 (1H, m), 1.76(1H, m), 2.27 (4H, m), 2.94(9H, m), 4.70(1H, m), 7.51 (1H, s).
Reaction SMILES: [H-].[Al+3].[Li+].[H-].[H-].[H-].[C:7]([C:10]([CH2:21][CH3:22])([C:16](OCC)=[O:17])[C:11](OCC)=[O:12])(=[O:9])[CH3:8].[OH-].[Na+].P([O-])([O-])(O)=O.[K+].[K+]>C(OCC)C.O.C(O)(=O)C>[CH2:21]([C:10]([CH2:16][OH:17])([CH:7]([OH:9])[CH3:8])[CH2:11][OH:12])[CH3:22]
Reactant: CCOC(=O)C(CC)(C(C)=O)C(=O)OCC
Agent: O=P([O-])([O-])O
Agent: [Al+3]
Agent: [H-]
Solvent: CCOCC
Solvent: O
Solvent: CC(=O)O
Product: CCC(CO)(CO)C(C)O
Temperature: 25 °C
Reaction time: 3 h

Procedure:
Lithium aluminium hydride (8.0 g.) in dry diethyl ether (200 ml) was stirred at 0°, under a current of dry nitrogen. Diethyl 2-acetyl-2- ethylmalonate (30 g.) in dry ether (50 ml) was added and the mixture was stirred at room temperature for three hours. The mixture was then refluxed, with stirring, for eight hours. A solution of sodium hydroxide (20 g.) and potassium hydrogen phosphate (20 g.) in water (150 ml) was added carefully to the cooled reaction mixture. The pH was adjusted to 5.0 with glacial acetic acid. The solid was removed by filtration and washed with water (20 ml). The combined filtrates and washings were evaporated in vacuo. The residue was washed with acetone (3×100 ml). The acetone washings were evaporated in vacuo. The reside was washed with chloroform (3×100 ml) and the washings were evaporated in vacuo. 2-Ethyl-2-hydroxymethylbutan-1,3-diol was obtained as a pale yellow oil (8.0 g.) Nuclear magnetic resonance spectrum (NMR) was as follows: ' H (ppm from TMS in CDCl3, integral, number of peaks, JHz): 4.2, 3H, broad singlet; 4.1, 1H, m; 3.8, 4H, m; 1.4, 5H, m; 1.0, 3H, m.
Reaction SMILES: C(NC(C)C)(C)C.C[Li].CCOCC.[C:15]1([S:21]([CH3:24])(=[O:23])=[O:22])[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1.CON(C)[C:28](=[O:37])[C:29]1[CH:34]=[CH:33][C:32]([Br:35])=[C:31]([CH3:36])[CH:30]=1.C([O-])([O-])=O.[Na+].[Na+]>C1COCC1>[C:15]1([S:21]([CH2:24][C:28](=[O:37])[C:29]2[CH:34]=[CH:33][C:32]([Br:35])=[C:31]([CH3:36])[CH:30]=2)(=[O:23])=[O:22])[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1
Reactant: CS(=O)(=O)c1ccccc1
Reactant: CON(C)C(=O)c1ccc(Br)c(C)c1
Agent: O=C([O-])[O-]
Agent: [Li]C
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CCOCC
Solvent: CC(C)NC(C)C
Product: Cc1cc(C(=O)CS(=O)(=O)c2ccccc2)ccc1Br
Reaction time: 0.25 h
Yield: 99.9 %

Procedure:
A stirred solution of diisopropylamine (3.6 ml, 0.026 mole) in dry THF (60 ml) at -60° C. under argon was treated with 1.5M methyllithium in ether (15.3 ml, 0.023 mole). After 15 minutes, the solution was treated dropwise over 5 minutes with a solution of methyl phenyl sulphone (2.8 g, 0.020 mole) in dry THF (20 ml). The mixture was kept at -60° C. for a further 10 minutes, then treated with a solution of N-methoxy-N-methyl-4-bromo-3-methylbenzamide (D41, 4.4 g, 0.017 mole) in dry THF (30 ml) and allowed to warm to room temp. over 1.5 h. The reaction mixture was treated with 10% Na2CO3 solution (70 ml), then concentrated in vacuo to approx. 100 ml volume and extracted with ethyl acetate (2×100 ml). The combined extract was dried and concentrated in vacuo to afford the title compound as a pale orange solid (6.0 g, 100%).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[C:9]([N:11]1[CH2:16][CH2:15][NH:14][C:13](=[O:17])[CH2:12]1)=[O:10].F[B-](F)(F)F.[CH2:23]([O+](CC)CC)[CH3:24].O.C(=O)([O-])O.[Na+]>ClCCl>[Cl:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[C:9]([N:11]1[CH2:12][C:13]([O:17][CH2:23][CH3:24])=[N:14][CH2:15][CH2:16]1)=[O:10]
Reactant: CC[O+](CC)CC
Reactant: O=C1CN(C(=O)c2ccc(F)cc2Cl)CCN1
Agent: F[B-](F)(F)F
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Solvent: ClCCl
Product: CCOC1=NCCN(C(=O)c2ccc(F)cc2Cl)C1
Temperature: 25 °C
Reaction time: 18 h
Yield: 65.1 %

Procedure:
4-[(2-Chloro-4-fluorophenyl)carbonyl]-2-piperazinone (0.770 g, 3 mmol, e.g. as prepared in Intermediate 2) was dissolved in Dichloromethane (8 mL) and to this was added triethyloxonium tetrafluoroborate (1.425 g, 7.50 mmol). The reaction mixture was stirred for 18 hours at room temperature. Dichloromethane (30 ml) and iced water (15 ml) were added and the pH was adjusted to pH 7 with solid sodium hydrogen carbonate. The organic phase was separated, washed with brine, dried and evaporated to give crude 1-[(2-chloro-4-fluorophenyl)carbonyl]-5-(ethyloxy)-1,2,3,6-tetrahydropyrazine (0.556 g) which was used without further purification.
Reaction SMILES: Br[C:2]1[CH:31]=[CH:30][C:5]2[N:6]([C:9]3[CH:10]=[C:11]([NH:23][S:24]([CH:27]4[CH2:29][CH2:28]4)(=[O:26])=[O:25])[CH:12]=[C:13]([C:15]4[CH:20]=[CH:19][C:18]([F:21])=[CH:17][C:16]=4[F:22])[CH:14]=3)[CH:7]=[N:8][C:4]=2[CH:3]=1.C(=O)([O-])[O-].[K+].[K+].[CH2:38]([N:40]1[CH2:45][CH2:44][NH:43][CH2:42][CH2:41]1)[CH3:39].N1CCC[C@H]1C(O)=O>CS(C)=O.[Cu]I>[CH2:38]([N:40]1[CH2:45][CH2:44][N:43]([C:2]2[CH:31]=[CH:30][C:5]3[N:6]([C:9]4[CH:10]=[C:11]([NH:23][S:24]([CH:27]5[CH2:29][CH2:28]5)(=[O:26])=[O:25])[CH:12]=[C:13]([C:15]5[CH:20]=[CH:19][C:18]([F:21])=[CH:17][C:16]=5[F:22])[CH:14]=4)[CH:7]=[N:8][C:4]=3[CH:3]=2)[CH2:42][CH2:41]1)[CH3:39]
Reactant: CCN1CCNCC1
Reactant: O=S(=O)(Nc1cc(-c2ccc(F)cc2F)cc(-n2cnc3cc(Br)ccc32)c1)C1CC1
Agent: [Cu]I
Agent: O=C(O)[C@@H]1CCCN1
Agent: O=C([O-])[O-]
Solvent: CS(C)=O
Product: CCN1CCN(c2ccc3c(c2)ncn3-c2cc(NS(=O)(=O)C3CC3)cc(-c3ccc(F)cc3F)c2)CC1
Reaction time: 24 h
Yield: 18 %

Procedure:
To a solution of the compound of N-(5-(5-bromo-1H-benzo[d]imidazol-1-yl)-2′,4′-difluoro-[1,1′-biphenyl]-3-yl)cyclopropanesulfonamide (110 mg, 0.198 mmol) in DMSO was added potassium carbonate (54 mg, 0.391 mmol, 2.0 eq.). The mixture was degassed by N2 bubbling for 10 min followed by addition of 1-ethylpiperazine (68 mg, 0.595 mmol, 3.0 eq.) and L-proline (4.5 mg) and CuI (3 mg). Then seal tube was closed and the mixture was kept at 95° C. for 24 h. The mixture was quenched and extracted as in Example 1(d). The solvent was distilled off to afford the crude residue which was purified by preparative HPLC to give the product in 18% yield (20 mg). 1H NMR (400 MHz, DMSO-D6): δ10.3 (s, 1H), 8.98 (s, 1H), 7.77 (m, 1H), 7.66 (s, 1H), 7.60 (brs, 2H), 7.50 (brs, 2H), 7.41 (s, 1H), 7.33-7.27 (m, 2H), 3.60 (m, 4H), 3.29-3.20 (m, 4H), 3.02 (q, 2H), 2.90 (t, 1H), 1.30 (t, 3H), 1.04 (q, 4H), LC-MS (ESI): Calculated mass: 537.62; Observed mass: 538.1 [M+H]+
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([OH:8])[CH:5]=[CH:4][C:3]=1[CH2:9][C:10]([OH:12])=O.C1C=[C:17]2[N:19]=NN(O)[C:16]2=[CH:15]C=1.O.CCN=C=NCCCN(C)C.Cl.N1CCC1>C(Cl)Cl>[N:19]1([C:10](=[O:12])[CH2:9][C:3]2[CH:4]=[CH:5][C:6]([OH:8])=[CH:7][C:2]=2[F:1])[CH2:17][CH2:16][CH2:15]1
Reactant: On1nnc2ccccc21
Reactant: O=C(O)Cc1ccc(O)cc1F
Agent: C1CNC1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Solvent: O
Solvent: ClCCl
Product: O=C(Cc1ccc(O)cc1F)N1CCC1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
2-(2-fluoro-4-hydroxyphenyl)acetic acid (1 g, 5.88 mmol), HOBT monohydrate (2.7 g, 17.6 mmol), and EDC.HCl (3.38 g, 17.6 mmol) were dissolved in 25 mL of DCM and stirred at rt for 30 min. Azetidine (1 g, 17.6 mmol) was added to this mixture and the reaction aged at rt for 3 hrs. The mixture was concentrated under reduced pressure and the residue purified by column chromatography on silica gel (KP-Sil 50 g SNAP column, Biotage system) eluting with 100% EtOAc over 14 CV to give the desired product. LC/MS (m/z): 210 (M+H)+.
Reaction SMILES: [NH2:1][C@H:2]([C:10]([OH:12])=[O:11])[CH2:3][C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1.C(=O)([O-])[O-].[K+].[K+].[CH2:19](Cl)[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1>O>[CH2:19]([O:11][C:10](=[O:12])[C@H:2]([CH2:3][C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1)[N:1]([CH2:3][C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1)[CH2:19][C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1)[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1
Reactant: ClCc1ccccc1
Reactant: N[C@@H](Cc1ccccc1)C(=O)O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Product: O=C(OCc1ccccc1)[C@H](Cc1ccccc1)N(Cc1ccccc1)Cc1ccccc1
Temperature: 95 °C
Yield: 84.7 %

Procedure:
25.0 g (151.3 mmol) of (L)-phenylalanine and 66.67 g (482.4 mmol) of potassium carbonate were dissolved in 100 ml of water, and then 57.51 g (454.3 mmol) of benzyl chloride was added thereto and stirred under heat at 95° C. for 19 hours. After having been cooled to room temperature, this was subjected to phase separation with 67 ml of n-heptane and 50 ml of water. The organic layer thus separated was washed two times with 50 ml of a solution of methanol/water (=1/2) and then dried with anhydrous sodium sulfate. This was filtered and concentrated to obtain 61.64 g (90.5 wt. %, 121.8 mmol) of the above-entitled compound. The yield was 84.7%.