Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl[C:2]1[CH:22]=[CH:21][C:5]([C:6]([NH:8][CH2:9][C:10]2[C:11]([CH2:16][NH:17][C:18](=[O:20])[O-:19])=[N:12][CH:13]=[CH:14][CH:15]=2)=[O:7])=[C:4]([NH:23][CH2:24][CH2:25][C:26]2[CH:31]=[CH:30][CH:29]=[C:28]([F:32])[CH:27]=2)[N:3]=1.C([O-])([O-])=O.[K+].[K+].[C:39]1(B(O)O)[CH2:43][CH2:42][CH2:41][CH:40]=1>C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.CN1C(=O)CCC1>[C:39]1([C:2]2[CH:22]=[CH:21][C:5]([C:6]([NH:8][CH2:9][C:10]3[C:11]([CH2:16][NH:17][C:18](=[O:20])[O:19][C:5]([CH3:21])([CH3:6])[CH3:4])=[N:12][CH:13]=[CH:14][CH:15]=3)=[O:7])=[C:4]([NH:23][CH2:24][CH2:25][C:26]3[CH:31]=[CH:30][CH:29]=[C:28]([F:32])[CH:27]=3)[N:3]=2)[CH2:43][CH2:42][CH2:41][CH:40]=1
Reactant: O=C([O-])NCc1ncccc1CNC(=O)c1ccc(Cl)nc1NCCc1cccc(F)c1
Reactant: OB(O)C1=CCCC1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN1CCCC1=O
Product: CC(C)(C)OC(=O)NCc1ncccc1CNC(=O)c1ccc(C2=CCCC2)nc1NCCc1cccc(F)c1

Procedure:
A mixture of (3-((6-chloro-2-(3-fluorophenethylamino)nicotinamido)methyl)pyridin-2-yl)methylcarbamate (0.10 g, 0.19 mmol), tetrakis(triphenylphosphine)palladium(0) (0.045 g, 0.039 mmol), K2CO3 (0.081 g, 0.59 mmol), cyclopenten-1-yl boronic acid (0.026 g, 0.23 mmol) and NMP (0.2 mL) was sealed in a tube and microwaved at 150° C. for 30 min. The reaction mixture was filtered through a silica plug with EtOAc, washed with H2O, brine, dried (Na2SO4) and concentrated to give tert-butyl (3-((6-cyclopentenyl-2-(3-fluorophenethylamino)nicotinamido)methyl)pyridin-2-yl)methylcarbamate. LC/MS (M+H+) m/z 546.2.
Reaction SMILES: [Cl:1][C:2]1[CH:11]=[CH:10][C:9]2[C:8]([NH2:12])=[C:7]([Cl:13])[CH:6]=[CH:5][C:4]=2[N:3]=1.[CH:14]1([CH2:20][C:21](O)=[O:22])[CH2:19][CH2:18][CH2:17][CH2:16][CH2:15]1.C1CN([P+](Br)(N2CCCC2)N2CCCC2)CC1.F[P-](F)(F)(F)(F)F.Cl>CN1CCCC1=O.O>[Cl:1][C:2]1[CH:11]=[CH:10][C:9]2[C:4](=[CH:5][CH:6]=[C:7]([Cl:13])[C:8]=2[NH:12][C:21](=[O:22])[CH2:20][CH:14]2[CH2:19][CH2:18][CH2:17][CH2:16][CH2:15]2)[N:3]=1
Reactant: Nc1c(Cl)ccc2nc(Cl)ccc12
Reactant: O=C(O)CC1CCCCC1
Agent: Br[P+](N1CCCC1)(N1CCCC1)N1CCCC1
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN1CCCC1=O
Solvent: O
Product: O=C(CC1CCCCC1)Nc1c(Cl)ccc2nc(Cl)ccc12
Temperature: 50 °C
Yield: 31 %

Procedure:
To a stirred solution of 2,6-dichloroquinolin-5-amine (prepared as described in (d) below) (1 g) in N-methylpyrrolidinone (12 mL) was added 4-N,N-dimethylaminopyridine (1.2 g), cyclohexaneacetic acid (1 g) and PyBroP (4.4 g). The reaction mixture was heated to 50° C. for 10 hours. The mixture was cooled to room temperature and poured into water (10 mL) which was subsequently acidified to pH1 with aqueous 2M hydrochloric acid. The resulting solution was extracted with dichloromethane (3×20 mL). The combined organic extracts were dried, filtered and partially concentrated to give a white precipitate which was removed by filtration. Purification by chromatography (SiO2, methanol:dichloromethane 1:10 as eluant) gave the sub-title compound (490 mg).
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[C:9]([C:11]([NH:13][CH:14]([C:16]2[NH:20][C:19]3[CH:21]=[CH:22][C:23]([Cl:25])=[CH:24][C:18]=3[N:17]=2)[CH3:15])=[O:12])[CH:8]=[CH:7][C:3]=1[C:4]([OH:6])=O.[NH:26]1[CH2:32][CH2:31][CH2:30][NH:29][CH2:28][CH2:27]1.C(N(C(C)C)CC)(C)C.ClCl>CS(C)=O>[Cl:1][C:2]1[CH:10]=[C:9]([CH:8]=[CH:7][C:3]=1[C:4]([N:26]1[CH2:32][CH2:31][CH2:30][NH:29][CH2:28][CH2:27]1)=[O:6])[C:11]([NH:13][CH:14]([C:16]1[NH:20][C:19]2[CH:21]=[CH:22][C:23]([Cl:25])=[CH:24][C:18]=2[N:17]=1)[CH3:15])=[O:12]
Reactant: CC(NC(=O)c1ccc(C(=O)O)c(Cl)c1)c1nc2cc(Cl)ccc2[nH]1
Reactant: C1CNCCNC1
Agent: ClCl
Solvent: CS(C)=O
Solvent: CCN(C(C)C)C(C)C
Product: CC(NC(=O)c1ccc(C(=O)N2CCCNCC2)c(Cl)c1)c1nc2cc(Cl)ccc2[nH]1

Procedure:
Prepared analogously to Example 1d from 2-chloro-4-{N-[1-(5-chloro-1H-benzimidazol-2-yl)ethyl]aminocarbonyl}benzoic acid, 1,4-diazepan, PFTU, and diisopropylethylamine in DMSO at ambient temperature. HPLC-MS results: retention time: 3.69 minutes; C22H23Cl2N5O2 (460.36); mass spectrum: (M−H)−=459/461/463 (chlorine isotope).
Reaction SMILES: [C:1]([C:5]1[CH:6]=[C:7]([NH:18][C:19]([NH:21][C@@H:22]2[C:31]3[C:26](=[CH:27][CH:28]=[CH:29][CH:30]=3)[C@H:25]([O:32][C:33]3[CH:34]=[CH:35][C:36]4[N:37]([C:39]([N:42]5[CH2:47][CH2:46][CH2:45][CH2:44][CH2:43]5)=[N:40][N:41]=4)[CH:38]=3)[CH2:24][CH2:23]2)=[O:20])[N:8]([C:10]2[N:11]=[CH:12][N:13]([CH2:15][CH2:16][OH:17])[CH:14]=2)[N:9]=1)([CH3:4])([CH3:3])[CH3:2].CCN(C(C)C)C(C)C.[CH3:57][S:58](Cl)(=[O:60])=[O:59]>C(Cl)Cl>[C:1]([C:5]1[CH:6]=[C:7]([NH:18][C:19]([NH:21][C@@H:22]2[C:31]3[C:26](=[CH:27][CH:28]=[CH:29][CH:30]=3)[C@H:25]([O:32][C:33]3[CH:34]=[CH:35][C:36]4[N:37]([C:39]([N:42]5[CH2:47][CH2:46][CH2:45][CH2:44][CH2:43]5)=[N:40][N:41]=4)[CH:38]=3)[CH2:24][CH2:23]2)=[O:20])[N:8]([C:10]2[N:11]=[CH:12][N:13]([CH2:15][CH2:16][O:17][S:58]([CH3:57])(=[O:60])=[O:59])[CH:14]=2)[N:9]=1)([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)c1cc(NC(=O)N[C@H]2CC[C@@H](Oc3ccc4nnc(N5CCCCC5)n4c3)c3ccccc32)n(-c2cn(CCO)cn2)n1
Reactant: CS(=O)(=O)Cl
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: CC(C)(C)c1cc(NC(=O)N[C@H]2CC[C@@H](Oc3ccc4nnc(N5CCCCC5)n4c3)c3ccccc32)n(-c2cn(CCOS(C)(=O)=O)cn2)n1
Reaction time: 1 h

Procedure:
To an ice-bath cooled solution of Intermediate 119e (65 mg, 0.10 mmol) in DCM (1.5 mL) was added DIPEA (71 μL, 0.41 mmol) followed by methanesulfonyl chloride (16 μL, 0.20 mmol). The reaction mixture was stirred for 1 h and then quenched with water. The aqueous phase was extracted with DCM (×3) and the combined organic layers were washed with brine, dried (MgSO4) and concentrated in vacuo to afford the title compound (Quantitative). Product used in the following step without further purification. LCMS (Method 4): Rt 3.23 min, m/z 717 [MH+].
Reaction SMILES: [NH:1]1[CH2:4][CH:3]([C:5]2[N:16]([C@H:17]3[CH2:22][CH2:21][C@H:20]([CH2:23][C:24]#[N:25])[CH2:19][CH2:18]3)[C:8]3=[C:9]4[S:15][CH:14]=[CH:13][C:10]4=[N:11][CH:12]=[C:7]3[N:6]=2)[CH2:2]1.O1CCC[CH2:27]1.C=O.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>CO.C(#N)C>[CH3:27][N:1]1[CH2:4][CH:3]([C:5]2[N:16]([C@H:17]3[CH2:18][CH2:19][C@H:20]([CH2:23][C:24]#[N:25])[CH2:21][CH2:22]3)[C:8]3=[C:9]4[S:15][CH:14]=[CH:13][C:10]4=[N:11][CH:12]=[C:7]3[N:6]=2)[CH2:2]1
Reactant: C1CCOC1
Reactant: N#CC[C@H]1CC[C@H](n2c(C3CNC3)nc3cnc4ccsc4c32)CC1
Agent: C=O
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: CC#N
Solvent: CO
Product: CN1CC(c2nc3cnc4ccsc4c3n2[C@H]2CC[C@H](CC#N)CC2)C1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a solution of [trans-4-(2-azetidin-3-yl-1H-imidazo[4,5-d]thieno[3,2-b]pyridin-1-yl)cyclohexyl]acetonitrile (14 mg, 0.038 mmol) in methanol (0.5 mL)/tetrahydrofuran (0.5 mL)/acetonitrile (0.5 mL) was added 37% aq. formaldehyde solution (12 μL, 0.16 mmol). The resulting mixture was stirred at room temperature for 10 min before sodium triacetoxyborohydride (16 mg, 0.077 mmol) was added. The mixture was stirred at room temperature for 1 h and then diluted with MeOH and purified by prep-HPLC (XBridge C18 column, eluting with a gradient of acetonitrile/water containing 0.1% ammonium hydroxide, at flow rate of 60 mL/min) to give the desired product (0.8 mg, 6%). LCMS calculated for C20H24N5S (M+H)+: m/z=366.2. Found: 366.1.
Reaction SMILES: [CH3:1][NH:2]C(=O)N.C1([O:12][C:13](=O)[NH:14][CH2:15][C:16]#[C:17][C:18]2[CH:19]=[C:20]3[C:25](=[CH:26][CH:27]=2)[N:24]=[CH:23][N:22]=[C:21]3[NH:28][C:29]2[CH:34]=[CH:33][C:32]([O:35][C:36]3[CH:37]=[N:38][C:39]([CH3:42])=[CH:40][CH:41]=3)=[C:31]([Cl:43])[CH:30]=2)C=CC=CC=1.CN>CS(C)=O>[Cl:43][C:31]1[CH:30]=[C:29]([NH:28][C:21]2[C:20]3[C:25](=[CH:26][CH:27]=[C:18]([C:17]#[C:16][CH2:15][NH:14][C:13]([NH:2][CH3:1])=[O:12])[CH:19]=3)[N:24]=[CH:23][N:22]=2)[CH:34]=[CH:33][C:32]=1[O:35][C:36]1[CH:37]=[N:38][C:39]([CH3:42])=[CH:40][CH:41]=1
Reactant: CNC(N)=O
Reactant: Cc1ccc(Oc2ccc(Nc3ncnc4ccc(C#CCNC(=O)Oc5ccccc5)cc34)cc2Cl)cn1
Agent: CN
Solvent: CS(C)=O
Product: CNC(=O)NCC#Cc1ccc2ncnc(Nc3ccc(Oc4ccc(C)nc4)c(Cl)c3)c2c1
Temperature: 80 °C
Reaction time: 8 h
Yield: 90 %

Procedure:
1-{4-[3-Chloro-4-(6-methyl-pyridin-3-yloxy)-phenylamino]-quinazolin-6-yl}-prop-2-ynyl)-3-methyl-urea: A mixture of (3-{4-[3-Chloro-4-(6-methyl-pyridin-3-yloxy) phenylamino]-quinazolin-6-yl}-prop-2-ynyl)-carbamic acid phenyl ester (0.1 g, 0.18 mmol) prepared by Method B, methyl amine (2.0M methanol solution, 1 mL, 2 mmol) and DMSO (0.5 mL) was stirred at 80° C. overnight. The solvents were removed under vacuum (GeneVac HT-8) and the residue was re-dissolved in MeOH (˜1 mL). HCl gas was bubbled through the solution and EtOAc resulting in precipitation of the desired product. The title compound (80 mg, 90% yield) was obtained by filtration as a yellow solid. 1HNMR (400 MHz, CD3OD) δ 2.72 (3H,s), 2.76 (3H, s), 4.19 (2H, s), 7.49 (1H, d, J=9 Hz), 7.84 (1H, d, J=2 Hz), 7.86 (1H, d, J=2 Hz), 7.92 (1H, d, J=9 Hz), 8.12 (2H, m, J=2 Hz), 8.16 (1H, d, J=2.4 Hz), 8.60 (1H, d, J=3.2 Hz), 8.74 (1H, d, J=1.2 Hz), 8.87 (1H, s). LRMS (M+): 473.0, 475.0, 476.0.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:16])[C:4]1[CH:9]=[CH:8][C:7]([O:10][CH2:11][C:12]([OH:14])=O)=[C:6]([CH3:15])[CH:5]=1.Cl.Cl.[CH3:19][C:20]([CH3:30])([CH3:29])[CH2:21][CH2:22][N:23]1[CH2:28][CH2:27][NH:26][CH2:25][CH2:24]1>CN(C1C=CN=CC=1)C.ClCCl.C(N(CC)CC)C>[CH3:1][O:2][C:3](=[O:16])[C:4]1[CH:9]=[CH:8][C:7]([O:10][CH2:11][C:12]([N:26]2[CH2:27][CH2:28][N:23]([CH2:22][CH2:21][C:20]([CH3:30])([CH3:29])[CH3:19])[CH2:24][CH2:25]2)=[O:14])=[C:6]([CH3:15])[CH:5]=1
Reactant: COC(=O)c1ccc(OCC(=O)O)c(C)c1
Reactant: CC(C)(C)CCN1CCNCC1
Agent: CN(C)c1ccncc1
Agent: Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: COC(=O)c1ccc(OCC(=O)N2CCN(CCC(C)(C)C)CC2)c(C)c1
Temperature: 25 °C
Reaction time: 1 h
Yield: 55 %

Procedure:
WSCD (5.14 g, 27.2 mmol) and DMAP (1.64 g, 13.6 mmol) were added to a solution of 4-carboxymethoxy-3-methyl-benzoic acid methyl ester from Example E41.2 (3.04 g, 13.6 mmol) in dichloromethane (100 ml) and triethylamine (5 ml). The mixture was stirred for 1 h at room temperature then 1-(3,3-dimethyl-butyl)-piperazine dihydro-chloride from Example E4 (3.67 g, 14.9 mmol) was added. The mixture was stirred for 20 h at room temperature then solvents were removed in vacuo. The residue was dissolved in EtOAc, washed with saturated NaHCO3 then brine, dried and concentrated in vacuo. The residue was purified by flash chromatography on silica gel (eluant; EtOAc) to yield the title compound (2.8 g, 55%).
Reaction SMILES: Br[C:2]1[C:3]([C:15]([F:18])([F:17])[F:16])=[CH:4][C:5]([NH:8][C:9](=[O:14])[C:10]([CH3:13])([CH3:12])[CH3:11])=[N:6][CH:7]=1.C([Li])CCC.CN(C)[CH:26]=[O:27].Cl>O1CCCC1>[CH:26]([C:2]1[C:3]([C:15]([F:18])([F:17])[F:16])=[CH:4][C:5]([NH:8][C:9](=[O:14])[C:10]([CH3:13])([CH3:12])[CH3:11])=[N:6][CH:7]=1)=[O:27]
Reactant: CN(C)C=O
Reactant: CC(C)(C)C(=O)Nc1cc(C(F)(F)F)c(Br)cn1
Agent: Cl
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: CC(C)(C)C(=O)Nc1cc(C(F)(F)F)c(C=O)cn1
Temperature: -78 °C
Reaction time: 1 h
Yield: 56.1 %

Procedure:
Compound 6 (15.0 g, 46.2 mmol) was dissolved in 350 mL of anhydrous tetrahydrofuran and cooled to −78° C. under nitrogen. 45 mL of 2.5 M n-butyl lithium solution in tetrahydrofuran was slowly added to the reaction solution within one hour. The reaction solution was stirred at −78° C. for 1 hour, and then 15 mL of anhydrous N,N-dimethylformamide was slowly added dropwise and stirred for another 2.5 h at −78° C. To the reaction solution was added 120 mL of 1 M diluted hydrochloric acid to quench the reaction. The reaction mixture was extracted with ethyl acetate (200 mL×3). The organic layers were combined and washed with water (200 mL×3), saturated brine (200 mL) respectively, then dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated and purified by column chromatography (petroleum ether: dichloromethane:ethyl acetate=60:10:1) to give 7.1 g of white solid (56.1%). m.p. 96-98° C. 1H NMR (300 MHz, CDCl3): δ 10.32 (br s, 1 H), 9.01 (s, 1 H), 8.73 (s, 1 H), 8.40 (s, 1 H), 1.38 (s, 9 H).
Reaction SMILES: C([NH:4][C:5]1[CH:10]=[CH:9][C:8]([CH:11]([O:15][CH2:16][CH3:17])[C:12]([OH:14])=[O:13])=[CH:7][CH:6]=1)(=O)C>O.NN>[CH2:16]([O:15][CH:11]([C:8]1[CH:7]=[CH:6][C:5]([NH2:4])=[CH:10][CH:9]=1)[C:12]([OH:14])=[O:13])[CH3:17]
Reactant: CCOC(C(=O)O)c1ccc(NC(C)=O)cc1
Agent: NN
Solvent: O
Product: CCOC(C(=O)O)c1ccc(N)cc1
Yield: 37 %

Procedure:
2-(4-Acetamidophenyl)-2-ethoxyacetic acid (7.54 g, 31.8 mmol) was heated with hydrazine monohydrate (40 ml) for 16 hr, the mixture cooled then concentrated in vacuo. The residual oil was then purified by silica column chromatography (20-40% methanol in CH2Cl2 eluent) to give (±)-2-ethoxy-2-(4′-aminophenyl)-acetic acid (2.3 g, 37%) as a white foam.
Reaction SMILES: Cl[C:2]1[C:7]([C:8]#[N:9])=[C:6]([NH:10][CH2:11][CH2:12][OH:13])[N:5]=[C:4]([NH:14][CH:15]2[CH2:17][CH2:16]2)[N:3]=1.[F:18][C:19]1[CH:24]=[CH:23][C:22]([CH:25]2[CH2:30][CH2:29][NH:28][CH2:27][CH2:26]2)=[CH:21][CH:20]=1.C(N(C(C)C)C(C)C)C>O1CCOCC1>[CH:15]1([NH:14][C:4]2[N:3]=[C:2]([N:28]3[CH2:29][CH2:30][CH:25]([C:22]4[CH:21]=[CH:20][C:19]([F:18])=[CH:24][CH:23]=4)[CH2:26][CH2:27]3)[C:7]([C:8]#[N:9])=[C:6]([NH:10][CH2:11][CH2:12][OH:13])[N:5]=2)[CH2:17][CH2:16]1
Reactant: Fc1ccc(C2CCNCC2)cc1
Reactant: N#Cc1c(Cl)nc(NC2CC2)nc1NCCO
Solvent: C1COCCO1
Solvent: CCN(C(C)C)C(C)C
Product: N#Cc1c(NCCO)nc(NC2CC2)nc1N1CCC(c2ccc(F)cc2)CC1

Procedure:
In analogy to the procedure described in example 47b, 4-chloro-2-cyclopropylamino-6-(2-hydroxy-ethylamino)-pyrimidine-5-carbonitrile (example 47a) was treated with the 4-(4-fluorophenyl)-piperidine in dioxane in the presence of N-ethyl-diisopropylamine at 100° C. to yield the 2-cyclopropylamino-4-[4-(4-fluoro-phenyl)-piperidin-1-yl]-6-(2-hydroxy-ethylamino)-pyrimidine-5-carbonitrile as an amorphous, white solid; MS: [M+H]+=397.
Reaction SMILES: [CH2:1]=[CH:2][C:3](=[CH2:5])[CH3:4].[C:6]([O:14][CH3:15])(=[O:13])/[CH:7]=[CH:8]\[C:9]([O:11][CH3:12])=[O:10]>>[CH3:12][O:11][C:9]([CH:8]1[CH2:1][CH:2]=[C:3]([CH3:5])[CH2:4][CH:7]1[C:6]([O:14][CH3:15])=[O:13])=[O:10]
Reactant: COC(=O)/C=C\C(=O)OC
Reactant: C=CC(=C)C
Product: COC(=O)C1CC=C(C)CC1C(=O)OC
Temperature: 150 °C
Reaction time: 1 h
Yield: 66.7 %

Procedure:
Isoprene (350 g, 5.1 mol) and dimethyl maleate (741 g, 5.1 mol) were loaded into a stainless steel autoclave. The autoclave was sealed and heated to 150° C. The temperature of the autoclave increased to 195° C. due to the heat of the reaction. The temperature was held at 160° C. for 1 hour. Gas chromatography (GC) analysis indicated the completion of the reaction. The autoclave was then cooled to room temperature. Simple distillation of the resulting mixture provided 4-methyl-cyclohex-4-ene-1,2-dicarboxylic acid dimethyl ester (725 g, 3.4 mol, 66% yield) as a light yellow liquid.
Reaction SMILES: [CH:1]1[CH2:7][CH2:6][CH2:5][CH2:4][CH2:3][CH:2]=1.C(O[K])(C)(C)C.[CH:14](Br)([Br:16])[Br:15].CCCCCC>CCCCC>[Br:15][C:14]1([Br:16])[CH:7]2[CH:1]1[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6]2
Reactant: C1=CCCCCC1
Reactant: BrC(Br)Br
Agent: CC(C)(C)O[K]
Solvent: CCCCC
Solvent: CCCCCC
Product: BrC1(Br)C2CCCCCC21
Temperature: 0 °C
Reaction time: 8 h

Procedure:
To a magnetically stirred solution of cycloheptene (500 mg, 5.20 mmol, 1 eq) in dry Pentane (52 ml) under Ar atmosphere, tBuOK (671 mg, 5.98 mmol, 1.15 eq) was added. Suspension was cooled to 0° C. and CHBr3 (466 μl, 5.20 mmol, 1 eq) was added in a time period of six hours. Then the solution was warmed to Room Temperature (RT) and the resulting dark-brown solution was stirred overnight at RT. Reaction was controlled by TLC (Hexane as eluent) and was quenched with water (10 ml) and concentrated HCl until neutralization. Layers were separated and the aqueous layer was extracted with pentane (3×50 ml). Combined organic phases were dried over Na2SO4, filtered and concentrated under vacuum to obtain product 8,8-dibromobicyclo[5.1.0]octane as a brown oil that was used for the next step without further purification.
Reaction SMILES: CSC.B.[Br:5][C:6]1[CH:11]=[CH:10][C:9]([C@@H:12]([N:14]2[CH2:23][CH2:22][C:17]3([CH2:21][CH:20]=[CH:19][CH2:18]3)[O:16][C:15]2=[O:24])[CH3:13])=[CH:8][CH:7]=1.C([OH:28])(C)C>O1CCCC1>[Br:5][C:6]1[CH:11]=[CH:10][C:9]([C@@H:12]([N:14]2[CH2:23][CH2:22][C:17]3([CH2:21][CH:20]([OH:28])[CH2:19][CH2:18]3)[O:16][C:15]2=[O:24])[CH3:13])=[CH:8][CH:7]=1
Reactant: C[C@@H](c1ccc(Br)cc1)N1CCC2(CC=CC2)OC1=O
Reactant: CC(C)O
Agent: B
Solvent: CSC
Solvent: C1CCOC1
Product: C[C@@H](c1ccc(Br)cc1)N1CCC2(CCC(O)C2)OC1=O
Temperature: 25 °C
Reaction time: 8 h

Procedure:
Borane dimethyl sulfide complex (2 mol/L in diethyl ether, 4.64 mL) is added dropwise to a solution of 8-[(S)-1-(4-bromo-phenyl)-ethyl]-6-oxa-8-aza-spiro[4.5]dec-2-en-7-one (2.60 g) in tetrahydrofuran (30 mL) chilled in an ice bath. The cooling bath is removed and the solution is stirred at room temperature overnight. The solution is then chilled again in an ice bath and 4 M aqueous NaOH solution (2.1 mL) is added followed by the dropwise addition of hydrogen peroxide (35% in water, 6 mL). The cooling bath is removed and the mixture is warmed to 40° C. and stirred at this temperature for 1 h. The mixture is diluted with water and extracted with diethyl ether. The combined extracts are washed with water, dried (Na2SO4), and concentrated. The residue is chromatographed on silica gel (methanol/ethyl acetate 0:1→4:1) to afford a mixture of the four title compounds which is submitted to SFC (Supercritical Fluid Chromatography) on chiral phase (column: phenomenex LUX 2A, 250×20 mm, 5 μM; eluent: isopropanol containing 0.2% diethylamine/sc carbon dioxide 25:75; flow: 60 mL/min) to give the four isomers in separate fractions.
Reaction SMILES: [CH2:1]([C@H:6]1[CH2:11][CH2:10][C@H:9](/[CH:12]=[CH:13]/[CH2:14][O:15][C:16]2[CH:23]=[CH:22][C:19]([CH:20]=[O:21])=[CH:18][CH:17]=2)[CH2:8][CH2:7]1)[CH2:2][CH2:3][CH2:4][CH3:5].CC(C)=[O:26].OS(O)(=O)=O.O=[Cr](=O)=O>CC(C)=O>[CH2:1]([C@H:6]1[CH2:11][CH2:10][C@H:9](/[CH:12]=[CH:13]/[CH2:14][O:15][C:16]2[CH:17]=[CH:18][C:19]([C:20]([OH:26])=[O:21])=[CH:22][CH:23]=2)[CH2:8][CH2:7]1)[CH2:2][CH2:3][CH2:4][CH3:5]
Reactant: CCCCC[C@H]1CC[C@H](/C=C/COc2ccc(C=O)cc2)CC1
Reactant: CC(C)=O
Agent: O=[Cr](=O)=O
Agent: O=S(=O)(O)O
Product: CCCCC[C@H]1CC[C@H](/C=C/COc2ccc(C(=O)O)cc2)CC1

Procedure:
4.0 g of 4-[(E)-3-(trans-4-pentylcyclohexyl)allyloxy]benzaldehyde, 10 ml of Jones' reagent and 100 ml of acetone were reacted in an analogous manner to Example 2(b) to give 2.6 g of 4-[(E)-3-(trans-4-pentylcyclohexyl)allyloxy]benzoic acid with m.p. 215° C.
Reaction SMILES: [CH2:1]([O:5][C:6]1[C:14]([C:15]2[CH:20]=[C:19]([C:21]([F:24])([F:23])[F:22])[CH:18]=[CH:17][C:16]=2[F:25])=[CH:13][C:9]([C:10]([OH:12])=O)=[CH:8][N:7]=1)[CH2:2][CH2:3][CH3:4].CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.[B-](F)(F)(F)F.C(N(CC)C(C)C)(C)C.[NH2:57][C@@H:58]1[CH2:63][CH2:62][CH2:61][CH2:60][C@H:59]1[OH:64]>CN(C=O)C>[CH2:1]([O:5][C:6]1[C:14]([C:15]2[CH:20]=[C:19]([C:21]([F:23])([F:24])[F:22])[CH:18]=[CH:17][C:16]=2[F:25])=[CH:13][C:9]([C:10]([NH:57][C@@H:58]2[CH2:63][CH2:62][CH2:61][CH2:60][C@H:59]2[OH:64])=[O:12])=[CH:8][N:7]=1)[CH2:2][CH2:3][CH3:4]
Reactant: CCCCOc1ncc(C(=O)O)cc1-c1cc(C(F)(F)F)ccc1F
Reactant: N[C@@H]1CCCC[C@H]1O
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[B-](F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: CCCCOc1ncc(C(=O)N[C@@H]2CCCC[C@H]2O)cc1-c1cc(C(F)(F)F)ccc1F
Temperature: 25 °C
Reaction time: 18 h
Yield: 57.2 %

Procedure:
6-Butoxy-5-(2-fluoro-5-trifluoromethyl-phenyl)-nicotinic acid (0.10 g, 0.3 mmol) was dissolved in DMF (5 mL). To the solution was added TBTU (0.10 g, 0.3 mmol), N,N-diisopropylethyl amine (0.24 mL, 1.4 mmol) and (1R,2R)-2-amino-cyclohexanol (47 mg, 0.3 mmol). The reaction mixture was stirred for 18 h at room temperature. The solvent was evaporated in vacuo and the residue was purified by column chromatography on silica (n-heptane/ethyl acetate gradient) to yield 78 mg of the title compound as a light yellow solid, mp 172-178° C., MS (ISP) 455.3 (M+H)+.
Reaction SMILES: [F:1][C:2]([F:10])([F:9])[C:3]([CH2:5][C:6](=O)[CH3:7])=O.[CH3:11][NH:12][NH2:13]>>[CH3:11][N:12]1[C:6]([CH3:7])=[CH:5][C:3]([C:2]([F:10])([F:9])[F:1])=[N:13]1
Reactant: CC(=O)CC(=O)C(F)(F)F
Reactant: CNN
Product: Cc1cc(C(F)(F)F)nn1C
Temperature: 25 °C
Reaction time: 3 h
Yield: 73.1 %

Procedure:
Into 100 ml of an ethanolic solution of 25 g (0.16 mol) of trifluoroacetylacetone, there was added dropwise 7.4 g (0.16 mol) of methylhydrazine. After stirring at room temperature for 3 hours, the mixture was left to stand overnight and the solvent was evaporated to give 19.2 g of 1,5-dimethyl-3-trifluoromethylpyrazole as an oil. Following then the procedures as Reference example 1, this product was allowed to react with chlorosulfonic acid and then with thionyl chloride to obtain 29 g of 1,5-dimethyl-3-trifluoromethylpyrazole-4-sulfonyl-chloride, which was in turn reacted with aqueous ammonia (28%) in tetrahydrofuran to give 21.5 g of 1,5-dimethyl-3-trifluoromethylpyrazole-4-sulfonamide melting at 204°-206° C.
Reaction SMILES: Br[CH2:2][C:3]([C:5]1[CH:10]=[CH:9][CH:8]=[C:7]([N+:11]([O-:13])=[O:12])[CH:6]=1)=O.[C:14]1([NH2:21])[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=1[NH2:20].C([O-])(=O)C.[Na+]>C(O)C>[N+:11]([C:7]1[CH:6]=[C:5]([C:3]2[CH:2]=[N:21][C:14]3[C:15](=[CH:16][CH:17]=[CH:18][CH:19]=3)[N:20]=2)[CH:10]=[CH:9][CH:8]=1)([O-:13])=[O:12]
Reactant: Nc1ccccc1N
Reactant: O=C(CBr)c1cccc([N+](=O)[O-])c1
Agent: CC(=O)[O-]
Agent: [Na+]
Solvent: CCO
Product: O=[N+]([O-])c1cccc(-c2cnc3ccccc3n2)c1
Temperature: 25 °C
Yield: 59.2 %

Procedure:
A mixture of 2-bromo-1-(3-nitrophenyl)ethanone (20.5 g, 84 mmol), 1,2-phenylenediamine (8.6 g, 80 mmol) and sodium acetate (12.2 g, 90 mmol) in ethanol (EtOH) (250 mL) was heated at reflux for 5 hrs. The reaction mixture was cooled to room temperature, filtered, washed with EtOH and water, and dried to afford 2-(3-nitrophenyl)quinoxaline (11.9 g, 59% yield). LCMS calculated for C14H9N3O2 (M+H): 252.25. found 252; (M+H+MeCN): 293.10. found 293. 1H-NMR (400 MHz, DMSO-d6) δH: 9.62 (1H, s), 9.12 (1H, m), 8.81 (1H, m), 7.42 (1H, m), 8.30-8.10 (2H, m), 8.00-7.82 (3H, m).
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[C:6]([CH3:8])[NH:5][C:4](=[O:9])[C:3]=1[CH2:10][NH:11][C:12]([C:14]1[CH:15]=[C:16]([C:30]2[CH:35]=[CH:34][C:33]([CH2:36][N:37]3[CH2:42][CH2:41][O:40][CH2:39][CH2:38]3)=[CH:32][CH:31]=2)[CH:17]=[C:18]([N:21]([CH2:28][CH3:29])[CH:22]2[CH2:27][CH2:26][NH:25][CH2:24][CH2:23]2)[C:19]=1[CH3:20])=[O:13].[C:43](O)(=[O:48])[C:44]([CH3:47])([CH3:46])[CH3:45].C(N(CC)CC)C.C1CN([P+](ON2N=NC3C=CC=CC2=3)(N2CCCC2)N2CCCC2)CC1.F[P-](F)(F)(F)(F)F>CS(C)=O>[CH3:1][C:2]1[CH:7]=[C:6]([CH3:8])[NH:5][C:4](=[O:9])[C:3]=1[CH2:10][NH:11][C:12]([C:14]1[CH:15]=[C:16]([C:30]2[CH:35]=[CH:34][C:33]([CH2:36][N:37]3[CH2:38][CH2:39][O:40][CH2:41][CH2:42]3)=[CH:32][CH:31]=2)[CH:17]=[C:18]([N:21]([CH2:28][CH3:29])[CH:22]2[CH2:23][CH2:24][N:25]([C:43](=[O:48])[C:44]([CH3:47])([CH3:46])[CH3:45])[CH2:26][CH2:27]2)[C:19]=1[CH3:20])=[O:13]
Reactant: CCN(c1cc(-c2ccc(CN3CCOCC3)cc2)cc(C(=O)NCc2c(C)cc(C)[nH]c2=O)c1C)C1CCNCC1
Reactant: CC(C)(C)C(=O)O
Agent: F[P-](F)(F)(F)(F)F
Agent: c1ccc2c(c1)nnn2O[P+](N1CCCC1)(N1CCCC1)N1CCCC1
Solvent: CCN(CC)CC
Solvent: CS(C)=O
Product: CCN(c1cc(-c2ccc(CN3CCOCC3)cc2)cc(C(=O)NCc2c(C)cc(C)[nH]c2=O)c1C)C1CCN(C(=O)C(C)(C)C)CC1
Reaction time: 8 h
Yield: 62.8 %

Procedure:
N-((4,6-dimethyl-2-oxo-1,2-dihydropyridin-3-yl)methyl)-5-(ethyl(piperidin-4-yl)amino)-4-methyl-4′-(morpholinomethyl)-[1,1′-biphenyl]-3-carboxamide (0.2 g, 0.34 mmol) was dissolved in DMSO (2 mL) and pivalic acid (0.107 g, 1.04 mmol) and triethyl amine (0.106 g, 1.04 mmol) was added to it. The reaction mixture was stirred at room temperature for 15 min before PYBOP (0.27 g, 0.52 mmol) was added to it and stirring was continued for overnight. After completion of the reaction, reaction mixture was poured into ice, extracted with 10% MeOH/DCM. Combined organic layers were dried, concentrated to obtain crude; which then purified by column chromatography to afford the title compound (0.14 g, 60.86%).