Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl.[CH3:2][O:3][C:4]1[CH:16]=[CH:15][C:7]([CH2:8][C@@H:9]([C:11]([O:13][CH3:14])=[O:12])[NH2:10])=[CH:6][CH:5]=1.C(N(CC)CC)C.[F:24][C:25]1[CH:26]=[C:27]([CH:33]=[CH:34][CH:35]=1)[CH:28]=[CH:29][C:30](O)=[O:31].CCN=C=NCCCN(C)C.Cl>C(Cl)Cl>[F:24][C:25]1[CH:26]=[C:27]([CH:28]=[CH:29][C:30]([NH:10][C@H:9]([C:11]([O:13][CH3:14])=[O:12])[CH2:8][C:7]2[CH:6]=[CH:5][C:4]([O:3][CH3:2])=[CH:16][CH:15]=2)=[O:31])[CH:33]=[CH:34][CH:35]=1
Reactant: COC(=O)[C@@H](N)Cc1ccc(OC)cc1
Reactant: O=C(O)C=Cc1cccc(F)c1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: COC(=O)[C@H](Cc1ccc(OC)cc1)NC(=O)C=Cc1cccc(F)c1
Yield: 99.7 %

Procedure:
The same procedures as in Example 2 were carried out from the compound obtained in Example 33 (2.0 g), triethylamine (1.4 mL), 3-fluorocinnamic acid (1.6 g), WSC.HCl (1.9 g), and methylene chloride (60 mL), to give the captioned compound (2.9 g, 99%) as an oily product.
Reaction SMILES: [S:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[CH2:6][CH2:7][OH:8].C(N(CC)CC)C.[CH3:16][S:17](Cl)(=[O:19])=[O:18]>C1COCC1>[CH3:16][S:17]([O:8][CH2:7][CH2:6][C:2]1[S:1][CH:5]=[CH:4][CH:3]=1)(=[O:19])=[O:18]
Reactant: OCCc1cccs1
Reactant: CS(=O)(=O)Cl
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: CS(=O)(=O)OCCc1cccs1

Procedure:
The 2-(2-thienyl)ethanol (Aldrich, 0.16 g, 1.2 mmol), triethylamine (0.56 mL, 4.1 mmol), and methanesulfonyl chloride (0.15 mL, 1.9 mmol) in 10 mL THF were processed as described in Example 1C to give the title compound that was used directly in the next reaction.
Reaction SMILES: [H-].[Na+].[Cl:3][C:4]1[CH:9]=[CH:8][C:7]([CH2:10][CH2:11][CH:12]([S:15]([C:18]([CH3:21])([CH3:20])[CH3:19])(=[O:17])=[O:16])[C:13]#[N:14])=[CH:6][CH:5]=1.Cl.Cl[CH2:24][N:25]1[CH:29]=[N:28][CH:27]=[N:26]1>CN(C=O)C>[Cl:3][C:4]1[CH:5]=[CH:6][C:7]([CH2:10][CH2:11][C:12]([S:15]([C:18]([CH3:21])([CH3:20])[CH3:19])(=[O:17])=[O:16])([CH2:24][N:25]2[CH:29]=[N:28][CH:27]=[N:26]2)[C:13]#[N:14])=[CH:8][CH:9]=1
Reactant: ClCn1cncn1
Reactant: CC(C)(C)S(=O)(=O)C(C#N)CCc1ccc(Cl)cc1
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CC(C)(C)S(=O)(=O)C(C#N)(CCc1ccc(Cl)cc1)Cn1cncn1
Yield: 47.3 %

Procedure:
Into a 3-neck, 300 mL round bottom flask was charged 2.0g (0.05 mole, 2.5 equivalents (eq)) of 60% NaH, which had been previously washed two times with successive 30 mL portions of hexane, in 50 mL of DMF. While stirring under nitrogen, 5.98 g (0.020 mole, 1.0 eq) of 4-(4-chlorophenyl)-2-(t-butylsulfonyl)butanenitrile in 50 mL of DMF was added dropwise over 0.5 hr. The mixture was stirred for an additional 45 minutes after which 1-(chloromethyl)-1,2,4-triazole hydrochloride (3.36 g, 0.022 mole), was added directly in two portions. The mixture was stirred at room temperature for 12 hrs, 40 ° C. for 8 hrs and 45 ° C. for 12 hrs after which analysis by GLC indicated the reaction was complete. The reaction was quenched by the addition of water and extracted with 150 mL of ethyl acetate, dried with sodium sulfate, filtered and concentrated to give 10 g of crude product. The product was purified by column chromatography on silica gel. Elution with hexane:ethyl acetate (2:1) gave 3.6 g of an oil (fractions 1-5) which was followed by elution with hexane:ethyl acetate (1:1) to give an additional 1.0 g of oil. Both fractions contained a major and minor product as observed using thin layer chromatography (TLC) in ethyl acetate:hexane (1:1). The 3.6 grams of oil was further purified by flash chromatography on silica gel with hexane:ethyl acetate (1:1). The product was collected in fractions 34-60 (20 mL fractions) and gave 1.4 g of a thick yellow oil.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[C:6]([CH3:8])[CH:5]=[C:4]([CH3:9])[C:3]=1[CH:10]1[C:18](=[O:19])[CH:17]2[CH:12]([CH:13]3[O:20][CH:16]2[CH:15]=[CH:14]3)[C:11]1=[O:21]>CO.[Pd]>[CH3:1][C:2]1[CH:7]=[C:6]([CH3:8])[CH:5]=[C:4]([CH3:9])[C:3]=1[CH:10]1[C:11](=[O:21])[CH:12]2[CH:17]([CH:16]3[O:20][CH:13]2[CH2:14][CH2:15]3)[C:18]1=[O:19]
Reactant: Cc1cc(C)c(C2C(=O)C3C4C=CC(O4)C3C2=O)c(C)c1
Agent: [Pd]
Solvent: CO
Product: Cc1cc(C)c(C2C(=O)C3C4CCC(O4)C3C2=O)c(C)c1

Procedure:
A solution of (1RS,2SR,6RS,7SR)-4-(2,4,6-trimethylphenyl)-10-oxatricyclo[5.2.1.02,6]dec-8-en-3,5-dione (205 mg, 0.66 mmol) in methanol (250 ml) is hydrogenated at 2 bar over 5% palladium on carbon (approximately 20 mgs) for 1 hour at room temperature. The catalyst is removed by filtration through diatomaceous earth and the solvent is evaporated under reduced pressure. Trituration with diethyl ether gives (1RS,2SR,6RS,7SR)-4-(2,4,6-trimethylphenyl)-10-oxatricyclo[5.2.1.02,6]decane-3,5-dione.
Reaction SMILES: [F:1][C:2]([F:31])([F:30])[C:3]1[CH:4]=[C:5]([C@H:9]([O:11][C:12](=[O:29])[NH:13][C:14]2[C:15]([CH3:28])=[N:16][O:17][C:18]=2[C:19]2[CH:24]=[CH:23][C:22](Br)=[CH:21][C:20]=2[O:26][CH3:27])[CH3:10])[CH:6]=[CH:7][CH:8]=1.[CH2:32]([O:34][C:35]([C:37]1([C:40]2[CH:45]=[CH:44][C:43](B3OC(C)(C)C(C)(C)O3)=[CH:42][CH:41]=2)[CH2:39][CH2:38]1)=[O:36])[CH3:33]>>[CH2:32]([O:34][C:35]([C:37]1([C:40]2[CH:45]=[CH:44][C:43]([C:22]3[CH:23]=[CH:24][C:19]([C:18]4[O:17][N:16]=[C:15]([CH3:28])[C:14]=4[NH:13][C:12]([O:11][C@@H:9]([C:5]4[CH:6]=[CH:7][CH:8]=[C:3]([C:2]([F:31])([F:30])[F:1])[CH:4]=4)[CH3:10])=[O:29])=[C:20]([O:26][CH3:27])[CH:21]=3)=[CH:42][CH:41]=2)[CH2:38][CH2:39]1)=[O:36])[CH3:33]
Reactant: COc1cc(Br)ccc1-c1onc(C)c1NC(=O)O[C@H](C)c1cccc(C(F)(F)F)c1
Reactant: CCOC(=O)C1(c2ccc(B3OC(C)(C)C(C)(C)O3)cc2)CC1
Product: CCOC(=O)C1(c2ccc(-c3ccc(-c4onc(C)c4NC(=O)O[C@H](C)c4cccc(C(F)(F)F)c4)c(OC)c3)cc2)CC1

Procedure:
Prepared according to the procedure described in Example 1, Step 6 using [5-(4-bromo-2-methoxy-phenyl)-3-methyl-isoxazol-4-yl]-carbamic acid (R)-1-(3-trifluoromethyl-phenyl)-ethyl ester and 1-[4-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-phenyl]-cyclopropanecarboxylic acid ethyl ester.
Reaction SMILES: Cl[C:2]1[N:3]=[N:4][C:5]([O:8][CH3:9])=[CH:6][CH:7]=1.[CH3:10][C:11]([CH3:16])([CH3:15])[C:12]([NH2:14])=[O:13].C1C=CC(P(C2C(C3C(P(C4C=CC=CC=4)C4C=CC=CC=4)=CC=C4C=3C=CC=C4)=C3C(C=CC=C3)=CC=2)C2C=CC=CC=2)=CC=1.C([O-])([O-])=O.[Cs+].[Cs+]>O1CCOCC1.CCOC(C)=O.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]>[CH3:9][O:8][C:5]1[N:4]=[N:3][C:2]([NH:14][C:12](=[O:13])[C:11]([CH3:16])([CH3:15])[CH3:10])=[CH:7][CH:6]=1
Reactant: CC(C)(C)C(N)=O
Reactant: COc1ccc(Cl)nn1
Agent: [Pd]
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Agent: O=C([O-])[O-]
Solvent: C1COCCO1
Solvent: CCOC(C)=O
Product: COc1ccc(NC(=O)C(C)(C)C)nn1
Temperature: 25 °C
Yield: 175.2 %

Procedure:
3-Chloro-6-methoxy-pyridazine (10.0 g, 69. 18 mmol) is mixed with 2,2-dimethyl-propionamide (8.40 g, 83.01 mmol), BINAP (2.15 g, 3.46 mmol), Cs2CO3 (33.8 g, 103.8 mmol) in dioxane (150 mL). It is degassed by passing N2 through for 10 min at rt. Pd2(dba)3 (3.16 g, 3.46 mmol) is then added and the resulting reaction is refluxed overnight. The reaction is cooled to rt, diluted with EtOAc (150 mL); filtered through silica gel; washed with EtOAc (2×150 mL). The filtrate is washed with H2O (2×300 mL); dried with MgSO4; filtered and concentrated. Purification of the crude material by chromatography gives the title compound (6.59 g, 31.53 mmol, 46%). 1H NMR (CDCl3): δ. 1.35 (s, 9H), 4.08 (s, 3H), 7.01 (d, J=9.7 Hz, 1H), 8.41 (d, J=9.7 Hz, 1H), 8.44 (bs, 1H) ppm. ES-MS (m/z): calcd for C10H15N3O2 (M+H)+: 210.3. found: 210.1.
Reaction SMILES: COC1C=CC(C[N:8]2[CH2:13][CH2:12][C:11]3[CH:14]=[C:15]([CH:17]4[S:21](=[O:23])(=[O:22])[NH:20][C:19](=[O:24])[CH2:18]4)[S:16][C:10]=3[CH:9]2[CH2:25][NH:26][C:27]([C:29]2[NH:30][C:31]3[C:36]([CH:37]=2)=[CH:35][C:34]([F:38])=[CH:33][CH:32]=3)=[O:28])=CC=1.C([SiH](C(C)C)C(C)C)(C)C.[F:51][C:52]([F:57])([F:56])[C:53]([OH:55])=[O:54]>C1(C)C=CC=CC=1>[F:51][C:52]([F:57])([F:56])[C:53]([OH:55])=[O:54].[O:23]=[S:21]1(=[O:22])[CH:17]([C:15]2[S:16][C:10]3[CH:9]([CH2:25][NH:26][C:27]([C:29]4[NH:30][C:31]5[C:36]([CH:37]=4)=[CH:35][C:34]([F:38])=[CH:33][CH:32]=5)=[O:28])[NH:8][CH2:13][CH2:12][C:11]=3[CH:14]=2)[CH2:18][C:19](=[O:24])[NH:20]1
Reactant: COc1ccc(CN2CCc3cc(C4CC(=O)NS4(=O)=O)sc3C2CNC(=O)c2cc3cc(F)ccc3[nH]2)cc1
Agent: CC(C)[SiH](C(C)C)C(C)C
Solvent: O=C(O)C(F)(F)F
Solvent: Cc1ccccc1
Product: O=C1CC(c2cc3c(s2)C(CNC(=O)c2cc4cc(F)ccc4[nH]2)NCC3)S(=O)(=O)N1
Yield: 18 %

Procedure:
A solution of 411-G of Example 4.11 (11 mg, 13 μmol) and triisopropylsilane (250 mL, 1.2 mmol) in trifluoroacetic acid (1.3 mL) was heated in a microwave at 170° C. for four minutes. The reaction mixture was diluted with toluene (5 mL) and evaporated. This was repeated until a residue appeared which was purified by preparative LCMS to yield the desired product (1.6 mg, 18%). 1H NMR (500 MHz, CD3OD): δ 7.46 (dd, J=8.8, 4.4 Hz, 1H), 7.32 (dd, J=9.3, 2.0 Hz, 1H), 7.19 (s, 1H), 7.14 (s, 1H), 7.08–7.04 (s, 1H), 5.44 (dd, J=8.8, 8.3 Hz, 1H), 4.03–3.98 (m, 1H), 3.98–3.84 (m, 2H), 3.79–3.70 (m, 1H), 3.52–3.42 (m, 1H), 3.41–3.39 (m, 1H), 3.33–3.27 (m, 1H), 3.13–3.01 (m, 3H); LCMS found for C20H20FN4O4S2 (M+H)+: m/z=463.
Reaction SMILES: [F:1][C:2]1[CH:9]=[C:8]([F:10])[CH:7]=[CH:6][C:3]=1[CH:4]=O.C(OC)(OC)OC.[CH2:18]([NH2:21])[CH2:19][CH3:20].[BH4-]>CO.C(Cl)Cl.C(O)(=O)C>[F:1][C:2]1[CH:9]=[C:8]([F:10])[CH:7]=[CH:6][C:3]=1[CH2:4][NH:21][CH2:18][CH2:19][CH3:20]
Reactant: CCCN
Reactant: O=Cc1ccc(F)cc1F
Agent: [BH4-]
Solvent: ClCCl
Solvent: CC(=O)O
Solvent: COC(OC)OC
Product: CCCNCc1ccc(F)cc1F
Temperature: 25 °C
Reaction time: 1 h
Yield: 71 %

Procedure:
2,4-Difluorbenzaldehyde (1.003 g, 7.055 mmol) was dissolved in methanol (5 ml). Trimethyl orthoformate (5 ml) was added. Propylamine (401 mg, 6.784 mmol) was then added and followed by acetic acid (0.2 ml). After 1 hour, DCM (5 ml) was added and followed by borohydride polymer-supported (2.5 mmol/g, 5.42 g, 13.55 mmol). The mixture was shaken at room temperature for 4 days and then filtered. The filtrate was evaporated. The residue was dissolved in acetonitrile, then divided into two portions and loaded on two columns (ISOLUTE®PRS, 10 g/70 ml, wetted with acetonitrile). It was eluted with acetonitrile, then methanol and then methanol (NH3 sat.). The product fractions were combined and evaporated. Oil product (892 mg) was obtained, yield 71%.
Reaction SMILES: [NH2:1][C:2]([NH:4][C:5]1[NH:6][C:7]2[C:12]([C:13]=1[C:14]([NH2:16])=[O:15])=[CH:11][CH:10]=[C:9]([O:17][C:18]1[CH:23]=[CH:22][C:21]([NH2:24])=[CH:20][CH:19]=1)[CH:8]=2)=[O:3].[C:25](O)(=[O:27])[CH3:26].C(N(CC)C(C)C)(C)C.F[P-](F)(F)(F)(F)F.N1(OC(N(C)C)=[N+](C)C)C2N=CC=CC=2N=N1>CN(C)C=O.O>[C:25]([NH:24][C:21]1[CH:22]=[CH:23][C:18]([O:17][C:9]2[CH:8]=[C:7]3[C:12]([C:13]([C:14]([NH2:16])=[O:15])=[C:5]([NH:4][C:2]([NH2:1])=[O:3])[NH:6]3)=[CH:11][CH:10]=2)=[CH:19][CH:20]=1)(=[O:27])[CH3:26]
Reactant: CC(=O)O
Reactant: NC(=O)Nc1[nH]c2cc(Oc3ccc(N)cc3)ccc2c1C(N)=O
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Solvent: O
Product: CC(=O)Nc1ccc(Oc2ccc3c(C(N)=O)c(NC(N)=O)[nH]c3c2)cc1
Yield: 47.6 %

Procedure:
The solution of 2-aminocarbonylamino-6-(4-aminophenyloxy)indole-3-carboxamide (Compound No.5-1, 40 mg, 0.12 mmol), acetic acid (8 μL, 0.14 mmol), N,N-diisopropylethylamine (46 μL, 0.26 mmol) and O-(7-azabenzotriazol-1-yl)-N,N,N′,N′-tetramethyluronium hexafluorophosphate (48 mg, 0.13 mmol) in anhydrous N,N-dimethylformamide (1 mL) was stirred overnight at room temperature. Water (10 mL) was added to the reaction solution, and the precipitated solid was filtered off and washed with water (10 mL). The solid was dried at 40° C. under reduced pressure to give the title compound (21 mg) as a purple solid (46%).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:26]=[CH:27][C:28]=1[F:29])[O:5][CH:6]1[CH2:11][CH2:10][N:9]([CH2:12][CH2:13][CH2:14][N:15]2C(=O)C3C(=CC=CC=3)C2=O)[CH2:8][CH2:7]1.O.NN>CCO>[F:1][C:2]1[CH:3]=[C:4]([CH:26]=[CH:27][C:28]=1[F:29])[O:5][CH:6]1[CH2:7][CH2:8][N:9]([CH2:12][CH2:13][CH2:14][NH2:15])[CH2:10][CH2:11]1
Reactant: O=C1c2ccccc2C(=O)N1CCCN1CCC(Oc2ccc(F)c(F)c2)CC1
Agent: NN
Solvent: CCO
Solvent: O
Product: NCCCN1CCC(Oc2ccc(F)c(F)c2)CC1

Procedure:
To the product of Example 3, Step (c) in EtOH (30 ml) was added hydrazine monohydrate (0.562 ml). The reaction was refluxed for 4 hrs and the solvent evaporated. Dichlorornethane (40 ml) was added and the solid by-product filtered. The organic residue was evaporated and the product purified by reverse phase HPLC {with a gradient eluent system [25% MeCN/NH4OAcaq (0.1%) to 95% MeCN//NH4OAcaq (0.1%)]} to give the sub-title compound as a solid (0.622 g).
Reaction SMILES: Cl.[CH2:2]([O:4][C:5]1[CH:10]=[CH:9][C:8]([CH:11]2[CH2:16][CH2:15][N:14]([C:17]3[CH:22]=[CH:21][C:20]([C@@H:23]([NH2:25])[CH3:24])=[CH:19][CH:18]=3)[CH2:13][CH2:12]2)=[CH:7][CH:6]=1)[CH3:3].CCN(C(C)C)C(C)C.Cl[C:36]([O:38][CH3:39])=[O:37]>C1COCC1>[CH3:39][O:38][C:36](=[O:37])[NH:25][C@H:23]([C:20]1[CH:19]=[CH:18][C:17]([N:14]2[CH2:13][CH2:12][CH:11]([C:8]3[CH:7]=[CH:6][C:5]([O:4][CH2:2][CH3:3])=[CH:10][CH:9]=3)[CH2:16][CH2:15]2)=[CH:22][CH:21]=1)[CH3:24]
Reactant: COC(=O)Cl
Reactant: CCOc1ccc(C2CCN(c3ccc([C@H](C)N)cc3)CC2)cc1
Agent: Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: C1CCOC1
Product: CCOc1ccc(C2CCN(c3ccc([C@H](C)NC(=O)OC)cc3)CC2)cc1
Temperature: 25 °C
Reaction time: 12 h

Procedure:
To a mixture of 36.1 mg (0.10 mmol) (S)-1-{4-[4-(4-ethoxy-phenyl)-piperidin-1-yl]-phenyl}-ethylamine hydrochloride (XII.1) and 42.7 μL (0.250 mmol) DIPEA in 2 mL THF are added 11.64 (0.150 mmol) methyl chloroformate at 0° C. The mixture is stirred for 12 h at rt. The solvent is removed under reduced pressure, the residue is taken up in DMF and purified by HPLC (Sunfire, narrow gradients, water (+0.1% TFA)/methanol) to yield the desired product.
Reaction SMILES: [CH3:1][N:2]([CH3:6])[CH2:3][CH2:4][SH:5].C[O-].[Na+].Cl[C:11]1[CH:12]=[CH:13][C:14]2[N:15]([CH:17]=[CH:18][N:19]=2)[N:16]=1>CO>[CH3:1][N:2]([CH3:6])[CH2:3][CH2:4][S:5][C:11]1[CH:12]=[CH:13][C:14]2[N:15]([CH:17]=[CH:18][N:19]=2)[N:16]=1
Reactant: CN(C)CCS
Reactant: Clc1ccc2nccn2n1
Agent: C[O-]
Agent: [Na+]
Solvent: CO
Product: CN(C)CCSc1ccc2nccn2n1
Temperature: 150 °C
Yield: 57.6 %

Procedure:
To 20 ml of methanol is dissolved 2.8 g of 2-dimethylaminoethanethiol. To this, 20 ml of 2M solution of sodium methoxide in methanol and 3 g of 6-chloroimidazo[1,2-b]pyridazine are added successively and the mixture is heated in a sealed tube for 4 hours at 150° C. After cooling, the solvent is evaporated and the residue is treated with water. The mixture is then extracted with methylene chloride. The organic layer is separated, washed with saturated aqueous solution of sodium chloride and dried over MgSO4. Evaporation of the solvent gives 2.5 g of the title compound as pale yellow crystals.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[N:8]1[CH:12]=[C:11]([C:13](OCC)=[O:14])[CH:10]=[N:9]1.[H-].[Al+3].[Li+].[H-].[H-].[H-].O.C(C(C(C([O-])=O)O)O)([O-])=O.[Na+].[K+]>C1COCC1>[Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[N:8]1[CH:12]=[C:11]([CH2:13][OH:14])[CH:10]=[N:9]1
Reactant: CCOC(=O)c1cnn(-c2ccccc2Cl)c1
Agent: O=C([O-])C(O)C(O)C(=O)[O-]
Agent: [Al+3]
Agent: [H-]
Solvent: C1CCOC1
Solvent: O
Product: OCc1cnn(-c2ccccc2Cl)c1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
80 mg (0.32 mmol) of the compound from Example 35A were dissolved in 2 ml of THF, and 335 μl (0.34 mmol) of a 1 N solution of lithium aluminum hydride in THF were added at −10° C. Over a period of one hour, the mixture was then warmed to RT. For work-up, 2 ml of water and 5 ml of saturated potassium sodium tartrate solution were added and the mixture was extracted twice with in each case 10 ml of ethyl acetate. The combined organic phases were dried over sodium sulfate, filtered and concentrated under reduced pressure. This gave 61 mg (83% of theory) of the target compound in a purity of 91%.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([NH2:8])=[C:4]([NH2:9])[CH:3]=1.Cl.C(O[C:14](=N)[CH2:15][O:16][C:17]1[CH:22]=[CH:21][C:20]([C:23]([F:26])([F:25])[F:24])=[CH:19][CH:18]=1)C>C(O)C>[Br:1][C:2]1[CH:7]=[CH:6][C:5]2[NH:8][C:14]([CH2:15][O:16][C:17]3[CH:22]=[CH:21][C:20]([C:23]([F:24])([F:25])[F:26])=[CH:19][CH:18]=3)=[N:9][C:4]=2[CH:3]=1
Reactant: Nc1ccc(Br)cc1N
Reactant: CCOC(=N)COc1ccc(C(F)(F)F)cc1
Agent: Cl
Solvent: CCO
Product: FC(F)(F)c1ccc(OCc2nc3cc(Br)ccc3[nH]2)cc1
Reaction time: 2.5 h
Yield: 97.7 %

Procedure:
A 5-L 4-neck round bottom flask equipped with a thermocouple, mechanical stirrer and an argon inlet adapter was charged with 4-bromo-1,2-phenylenediamine (166.4 g, 0.863 mol), ethanol (2 L), followed by the addition of 2-(4-trifluoromethyl-phenoxy)-acetimidic acid ethyl ester hydrochloride (272.0 g, 0.959 mol) and ethanol (0.9 L). The initial solution of diamine turned to a suspension upon the addition of 2-(4-trifluoromethyl-phenoxy)-acetimidic acid ethyl ester hydrochloride, and an exotherm from 17° C. to 28° C. was noted. The reaction was assayed at 2.5 h and found to be complete. The reaction was filtered though Celite (60 g) and the gray solid was washed with ethanol (200 mL) until the filtrates were no longer colored. A clean 12-L 4-neck round bottom flask equipped with a mechanical stirrer, a 1-L addition funnel and ice bath for cooling was set-up and the ethanol filtrates were transferred into the 12-L flask. While cooling the flask, water (3.5 L) was added to the ethanol, and the resulting brown suspension was stirred for 1 h in the ice bath to enhance recovery. The brown solid was filtered evenly between two Buchner funnels, each washed with cold water (150 mL, 2×200 mL), and the brown solid was air-dried for a few hours. The brown solid was transferred to two amber bottles, dried in a hi-vac oven (60 mm) at 60° C., to a constant weight and afforded a total of 331.9 g (103% isolated yield; 97.7-98%, HPLC area %) of the title compound as a brown powder.
Reaction SMILES: [Cl:1][C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[N:5]([CH2:12][CH:13]=O)[C:4](=[O:15])[CH:3]=1.[O:16]1[C:21]2[CH:22]=[CH:23][C:24]([CH2:26][N:27]([CH:35]3[CH2:40][CH2:39][NH:38][CH2:37][CH2:36]3)[C:28](=[O:34])[O:29][C:30]([CH3:33])([CH3:32])[CH3:31])=[CH:25][C:20]=2[O:19][CH2:18][CH2:17]1.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].C(=O)([O-])O.[Na+]>C(O)(=O)C.C(Cl)(Cl)Cl>[O:16]1[C:21]2[CH:22]=[CH:23][C:24]([CH2:26][N:27]([CH:35]3[CH2:40][CH2:39][N:38]([CH2:13][CH2:12][N:5]4[C:6]5[C:11](=[CH:10][CH:9]=[CH:8][CH:7]=5)[C:2]([Cl:1])=[CH:3][C:4]4=[O:15])[CH2:37][CH2:36]3)[C:28](=[O:34])[O:29][C:30]([CH3:33])([CH3:31])[CH3:32])=[CH:25][C:20]=2[O:19][CH2:18][CH2:17]1
Reactant: O=CCn1c(=O)cc(Cl)c2ccccc21
Reactant: CC(C)(C)OC(=O)N(Cc1ccc2c(c1)OCCO2)C1CCNCC1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClC(Cl)Cl
Solvent: CC(=O)O
Product: CC(C)(C)OC(=O)N(Cc1ccc2c(c1)OCCO2)C1CCN(CCn2c(=O)cc(Cl)c3ccccc32)CC1
Temperature: 25 °C
Reaction time: 1 h
Yield: 39.6 %

Procedure:
To 20 mL of a chloroform solution containing 179 mg of (4-chloro-2-oxoquinolin-1(2H)-yl)acetaldehyde and 286 mg of tert-butyl (2,3-dihydro-1,4-benzodioxin-6-ylmethyl)(piperidin-4-yl)carbamate, 47 μL of acetic acid was added, and stirred at room temperature for 1 hour. To the reaction mixture, 269 mg of sodium triacetoxyborohydride was added and stirred for 1 hour. Aqueous saturated sodium hydrogen carbonate solution was added, the organic layer was separated. The organic layer was washed with aqueous saturated sodium chloride solution, dried over anhydrous magnesium sulfate, and the solvent was removed under reduced pressure. The residue thus obtained was purified by silica gel column chromatography[Silica Gel; Kanto Chemical Co., Inc., Silica Gel 60, eluent; chloroform:methanol=50:1], to give 177 mg of tert-butyl (2,3-dihydro-1,4-benzodioxin-6-ylmethyl)(1-(2-(4-chloro-2-oxoquinolin-1(2H)-yl)ethyl)piperidin-4-yl)carbamate as a white solid.
Reaction SMILES: [CH2:1]1[C:10]2[C:5](=[CH:6][CH:7]=[C:8]([C:11]([O:13][CH3:14])=[O:12])[CH:9]=2)[CH2:4][CH2:3][N:2]1C(OC(C)(C)C)=O.FC(F)(F)C(O)=O>ClCCl>[CH2:1]1[C:10]2[C:5](=[CH:6][CH:7]=[C:8]([C:11]([O:13][CH3:14])=[O:12])[CH:9]=2)[CH2:4][CH2:3][NH:2]1
Reactant: COC(=O)c1ccc2c(c1)CN(C(=O)OC(C)(C)C)CC2
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: COC(=O)c1ccc2c(c1)CNCC2
Reaction time: 0.5 h
Yield: 199.6 %

Procedure:
At 0° C. a mixture of 16.93 g 2-tert-butyl 7-methyl 3,4-dihydroisoquinoline-2,7(1H)-dicarboxylate, 160 ml dichloromethane and 80 ml trifluoroacetic acid is stirred for 30 min. Then, the mixture is stirred for 5 h at ambient temperature. The reaction mixture is evaporated and the residue is treated with a 10% KOH solution and dichloromethane. The organic layer is dried and evaporated. 22.18 g of the title compound are obtained.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[CH:13]=[CH:12][C:11]([O:14][C:15]([F:18])([F:17])[F:16])=[CH:10][CH:9]=1.Br[C:20]1[CH:25]=[CH:24][C:23]([C:26]([CH3:29])([CH3:28])[CH3:27])=[CH:22][CH:21]=1.CC(C)([O-])C.[K+].[Cl-].[NH4+]>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].C1(P(C2C=CC=CC=2)C2C=CC3C(=CC=CC=3)C=2C2C3C(=CC=CC=3)C=CC=2P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(C)C=CC=CC=1>[C:26]([C:23]1[CH:24]=[CH:25][C:20]([NH:1][C:2]2[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=2[C:8]2[CH:13]=[CH:12][C:11]([O:14][C:15]([F:16])([F:17])[F:18])=[CH:10][CH:9]=2)=[CH:21][CH:22]=1)([CH3:29])([CH3:28])[CH3:27]
Reactant: CC(C)(C)c1ccc(Br)cc1
Reactant: Nc1ccccc1-c1ccc(OC(F)(F)F)cc1
Agent: [Pd]
Agent: CC(C)(C)[O-]
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Solvent: Cc1ccccc1
Product: CC(C)(C)c1ccc(Nc2ccccc2-c2ccc(OC(F)(F)F)cc2)cc1
Temperature: 25 °C
Reaction time: 5 h
Yield: 88.9 %

Procedure:
A mixture of 2-amino-4′-(trifluoromethoxy)biphenyl (633 mg, 2.50 mmol), 1-bromo-4-(tert-butyl)benzene (533 mg, 2.50 mmol), rac-2,2′-bis(diphenylphosphino)-1,1′-binaphthyl (124 mg, 0.2 mmol), bis(dibenzylideneacetone)palladium (0) (72 mg, 0.125 mmol), potassium tert-butoxide (1.68 g, 15.0 mmol) and toluene (10 ml) was stirred at 60° for 5 hours under argon atmosphere. After the reaction mixture was cooled to room temperature, saturated aqueous ammonium chloride. The mixture was filtered through celite and extracted with ethyl acetate. The residue obtained by evaporation of the solvent under reduced pressure was purified by column chromatography on silica gel (n-hexane:ethyl acetate=5:1) to give the title compound (857 mg, 89%) as a brown oil.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[CH:5][CH:6]=[C:7]2[C:11]=1[N:10]([CH:12]([C:16]1[CH:17]=[N:18][CH:19]=[CH:20][CH:21]=1)[CH2:13][CH2:14]O)[CH:9]=[CH:8]2.[CH2:22]([N:24](CC)CC)C.CS(Cl)(=O)=O>ClCCl>[CH3:1][O:2][C:3]1[CH:4]=[CH:5][CH:6]=[C:7]2[C:11]=1[N:10]([CH:12]([C:16]1[CH:17]=[N:18][CH:19]=[CH:20][CH:21]=1)[CH2:13][CH2:14][NH:24][CH3:22])[CH:9]=[CH:8]2
Reactant: CCN(CC)CC
Reactant: COc1cccc2ccn(C(CCO)c3cccnc3)c12
Agent: CS(=O)(=O)Cl
Solvent: ClCCl
Product: CNCCC(c1cccnc1)n1ccc2cccc(OC)c21
Reaction time: 0.5 h

Procedure:
To a solution of 3-(7-methoxy-indol-1-yl)-3-pyridin-3-yl-propan-1-ol in dichloromethane (10 ml) was added triethylamine (0.086 g) followed by methanesulfonyl chloride (0.071 g) dropwise at 0° C. The mixture was stirred for 30 minutes at the same temperature and then the reaction was quenched by partitioning between water and dichloromethane. The organic layer was washed with bicarbonate solution, dried and evaporated to dryness. The crude product was taken up in an ethanolic solution of methyl amine (33%, 4 ml), stirred for 30 minutes at room temperature and then at 100° C. in a microwave reactor. After cooling, the solvents were removed, the crude product was partitioned between dichloromethane and bicarbonate solution, and the organic layer separated. The resulting residue was purified by chromatography on silica gel eluting with mixtures of dichloromethane, methanol and ammonium hydroxide to give 0.088 g of [3-(7-methoxy-indol-1-yl)-3-pyridin-3-yl-propyl]-methyl-amine.