Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][CH2:2][C:3]1[CH2:8][N:7]([NH:9][C:10]([O:12][C:13]([CH3:16])([CH3:15])[CH3:14])=[O:11])[CH2:6][CH2:5][CH:4]=1.[O:17]1[C:22]2[CH:23]=[CH:24][C:25]([CH:27]=O)=[CH:26][C:21]=2[O:20][CH2:19][CH2:18]1.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>C1COCC1.ClCCCl>[O:17]1[C:22]2[CH:23]=[CH:24][C:25]([CH2:27][NH:1][CH2:2][C:3]3[CH2:8][N:7]([NH:9][C:10]([O:12][C:13]([CH3:16])([CH3:15])[CH3:14])=[O:11])[CH2:6][CH2:5][CH:4]=3)=[CH:26][C:21]=2[O:20][CH2:19][CH2:18]1
Reactant: CC(C)(C)OC(=O)NN1CCC=C(CN)C1
Reactant: O=Cc1ccc2c(c1)OCCO2
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: ClCCCl
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)NN1CCC=C(CNCc2ccc3c(c2)OCCO3)C1
Temperature: 25 °C
Reaction time: 5 h

Procedure:
A solution of tert-butyl 5-aminomethyl-3,6-dihydro-2H-pyridine-1-carbamate (0.7 g, 3.3 mmol) and 1,4-benzodioxane-6-carbaldehyde (0.54 g, 3.3 mmol) in THF (2 ml) and DCE (4 ml) was stirred at room temperature for 1 hour. Sodium triacetoxyborohydride (0.770 g, 3.81 mmol) was then added thereto. The reaction mixture was stirred at room temperature for 5 hours and filtered through Hydromatrix (wetted with saturated NaHCO3 solution) and the filtrate was concentrated. The residue was purified by chromatography on silica gel (EtOAc/hex 2/1 and then EtOAc/MeOH 9/1).
Reaction SMILES: [NH2:1][C:2]1[C:7]2=[C:8]([C:18]3[CH:23]=[CH:22][C:21]([NH:24][C:25]([NH:27][C:28]4[CH:33]=[CH:32][CH:31]=[C:30]([C:34]([F:37])([F:36])[F:35])[N:29]=4)=[O:26])=[CH:20][CH:19]=3)[CH:9]=[C:10]([C:11]([O:13]CCCC)=[O:12])[N:6]2[N:5]=[CH:4][N:3]=1.[OH-].[Na+].Cl>C1COCC1.CO>[NH2:1][C:2]1[C:7]2=[C:8]([C:18]3[CH:23]=[CH:22][C:21]([NH:24][C:25]([NH:27][C:28]4[CH:33]=[CH:32][CH:31]=[C:30]([C:34]([F:37])([F:36])[F:35])[N:29]=4)=[O:26])=[CH:20][CH:19]=3)[CH:9]=[C:10]([C:11]([OH:13])=[O:12])[N:6]2[N:5]=[CH:4][N:3]=1
Reactant: CCCCOC(=O)c1cc(-c2ccc(NC(=O)Nc3cccc(C(F)(F)F)n3)cc2)c2c(N)ncnn12
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: C1CCOC1
Product: Nc1ncnn2c(C(=O)O)cc(-c3ccc(NC(=O)Nc4cccc(C(F)(F)F)n4)cc3)c12
Temperature: 25 °C
Reaction time: 4 h
Yield: 72.5 %

Procedure:
A mixture of butyl 4-amino-5-{4-[({[6-(trifluoromethyl)pyridin-2-yl]amino}carbonyl)amino]phenyl}pyrrolo[2,1-f][1,2,4]triazine-7-carboxylate (96.0 mg, 0.19 mmol) and 1 N aqueous sodium hydroxide solution (0.94 mL, 0.94 mmol) in THF (4 mL) and MeOH (5 mL) was stirred at rt for 4 h and acidified to pH 3 using 2N hydrochloric acid. The organic solvents were evaporated under reduced pressure and the residue was suspended in water (5 mL). The solid was filtered, washed with water and air-dried to give 63.0 mg (74%) of the title compound. 1H-NMR (DMSO-d6) δ 12.76 (s, 1 H), 9.87 (s, 1 H), 9.71 (s, 1 H), 8.08 (s, 1 H), 8.04-7.97 (m, 2 H), 7.57 (d, J=8.6 Hz, 2 H), 7.50-7.49 (m, 1 H), 7.43 (d, J=8.5 Hz, 2 H), 7.20 (s, 1 H); MS [M+H]+=458.0; LCMS RT=2.90 min.
Reaction SMILES: [C:1]([C@H:5]1[CH2:10][CH2:9][C@H:8]([O:11][C:12]2[CH:13]=[C:14]3[C:19](=[CH:20][CH:21]=2)[CH:18]=[C:17]([CH2:22][NH:23][CH2:24][CH3:25])[CH:16]=[CH:15]3)[CH2:7][CH2:6]1)([CH3:4])([CH3:3])[CH3:2].[C:26]([O:30][CH3:31])(=[O:29])[CH:27]=[CH2:28]>CO>[C:1]([C@H:5]1[CH2:10][CH2:9][C@H:8]([O:11][C:12]2[CH:13]=[C:14]3[C:19](=[CH:20][CH:21]=2)[CH:18]=[C:17]([CH2:22][N:23]([CH2:24][CH3:25])[CH2:28][CH2:27][C:26]([O:30][CH3:31])=[O:29])[CH:16]=[CH:15]3)[CH2:7][CH2:6]1)([CH3:4])([CH3:2])[CH3:3]
Reactant: CCNCc1ccc2cc(O[C@H]3CC[C@H](C(C)(C)C)CC3)ccc2c1
Reactant: C=CC(=O)OC
Solvent: CO
Product: CCN(CCC(=O)OC)Cc1ccc2cc(O[C@H]3CC[C@H](C(C)(C)C)CC3)ccc2c1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
N-((6-((trans)-4-tert-butylcyclohexyloxy)naphthalen-2-yl)methyl)ethanamine (250 mg, 0.64 mmol, 1 equiv) was dissolved in CH3OH (1 mL). Then methyl acrylate (4 mL, 44 mmol, 70 equiv) was added to the mixture and stirred at r.t. for 16 h. The reaction was concentrated and purified by prep-TLC to give the title compound as a white solid (217 mg, 52%), (mobile phase:EA/PE=1:8). ESI-MS (M+1)+: 426.3, HPLC: 97.34%. 1H NMR (400 MHz, CDCl3) δ: 7.71˜7.60 (m, 3H), 7.44˜7.38 (m, 1H), 7.16˜7.09 (m, 2H), 4.30˜4.20 (m, 1H), 3.69 (s, 2H), 3.64 (s, 3H), 2.85 (t, 2H), 2.65˜2.46 (m, 4H), 2.31˜2.24 (m, 2H), 1.92˜1.85 (m, 2H), 1.49˜1.37 (m, 2H), 1.30˜1.10 (m, 3H), 1.05 (t, 3H), 0.89 (s, 9H).
Reaction SMILES: [C:1]([C:3]1[CH:8]=[CH:7][C:6](B(O)O)=[CH:5][C:4]=1[F:12])#[N:2].Cl[C:14]1[N:19]=[C:18]([NH:20][CH3:21])[N:17]=[C:16]([N:22]2[C@H:27]([CH2:28][CH3:29])[CH2:26][O:25][C@H:24]([C:30]([NH:32][CH2:33][C:34]3[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=3)=[O:31])[CH2:23]2)[CH:15]=1.C([O-])(O)=O.[Na+]>O1CCOCC1.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>[C:1]([C:3]1[CH:8]=[CH:7][C:6]([C:14]2[N:19]=[C:18]([NH:20][CH3:21])[N:17]=[C:16]([N:22]3[C@H:27]([CH2:28][CH3:29])[CH2:26][O:25][C@H:24]([C:30]([NH:32][CH2:33][C:34]4[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=4)=[O:31])[CH2:23]3)[CH:15]=2)=[CH:5][C:4]=1[F:12])#[N:2]
Reactant: CC[C@@H]1CO[C@H](C(=O)NCc2ccccc2)CN1c1cc(Cl)nc(NC)n1
Reactant: N#Cc1ccc(B(O)O)cc1F
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: [Na+]
Solvent: C1COCCO1
Product: CC[C@@H]1CO[C@H](C(=O)NCc2ccccc2)CN1c1cc(-c2ccc(C#N)c(F)c2)nc(NC)n1
Temperature: 25 °C
Reaction time: 2 h
Yield: 95.6 %

Procedure:
(4-Cyano-3-fluorophenyl)boronic acid (0.266 g, 1.61 mmol) was added to a 20 mL microwave vessel followed by the addition of Pd(PPh3)4 (0.047 g, 0.040 mmol) and (2S,5R)-4-[6-chloro-2-(methylamino)-4-pyrimidinyl]-5-ethyl-N-(phenylmethyl)-2-morpholinecarboxamide (0.314 g, 0.805 mmol) dissolved in 1,4-dioxane (5 mL). Saturated aqueous NaHCO3 (2.5 mL) was added and the reaction was irradiated at 130° C. for 30 minutes. SiliaBond® Thiol (3.10 g, 4.03 mmol) was added to the reaction and it was stirred at room temperature for 2 hours and then filtered. The filtrate was then diluted with H2O and extracted with EtOAc (×2). The organics were dried and concentrated to afford the title compound (0.365 g) as a dark brown oil. LC-MS (ES) m/z=475 [M+H]+.
Reaction SMILES: C(O)(=O)C.[C:5]1([NH:11][NH2:12])[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1.[CH3:13][C:14](=O)[CH2:15][CH3:16]>C(O)C>[CH3:13]/[C:14](=[N:12]\[NH:11][C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1)/[CH2:15][CH3:16]
Reactant: CCC(C)=O
Reactant: NNc1ccccc1
Solvent: CC(=O)O
Solvent: CCO
Product: CC/C(C)=N/Nc1ccccc1

Procedure:
Add acetic acid (1.00 mL, 17.45 mmol) and phenyl hydrazine (1.98 mL, 20.00 mmol) to a solution of 2-butanone (2.15 mL, 24.00 mmol) in ethanol (90 mL) at room temperature. Stir the reaction for 1 hr., then remove the solvents in vacuo to give a N-[1-methyl-prop-(E)-ylidene]-N′-phenyl-hydrazine as a crude orange oil (3.21 g, 99%). MS (m/z): 163 (M+1).
Reaction SMILES: [N:1]1[C:9]2[C:4](=[N:5][CH:6]=[CH:7][CH:8]=2)[S:3][C:2]=1[SH:10].[F:11][C:12]([F:18])=[C:13]([F:17])[CH2:14][CH2:15]Br.C(=O)([O-])[O-].[K+].[K+].O>C(N(CC)C=O)C>[F:17][C:13](=[C:12]([F:18])[F:11])[CH2:14][CH2:15][S:10][C:2]1[S:3][C:4]2[C:9]([N:1]=1)=[CH:8][CH:7]=[CH:6][N:5]=2
Reactant: Sc1nc2cccnc2s1
Reactant: FC(F)=C(F)CCBr
Agent: CCN(C=O)CC
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Product: FC(F)=C(F)CCSc1nc2cccnc2s1
Temperature: 60 °C
Reaction time: 24 h
Yield: 87.4 %

Procedure:
A solution of thiazolo[5,4-b]pyridine-2-thiol (6.2 g) in N,N-diethyl formamide under nitrogen was treated with 1,1,2-trifluoro-4-bromobutene (8.3 g) and potassium carbonate (1.5 g), stirred at 60° C. for 24 hours, cooled, and poured into water. The resultant aqueous mixture was extracted with diethyl ether. The organic extract was dried over anhydrous sodium sulfate and concentrated in vacuo to obtain a residue. Column chromatography of the residue using silica gel and a 9:1 hexanes/ethyl acetate solution gave the title product as a colorless oil (8.9 g).
Reaction SMILES: [O:1]([C:8]1[CH:9]=[C:10]([C:14]23[CH2:21][CH2:20][C:17]([CH2:22][CH2:23][O:24][CH2:25][C:26]([O:28][C:29]([CH3:32])([CH3:31])[CH3:30])=[O:27])([CH2:18][CH2:19]2)[CH2:16][O:15]3)[CH:11]=[CH:12][CH:13]=1)[C:2]1C=[CH:6][CH:5]=[CH:4][CH:3]=1.[O:33](C1C=C(C23CCC(CC(O)=O)(CC2)CO3)C=CC=1)C1C=CC=CC=1.O1CCCCC1OC1C=C(C23CCC(CC(OC)=O)(CC2)CO3)C=CC=1>>[O:33]1[CH2:6][CH2:5][CH2:4][CH2:3][CH:2]1[O:1][C:8]1[CH:9]=[C:10]([C:14]23[CH2:21][CH2:20][C:17]([CH2:22][CH2:23][O:24][CH2:25][C:26]([O:28][C:29]([CH3:32])([CH3:31])[CH3:30])=[O:27])([CH2:18][CH2:19]2)[CH2:16][O:15]3)[CH:11]=[CH:12][CH:13]=1
Reactant: O=C(O)CC12CCC(c3cccc(Oc4ccccc4)c3)(CC1)OC2
Reactant: CC(C)(C)OC(=O)COCCC12CCC(c3cccc(Oc4ccccc4)c3)(CC1)OC2
Agent: COC(=O)CC12CCC(c3cccc(OC4CCCCO4)c3)(CC1)OC2
Product: CC(C)(C)OC(=O)COCCC12CCC(c3cccc(OC4CCCCO4)c3)(CC1)OC2

Procedure:
tert-Butyl 2-(2-(1-(3-(tetrahydro-2H-pyran-2-yloxy)phenyl)-2-oxabicyclo[2.2.2]octan-4-yl)ethoxy)acetate was prepared using a procedure analogous to tert-butyl 2-(2-(1-(3-phenoxyphenyl)-2-oxabicyclo[2.2.2]octan-4-yl)ethoxy)acetate except that 2-(1-(3-phenoxyphenyl)-2-oxabicyclo[2.2.2]octan-4-yl)acetic acid was replace with methyl 2-(1-(3-(tetrahydro-2H-pyran-2-yloxy)phenyl)-2-oxabicyclo[2.2.2]octan-4-yl)acetate. The title compound was obtained (1 g, 2.24 mmol, 91% yield) as a clear oil. 1H NMR (500 MHz, CDCl3) δ 7.23-7.19 (m, 1H), 7.12-7.09 (m, 1H), 7.02-6.98 (m, 1H), 6.93 (ddd, J=8.3, 2.5, 0.8 Hz, 1H), 5.43 (t, J=3.3 Hz, 1H), 5.31 (s, 1H), 3.94 (s, 2H), 3.88-3.86 (m, 2H), 3.63-3.54 (m, 3H), 2.05-1.99 (m, 5H), 1.88-1.82 (m, 2H), 1.75-1.69 (m, 5H), 1.69-1.56 (m, 4H), 1.55-1.51 (m, 2H), 1.50 (s, 9H).
Reaction SMILES: Br[C:2]1[CH:3]=[N:4][CH:5]=[CH:6][C:7]=1[C:8]#[N:9].O=P12OP3(OP(OP(O3)(O1)=O)(=O)O2)=O.[CH3:24][C:25]1[CH:30]=[CH:29][C:28](B(O)O)=[CH:27][CH:26]=1>>[C:8]([C:7]1[CH:6]=[CH:5][N:4]=[CH:3][C:2]=1[C:28]1[CH:29]=[CH:30][C:25]([CH3:24])=[CH:26][CH:27]=1)#[N:9]
Reactant: N#Cc1ccncc1Br
Reactant: Cc1ccc(B(O)O)cc1
Agent: O=P12OP3(=O)OP(=O)(O1)OP(=O)(O2)O3
Product: Cc1ccc(-c2cnccc2C#N)cc1

Procedure:
Synthetic Scheme XXVI shows the 6-step preparation of the alkylating reagent 3-(4bromomethylphenyl)-4-cyanopyridine (66) from 4-picoline (67) (Aldrich). In step 1, 4-picoline was brominated with bromine in fuming sulfuric acid at high temperatures to give 3-bromo-4-picoline (68). In step 2, the picoline 68 was oxidized to the corresponding carboxylic acid 69 with KMnO4. In step 3, the acid 69 was first converted to its acid chloride with oxalyl chloride and subsequently treated with condensed ammonia to give the amide 70. In step 4, the amide 70 was converted to 3-bromo-4-cyanopyridine (71) by treatment with P2O5 at high temperatures. In step 5, the nitrile 71 was coupled with 4-methylphenylboronic acid (56) (Scheme XXIV) using Snieckus conditions (Scheme XIII) to give 4-cyano-3-(4-methylphenyl)pyridine (72). In step 6, 72 was brominated with NBS/AIBN in carbon tetrachloride at reflux to give the desired alkylating reagent 66.
Reaction SMILES: [F:1][C:2]1[CH:10]=[C:9]2[C:5]([CH:6]=[CH:7][NH:8]2)=[C:4]([C:11]2[N:12]=[C:13]([N:30]3[CH2:35][CH2:34][O:33][CH2:32][CH2:31]3)[C:14]3[S:19][C:18]([CH2:20][N:21]4[CH2:26][CH2:25]N5C[CH2:28][CH2:29][C@H:23]5[CH2:22]4)=[CH:17][C:15]=3[N:16]=2)[CH:3]=1.Cl.C(O[C:42]([N:44]1CC2(CCNCC2)C1)=O)(C)(C)C.C(O)(C(F)(F)F)=O.C(Cl)Cl>>[CH2:42]1[C:29]2([CH2:23][CH2:22][N:21]([CH2:20][C:18]3[S:19][C:14]4[C:13]([N:30]5[CH2:35][CH2:34][O:33][CH2:32][CH2:31]5)=[N:12][C:11]([C:4]5[CH:3]=[C:2]([F:1])[CH:10]=[C:9]6[C:5]=5[CH:6]=[CH:7][NH:8]6)=[N:16][C:15]=4[CH:17]=3)[CH2:26][CH2:25]2)[CH2:28][NH:44]1
Reactant: Fc1cc(-c2nc(N3CCOCC3)c3sc(CN4CCN5CCC[C@H]5C4)cc3n2)c2cc[nH]c2c1
Reactant: CC(C)(C)OC(=O)N1CC2(CCNCC2)C1
Agent: Cl
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: Fc1cc(-c2nc(N3CCOCC3)c3sc(CN4CCC5(CC4)CNC5)cc3n2)c2cc[nH]c2c1

Procedure:
Prepared according to the method used in the preparation of 2-(6-fluoro-1H-indol-4-yl)-6-[(S)-1-(hexahydro-pyrrolo[1,2-a]pyrazin-2-yl)methyl]-4-morpholin-4-yl-thieno-[3,2-d]pyrimidine using 2,7-diaza-spiro[3.5]nonane-2-carboxylic acid tert-butyl ester hydrochloride in place of (S)-octahydro-pyrrolo[1,2-a]pyrazine, followed by BOC-deprotection using TFA:DCM (1:1). The title compound was obtained as a white solid (27 mg, 44%).
Reaction SMILES: [NH2:1][C:2]1[CH:9]=[C:8]([O:10][CH3:11])[C:7]([O:12][CH3:13])=[CH:6][C:3]=1[C:4]#[N:5].[N:14]1[CH:19]=[CH:18][CH:17]=[C:16]([C:20]2([CH2:25][C:26](O)=[O:27])[NH:24][CH:23]=[CH:22][S:21]2)[CH:15]=1>>[C:4]([C:3]1[CH:6]=[C:7]([O:12][CH3:13])[C:8]([O:10][CH3:11])=[CH:9][C:2]=1[NH:1][C:26](=[O:27])[CH2:25][C:20]1([C:16]2[CH:15]=[N:14][CH:19]=[CH:18][CH:17]=2)[NH:24][CH:23]=[CH:22][S:21]1)#[N:5]
Reactant: COc1cc(N)c(C#N)cc1OC
Reactant: O=C(O)CC1(c2cccnc2)NC=CS1
Product: COc1cc(C#N)c(NC(=O)CC2(c3cccnc3)NC=CS2)cc1OC

Procedure:
This compound was prepared according to the method described in Example 1c by employing 2-amino-4,5-dimethoxybenzonitrile (Aldrich) and 2-(3-pyridyl)-thiazole acetic acid (Example 2, Step b). Mp: 65-67° C. MS m/z: 381.1 (M+1). Calc'd for C19H16N4O3S: 380.09.
Reaction SMILES: [CH3:1][NH2:2].O.CS[C:6]([NH:11][CH2:12][CH2:13][S:14][CH2:15][C:16]1[CH:21]=[C:20]([O:22][CH3:23])[CH:19]=[CH:18][N:17]=1)=[CH:7][N+:8]([O-:10])=[O:9]>C(O)C>[CH3:1][NH:2][C:6]([NH:11][CH2:12][CH2:13][S:14][CH2:15][C:16]1[CH:21]=[C:20]([O:22][CH3:23])[CH:19]=[CH:18][N:17]=1)=[CH:7][N+:8]([O-:10])=[O:9]
Reactant: CN
Reactant: COc1ccnc(CSCCNC(=C[N+](=O)[O-])SC)c1
Solvent: CCO
Solvent: O
Product: CNC(=C[N+](=O)[O-])NCCSCc1cc(OC)ccn1
Reaction time: 0.33 h

Procedure:
Methylamine in ethanol (33% 20 cc) was added to 1-methylthio-1-[2-(4-methoxy-2-pyridylmethylthio)ethylamino]-2-nitroethylene monohydrate (2.01 g) and the mixture was stirred at 18° for 20 minutes and evaporated to an oil which was crystallised from propan-2-ol to give the title product (1.1 g) m.p. 107°-108.5°.
Reaction SMILES: [Br:1][C:2]1[CH:10]=[CH:9][CH:8]=[C:7]2[C:3]=1[C:4](=[O:12])[C:5](=[O:11])[NH:6]2.[H-].[Na+].[F:15][C:16]1[CH:17]=[C:18]([CH:21]=[CH:22][CH:23]=1)[CH2:19]Br>CN(C=O)C>[Br:1][C:2]1[CH:10]=[CH:9][CH:8]=[C:7]2[C:3]=1[C:4](=[O:12])[C:5](=[O:11])[N:6]2[CH2:19][C:18]1[CH:21]=[CH:22][CH:23]=[C:16]([F:15])[CH:17]=1
Reactant: O=C1Nc2cccc(Br)c2C1=O
Reactant: Fc1cccc(CBr)c1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: O=C1C(=O)N(Cc2cccc(F)c2)c2cccc(Br)c21
Reaction time: 0.33 h

Procedure:
4-Bromo-1H-indole-2,3-dione (6.38 g) was dissolved in 100 mL of DMF and at 0° C., and 60% NaH (1.32 g) was added in portions. The mixture was stirred for 20 minutes before adding 3-fluorobenzyl bromide. The solution was stirred for approximately 30 minutes, quenched with water, and partitioned between water and diethyl ether. The organic layer was dried over sodium sulfate and evaporated to dryness under reduced pressure to yield 9.18 g 4-Bromo-1-(3-fluoro-benzyl)-1H-indole-2,3-dione that was sufficiently pure for use in step 2 below. MS: 385 (M+H)+.
Reaction SMILES: Cl.[NH2:2][C:3]1[C:8]([O:9][CH2:10][C:11](N)=[O:12])=[C:7]([Cl:14])[N:6]=[C:5](/[CH:15]=[CH:16]/[C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[N:4]=1.[CH2:23]([OH:25])[CH3:24]>>[NH2:2][C:3]1[C:8]([O:9][CH2:10][C:11]([O:25][CH2:23][CH3:24])=[O:12])=[C:7]([Cl:14])[N:6]=[C:5](/[CH:15]=[CH:16]/[C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[N:4]=1
Reactant: NC(=O)COc1c(N)nc(/C=C/c2ccccc2)nc1Cl
Reactant: CCO
Agent: Cl
Product: CCOC(=O)COc1c(N)nc(/C=C/c2ccccc2)nc1Cl
Temperature: 100 °C
Yield: 84 %

Procedure:
Hydrogen chloride gas was bubbled into a solution of 2-({4-amino-6-chloro-2-[(E)-2-phenylethenyl]-5-pyrimidinyl}oxy)acetamide (0.6 g, 1.97 mmol) in ethanol (20 mL). The resulting mixture was heated at 100° C. for 3 h. The mixture was evaporated under reduced pressure to give the desired product as a solid (0.55 g, 84%) which was used without purification.
Reaction SMILES: [Cl:1][C:2]1[C:11]2[C:6](=[CH:7][C:8]([Cl:12])=[CH:9][CH:10]=2)[N:5]=[CH:4][CH:3]=1.[F:13][C:14]1[CH:20]=[C:19]([CH3:21])[C:18]([OH:22])=[CH:17][C:15]=1[NH2:16].Cl>CC(O)CCC.C(O)(C)C>[ClH:1].[Cl:12][C:8]1[CH:7]=[C:6]2[C:11]([C:2]([NH:16][C:15]3[CH:17]=[C:18]([OH:22])[C:19]([CH3:21])=[CH:20][C:14]=3[F:13])=[CH:3][CH:4]=[N:5]2)=[CH:10][CH:9]=1
Reactant: Clc1ccc2c(Cl)ccnc2c1
Reactant: Cc1cc(F)c(N)cc1O
Agent: Cl
Solvent: CC(C)O
Solvent: CCCC(C)O
Product: Cc1cc(F)c(Nc2ccnc3cc(Cl)ccc23)cc1O
Yield: 88.4 %

Procedure:
A solution of 4,7-dichloroquinoline (198 mg, 1 mmol) and 2-fluoro-5-hydroxy-4-methylaniline (1 69 mg, 1.2 mmol), (prepared as described for the starting material in Example 1), in 2-pentanol (5 ml) containing 5M hydrochloric acid in isopropanol (0.5 ml) was heated at reflux for 2 hours. The volatiles were removed by evaporation and the residue was triturated with ether. The solid was collected by filtration, washed with isopropanol, followed by ether and dried under vacuum to give 7-chloro-4-(2-fluoro-5-hydroxy-4-methylanilino)quinoline hydrochloride (300 mg, 88%).
Reaction SMILES: Cl.[CH2:2]([O:9][C:10]1[CH:15]=[CH:14][N:13]([C:16]2[CH:24]=[C:23]3[C:19]([C:20]4[CH2:29][CH2:28][NH:27][CH:26]([CH3:30])[C:21]=4[N:22]3[CH3:25])=[CH:18][CH:17]=2)[C:12](=[O:31])[CH:11]=1)[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.C=O.[BH-](OC(C)=O)(OC(C)=O)O[C:36](C)=O.[Na+]>CO>[CH2:2]([O:9][C:10]1[CH:15]=[CH:14][N:13]([C:16]2[CH:24]=[C:23]3[C:19]([C:20]4[CH2:29][CH2:28][N:27]([CH3:36])[CH:26]([CH3:30])[C:21]=4[N:22]3[CH3:25])=[CH:18][CH:17]=2)[C:12](=[O:31])[CH:11]=1)[C:3]1[CH:4]=[CH:5][CH:6]=[CH:7][CH:8]=1
Reactant: CC1NCCc2c1n(C)c1cc(-n3ccc(OCc4ccccc4)cc3=O)ccc21
Reactant: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: C=O
Agent: Cl
Agent: [Na+]
Solvent: CO
Product: CC1c2c(c3ccc(-n4ccc(OCc5ccccc5)cc4=O)cc3n2C)CCN1C
Temperature: 25 °C
Yield: 77.2 %

Procedure:
To a solution of 4-(benzyloxy)-1-(1,9-dimethyl-2,3,4,9-tetrahydro-1H-pyrido[3,4-b]indol-7-yl)pyridin-2(1H)-one hydrochloride (205 mg, 0.470 mmol) in CH3OH (8 mL) was added formaldehyde (53 μL, 0.71 mmol) and NaBH(OAc)3 (200 mg, 0.94 mmol). The reaction was stirred at room temperature until complete and then concentrated under reduced pressure. The residue was dissolved in CH2Cl2 and washed with H2O and 5% aqueous LiCl and dried over Na2SO4. The organic solution was filtered and concentrated. The residue was purified by flash column chromatography (silica gel, 10% CH3OH in CH2Cl2) to give 4-(benzyloxy)-1-(1,2,9-trimethyl-2,3,4,9-tetrahydro-1H-pyrido[3,4-b]indol-7-yl)pyridin-2(1H)-one as a white solid (0.15 g, 77%). The free base was converted to the HCl salt to give the title compound (147 mg, 90%) as an off-white powder: 1H NMR (500 MHz, CD3OD) δ 7.58-7.55 (m, 2H), 7.47-7.34 (m, 6H), 6.99 (d, J=8.5, 1.0 Hz, 1H), 6.28 (dd, J=7.5, 2.5 Hz, 1H), 6.11 (d, J=2.5 Hz, 1H), 5.18 (s, 2H), 4.27 (q, J=6.5 Hz, 1H), 3.69 (s, 3H), 3.36-3.33 (m, 1H), 3.10-2.96 (m, 2H), 2.84-2.80 (m, 1H), 2.65 (s, 3H), 1.51 (d, J=6.5 Hz, 3H); ESI MS m/z 414 [M+H]+; HPLC (Method A)>99% (AUC), tR=13.0 min.
Reaction SMILES: [O-2].[Al+3].[O-2].[O-2].[Al+3].C(OCC)C.[CH2:11]([N:18]1[CH2:25][CH2:24][C:21]2([CH2:23][O:22]2)[CH2:20][CH2:19]1)[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1.[CH2:26]([O:30][C:31]1[CH:38]=[CH:37][C:34]([NH:35][CH3:36])=[CH:33][CH:32]=1)[CH2:27][CH2:28][CH3:29]>CO>[CH2:11]([N:18]1[CH2:25][CH2:24][C:21]([CH2:23][N:35]([C:34]2[CH:37]=[CH:38][C:31]([O:30][CH2:26][CH2:27][CH2:28][CH3:29])=[CH:32][CH:33]=2)[CH3:36])([OH:22])[CH2:20][CH2:19]1)[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1
Reactant: c1ccc(CN2CCC3(CC2)CO3)cc1
Reactant: CCCCOc1ccc(NC)cc1
Agent: [Al+3]
Agent: [O-2]
Solvent: CCOCC
Solvent: CO
Product: CCCCOc1ccc(N(C)CC2(O)CCN(Cc3ccccc3)CC2)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 75.5 %

Procedure:
Activated neutral aluminum oxide 90 (activity I, made by Merck Co.) (5 g) was added to a diethyl ether solution (10 mL) of 1-benzylpiperidin-4-spiro-2′-oxirane (0.50 g) and 4-butoxy-N-methylaniline (0.53 g) and stirred at room temperature overnight. Methanol (20 mL) was added to the reaction solution and stirred at room temperature for 2 hours. The reaction solution was filtered, and the filtrate was concentrated under reduced pressure. The residue obtained was purified by silica gel column chromatography (elution solvent; ethyl acetate) to obtain the titled compound (0.71 g).
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]#[CH:9])=[CH:4][CH:3]=1.[Cl:10][C:11]1[CH:18]=[CH:17][CH:16]=[CH:15][C:12]=1[CH2:13][SH:14].[Na]>>[CH3:1][C:2]1[CH:7]=[CH:6][C:5](/[CH:8]=[CH:9]\[CH:13]([S:14][CH:13](/[CH:9]=[CH:8]\[C:5]2[CH:6]=[CH:7][C:2]([CH3:1])=[CH:3][CH:4]=2)[C:12]2[CH:15]=[CH:16][CH:17]=[CH:18][C:11]=2[Cl:10])[C:12]2[CH:15]=[CH:16][CH:17]=[CH:18][C:11]=2[Cl:10])=[CH:4][CH:3]=1
Reactant: SCc1ccccc1Cl
Reactant: C#Cc1ccc(C)cc1
Agent: [Na]
Product: Cc1ccc(/C=C\C(SC(/C=C\c2ccc(C)cc2)c2ccccc2Cl)c2ccccc2Cl)cc1

Procedure:
A solution of 4-methylphenylacetylene (0.02 mol) and 2-chlorobenzyl mercaptan (0.02 mol) and metallic sodium (0.02 g atom) was subjected to the General Procedure to form Z-4-methylstyryl 2-chlorobenzylsulfide. The title compound was obtained in 76% yield following oxidation. 1HNMR (CDC13) δ2.50 (3H, s), 4.58 (2H, s), 6.80 (1H, d, JH,H=11.88), 7.20-7.63 (9H aromatic+1H ethylenic).
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([N:8]([CH3:26])[CH:9]2[CH2:25][CH2:24][C:12]3([CH2:16][N:15]([C:17]([O:19][C:20]([CH3:23])([CH3:22])[CH3:21])=[O:18])[CH2:14][CH2:13]3)[CH2:11][CH2:10]2)[C:5]([Cl:27])=[CH:4][N:3]=1.Cl.[CH3:29][N:30]1[CH:34]=[C:33]([NH2:35])[CH:32]=[N:31]1.CCN(C(C)C)C(C)C>CCCCO>[Cl:27][C:5]1[C:6]([N:8]([CH3:26])[CH:9]2[CH2:10][CH2:11][C:12]3([CH2:16][N:15]([C:17]([O:19][C:20]([CH3:21])([CH3:22])[CH3:23])=[O:18])[CH2:14][CH2:13]3)[CH2:24][CH2:25]2)=[N:7][C:2]([NH:35][C:33]2[CH:32]=[N:31][N:30]([CH3:29])[CH:34]=2)=[N:3][CH:4]=1
Reactant: Cn1cc(N)cn1
Reactant: CN(c1nc(Cl)ncc1Cl)C1CCC2(CC1)CCN(C(=O)OC(C)(C)C)C2
Agent: Cl
Solvent: CCCCO
Solvent: CCN(C(C)C)C(C)C
Product: CN(c1nc(Nc2cnn(C)c2)ncc1Cl)C1CCC2(CC1)CCN(C(=O)OC(C)(C)C)C2
Temperature: 150 °C
Yield: 93 %

Procedure:
To a suspension of tert-butyl 8-((2,5-dichloropyrimidin-4-yl)(methyl)amino)-2-azaspiro[4.5]decane-2-carboxylate (3.8 A: 0.14 g, 0.34 mmol) in n-BuOH (2.0 mL) was added 1-methyl-1H-pyrazol-4-amine hydrochloride (89 mg, 0.67 mmol) and DIPEA (0.17 g, 1.35 mmol). The mixture was stirred in a sealed tube and heated to 150° C. for 12 h and then concentrated in vacuo. The residue was purified by silica gel column chromatography (EA/PE (v/v)=4/1) to afford 3.9A as a light yellow solid (0.15 g, 93%).
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:35])[C:5]([N:7]([CH2:19][C:20]1[CH:25]=[CH:24][C:23]([C:26]2[CH:31]=[CH:30][C:29]([C:32](O)=[O:33])=[CH:28][CH:27]=2)=[CH:22][CH:21]=1)[CH2:8][C:9]1[CH:14]=[CH:13][C:12]([C:15]([F:18])([F:17])[F:16])=[CH:11][CH:10]=1)=[O:6])[CH3:2].C1C=CC2N(O)N=NC=2C=1.[CH2:46]([NH2:54])[CH2:47][CH2:48][CH2:49][CH2:50][CH2:51][CH2:52][CH3:53].Cl>C(Cl)Cl.C(Cl)CCl>[CH2:1]([O:3][C:4](=[O:35])[C:5]([N:7]([CH2:19][C:20]1[CH:21]=[CH:22][C:23]([C:26]2[CH:31]=[CH:30][C:29]([C:32]([NH:54][CH2:46][CH2:47][CH2:48][CH2:49][CH2:50][CH2:51][CH2:52][CH3:53])=[O:33])=[CH:28][CH:27]=2)=[CH:24][CH:25]=1)[CH2:8][C:9]1[CH:14]=[CH:13][C:12]([C:15]([F:17])([F:16])[F:18])=[CH:11][CH:10]=1)=[O:6])[CH3:2]
Reactant: CCCCCCCCN
Reactant: CCOC(=O)C(=O)N(Cc1ccc(-c2ccc(C(=O)O)cc2)cc1)Cc1ccc(C(F)(F)F)cc1
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: ClCCCl
Solvent: ClCCl
Product: CCCCCCCCNC(=O)c1ccc(-c2ccc(CN(Cc3ccc(C(F)(F)F)cc3)C(=O)C(=O)OCC)cc2)cc1
Reaction time: 3 h
Yield: 33 %

Procedure:
To a solution of 4′-({[ethoxy(oxo)acetyl][4-(trifluoromethyl)benzyl]amino}methyl)-1,1′-biphenyl-4-carboxylic acid (100 mg), EDC (47 mg) and HOBt (28 mg) in DCM (4 mL) was added octylamine (0.041 mL). The resulting reaction mixture was stirred for 3 h. DCM (15 mL) and an aqueous solution of HCl (1N, 10 mL) was added. The aqueous layer was extracted with DCM (3×15 mL). The combined organic layers were washed with a saturated solution of NaHCO3 (15 mL) and dried over MgSO4. Evaporation of the solvents gave an oil which was purified by flash chromatography over silica gel (c-Hex/AcOEt 2/1) to give the title compound as a colorless oil (41 mg, 33%). M+(LC/MS(ESI)): 597.8; M−(LC/MS(ESI)): 595.0. HPLC (Condition A), Rt: 6.61 min (HPLC purity: 99.87%)