Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]1([CH3:22])[CH:6]=[CH:5][CH:4]=[C:3]([NH:7][C:8]([C:10]2[CH:11]=[C:12]3[C:17](=[CH:18][CH:19]=2)[C:16]([Cl:20])=[N:15][N:14]=[C:13]3Cl)=[O:9])[CH:2]=1.[OH-].[Na+].[O:25]1CCOCC1.Cl>O>[C:1]1([CH3:22])[CH:6]=[CH:5][CH:4]=[C:3]([NH:7][C:8]([C:10]2[CH:11]=[C:12]3[C:17](=[CH:18][CH:19]=2)[C:16]([Cl:20])=[N:15][NH:14][C:13]3=[O:25])=[O:9])[CH:2]=1
Reactant: C1COCCO1
Reactant: Cc1cccc(NC(=O)c2ccc3c(Cl)nnc(Cl)c3c2)c1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: Cc1cccc(NC(=O)c2ccc3c(Cl)n[nH]c(=O)c3c2)c1
Temperature: 50 °C

Procedure:
A mixture of 1,4-dichloro-phthalazine-6-carboxylic acid m-tolylamide (350 mg, 0.87 mmol), 2N NaOH (4.4 mL, 8.70 mmol) and dioxane (4 mL) was heated to 50° C. for 3 h. The reaction was diluted with water, acidified with conc. HCl to ˜pH 6. The reaction mixture was concentrated to low volume and filtered through celite. Chromatography (Hex/EtOAc) afforded 1-chloro-4-oxo-3,4-dihydro-phthalazine-6-carboxylic acid m-tolylamide (8 mg) as a pale yellow solid, 1H NMR (400 MHz, d6-DMSO) δ: 2.32 (s, 3H), 7.96 (d, 1H), 7.26 (t, 1H), 7.60 (d, 1H), 7.65 (s, 1H), 8.14 (d, 1H), 8.52 (dd, 1H), 8.87 (s, 1H), 10.67 (s, 1H), 13.00 (bs, 1H) ppm; m/z (M−1) 312.13; and 4-chloro-1-oxo-1,2-dihydro-phthalazine-6-carboxylic acid m-tolylamide (23 mg) as a pale yellow solid. 1H NMR (400 MHz, d6-DMSO) δ: 2.11 (s, 3H), 6.76 (m, 1H), 7.05 (m, 1H), 7.40 (m, 2H), 8.25 (m, 3H), 10.42 (s, 1H), 12.80 (s, 1H) ppm; m/z (M−1) 312.13.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH2:11][CH2:12][CH:13]([C:15]2([CH2:18][CH3:19])[CH2:17][CH2:16]2)O)[CH:6]=[CH:7][C:8]=1[O:9][CH3:10].[Br-:20].[Li+]>[Br-].[Zn+2].[Br-]>[CH2:18]([C:15](=[CH:13][CH2:12][CH2:11][C:5]1[CH:6]=[CH:7][C:8]([O:9][CH3:10])=[C:3]([O:2][CH3:1])[CH:4]=1)[CH2:16][CH2:17][Br:20])[CH3:19]
Reactant: CCC1(C(O)CCc2ccc(OC)c(OC)c2)CC1
Reactant: [Br-]
Agent: [Li+]
Agent: [Zn+2]
Product: CCC(=CCCc1ccc(OC)c(OC)c1)CCBr

Procedure:
3-Ethyl-6-(3,4-dimethoxyphenyl)-3-hexenyl bromide [V; Ar is 3,4-(CH3O)2C6H3, R is C2H5 ] was prepared from 16 g. of 2-(3,4-dimethoxyphenyl)ethyl 1-ethylcyclopropyl carbinol (Preparation B4), 16.8 g. of phosphours tribromide, 16.8 g. of lithium bromide and 17.6 g. of zinc bromide according to the procedure given above in Preparation C1. The product was used directly in the succeeding step (Preparation D4) without isolation.
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.[NH2:13][C:14]1[CH:21]=[CH:20][C:17]([CH:18]=[O:19])=[CH:16][CH:15]=1.Cl>CO>[ClH:1].[Cl:12][C:8]1[CH:7]=[C:6]2[C:11]([C:2]([NH:13][C:14]3[CH:21]=[CH:20][C:17]([CH:18]=[O:19])=[CH:16][CH:15]=3)=[CH:3][CH:4]=[N:5]2)=[CH:10][CH:9]=1
Reactant: Clc1ccc2c(Cl)ccnc2c1
Reactant: Nc1ccc(C=O)cc1
Agent: Cl
Solvent: CO
Product: O=Cc1ccc(Nc2ccnc3cc(Cl)ccc23)cc1
Temperature: 25 °C
Reaction time: 3 h
Yield: 80.6 %

Procedure:
4,7-Dichloroquinoline (50 g, 252 mmol) and 4-aminobenzaldehyde (30.6 g, 252 mmol) are stirred in 300 mL of methanol and treated with 126 mL of 2 N HCl. The mixture is boiled on a hot plate and after ~15 minutes, a thick yellow precipitate forms. The heating is continued at a low setting for 3 hours at which point the mixture is allowed to cool to room temperature. The yellow solid is filtered, washed with cold methanol, then ether and dried in vacuo at 60° C. for three days affording 64.65 g (203 mmol, 80% yield) of product: 1H NMR (Me2SO-d6, 300 MHz) δ11.4 (br s, 1H), 10.06 (s, 1H), 8.95 (d,J=9.2 Hz, 1H), 8.65 (d,J=6.9 Hz, 1H), 8.24 (d,J=2.1 Hz, 1H), 8.09 (d,J=8.5 Hz, 2H), 7.92 (d of d,J=2.0, 9.2 Hz, 1H), 7.76 (d,J=8.5 Hz, 2H), 7.13 (d,J=7.0 Hz, 1H).
Reaction SMILES: [C:1]([N:4]1[CH2:9][CH2:8][C:7](=[N:10][NH:11][C:12](=[O:19])[C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)[CH2:6][CH2:5]1)(=[O:3])[CH3:2].C(OCC)C>C(O)(=O)C.O=[Pt]=O>[C:1]([N:4]1[CH2:9][CH2:8][CH:7]([NH:10][NH:11][C:12](=[O:19])[C:13]2[CH:14]=[CH:15][CH:16]=[CH:17][CH:18]=2)[CH2:6][CH2:5]1)(=[O:3])[CH3:2]
Reactant: CC(=O)N1CCC(=NNC(=O)c2ccccc2)CC1
Agent: O=[Pt]=O
Solvent: CCOCC
Solvent: CC(=O)O
Product: CC(=O)N1CCC(NNC(=O)c2ccccc2)CC1
Reaction time: 12 h
Yield: 91.2 %

Procedure:
30 g (0.12 mol) of N′-(1-acetylpiperidin-4-ylidene)benzohydrazide were dissolved in 500 mL of glacial acetic acid and 1 g of PtO2 were added. The mixture was hydrogenated at 40 psi for 12 hours at room temperature. The catalyst was then filtered on celite and the filtrate evaporated in vacuo. The residue was redissolved with dichloromethane and washed with aqueous NaHCO3. The solvent was dried over sodium sulfate and removed under reduced pressure to give, after trituration with diethylether, 28.6 g (92% yield) of the title compound.
Reaction SMILES: [CH2:1]([O:8][CH2:9][C@@H:10]([NH:14]C(OC(C)(C)C)=O)[C:11]([OH:13])=[O:12])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH3:22]O>>[CH3:22][O:13][C:11](=[O:12])[C@H:10]([NH2:14])[CH2:9][O:8][CH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CO
Reactant: CC(C)(C)OC(=O)N[C@H](COCc1ccccc1)C(=O)O
Product: COC(=O)[C@H](N)COCc1ccccc1
Temperature: 25 °C
Reaction time: 17 h
Yield: 100 %

Procedure:
A solution of (2R)-3-benzyloxy-2-(N-(t-butoxycarbonyl)amino)propanoic acid (23 g, 78 mmol, [α]D−4.4° (c=2, H2O)) in methanol (250 mL) was cooled to 0° C. and HCl (g) bubbled into the solution until saturated. The resulting mixture was stirred at ambient temperature for 17 hours and then concentrated in vacuo to afford 17 g (100% yield) of (2R)-3-benzyloxy-2-aminopropanoic acid methyl ester, a compound of formula (M), as a white solid; NMR (DMSO-d6) 8.7 (br s, 3), 7.4-7.3 (m, 5), 4.5 (q, 2), 4.4 (br s, 1), 3.8 (s, 2), 3.7 (s, 3) ppm.
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4]2[C:8](=[C:9]([NH:11][CH:12]3[CH2:17][CH2:16][NH:15][CH2:14][CH2:13]3)[CH:10]=1)[NH:7][C:6]([C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1)=[CH:5]2.[OH:24][CH2:25][C:26](O)=[O:27].C(Cl)CCl.C1C=CC2N(O)N=NC=2C=1.CCN(CC)CC.C([O-])(O)=O.[Na+]>CN(C=O)C>[OH:27][CH2:26][C:25]([N:15]1[CH2:14][CH2:13][CH:12]([NH:11][C:9]2[CH:10]=[C:2]([CH3:1])[CH:3]=[C:4]3[C:8]=2[NH:7][C:6]([C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)=[CH:5]3)[CH2:17][CH2:16]1)=[O:24]
Reactant: Cc1cc(NC2CCNCC2)c2[nH]c(-c3ccccc3)cc2c1
Reactant: O=C(O)CO
Agent: O=C([O-])O
Agent: On1nnc2ccccc21
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Solvent: ClCCCl
Product: Cc1cc(NC2CCN(C(=O)CO)CC2)c2[nH]c(-c3ccccc3)cc2c1
Temperature: 25 °C
Reaction time: 4 h

Procedure:
(5-Methyl-2-phenyl-1H-indol-7-yl)-piperidin-4-yl-amine (305 mg, 1 mmol) prepared in Example 90 was dissolved in DMF (5 mL). Hydroxyacetic acid (76 mg, 1 mmol), EDC (232 mg, 1.3 mmol), HOBT (229 mg, 1.5 mmol) and Et3N (280 uL, 2 mmol) were added thereto, and the mixture was stirred for 4 h at room temperature. After completion of the reaction, saturated aqueous NaHCO3 solution was added to the reaction mixture, which was then extracted with EtOAc, washed with saturated aqueous NaCl solution and 1N HCl, dried over anhydrous magnesium sulfate, and filtered. The solvent was removed under reduced pressure, and the residue was purified by column chromatography to give the title compound.
Reaction SMILES: [Cl:1][C:2]1[CH:42]=[CH:41][C:5]([CH2:6][N:7]2[CH2:12][CH2:11][N:10]([CH2:13][CH2:14][CH2:15][O:16][C:17]3[CH:18]=[C:19]([CH:38]=[CH:39][CH:40]=3)[O:20][C:21]3[N:25]([CH2:26][C:27]4[CH:32]=[CH:31][C:30]([O:33][CH3:34])=[CH:29][CH:28]=4)[N:24]=[N:23][C:22]=3[C:35]([OH:37])=O)[CH2:9][CH2:8]2)=[CH:4][CH:3]=1.C(Cl)(=O)C(Cl)=O.[Cl-].[Cl-].C([Al+2])C.CCCCCC>ClCCl.CN(C)C=O>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([CH2:6][N:7]2[CH2:12][CH2:11][N:10]([CH2:13][CH2:14][CH2:15][O:16][C:17]3[CH:40]=[CH:39][C:38]4[C:35](=[O:37])[C:22]5[N:23]=[N:24][N:25]([CH2:26][C:27]6[CH:32]=[CH:31][C:30]([O:33][CH3:34])=[CH:29][CH:28]=6)[C:21]=5[O:20][C:19]=4[CH:18]=3)[CH2:9][CH2:8]2)=[CH:41][CH:42]=1
Reactant: COc1ccc(Cn2nnc(C(=O)O)c2Oc2cccc(OCCCN3CCN(Cc4ccc(Cl)cc4)CC3)c2)cc1
Agent: CC[Al+2]
Agent: O=C(Cl)C(=O)Cl
Agent: [Cl-]
Solvent: ClCCl
Solvent: CCCCCC
Solvent: CN(C)C=O
Product: COc1ccc(Cn2nnc3c(=O)c4ccc(OCCCN5CCN(Cc6ccc(Cl)cc6)CC5)cc4oc32)cc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
5-{3-{3-[4-(4-Chlorobenzyl)-1-piperazinyl]-propoxy}phenoxy}-1-(4-methoxybenzyl)-1,2,3-triazole-4-carboxylic acid, (0.50 g, 0.84 mmole), was dissolved in dry dichloromethane (20 ml) and oxalyl chloride, (1.00 ml, 11.7 mmole), added, followed by 1 drop of dimethylformamide. The reaction was stirred overnight, then excess oxalyl chloride and solvent evaporated in vacuo. The acid chloride was resuspended in dry dichloromethane, (20 ml), under nitrogen and cooled with stirring in an ice bath. A 25% solution of ethyl aluminium dichloride in hexane, (1.61 ml, 3.38 mmole) was added dropwise and the reaction stirred in ice for 2 hours, warmed to room temperature over 1 hour, and stirred for a further 3 hours. The mixture was quenched with dilute hydrochloric acid, (50 ml) and left to stand overnight. The resultant cream solid was filtered, stirred in water, (25 ml), and neutralized to pH7 with dilute sodium hydrogen carbonate solution. The aqueous phase was decanted and the gummy residue purified by column chromatography using silica gel, eluting with chloroform to give the title compound as a colourless oil which crystallized on trituration with methanol. 171 mg (35%) mp (MeOH) 135°-138° C. νmax (mull) 1518, 1535, 1565, 1620, 1680 cm-1 δ(CDCl3) 2.00 (2H, m, CH2), 2.50 (10H, bs, piperazinyl+CH2), 3.43 (2H, s, N--CH2), 3.77 (3H, s, OCH3), 4.13 (2H, t, J 6 Hz, OCH2), 5.56 (2H, s, N--CH2), 6.93 (2H, m, aromatics), 7.12 (4H, ABq, Δν 45 Hz, J 9 Hz, C6H4OCH3), 7.29 (4H, s, C6H4Cl) 8.28 (1H, d, J 9 Hz, aromatic).
Reaction SMILES: Cl[C:2]1[CH:10]=[CH:9][C:8]([S:11]([CH3:14])(=[O:13])=[O:12])=[CH:7][C:3]=1[C:4]([OH:6])=[O:5]>[Cu].[OH-].[NH4+]>[CH3:14][S:11]([C:8]1[CH:7]=[C:3]([C:4]([OH:6])=[O:5])[C:2]([C:2]2[CH:10]=[CH:9][CH:8]=[CH:7][CH:3]=2)=[CH:10][CH:9]=1)(=[O:13])=[O:12]
Reactant: CS(=O)(=O)c1ccc(Cl)c(C(=O)O)c1
Agent: [Cu]
Agent: [NH4+]
Agent: [OH-]
Product: CS(=O)(=O)c1ccc(-c2ccccc2)c(C(=O)O)c1
Temperature: 127.5 °C
Reaction time: 18 h

Procedure:
A mixture of 4.26 mmol 2-chloro-5-methanesulfonyl-benzoic acid, 0.39 mmol Copper powder and 10 ml ammonium hydroxide 25% was heated at 125-130° C. with stirring for 18 hours. Mixture was cooled to room temperature and filtered. The solid was washed with methanol. The filtrate was concentrated in vacuo. The residue was acidified with HCl 1N to pH=2. The obtained solid was washed with water and dried (HV, 50° C., 1 hour) to yield the title compound. MS (m/e): 214.1 (M−H+, 100%)
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([N:22]2[C:26](=[O:27])[NH:25][N:24]=[CH:23]2)[CH:5]=[CH:6][C:7]=1[N:8]1[CH2:13][CH2:12][N:11]([C:14]2[CH:19]=[CH:18][C:17]([O:20][CH3:21])=[CH:16][CH:15]=2)[CH2:10][CH2:9]1.C([O-])([O-])=O.[K+].[K+].Br[CH:35]([CH2:37][CH3:38])[CH3:36]>CS(C)=O.O>[CH:35]([N:25]1[C:26](=[O:27])[N:22]([C:4]2[CH:5]=[CH:6][C:7]([N:8]3[CH2:9][CH2:10][N:11]([C:14]4[CH:15]=[CH:16][C:17]([O:20][CH3:21])=[CH:18][CH:19]=4)[CH2:12][CH2:13]3)=[C:2]([F:1])[CH:3]=2)[CH:23]=[N:24]1)([CH2:37][CH3:38])[CH3:36]
Reactant: CCC(C)Br
Reactant: COc1ccc(N2CCN(c3ccc(-n4cn[nH]c4=O)cc3F)CC2)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CS(C)=O
Product: CCC(C)n1ncn(-c2ccc(N3CCN(c4ccc(OC)cc4)CC3)c(F)c2)c1=O
Temperature: 25 °C
Reaction time: 1 h
Yield: 86.2 %

Procedure:
To a suspension of triazolone 7 (0.11 g, 0.3 mmol) in dimethylsulfoxide (4 mL) was added K2CO3 (0.08 g, 0.6 mmol). The resulting mixture was stirred at room temperature for 1 h. After the addition of 2-bromo butane (0.05 mL, 0.45 mmol), the temperature increased to 80° C. for overnight. After cooling to room temperature, the reaction mixture was diluted with water and extracted with dichlormethane. The combined organic layer was dried over Na2SO4, filtered, and concentrated to yield the crude product, which was purified by column chromatography to obtain triazolone 8 (0.11 g, 87%). 1H NMR (400 MHz, CDCl3, δH): 7.64 (s, 1H), 7.37 (dd, J=13.0, 2.2 Hz, 1H), 7.26-7.24 (m, 1H), 7.04 (t, J=8.8 Hz, 1H), 6.99-6.97 (m, 2H), 6.88-6.84 (m, 2H), 4.31-4.26 (m, 1H), 3.77 (s, 3H), 3.26 (bs, 8H), 1.86-1.81 (m, 1H), 1.73-1.71 (m, 1H), 1.38 (d, J=6.8 Hz, 3H), 0.89 (t, J=7.4 Hz, 3H). 13C NMR (100 MHz, CDCl3, δC): 154.6, 154.2, 151.6, 139.4, 133.3, 128.4, 119.4, 118.7, 118.0, 114.5, 111.0, 110.8, 55.6, 52.8, 51.0, 50.5, 28.4, 19.3, 10.8.
Reaction SMILES: [CH3:1][C:2]1[C:3]([N:9]2[CH2:16][CH:15]3[CH:11]([CH2:12][NH:13][CH2:14]3)[CH2:10]2)=[N:4][C:5]([CH3:8])=[CH:6][N:7]=1.[CH3:17][C:18]1[CH:19]=[CH:20][C:21]([C:27]2[N:32]=[CH:31][CH:30]=[CH:29][N:28]=2)=[C:22]([CH:26]=1)[C:23](O)=[O:24]>>[CH3:1][C:2]1[C:3]([N:9]2[CH2:16][CH:15]3[CH:11]([CH2:12][N:13]([C:23]([C:22]4[CH:26]=[C:18]([CH3:17])[CH:19]=[CH:20][C:21]=4[C:27]4[N:28]=[CH:29][CH:30]=[CH:31][N:32]=4)=[O:24])[CH2:14]3)[CH2:10]2)=[N:4][C:5]([CH3:8])=[CH:6][N:7]=1
Reactant: Cc1cnc(C)c(N2CC3CNCC3C2)n1
Reactant: Cc1ccc(-c2ncccn2)c(C(=O)O)c1
Product: Cc1ccc(-c2ncccn2)c(C(=O)N2CC3CN(c4nc(C)cnc4C)CC3C2)c1

Procedure:
The title compound was prepared in a manner analogous to Example 15 utilizing Intermediate 34 and 5-methyl-2-pyrimidin-2-yl-benzoic acid. MS (ESI): mass calculated for C24H26N6O, 414.51; m/z found 415.2 [M+H]+. 1H NMR (400 MHz, CDCl3): 8.77 (d, J=4.9, 2H), 8.22 (d, J=8.1, 1H), 7.73 (s, 1H), 7.34-7.29 (m, 1H), 7.21-7.16 (m, 1H), 7.11 (t, J=4.8, 1H), 3.96-3.89 (m, 1H), 3.86-3.79 (m, 1H), 3.74-3.61 (m, 2H), 3.57-3.51 (m, 1H), 3.49-3.38 (m, 2H), 3.18-3.12 (m, 1H), 3.08-2.98 (m, 1H), 2.96-2.86 (m, 1H), 2.50 (s, 3H), 2.42 (s, 3H), 2.36 (s, 3H).
Reaction SMILES: [OH:1][C:2]1[CH:3]=[CH:4][C:5]2[CH2:6][N:7]3[NH:18][CH2:17][CH2:16][C@@:13]4([C:14]=2[CH:15]=1)[C@H:8]3[CH2:9][CH2:10][CH2:11][CH2:12]4.[CH:19]1([C:22](Cl)=[O:23])[CH2:21][CH2:20]1>CCOCC.[OH-].[Na+]>[CH:19]1([C:22]([N:18]2[CH2:17][CH2:16][C@@:13]34[C:14]5[CH:15]=[C:2]([O:1][C:22]([CH:19]6[CH2:21][CH2:20]6)=[O:23])[CH:3]=[CH:4][C:5]=5[CH2:6][N:7]2[C@@H:8]3[CH2:9][CH2:10][CH2:11][CH2:12]4)=[O:23])[CH2:21][CH2:20]1
Reactant: Oc1ccc2c(c1)[C@@]13CCCC[C@H]1N(C2)NCC3
Reactant: O=C(Cl)C1CC1
Agent: [Na+]
Agent: [OH-]
Solvent: CCOCC
Product: O=C(Oc1ccc2c(c1)[C@@]13CCCC[C@H]1N(C2)N(C(=O)C1CC1)CC3)C1CC1
Temperature: 25 °C
Yield: 53.5 %

Procedure:
To a suspension of 0.6 g of (+)-3-hydroxy-9-azamorphinan in 50 ml of Et2O and 20 ml of 20% NaOH aq. solution was added 1.0 g of cyclopropylcarbonyl chloride with stirring at room temperature. After stirring for 1 hr., the organic layer was washed (10% NaOH and then H2O), dried (K2CO3), and evaporated to give an oil, which was triturated with Et2O-pet. ether to form a solid. Recrystallization of this from Et2O afforded 0.5 g (53.5%) of (+)-N-cyclopropylcarbonyl-3-cyclopropylcarbonyloxy-9-azamorphinan as colorless plates; mp 144°-145.5.°.
Reaction SMILES: C(OC([N:8]1[CH2:13][CH2:12][CH:11]([O:14][C:15]2[CH:39]=[C:38]([C:40]([CH3:43])([CH3:42])[CH3:41])[CH:37]=[CH:36][C:16]=2[C:17]([NH:19][C:20]2[CH:21]=[N:22][CH:23]=[CH:24][C:25]=2[C:26]([NH:28][C:29]2[CH:34]=[CH:33][C:32]([Cl:35])=[CH:31][N:30]=2)=[O:27])=[O:18])[CH2:10][CH2:9]1)=O)(C)(C)C.C1(OC)C=CC=CC=1.FC(F)(F)C(O)=O>C(Cl)Cl>[C:40]([C:38]1[CH:37]=[CH:36][C:16]([C:17]([NH:19][C:20]2[CH:21]=[N:22][CH:23]=[CH:24][C:25]=2[C:26]([NH:28][C:29]2[CH:34]=[CH:33][C:32]([Cl:35])=[CH:31][N:30]=2)=[O:27])=[O:18])=[C:15]([O:14][CH:11]2[CH2:12][CH2:13][NH:8][CH2:9][CH2:10]2)[CH:39]=1)([CH3:43])([CH3:41])[CH3:42]
Reactant: CC(C)(C)OC(=O)N1CCC(Oc2cc(C(C)(C)C)ccc2C(=O)Nc2cnccc2C(=O)Nc2ccc(Cl)cn2)CC1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Solvent: COc1ccccc1
Product: CC(C)(C)c1ccc(C(=O)Nc2cnccc2C(=O)Nc2ccc(Cl)cn2)c(OC2CCNCC2)c1
Temperature: 25 °C
Reaction time: 4 h
Yield: 63 %

Procedure:
The 3-[2-(1-tert-butoxycarbonylpiperidin-4-yloxy)-4-(tert-butyl)benzoylamino]-N-(5-chloropyridin-2-yl)pyridine-4-carboxamide (60 mg, 0.1 mmol) was mixed with anisole (1 mL) and CH2Cl2 (2 mL) then treated with trifluoroacetic acid (1 mL). The reaction was stirred at ambient temperature for 4 h, concentrated under vacuum to dryness and mixed with CH2Cl2. This was filtered through a 1 g SCX ion exchange column using 2 M NH3 in MeOH. Concentration to dryness gave 32 mg of the title compound as a solid.
Reaction SMILES: [Cl:1][C:2]1[N:3]=[C:4]([C:9]2[CH:10]=[N:11][CH:12]=[CH:13][CH:14]=2)[S:5][C:6]=1[NH:7][CH3:8].N1C=CC=CC=1.[CH3:21][CH:22]([CH2:26][S:27][CH3:28])[C:23](Cl)=[O:24].C(O)(C(F)(F)F)=O>CN(C1C=CN=CC=1)C.ClCCl.O.C(#N)C>[Cl:1][C:2]1[N:3]=[C:4]([C:9]2[CH:10]=[N:11][CH:12]=[CH:13][CH:14]=2)[S:5][C:6]=1[N:7]([CH3:8])[C:23](=[O:24])[CH:22]([CH3:21])[CH2:26][S:27][CH3:28]
Reactant: CSCC(C)C(=O)Cl
Reactant: CNc1sc(-c2cccnc2)nc1Cl
Agent: CN(C)c1ccncc1
Solvent: O=C(O)C(F)(F)F
Solvent: CC#N
Solvent: ClCCl
Product: CSCC(C)C(=O)N(C)c1sc(-c2cccnc2)nc1Cl
Temperature: 25 °C
Reaction time: 16 h
Yield: 101.3 %

Procedure:
To a dry 500 ml round bottom flask equipped with magnetic stirrer, thermometer, and nitrogen inlet was added 4-chloro-N-methyl-2-(pyridin-3-yl)thiazol-5-amine (22 g, 97 mmol) and dichloromethane (250 mL). The suspension was stiffed at room temperature while pyridine (8.48 g, 107 mmol) and DMAP (1.20 g, 9.75 mmol) were added. To this suspension was added 2-methyl-3-(methylthio)propanoyl chloride (17.8 g, 117 mmol) over 5 minutes. During the addition all solids went into solution and the reaction was exothermic from 20° C. to 30° C. The reaction was stirred at ambient temperature for 16 h. The mixture was checked by HPLC(YMC AQ column 5% ACN 95% water-0.05% TFA to 95% ACN 5% water with 0.05% TFA over 20 Min @ 1.0 ml/min) which showed complete conversion of all starting material. The reaction mixture was diluted with dichloromethane and water was then added. The mixture was poured into a separatory funnel with dichloromethane and water and the layers separated. The organic phase was washed with brine, dried over anhydrous magnesium sulfate, filtered, and rotary evaporated to afford 33.6 g of a dark oil. The oil was purified on an ISCO Combiflash Rf (330 g silica gel cartridge, mobile phase A=hexane, B=ethyl acetate, gradient 0% B to 100% B over 20 minutes). The fractions were collected into 25 mL test tubes. The tubes containing the desired product were combined and the solvent removed by rotary evaporation. This afforded 22.8 g of a thick yellow liquid in 68.4% isolated yield. The entire sample crystallized and hexane (200 mL) was added to give a slurry. The slurry was vacuum filtered and the solid allowed to air dry. This gave N-(4-chloro-2-(pyridin-3-yl)thiazol-5-yl)-N,2-dimethyl-3-(methylthio)propanamide as an off-white solid; mp 75-80° C.; 1H NMR (400 MHz, CDCl3) δ 9.12 (d, J=1.4 Hz, 1H), 8.73 (d, J=3.8 Hz, 1H), 8.34-8.09 (m, 1H), 7.43 (dd, J=7.9, 4.9 Hz, 1H), 3.30 (s, 3H), 3.06-2.70 (m, 2H), 2.49 (d, J=7.4 Hz, 1H), 2.04 (s, 3H), 1.21 (d, J=6.4 Hz, 3H); 13C NMR (101 MHz, DMSO-d6) δ 175.22, 162.37, 151.91, 146.53, 136.46, 134.64, 133.35, 127.98, 124.27, 37.47, 36.71, 36.47, 17.56, 15.44; Anal. Calcd. for C14H16ClN3OS2: C, 49.18; H, 4.72; N, 12.29; S, 18.76. Found: C, 49.04: H, 4.68; N, 12.29; S, 18.68.
Reaction SMILES: [NH2:1][C@@H:2]([CH2:5][C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1)[CH2:3][OH:4].[CH2:12]([O:19][C:20]1[CH:28]=[CH:27][CH:26]=[C:25]2[C:21]=1[CH:22]=[C:23]([C:30](Cl)=[O:31])[N:24]2[CH3:29])[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1>>[CH2:5]([C@H:2]([NH:1][C:30]([C:23]1[N:24]([CH3:29])[C:25]2[C:21]([CH:22]=1)=[C:20]([O:19][CH2:12][C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1)[CH:28]=[CH:27][CH:26]=2)=[O:31])[CH2:3][OH:4])[C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1
Reactant: Cn1c(C(=O)Cl)cc2c(OCc3ccccc3)cccc21
Reactant: N[C@H](CO)Cc1ccccc1
Product: Cn1c(C(=O)N[C@H](CO)Cc2ccccc2)cc2c(OCc3ccccc3)cccc21

Procedure:
From (S)-2-amino-3-phenylpropan-1-ol and 4-benzyloxy-1-methyl-1H-indole-2-carbonyl chloride the intermediate compound (S)-N-[1-benzyl-2-hydroxyethyl]-4-(benzyloxy)-1-methyl-1H-indole-2-carboxamide was prepared by a method analogous to that described in Example 23.
Reaction SMILES: I[C:2]1[CH:15]=[C:14]2[C:5]([NH:6][CH:7]=[C:8]2[CH2:9][CH2:10][N:11]([CH3:13])[CH3:12])=[CH:4][CH:3]=1.[Cu][C:17]#[N:18].[I-]>CN1CCCC1=O>[CH3:12][N:11]([CH2:10][CH2:9][C:8]1[C:14]2[C:5](=[CH:4][CH:3]=[C:2]([C:17]#[N:18])[CH:15]=2)[NH:6][CH:7]=1)[CH3:13]
Reactant: CN(C)CCc1c[nH]c2ccc(I)cc12
Reactant: N#C[Cu]
Agent: [I-]
Solvent: CN1CCCC1=O
Product: CN(C)CCc1c[nH]c2ccc(C#N)cc12
Temperature: 180 °C
Yield: 82.4 %

Procedure:
A flask with mechanical stirrer is charged with 5-iodo-dimethyltryptamine (179 g of 75% purity, 0.427 mol), copper (I)cyanide (90 g, 1.0 mol), and N-methylpyrrolidone (1.5 l). The pink suspension is heated at 180° C. under a nitrogen atmosphere and vigorously stirred, until the iodide is completely consumed (7 h). After cooling to ambient temperature ammonia (2 l 25% solution in water) is added, and the resulting mixture is stirred over night. The mixture is then extracted with TBME (6*1.5 l), and the combined organic layers are washed with water (3*3 l), and brine (1*3 l), and dried (sodium sulfate). Removal of the solvent leaves 75 g (82%) of the product which is >95% pure by HPLC (other properties cf. Reference Example 3).
Reaction SMILES: [NH2:1][C:2]1[N:7]=[C:6]([C:8]2[C:17]3[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=3)[C:11]([F:18])=[CH:10][CH:9]=2)[CH:5]=[C:4]([CH:19]([CH3:21])[CH3:20])[N:3]=1.C(N(CC)CC)C.[CH3:29][S:30](Cl)(=[O:32])=[O:31]>ClCCl>[CH3:29][S:30]([N:1]([S:30]([CH3:29])(=[O:32])=[O:31])[C:2]1[N:7]=[C:6]([C:8]2[C:17]3[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=3)[C:11]([F:18])=[CH:10][CH:9]=2)[CH:5]=[C:4]([CH:19]([CH3:21])[CH3:20])[N:3]=1)(=[O:32])=[O:31]
Reactant: CC(C)c1cc(-c2ccc(F)c3ccccc23)nc(N)n1
Reactant: CS(=O)(=O)Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CC(C)c1cc(-c2ccc(F)c3ccccc23)nc(N(S(C)(=O)=O)S(C)(=O)=O)n1
Temperature: 0 °C
Reaction time: 0.25 h

Procedure:
2-Amino-4-(4-fluoronaphth-1-yl)-6-isopropylpyrimidine (0.374 g) was dissolved in dichloromethane (25 mL) and cooled to 0° C. Triethyl amine (0.5 mL) was added to the solution and methanesulfonyl chloride (0.12 mL) in dichloromethane (5 mL) was added dropwise. After stirring the mixture for 15 miutes, another portion of triethyl amine (0.25 mL) and methanesulfonyl chloride (0.12 mL) were added sequentially. After 15 minutes, the process was repeated and the examination showed a single new product. The reaction mixture was evaporated to dryness and purified by silica gel chromatography, eluting with ethyl acetate/hexane mixture. The colorless crystalline material was recrystallized from hexane-ether to afford 2-(bis-methanesulfonyl)amino-4-(4-fluoronaphth-1-yl)-6-isopropylpyrimidine, (354 mg), m.p. 143.8-144.2° C.
Reaction SMILES: [Cl:1][C:2]1[CH:11]=[C:10]([C:12]#[C:13][C:14]([CH3:17])([CH3:16])[CH3:15])[CH:9]=[CH:8][C:3]=1[C:4]([O:6]C)=[O:5].[OH-].[Na+].C1COCC1>CO>[Cl:1][C:2]1[CH:11]=[C:10]([C:12]#[C:13][C:14]([CH3:17])([CH3:16])[CH3:15])[CH:9]=[CH:8][C:3]=1[C:4]([OH:6])=[O:5]
Reactant: COC(=O)c1ccc(C#CC(C)(C)C)cc1Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: C1CCOC1
Product: CC(C)(C)C#Cc1ccc(C(=O)O)c(Cl)c1
Temperature: 25 °C
Reaction time: 5 h
Yield: 99.1 %

Procedure:
A mixture of methyl 2-chloro-4-(3,3-dimethylbut-1-ynyl)benzoate (330 mg, 0.0013 mol), 2N aq. NaOH (3.0 mL), THF (5 mL), and MeOH (5 mL) was stirred at rt for 5 h. The mixture was concentrated under vacuum and the residue was treated with water and acidified with 1N HCl to pH 2-3, and extracted with EtOAc. The organic layer was washed with brine, dried (Na2SO4), and concentrated under vacuum to give the product (305 mg, 98%) as a white solid. tR=3.56 min, 234.9 & 236.9 (M−1).