Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][CH:2]([CH2:12][C:13]1[CH:18]=[CH:17][C:16]([C:19]([CH3:22])([CH3:21])[CH3:20])=[CH:15][CH:14]=1)[CH:3]([C:5]1[CH:10]=[CH:9][CH:8]=[C:7]([Cl:11])[CH:6]=1)[OH:4].[C:23]1([C:34](O)=[O:35])[CH:24]=[CH:25][CH:26]=[C:27]2[CH2:33][CH2:32][CH2:31][CH:30]=[CH:29][C:28]=12.Cl.C(N=C=NCCCN(C)C)C.O.ON1C2C=CC=CC=2N=N1>C(#N)C.O>[C:19]([C:16]1[CH:15]=[CH:14][C:13]([CH2:12][CH:2]([NH:1][C:34]([C:23]2[CH:24]=[CH:25][CH:26]=[C:27]3[CH2:33][CH2:32][CH2:31][CH:30]=[CH:29][C:28]=23)=[O:35])[CH:3]([C:5]2[CH:10]=[CH:9][CH:8]=[C:7]([Cl:11])[CH:6]=2)[OH:4])=[CH:18][CH:17]=1)([CH3:22])([CH3:21])[CH3:20]
Reactant: O=C(O)c1cccc2c1C=CCCC2
Reactant: CC(C)(C)c1ccc(CC(N)C(O)c2cccc(Cl)c2)cc1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: O
Solvent: CC#N
Product: CC(C)(C)c1ccc(CC(NC(=O)c2cccc3c2C=CCCC3)C(O)c2cccc(Cl)c2)cc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of (1RS,2SR)-2-amino-3-(4-tert-butylphenyl)-1-(3-chlorophenyl)propan-1-ol (355 mg, 1.17 mmol) in acetonitrile (20 ml) were added 6,7-dihydro-5H-benzo[a]cycloheptene-1-carboxylic acid (220 mg, 1.17 mmol), 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (336 mg, 1.76 mmol) and 1-hydroxybenzotriazole hydrate (179 mg, 1.17 mmol), and the mixture was stirred overnight at room temperature. The reaction solution was diluted with water (100 ml) and extracted with ethyl acetate (100 ml×2). The extract was washed successively with water and saturated brine, dried (anhydrous magnesium sulfate) and evaporated under reduced pressure. The residue was purified by silica gel column chromatography (hexane:ethyl acetate=4:1-2:1). Recrystallization from ethyl acetate-hexane gave the objective substance (348 mg, 64%).
Reaction SMILES: [Br:1][C:2]1[C:10]([CH3:11])=[CH:9][C:5]([C:6](O)=[O:7])=[C:4]([CH3:12])[CH:3]=1.S(Cl)([Cl:15])=O>ClCCl>[Br:1][C:2]1[C:10]([CH3:11])=[CH:9][C:5]([C:6]([Cl:15])=[O:7])=[C:4]([CH3:12])[CH:3]=1
Reactant: O=S(Cl)Cl
Reactant: Cc1cc(C(=O)O)c(C)cc1Br
Solvent: ClCCl
Product: Cc1cc(C(=O)Cl)c(C)cc1Br

Procedure:
10.3 g (45 mmol) of 4-bromo-2,5-dimethylbenzoic acid are dissolved in 250 ml of dichloromethane and after the addition of 9.9 ml of (135 mmol) of thionyl chloride refluxed for two hours. Then the mixture is evaporated to dryness.
Reaction SMILES: Cl[C:2]1[N:7]=[C:6](Cl)[C:5]([F:9])=[CH:4][N:3]=1.[NH2:10][C:11]1[CH:12]=[C:13]([CH:18]=[CH:19][CH:20]=1)[O:14][CH2:15][CH2:16][OH:17]>>[OH:17][CH2:16][CH2:15][O:14][C:13]1[CH:12]=[C:11]([NH:10][C:2]2[N:7]=[C:6]([NH:10][C:11]3[CH:20]=[CH:19][CH:18]=[C:13]([O:14][CH2:15][CH2:16][OH:17])[CH:12]=3)[C:5]([F:9])=[CH:4][N:3]=2)[CH:20]=[CH:19][CH:18]=1
Reactant: Nc1cccc(OCCO)c1
Reactant: Fc1cnc(Cl)nc1Cl
Product: OCCOc1cccc(Nc2ncc(F)c(Nc3cccc(OCCO)c3)n2)c1

Procedure:
In like manner to the preparation of N2,N4-bis(3-hydroxyphenyl)-5-fluoro-2,4-pyrimidinediamine, 2,4-dichloro-5-fluoropyrimidine and 2-(3-aminophenoxy)ethanol were reacted to produce N2,N4-bis[3-(2-hydroxyethoxy)phenyl]-5-fluoro-2,4-pyrimidinediamine. 1H NMR (DMSO-d6): δ 9.50 (br s, 1H), 9.35 (br s, 1H), 8.13 (d, 1H, J=4.1 Hz), 7.44 (d, 1H, J=7.6 Hz), 7.26-7.19 (m, 4H), 7.10 (t, 1H, J=7.6 Hz), 6.65 (dd, 1H, J=2.3 and 8.2 Hz), 6.50 (dd, 1H, J=2.3 and 8.2 Hz), 5.0 (br s, 2H), 3.91 (t, 2H, J=5.2 Hz), 3.85 (t, 2H, J=5.2 Hz), 3.68 (qt, 2H, J=5.2 Hz), 3.66 (qt, 2H, J=5.2 Hz); LCMS: ret. time: 15.76 min.; purity: 97%; MS (m/e): 401 (MH+).
Reaction SMILES: [CH2:1]1[O:9][C:8]2[C:3](=[CH:4][C:5]([C:15](=O)[C:16]3[CH:21]=[CH:20][C:19]([N+:22]([O-:24])=[O:23])=[CH:18][C:17]=3[Cl:25])=[C:6]([CH2:10][C:11](OC)=[O:12])[CH:7]=2)[O:2]1.O.[NH2:28][NH2:29].C(O)C>>[Cl:25][C:17]1[CH:18]=[C:19]([N+:22]([O-:24])=[O:23])[CH:20]=[CH:21][C:16]=1[C:15]1[C:5]2[CH:4]=[C:3]3[O:2][CH2:1][O:9][C:8]3=[CH:7][C:6]=2[CH2:10][C:11](=[O:12])[NH:29][N:28]=1
Reactant: NN
Reactant: COC(=O)Cc1cc2c(cc1C(=O)c1ccc([N+](=O)[O-])cc1Cl)OCO2
Solvent: CCO
Solvent: O
Product: O=C1Cc2cc3c(cc2C(c2ccc([N+](=O)[O-])cc2Cl)=NN1)OCO3

Procedure:
The title compound was prepared from methyl 4,5-methylenedioxy-2-(2-chloro-4-nitrobenzoyl)phenylacetate (11 g, 29 mmol) and hydrazine hydrate (5.0 mL, 88 mmol) in ethanol (60 mL) as a yellow solid (1.4 g, 3.9 mmol, 13%), mp: 202°-204° C. 1H NMR (CDCl3) 8.64 (s, 1H), 8.29-8.26 (m, 2H), 7.82 (d, J=8.2, 1H), 6.84 (s, 1H), 6.28 (s, 1H), 6.02 (s, 2H), 3.59 (s, 2H). Anal. Calcd. for C16H10N3O5.(1/2)H2O: C, 52.12; H, 3.01; N, 11.40. Found: C, 52.50; H, 3.36; N, 10.35.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([C:8]([O:10][CH3:11])=[O:9])[C:3]=1[NH:12][S:13]([C:16]1[N:26]=[C:19]2[C:20](Br)=[N:21][CH:22]=[C:23]([Br:24])[N:18]2[N:17]=1)(=[O:15])=[O:14].[CH3:27][O-:28].[Na+]>C(#N)C.CO>[F:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([C:8]([O:10][CH3:11])=[O:9])[C:3]=1[NH:12][S:13]([C:16]1[N:26]=[C:19]2[C:20]([O:28][CH3:27])=[N:21][CH:22]=[C:23]([Br:24])[N:18]2[N:17]=1)(=[O:15])=[O:14]
Reactant: COC(=O)c1cccc(F)c1NS(=O)(=O)c1nc2c(Br)ncc(Br)n2n1
Reactant: C[O-]
Agent: [Na+]
Solvent: CO
Solvent: CC#N
Product: COC(=O)c1cccc(F)c1NS(=O)(=O)c1nc2c(OC)ncc(Br)n2n1

Procedure:
A solution of 686 mg (1.35 mmol) of N-(2-fluoro-6-methoxycarbonylphenyl)-5,8-dibromo[1,2,4]triazolo-[1,5-a]pyrazine-2-sulfonamide in 10 mL dry acetonitrile was treated with 3.0 mL (3.0 mmol) of a 1M solution of 15 sodium methoxide in dry methanol at 0° C. with stirring. The reaction was quenched after 5min with 0.5mL of glacial acetic acid and the volatiles were removed by evaporation under reduced pressure. The residue was triturated with water and the resulting light brown solid was collected by filtration and dried in a vacuum oven. This crude material was purified by flash column chromatography on silica gel using a 0.5 to 2percent ethanol/dichloromethane gradient as eluent to obtain 538 mg (87 percent of theory) of the title compound as a white glassy foam solid melting at 201°-202° C.
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[C:9]([C:11](=O)[CH3:12])[C:8]([C:14]2[CH:19]=[C:18]([F:20])[CH:17]=[C:16]([F:21])[CH:15]=2)=[C:7]2[C:3]=1[CH:4]=[N:5][N:6]2[CH3:22].C([O-])(=O)C.[NH4+].C([BH3-])#[N:29].[Na+]>CO.C(#N)C>[Cl:1][C:2]1[CH:10]=[C:9]([CH:11]([NH2:29])[CH3:12])[C:8]([C:14]2[CH:19]=[C:18]([F:20])[CH:17]=[C:16]([F:21])[CH:15]=2)=[C:7]2[C:3]=1[CH:4]=[N:5][N:6]2[CH3:22]
Reactant: [BH3-]C#N
Reactant: CC(=O)c1cc(Cl)c2cnn(C)c2c1-c1cc(F)cc(F)c1
Agent: CC(=O)[O-]
Agent: [NH4+]
Agent: [Na+]
Solvent: CO
Solvent: CC#N
Product: CC(N)c1cc(Cl)c2cnn(C)c2c1-c1cc(F)cc(F)c1
Temperature: 65 °C

Procedure:
A mixture of 1-[4-chloro-7-(3,5-difluorophenyl)-1-methyl-1H-indazol-6-yl]ethanone (0.438 g, 1.36 mmol), ammonium acetate (1.05 g, 13.6 mmol) and sodium cyanoborohydride (0.172 g, 2.73 mmol) in methanol (5 mL) and acetonitrile (5 mL) was heated at 65° C. overnight, in a sealed tube. The mixture was then cooled to room temperature and quenched with sat. sodium bicarbonate, extracted with dichloromethane. The combined extracts were dried over magnesium sulfate and evaporated to dryness to give the desired product. LCMS calculated for C16H12ClF2N2 (M−NH2)+: m/z=305.1; Found: 305.0.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([C:8]#[CH:9])[CH:5]=[CH:6][CH:7]=1.[C:10](OC(=O)C)(=[O:12])[CH3:11]>>[C:8]([C:4]1[CH:3]=[C:2]([NH:1][C:10](=[O:12])[CH3:11])[CH:7]=[CH:6][CH:5]=1)#[CH:9]
Reactant: C#Cc1cccc(N)c1
Reactant: CC(=O)OC(C)=O
Product: C#Cc1cccc(NC(C)=O)c1
Reaction time: 0.5 h
Yield: 89 %

Procedure:
A 30.0 g (0.256 mole) sample of 3-aminophenylacetylene was cooled at ice bath temperature and 27.0 ml (0.282 mole) of acetic anhydride was added dropwise. The ice bath was removed and the mixture stirred for 30 min. The mixture was diluted with ether and the resulting solution washed with water, NaHCO3 solution and brine. The organic phase was dried (K2CO3) and the solvent evaporated in vacuo. The crystalline residue was recrystallized from CHCl3 -hexane to give 60.7 g (89% yield) of crystalline N-(3-ethynylphenyl)acetamide, mp 94°-96° C.
Reaction SMILES: [C:1]([C:4]1[CH:5]=[CH:6][C:7]([OH:20])=[C:8]([CH:19]=1)[C:9](=[O:18])[CH:10]=[CH:11][C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1)([OH:3])=[O:2].[OH-:21].[Na+].Cl>C(O)C.OO>[C:1]([C:4]1[CH:19]=[C:8]2[C:7](=[CH:6][CH:5]=1)[O:20][C:11]([C:12]1[CH:13]=[CH:14][CH:15]=[CH:16][CH:17]=1)=[C:10]([OH:21])[C:9]2=[O:18])([OH:3])=[O:2]
Reactant: O=C(O)c1ccc(O)c(C(=O)C=Cc2ccccc2)c1
Reactant: [OH-]
Agent: Cl
Agent: OO
Agent: [Na+]
Solvent: CCO
Product: O=C(O)c1ccc2oc(-c3ccccc3)c(O)c(=O)c2c1
Temperature: 0 °C
Reaction time: 2 h
Yield: 83 %

Procedure:
5'-Carboxy-2'-hydroxychalcone (30 mmol) and sodium hydroxide (5.2 g, 130 mmol) were dissolved in 200 ml of ethanol, to which 11.4 ml (100 mmol) of a 30% aqueous solution of hydrogen peroxide were added under ice cooling. The reaction mixture was stirred at 0° C. for 2 hours and then at room temperature for 16 hours. 2 N hydrochloric acid was added to the reaction mixture to acidify the same. The resulting precipitate was collected by filtration, washed with water, dried in air, and then recrystallized from THF-EtOH, whereby the title compound represented by the following formula was obtained (yield: 83%). ##STR58##
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[CH2:12][CH2:11][C@H:10]([N:13]([CH3:15])[CH3:14])[CH2:9]2)=[CH:4][CH:3]=1.[CH2:16]([N:19]1[C:27](=[O:28])[C:26]2[C:21](=[N:22][C:23](SC)=[N:24][CH:25]=2)[N:20]1[C:31]1[N:36]=[C:35]([N:37]2[CH:42]=[CH:41][CH:40]=[CH:39][C:38]2=[O:43])[CH:34]=[CH:33][CH:32]=1)[CH:17]=[CH2:18]>>[CH2:16]([N:19]1[C:27](=[O:28])[C:26]2[C:21](=[N:22][C:23]([NH:1][C:2]3[CH:7]=[CH:6][C:5]([N:8]4[CH2:12][CH2:11][C@H:10]([N:13]([CH3:15])[CH3:14])[CH2:9]4)=[CH:4][CH:3]=3)=[N:24][CH:25]=2)[N:20]1[C:31]1[N:36]=[C:35]([N:37]2[CH:42]=[CH:41][CH:40]=[CH:39][C:38]2=[O:43])[CH:34]=[CH:33][CH:32]=1)[CH:17]=[CH2:18]
Reactant: CN(C)[C@H]1CCN(c2ccc(N)cc2)C1
Reactant: C=CCn1c(=O)c2cnc(SC)nc2n1-c1cccc(-n2ccccc2=O)n1
Product: C=CCn1c(=O)c2cnc(Nc3ccc(N4CC[C@H](N(C)C)C4)cc3)nc2n1-c1cccc(-n2ccccc2=O)n1

Procedure:
The entitled compound was obtained as a yellow solid (36.7 mg) in the same manner as in Production Example 12-2, for which, however, (3S)-1-(4-aminophenyl)-N,N-dimethylpyrrolidin-3-amine was used in place of [5-amino-2-(4-methylpiperazin-1-yl)phenyl]methanol used in Production Example 12-2, and 6′-[2-allyl-6-(methylthio)-3-oxo-2,3-dihydro-1H-pyrazolo[3,4-d]pyrimidin-1-yl]-2H-1,2′-bipyridin-2-one was used in place of 2-allyl-6-(methylthio)-1-pyridin-2-yl-3H-pyrazolo[3,4-d]pyrimidin-3-one.
Reaction SMILES: [O:1]1[CH2:6][CH2:5][CH2:4][CH2:3][CH:2]1[O:7][CH2:8][CH2:9][C:10]#[C:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][F:20].[H][H]>CO.N1C2C(=CC=CC=2)C=CC=1.[Pd]>[O:1]1[CH2:6][CH2:5][CH2:4][CH2:3][CH:2]1[O:7][CH2:8][CH2:9]/[CH:10]=[CH:11]\[CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][F:20]
Reactant: [H][H]
Reactant: FCCCCCCCCC#CCCOC1CCCCO1
Agent: [Pd]
Solvent: CO
Solvent: c1ccc2ncccc2c1
Product: FCCCCCCCC/C=C\CCOC1CCCCO1
Yield: 98.1 %

Procedure:
A solution of 12-fluoro-3-dodecyn-1-yl tetrahydropyranyl ether (0.5262 g, 1.85 mmol) (prepared as in Example 3 above) in methanol (10 mL) containing about 4 drops of quinoline is hydrogenated at room temperature over 5% palladium on barium sulfate (25 mg). The mixture is kept at about 762 psi of hydrogen until 41.5 ml (1.85 mmol) of hydrogen has been absorbed. The catalyst is then filtered off and the solvent removed in vacuo. The residue is purified by flash chromatography using hexane/ethyl acetate (9:1, v/v) to give 12-fluoro-(Z)-3-dodecen-1-yl tetrahydropyranyl ether (0.52 g, 99%) as a clear oil: Rf=0.65, hexane/ethyl acetate (7:3, v/v); IR (film) ν3025 (C=CH); and 1H-NMR δ1.20-1.80 (m, 18H), 2.05 (m,2H), 2.35 (br q, J=4 Hz, 2H), 3.60 (m, 4H), 4.41(dt, J=48 Hz, 2H), 4.56 (br s, 1H), 5.41 (m, 2H).
Reaction SMILES: [C:1]1(=[O:13])[N:5]([CH2:6][CH2:7][CH2:8][C:9]([OH:11])=O)[C:4](=[O:12])[CH:3]=[CH:2]1.[NH:14]([C:16]([O:18][C:19]([CH3:22])([CH3:21])[CH3:20])=[O:17])[NH2:15].C(Cl)CCl>C(Cl)Cl>[O:13]=[C:1]1[CH:2]=[CH:3][C:4](=[O:12])[N:5]1[CH2:6][CH2:7][CH2:8][C:9]([NH:15][NH:14][C:16]([O:18][C:19]([CH3:22])([CH3:21])[CH3:20])=[O:17])=[O:11]
Reactant: CC(C)(C)OC(=O)NN
Reactant: O=C(O)CCCN1C(=O)C=CC1=O
Solvent: ClCCl
Solvent: ClCCCl
Product: CC(C)(C)OC(=O)NNC(=O)CCCN1C(=O)C=CC1=O
Yield: 84.7 %

Procedure:
4-Maleimidobutyric acid (245 mg, 1.33 mmol), tert-butyl hydrazinecarboxylate (201 mg, 1.52 mmol) and EDC (400 mg, 2.08 mmol) in 5 ml of CH2Cl2, were stirred overnight under Ar, washed with 1 M NaH2PO4/NaCl (conc), dried over MgSO4, filtered, evaporated and purified on SiO2 chromatography eluted with MeOH/DCM (1:25) to afford 335 mg (85%) of the title compound. 1H NMR (CDCl3), 7.83 (br, 1H), 6.65 (s, 2H), 6.50 (br, 1H), 3.58 (t, 2H, J=6.3 Hz), 2.15 (t, 2H, J=7.0 Hz), 1.90 (dt, 2H, J=6.8, 13.4 Hz), 1.40 (s, 9H); 13C NMR 171.30, 155.61, 134.41, 82.00, 37.13, 31.38, 28.36, 24.95; MS m/z+320.2 (M+Na).
Reaction SMILES: [CH3:1][C:2]1[C:7]([C:8]2[CH:13]=[CH:12][CH:11]=[C:10]([N+:14]([O-])=O)[CH:9]=2)=[CH:6][C:5]([NH:17][C:18](=[O:29])[C:19]2[CH:24]=[CH:23][CH:22]=[C:21]([C:25]([F:28])([F:27])[F:26])[CH:20]=2)=[CH:4][CH:3]=1.C(O)C>[Fe].C(O)(=O)C>[NH2:14][C:10]1[CH:9]=[C:8]([C:7]2[C:2]([CH3:1])=[CH:3][CH:4]=[C:5]([NH:17][C:18](=[O:29])[C:19]3[CH:24]=[CH:23][CH:22]=[C:21]([C:25]([F:26])([F:27])[F:28])[CH:20]=3)[CH:6]=2)[CH:13]=[CH:12][CH:11]=1
Reactant: Cc1ccc(NC(=O)c2cccc(C(F)(F)F)c2)cc1-c1cccc([N+](=O)[O-])c1
Agent: [Fe]
Solvent: CCO
Solvent: CC(=O)O
Product: Cc1ccc(NC(=O)c2cccc(C(F)(F)F)c2)cc1-c1cccc(N)c1
Temperature: 25 °C

Procedure:
To N-(6-methyl-3′-nitrobiphenyl-3-yl)-3-(trifluoromethyl)benzamide (1.00 g, 2.50 mmol) was added ethanol (18 mL) and acetic acid (1.7 mL) and iron (770 mg). The resulting mixture was heated to reflux until LCMS indicated complete reduction, typically 2-4 hours. The reaction was cooled to ambient temperature, and the unreacted iron was removed by filtration. The ethanolic filtrate was evaporated to dryness and EtOAc was added to the residue. The resulting rust-like particulates were removed by filtration through a small pad of diatomaceous earth, and the filtrate was evaporated to dryness to leave the crude aniline. The compound was recovered in quantitative yield and was used without further purification in the subsequent reaction. MS (EI) m/z=371 (M+H).
Reaction SMILES: [C:1]([O:4][C:5]1[C:6]2[CH:7]=[CH:8][C:9](C#CC3C=CC(C(OCC)=O)=CC=3)=[CH:10][C:11]=2[C:12]([CH3:16])([CH3:15])[CH2:13][CH:14]=1)(=[O:3])[CH3:2].CC1(C)C2C=CC([C:41]#[C:42][C:43]3[CH:53]=[CH:52][C:46]([C:47]([O:49][CH2:50][CH3:51])=[O:48])=[CH:45][CH:44]=3)=CC=2C(=O)CC1>>[C:1]([O:4][C:5]1[C:6]2[CH:7]=[C:8]([C:41]#[C:42][C:43]3[CH:53]=[CH:52][C:46]([C:47]([O:49][CH2:50][CH3:51])=[O:48])=[CH:45][CH:44]=3)[CH:9]=[CH:10][C:11]=2[C:12]([CH3:16])([CH3:15])[CH2:13][CH:14]=1)(=[O:3])[CH3:2]
Reactant: CCOC(=O)c1ccc(C#Cc2ccc3c(c2)C(=O)CCC3(C)C)cc1
Reactant: CCOC(=O)c1ccc(C#Cc2ccc3c(c2)C(C)(C)CC=C3OC(C)=O)cc1
Product: CCOC(=O)c1ccc(C#Cc2ccc3c(c2)C(OC(C)=O)=CCC3(C)C)cc1

Procedure:
Employing the same general procedure as for the preparation of ethyl 4-[(5-acetoxy-7,8-dihydro-8,8-dimethylnaphth-2-yl)ethynyl]benzoate (Compound 105), 90.0 mg (0.26 mmol) of ethyl 4-[(5,6,7,8-tetrahydro-8,8-dimethyl-5-oxonaphth-3-yl)ethynyl]benzoate (Compound 2) was converted into the title compound (light yellow powder) using 0.06 ml (0.78 mmol) of acetic anhydride and 5 mg (0.03 mmol) of p-toluenesulfonic acid.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]2[C:12](=[CH:13][CH:14]=1)[NH:11][C:10]1[CH:9]([NH:15][C@@H:16]([C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=3)[CH3:17])[CH2:8][CH2:7][CH2:6][C:5]2=1.C(NCC)C.[ClH:29]>CO>[ClH:29].[Br:1][C:2]1[CH:3]=[C:4]2[C:12](=[CH:13][CH:14]=1)[NH:11][C:10]1[C@H:9]([NH:15][C@@H:16]([C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=3)[CH3:17])[CH2:8][CH2:7][CH2:6][C:5]2=1
Reactant: C[C@@H](NC1CCCc2c1[nH]c1ccc(Br)cc21)c1ccccc1
Agent: Cl
Solvent: CO
Solvent: CCNCC
Product: C[C@@H](N[C@@H]1CCCc2c1[nH]c1ccc(Br)cc21)c1ccccc1

Procedure:
(1R)-6-Bromo-N-[(1R)-1-phenylethyl]-2,3,4,9-tetrahydro-1H-carbazol-1-amine hydrochloride salt was prepared by separation of diastereomeric 6-bromo-N-[(1R)-1-phenylethyl]-2,3,4,9-tetrahydro-1H-carbazol-1-amine by SFC (Berger Amino, Chiral Technologies, 10% methanol, (2% diethyl amine/10% chloroform) 1500 psi, 50° C., 2 mL/min, retention time: 17.5 min.) The oil obtained was converted to the HCl salt to give a white solid. [α]25=160 (c 0.20, MeOH); 1H-NMR (DMSO-d6): δ 11.6 (s, 1H), 9.85 (s, 1H), 9.30 (s, 1H), 7.80 (d, J=6.8 Hz, 1H), 7.70 (d, J=1.8 Hz, 1H), 7.52-7.45 (m, 3H), 7.43 (d, J=8.6 Hz, 1H), 7.29 (dd, J=6.8 Hz, J=1.8 Hz, 1H), 4.78 (m, J=6.4 Hz, 1H), 4.60 (m, 1H), 2.77-2.65 (m, 2H), 2.20-2.05 (m, 1H), 2.05-1.95 (m, 2H), 1.88-1.80 (m, 1H), 1.71 (d, J=6.8 Hz, 3H); MS m/z 367, 369 (M−1); Anal. Calcd. For C20H22BrN2Cl: C, 59.20; H, 5.46; N, 6.90; Cl, 8.69. Found: C, 59.34; H, 5.45; N, 6.87; Cl, 8.67.
Reaction SMILES: [C:1]([C:3]([C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1)([CH:8]([CH3:10])[CH3:9])[CH2:4][CH2:5][CH2:6]O)#[N:2].S(Cl)(C)(=O)=O.[I-:22].[Na+]>C(#N)C.C(N(CC)CC)C>[C:1]([C:3]([C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1)([CH:8]([CH3:10])[CH3:9])[CH2:4][CH2:5][CH2:6][I:22])#[N:2]
Reactant: CC(C)C(C#N)(CCCO)c1ccccc1
Reactant: [I-]
Agent: CS(=O)(=O)Cl
Agent: [Na+]
Solvent: CC#N
Solvent: CCN(CC)CC
Product: CC(C)C(C#N)(CCCI)c1ccccc1
Reaction time: 0.42 h

Procedure:
5.00 g 23.0 mmol of 4-Cyano-5-methyl-4-phenylhexanol disclosed in Example 2 or 3 of JP 11-70613-A was added to and dissolved in acetonitrile 150 ml and triethylamine 3.53 ml. Mesyl chloride, 1.96 ml 25.3 mmol, was added thereto. After 25 minutes, sodium iodide 20.7 g was added thereto. The reaction mixture was partitioned by adding brine and ethyl acetate. The organic layer was washed with aqueous sodium thiosulfate and then with brine, dried over magnesium sulfate, and evaporated. The residue was purified by silica gel column chromatography (ethyl acetate/hexane system), whereby the title compound, 5. 89 g 18.0 mmol, 78.2%, was obtained as a pale yellow oil.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[C:8]1([CH2:16][CH2:15][C:14]3([O:21][CH2:20][C:19]([CH3:23])([CH3:22])[CH2:18][O:17]3)[CH2:13][CH2:12]1)[C:7](=[O:24])[C:6]([C:25](OCC)=[O:26])=[C:5]2[OH:30].Cl.[NH2:32][CH2:33][C:34]([O:36][C:37]([CH3:40])([CH3:39])[CH3:38])=[O:35].C(N(C(C)C)C(C)C)C>O1CCOCC1>[Cl:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[C:8]1([CH2:12][CH2:13][C:14]3([O:21][CH2:20][C:19]([CH3:22])([CH3:23])[CH2:18][O:17]3)[CH2:15][CH2:16]1)[C:7](=[O:24])[C:6]([C:25]([NH:32][CH2:33][C:34]([O:36][C:37]([CH3:40])([CH3:39])[CH3:38])=[O:35])=[O:26])=[C:5]2[OH:30]
Reactant: CC(C)(C)OC(=O)CN
Reactant: CCOC(=O)C1=C(O)c2cc(Cl)ccc2C2(CCC3(CC2)OCC(C)(C)CO3)C1=O
Agent: Cl
Solvent: C1COCCO1
Solvent: CCN(C(C)C)C(C)C
Product: CC1(C)COC2(CCC3(CC2)C(=O)C(C(=O)NCC(=O)OC(C)(C)C)=C(O)c2cc(Cl)ccc23)OC1
Temperature: 95 °C
Reaction time: 2 h
Yield: 79.8 %

Procedure:
A mixture of ethyl 6″-chloro-4″-hydroxy-5,5-dimethyl-2″-oxo-dispiro[1,3-dioxane-2,1′-cyclohexane-4′,1″-naphthalene]-3″-carboxylate (69 mg, 159 μmol) and tert-butyl 2-aminoacetate hydrochloride (53 mg, 317 μmol) in 1.5 mL dioxane was treated with N-ethyl-N-isopropylpropan-2-amine (62 mg, 476 μmol). The mixture was warmed to 95° C. and stirred for 2 hours, M+1=420. The mixture was cooled to room temperature and concentrated in vacuo. The crude product was purified by column chromatography eluting with 10-20% EtOAc/hexane to give 66 mg of the title compound as a white yellow solid. MS (m/z)=520 (M+H)+.
Reaction SMILES: [CH2:1]1[C:6]2([CH2:16][NH:15][CH2:14][C:8]3([CH2:13][CH2:12][CH2:11][CH2:10][CH2:9]3)[NH:7]2)[CH2:5][CH2:4][CH2:3][CH2:2]1.N1C=CC=CC=1.[C:23](Cl)(=[O:41])[CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][CH2:36][CH2:37][CH2:38][CH2:39][CH3:40]>CCCCCC>[C:23]([N:15]1[CH2:14][C:8]2([CH2:13][CH2:12][CH2:11][CH2:10][CH2:9]2)[NH:7][C:6]2([CH2:1][CH2:2][CH2:3][CH2:4][CH2:5]2)[CH2:16]1)(=[O:41])[CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][CH2:36][CH2:37][CH2:38][CH2:39][CH3:40]
Reactant: CCCCCCCCCCCCCCCCCC(=O)Cl
Reactant: C1CCC2(CC1)CNCC1(CCCCC1)N2
Solvent: CCCCCC
Solvent: c1ccncc1
Product: CCCCCCCCCCCCCCCCCC(=O)N1CC2(CCCCC2)NC2(CCCCC2)C1
Temperature: 5 °C
Reaction time: 0.33 h

Procedure:
In a 500 ml. 3-necked flask equipped with stirrer, condenser with drying tube, thermometer, dropping funnel and nitrogen inlet was placed a solution of 15.6 g. (0.07 moles) of 7,15-diazadispiro[5,1,5,3]hexadecane in 150 ml. of dry pyridine. Under a dry nitrogen atmosphere, the solution was cooled to 5° C with an external ice bath and a solution of 21.2 g. (0.07 moles) of stearoyl chloride in 50 ml. of hexane was added dropwise with stirring over a 20 minute period. The reaction mixture was then allowed to warm to room temperature and stir for about 16 hours. The reaction mixture was filtered and the filtrate was taken up in ether, washed well with water, then with 2N NaOH solution. The filtrate was again filtered by suction, and the ether solution dried over anhydrous sodium sulfate and concentrated to dryness under reduced pressure. The residue was recrystallized from acetonitrile, yielding colorless crystals, m.p. 56°-59° C.
Reaction SMILES: [C:1]([C:3]1[CH:9]=[CH:8][C:6]([NH2:7])=[CH:5][CH:4]=1)#[CH:2].[C:10](N1C=CN=C1)(N1C=CN=C1)=[O:11]>C(Cl)Cl>[C:1]([C:3]1[CH:9]=[CH:8][C:6]([N:7]=[C:10]=[O:11])=[CH:5][CH:4]=1)#[CH:2]
Reactant: C#Cc1ccc(N)cc1
Reactant: O=C(n1ccnc1)n1ccnc1
Solvent: ClCCl
Product: C#Cc1ccc(N=C=O)cc1

Procedure:
4-Ethynylphenylisocyanate was prepared from reaction of 4-ethynylaniline with one equivalent of carbonyldiimidazole in CH2Cl2.
Reaction SMILES: [Cl:1][C:2]1[C:3]2[C:10]([I:11])=[CH:9][N:8]([CH:12]3[CH2:17][CH2:16][N:15](C(OC(C)(C)C)=O)[CH2:14][CH2:13]3)[C:4]=2[N:5]=[CH:6][N:7]=1.FC(F)(F)C(O)=O>ClCCl>[Cl:1][C:2]1[C:3]2[C:10]([I:11])=[CH:9][N:8]([CH:12]3[CH2:17][CH2:16][NH:15][CH2:14][CH2:13]3)[C:4]=2[N:5]=[CH:6][N:7]=1
Reactant: CC(C)(C)OC(=O)N1CCC(n2cc(I)c3c(Cl)ncnc32)CC1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: Clc1ncnc2c1c(I)cn2C1CCNCC1
Temperature: 0 °C
Reaction time: 3 h

Procedure:
A mixture of tert-butyl 4-(4-chloro-5-iodo-7H-pyrrolo[2,3-d]pyrimidin-7-yl)-1-piperidinecarboxylate (1.0 g, 2.16 mmol) in dichloromethane (10 mL) at 0° C. was treated with a cold solution of trifluoroacetic acid (20%) in dichloromethane (total volume 56 mL). Reaction stirred at 0° C. under a nitrogen atmosphere for 3 hours. The solvent was evaporated under reduced pressure at ambient temperature. Ethyl acetate (50 mL) and 5 N hydrochloric acid (50 mL) were added to the solid. The layers were partitioned, and the organic layer was extracted with 5 N hydrochloric acid (150 mL). The aqueous layers were combined, cooled to 0° C., and basified using 50% sodium hydroxide aqueous solution at 0° C. The aqueous layer was extracted with dichloromethane (300 mL). The organic layers were combined, dried over magnesium sulfate, filtered, and evaporated under reduced pressure. The resulting product, 4-chloro-5-iodo-7-(4-piperidyl)-7H-pyrrolo[2,3-d]pyrimidine (0.520 g, 99%) was dried 5 under high vacuum. 1H NMR (DMSO-d6, 400 MHz); 8.63(s, 1H), 8.12(s, 1H), 4.75-4.68 (m, 1H), 3.09-3.06(d, 2H, J=12 Hz), 2.70-2.60(m, 2H), 1.99-1.83(m, 4H); Waters 2690 Alliance HPLC (Symmetry Shield RP18 3.5 m, 2.1×50 mm; 5%-95% acetonitrile-0.1 M ammonium acetate over 15 min, 0.5 mL/min) Rt 4.022 min.