Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH:1](=[O:5])/[CH:2]=[CH:3]/[CH3:4].[CH2:6]([N:13]1[C:21]2[C:16](=[CH:17][CH:18]=[CH:19][CH:20]=2)[CH:15]=[CH:14]1)[C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1.[N+](C1C=C([N+]([O-])=O)C=CC=1C(O)=O)([O-])=O.C([C@@H]1N[C@H](C(C)(C)C)N(C)C1=O)C1C=CC=CC=1>C(Cl)Cl.C(O)(C)C>[CH2:6]([N:13]1[C:21]2[C:16](=[CH:17][CH:18]=[CH:19][CH:20]=2)[C:15]([C@H:3]([CH3:4])[CH2:2][CH:1]=[O:5])=[CH:14]1)[C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1
Reactant: C/C=C/C=O
Reactant: c1ccc(Cn2ccc3ccccc32)cc1
Agent: CN1C(=O)[C@H](Cc2ccccc2)N[C@@H]1C(C)(C)C
Agent: O=C(O)c1ccc([N+](=O)[O-])cc1[N+](=O)[O-]
Solvent: ClCCl
Solvent: CC(C)O
Product: C[C@H](CC=O)c1cn(Cc2ccccc2)c2ccccc12
Temperature: -40 °C
Reaction time: 70 h
Yield: 79.3 %

Procedure:
Prepared according to the general procedure from crotonaldehyde (125 μL, 1.50 mmol), 1-benzyl-1H-indole (104 mg, 0.500 mmol), 2,4-dinitrobenzoic acid (21.2 mg, 0.100 mmol) and (2S,5S)-5-benzyl-2-tert-butyl-3-methyl-imidazolidin-4-one (24.6 mg, 0.100 mmol) in CH2Cl2 (0.90 mL) and isopropanol (0.10 mL) at −60° C. for 41 h, at which time an additional 125 μL (1.50 mmol) of crotonaldehyde was added. The reaction was continued for an additional 70 h, at which time an additional 42 μL (0.50 mmol) of crotonaldehyde was added. The reaction was continued at this temperature for an additional 5 h, at which time the temperature was raised to −40° C. for 2 h, then −10° C. for an additional 2 h to provide, after silica gel chromatography (15:85 EtOAc/hexanes), the title compound as a colorless oil (110 mg, 80% yield, 89% ee). IR (film) 3062, 3030, 2965, 2925, 2877, 2820, 2724, 1722, 1613, 1589, 1549, 1496, 1480, 1468, 1452, 1392, 1372, 1356, 1331, 1303, 1251, 1203, 1174, 1017 cm−1; 1H NMR (300 MHz, CDCl3) δ 9.76 (dd, J=2.4, 2.4 Hz, 1H, CHO), 7.66 (dt, J=0.6, 7.5 Hz, 1H, ArH), 7.33-7.08 (m, 8H, ArH), 6.92 (s, 1H, NCH), 5.28 (s, 2H, NCH2), 3.70 (dt, J=6.9, 21 Hz, 1H, ArCH), 2.89 (ddd, J=2.4, 6.6, 16.5 Hz, 1H, CH2CO); 2.72 (ddd, J=1.8, 7.8, 15.9 Hz, 1H, CH2CO); 1.44 (d, J=6.9 Hz, 3H, CHCH3); 13C NMR (75 MHz, CDCl3) δ 202.7, 137.5, 131.9, 128.8, 127.6, 126.9, 126.8, 124.6, 122.0, 119.6, 119.3, 119.2, 110.0, 51.2, 50.1, 26.1, 21.0; HRMS (CI) exact mass calcd for (C19H19 NO) requires m/z 277.1467, found m/z 277.1464. [α]D=+3.5 (c=1.0, CHCl3). The enantiomeric ratio was determined by HPLC analysis of the alcohol, obtained by NaBH4 reduction of the aldehyde, using a Chiracel AD and AD guard column (2:98 isopropanol/hexanes, 1 mL/min); S isomer tr=26.5 min and R isomer tr=29.5 min.
Reaction SMILES: [Cl:1][C:2]1[CH:8]=[CH:7][CH:6]=[C:5]([CH3:9])[C:3]=1[NH2:4].[O:10]1[CH:12]([CH3:13])[CH2:11]1>>[OH:10][CH:12]([CH3:13])[CH2:11][NH:4][C:3]1[C:5]([CH3:9])=[CH:6][CH:7]=[CH:8][C:2]=1[Cl:1]
Reactant: CC1CO1
Reactant: Cc1cccc(Cl)c1N
Product: Cc1cccc(Cl)c1NCC(C)O
Yield: 30.1 %

Procedure:
2-Chloro-6-methyl-aniline is reacted with 1,2-epoxypropane as described in Example 3, Method (b), point (a) to obtain N-(β-hydroxypropyl)-2-chloro-6-methyl-aniline with a yield of 30.1%; b.p.: 118°-122° C./0.2 mm Hg.
Reaction SMILES: [CH3:1][C:2]1[NH:3][C:4]([CH3:26])=[C:5]([C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][N:21]=2)[CH:6]([C:11]2[CH:16]=[CH:15][CH:14]=[C:13]([N+:17]([O-:19])=[O:18])[CH:12]=2)[C:7]=1[C:8]([OH:10])=[O:9].[CH2:27](O)[CH2:28][CH2:29][CH2:30][CH2:31][CH3:32].C1(N=C=NC2CCCCC2)CCCCC1.C(Cl)(Cl)Cl>C1(C)C=CC=CC=1>[CH3:1][C:2]1[NH:3][C:4]([CH3:26])=[C:5]([C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][N:21]=2)[CH:6]([C:11]2[CH:16]=[CH:15][CH:14]=[C:13]([N+:17]([O-:19])=[O:18])[CH:12]=2)[C:7]=1[C:8]([O:10][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH3:32])=[O:9]
Reactant: CC1=C(C(=O)O)C(c2cccc([N+](=O)[O-])c2)C(c2ccccn2)=C(C)N1
Reactant: CCCCCCO
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Solvent: Cc1ccccc1
Solvent: ClC(Cl)Cl
Product: CCCCCCOC(=O)C1=C(C)NC(C)=C(c2ccccn2)C1c1cccc([N+](=O)[O-])c1
Temperature: 25 °C

Procedure:
350 mg (1 mmol) of 1,4-dihydro-2,6-dimethyl-4-(3-nitrophenyl)-5-pyridylpyridine-3-carboxylic acid, 102 mg (1 mmol) of hexyl alcohol, 309 mg (1.4 mmol) of N,N'-dicyclohexylcarbodiimide, 134 mg (1.1 mmol) of 4-N,N-dimethylaminopyridine were dissolved in 10 ml of toluene, with application of heat thereto. This reaction mixture was refluxed with application of heat for 1 hour, and then cooled to room temperature. To this reaction mixture, 20 ml of chloroform was added. The reaction mixture was then washed with water and dried over anhydrous sodium sulfate. The solvents contained in the reaction mixture were then distilled of and the residue was chromatographed on a silica gel column, whereby the captioned compound was obtained. The yield was 389 mg (89.5%).
Reaction SMILES: [N+:1]([C:4]1[CH:10]=[CH:9][C:7]([NH2:8])=[CH:6][CH:5]=1)([O-:3])=[O:2].[Cl:11][CH2:12][CH2:13][CH2:14][S:15](Cl)(=[O:17])=[O:16]>N1C=CC=CC=1>[N+:1]([C:4]1[CH:10]=[CH:9][C:7]([NH:8][S:15]([CH2:14][CH2:13][CH2:12][Cl:11])(=[O:17])=[O:16])=[CH:6][CH:5]=1)([O-:3])=[O:2]
Reactant: Nc1ccc([N+](=O)[O-])cc1
Reactant: O=S(=O)(Cl)CCCCl
Solvent: c1ccncc1
Product: O=[N+]([O-])c1ccc(NS(=O)(=O)CCCCl)cc1

Procedure:
A solution of 5.00 g (36.2 mmol) of 4-nitroaniline and 6.41 g (36.2 mmol) of 3-chloropropanesulfonyl chloride in 20 ml of pyridine is stirred overnight at room temperature. The reaction mixture is then poured onto ice. The precipitate which deposits in the process is filtered off with suction and dried, giving N-(4-nitrophenyl)-3-chloropropane-1-sulfonamide as a yellowish solid; ESI 279.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:16])[C:5]([C:7]1[C:15]2[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=2)[NH:9][CH:8]=1)=[O:6])[CH3:2].[C:17]([O-:20])([O-])=[O:18].[Cs+].[Cs+]>>[CH2:1]([O:3][C:4](=[O:16])[C:5]([C:7]1[C:15]2[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=2)[N:9]([CH2:11][CH2:10][NH:9][C:17]([O:20][C:7]([CH3:15])([CH3:8])[CH3:5])=[O:18])[CH:8]=1)=[O:6])[CH3:2]
Reactant: CCOC(=O)C(=O)c1c[nH]c2ccccc12
Reactant: O=C([O-])[O-]
Agent: [Cs+]
Product: CCOC(=O)C(=O)c1cn(CCNC(=O)OC(C)(C)C)c2ccccc12
Yield: 135.9 %

Procedure:
The general procedure 1 was then followed using the above product (6.68 mmol, 1.54 g), ethyl-2-(1H-indol-3-yl)-2-oxoacetate (6.68 mmol, 1.45 g) and Cs2CO3 (9.82 mmol, 3.20 g). The purification was achieved by column chromatography (petrol-ether:ethylacetate:diethylamine 5:4:1) to yield ethyl-2-(1-{2-[(tert.-butoxycarbonyl)-amino]ethyl}-1H-indol-3-yl)-2-oxoacetate (4.54 mmol, 68%) as white crystals. Mp=114-115° C. IR {tilde over (ν)} [cm−1]=3357; 2977; 1727; 1686; 1638; 1518. EI-MS (m/z)=360 (7.59%; M+•). 1H NMR (300 MHz, CDCl3) 8.44 (m; 1H; indole-H); 8.34 (s; 1H; indole-H); 7.42 (m; 1H; indole-H); 7.35 (m; 1H; indole-H); 4.63 (bs; 1H; NH); 4.37 (m; 4H; OCH2CH3; indole-CH2); 3.54 (q; 3J=6.2 Hz; 2H; CH2—N); 1.43 (t; 3H; 3J=7.1 Hz; OCH2CH3); 1.43 (s; 9H; C(CH3)3).
Reaction SMILES: Cl[C:2]1[C:11]2[C:10](=[O:12])[N:9]([CH3:13])[CH:8]=[N:7][C:6]=2[CH:5]=[C:4]([Cl:14])[N:3]=1.C1(C)C=CC(S(O)(=O)=O)=CC=1.[NH2:26][C@@H:27]1[CH2:31][CH2:30][O:29][CH2:28]1.CCN(C(C)C)C(C)C>O1CCOCC1>[Cl:14][C:4]1[N:3]=[C:2]([NH:26][C@@H:27]2[CH2:31][CH2:30][O:29][CH2:28]2)[C:11]2[C:10](=[O:12])[N:9]([CH3:13])[CH:8]=[N:7][C:6]=2[CH:5]=1
Reactant: N[C@@H]1CCOC1
Reactant: Cn1cnc2cc(Cl)nc(Cl)c2c1=O
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: CCN(C(C)C)C(C)C
Solvent: C1COCCO1
Product: Cn1cnc2cc(Cl)nc(N[C@@H]3CCOC3)c2c1=O
Temperature: 90 °C
Reaction time: 8 h

Procedure:
A mixture of 5,7-dichloro-3-methylpyrido[4,3-d]pyrimidin-4(3H)-one (75 mg, 0.33 mmol), (R)-3-aminotetrahydrofuran toluene-4-sulfonate (101 mg, 0.39 mmol), Hunig's base (0.23 mL, 1.32 mmol) and dioxane (4 mL) was stirred at 90° C. overnight. The reaction mixture was cooled to room temperature and worked-up. The residue was purified using slilica gel flash column chromatography (eluent: 0-10% methanol in dichloromethane) to afford (R)-7-chloro-3-methyl-5-(tetrahydrofuran-3-ylamino)pyrido[4,3-d]pyrimidin-4(3H)-one as a white solid.
Reaction SMILES: Cl[CH2:2][C:3]1[CH:18]=[CH:17][C:6]([O:7][C:8]2[CH:13]=[CH:12][C:11]([N+:14]([O-:16])=[O:15])=[CH:10][N:9]=2)=[CH:5][CH:4]=1.C(N(CC)CC)C.[N:26]1([C:32]([O:34][C:35]([CH3:38])([CH3:37])[CH3:36])=[O:33])[CH2:31][CH2:30][NH:29][CH2:28][CH2:27]1.O>CN(C=O)C>[N+:14]([C:11]1[CH:12]=[CH:13][C:8]([O:7][C:6]2[CH:17]=[CH:18][C:3]([CH2:2][N:29]3[CH2:28][CH2:27][N:26]([C:32]([O:34][C:35]([CH3:38])([CH3:37])[CH3:36])=[O:33])[CH2:31][CH2:30]3)=[CH:4][CH:5]=2)=[N:9][CH:10]=1)([O-:16])=[O:15]
Reactant: O=[N+]([O-])c1ccc(Oc2ccc(CCl)cc2)nc1
Reactant: CC(C)(C)OC(=O)N1CCNCC1
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Solvent: O
Product: CC(C)(C)OC(=O)N1CCN(Cc2ccc(Oc3ccc([N+](=O)[O-])cn3)cc2)CC1
Temperature: 50 °C
Reaction time: 3 h

Procedure:
To a solution of 2-(4-chloromethylphenoxy)-5-nitropyridine (12.32 g, 47 mmol) in DMF (120 mL) were added triethylamine (19.4 mL, 140 mmol) and t-butyl piperazine-1-carboxylate (11.27 g, 61 mmol), and the resulting solution was stirred for 3 hours at 50° C. Water was added to the residue, and extracted with ethyl acetate. The ethyl acetate layer was washed with water and brine. The ethyl acetate layer was dried over anhydrous magnesium sulfate, and evaporated. The residue was purified by silica gel column chromatography (n-hexane:ethyl acetate=1:1), to thereby yield 11.26 g of the title compound.
Reaction SMILES: [OH:1][N:2]=[C:3]([CH:6]=[CH:7][C:8]1[CH:13]=[CH:12][C:11]([CH3:14])=[CH:10][CH:9]=1)[C:4]#[N:5].[CH3:15][S:16](Cl)(=[O:18])=[O:17].C(N(CC)CC)C.O>O1CCCC1>[CH3:15][S:16]([O:1][N:2]=[C:3]([CH:6]=[CH:7][C:8]1[CH:9]=[CH:10][C:11]([CH3:14])=[CH:12][CH:13]=1)[C:4]#[N:5])(=[O:18])=[O:17]
Reactant: CS(=O)(=O)Cl
Reactant: Cc1ccc(C=CC(C#N)=NO)cc1
Solvent: O
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: Cc1ccc(C=CC(C#N)=NOS(C)(=O)=O)cc1
Temperature: 0 °C
Reaction time: 3.5 h
Yield: 64.3 %

Procedure:
2-Hydroxyimino-4-p-tolyl-but-3-enenitrile (1.9 g; 0.01 mol) is dissolved in 15 ml of anhydrous tetrahydrofuran, and cooled to 0° C. Methanesulfonyl chloride (0.93 ml, 0.012 mol) is added at once, followed by triethylamine (2.1 ml, 0.015 mol) dropwise over 20 min, keeping the temperature of the mixture below 5° C. The mixture is then stirred at 5-10° C. for 3.5 hours, and poured into 200 ml of iced water. The suspension is extracted with ethyl acetate, the organic extract is washed neutral with water, then with brine, and dried over magnesium sulfate. Rotary evaporation of the solvent and recrystallization from 50 ml of ethanol yields 2-methanesulfonyloxyimino-4-p-tolyl-but-3-enenitrile (1.7 g; 64%) as off-white crystals, mp 134-135° C. with one part melting at 145° C. 1H-NMR reveals the presence of two isomers (probably E/Z around the imino double bond).
Reaction SMILES: [F:1][C:2]([F:23])([F:22])[CH2:3][CH2:4][CH:5]([C:11]1[CH:21]=[CH:20][C:14]([C:15]([O:17][CH2:18][CH3:19])=[O:16])=[CH:13][CH:12]=1)OS(C)(=O)=O.[NH2:24][C:25]1[CH:26]=[N:27][C:28]2[C:33]([CH:34]=1)=[CH:32][CH:31]=[CH:30][CH:29]=2.P([O-])([O-])([O-])=O.[K+].[K+].[K+]>C(#N)C.O>[F:1][C:2]([F:23])([F:22])[CH2:3][CH2:4][CH:5]([C:11]1[CH:21]=[CH:20][C:14]([C:15]([O:17][CH2:18][CH3:19])=[O:16])=[CH:13][CH:12]=1)[NH:24][C:25]1[CH:26]=[N:27][C:28]2[C:33]([CH:34]=1)=[CH:32][CH:31]=[CH:30][CH:29]=2
Reactant: Nc1cnc2ccccc2c1
Reactant: CCOC(=O)c1ccc(C(CCC(F)(F)F)OS(C)(=O)=O)cc1
Agent: O=P([O-])([O-])[O-]
Agent: [K+]
Solvent: CC#N
Solvent: O
Product: CCOC(=O)c1ccc(C(CCC(F)(F)F)Nc2cnc3ccccc3c2)cc1
Temperature: 60 °C

Procedure:
To a solution of ethyl (+/−)-4-(4,4,4-trifluoro-1-((methylsulfonyl)oxy)butyl)benzoate (123 mg, 0.347 mmol) in acetonitrile (1.74 mL) was added 3-amino quinoline (60.6 mg, 0.416 mmol), followed by potassium phosphate (155 mg, 0.694 mmol). The resulting mixture was heated to 60° C. for 20 hours. The reaction mixture was cooled to room temperature, diluted with water (20 mL), and extracted with ethyl acetate (3×20 mL). The combined organic layers were dried over Na2SO4 and filtered, and the filtrate was concentrated under reduced pressure. Purification by silica gel flash chromatography (ethyl acetate/heptane) gave ethyl (+/−)-4-(4,4,4-trifluoro-1-(quinolin-3-ylamino)butyl)benzoate. 1H NMR (400 MHz, CDCl3) δ 8.51 (d, J=2.5 Hz, 1H), 8.06 (d, J=8.4 Hz, 2 H), 7.92 (d, J=7.8 Hz, 1 H), 7.50-7.44 (m, 3 H), 7.44-7.35 (m, 2 H), 6.81 (d, J=2.5 Hz, 1 H), 4.62-4.54 (m, 1 H), 4.44-4.33 (m, 3 H), 2.36-2.10 (m, 4 H), 1.38 (t, J=7.1 Hz, 3 H).
Reaction SMILES: [NH2:1][C:2]1[C:7]([C:8]([C:10]2[C:15]([O:16][CH3:17])=[CH:14][CH:13]=[C:12]([F:18])[C:11]=2[F:19])=[O:9])=[CH:6][N:5]=[C:4]([NH:20][CH:21]2[CH2:26][CH2:25][N:24]([S:27]([CH2:30][CH2:31][CH2:32]Cl)(=[O:29])=[O:28])[CH2:23][CH2:22]2)[N:3]=1.[NH2:34][CH2:35][CH:36]([OH:38])[CH3:37]>>[NH2:1][C:2]1[C:7]([C:8]([C:10]2[C:15]([O:16][CH3:17])=[CH:14][CH:13]=[C:12]([F:18])[C:11]=2[F:19])=[O:9])=[CH:6][N:5]=[C:4]([NH:20][CH:21]2[CH2:26][CH2:25][N:24]([S:27]([CH2:30][CH2:31][CH2:32][NH:34][CH2:35][CH:36]([OH:38])[CH3:37])(=[O:29])=[O:28])[CH2:23][CH2:22]2)[N:3]=1
Reactant: CC(O)CN
Reactant: COc1ccc(F)c(F)c1C(=O)c1cnc(NC2CCN(S(=O)(=O)CCCCl)CC2)nc1N
Product: COc1ccc(F)c(F)c1C(=O)c1cnc(NC2CCN(S(=O)(=O)CCCNCC(C)O)CC2)nc1N

Procedure:
The compound was prepared from [4-amino-2-[1-(3-chloro-propane-1-sulfonyl)-piperidin-4-ylamino]-pyrimidin-5-yl]-(2,3-difluoro-6-methoxy-phenyl)-methanone (Example 226) and 1-amino-2-propanol (Eastman Kodak) in an analogous manner as described in Example 227. HR-MS (ES, m/z) calculated for C23H33N6O5SF2 [(M+H)+] 543.2196, observed 543.2200.
Reaction SMILES: [Cl:1][C:2]1[C:7]([O:8][CH:9]([CH3:11])[CH3:10])=[CH:6][C:5]([NH:12][C:13]([NH2:15])=[O:14])=[C:4]([F:16])[CH:3]=1.[C:17]([O:23][CH2:24][CH3:25])(=[O:22])[CH2:18][C:19]([CH3:21])=O>>[Cl:1][C:2]1[C:7]([O:8][CH:9]([CH3:11])[CH3:10])=[CH:6][C:5]([NH:12][C:13](=[O:14])[NH:15]/[C:19](/[CH3:21])=[CH:18]\[C:17]([O:23][CH2:24][CH3:25])=[O:22])=[C:4]([F:16])[CH:3]=1
Reactant: CC(C)Oc1cc(NC(N)=O)c(F)cc1Cl
Reactant: CCOC(=O)CC(C)=O
Product: CCOC(=O)/C=C(/C)NC(=O)Nc1cc(OC(C)C)c(Cl)cc1F

Procedure:
from 4-chloro-2-fluoro-5-isopropoxyphenylurea and ethyl acetoacetate using finely powdered Amberlyst®-15 (an organic, polymeric resin having free sulphonyl groups) as the catalyst there is obtained ethyl 3-[3-(4-chloro-2-fluoro-5-isopropoxyphenyl)ureido]crotonate, m.p. 142°-144° C. and from this intermediate in dimethylformamide with sodium hydride there is obtained 3-(4-chloro-2-fluoro-5-isopropoxyphenyl)-6 -methyl-2,4(1H,3H)-pyrimidinedione, m.p. 228°-230° C.;
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][NH:9][CH2:10][CH2:11][NH2:12])=[CH:4][N:3]=1.[N+:13]([CH2:16][C:17](SC)=[S:18])([O-:15])=[O:14]>CO>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][NH:9][CH2:10][CH2:11][NH:12][C:17]([SH:18])=[CH:16][N+:13]([O-:15])=[O:14])=[CH:4][N:3]=1
Reactant: NCCNCc1ccc(Cl)nc1
Reactant: CSC(=S)C[N+](=O)[O-]
Solvent: CO
Product: O=[N+]([O-])C=C(S)NCCNCc1ccc(Cl)nc1
Temperature: 50 °C
Yield: 38.6 %

Procedure:
N-(2-chloro-5-pyridylmethyl)ethylenediamine (2.0 g) and methyl 2-nitrodithioacetate (1.7 g) were dissolved in methanol (40 ml), and the solution was heated at 50° C. for 1 hour in a stream of nitrogen. The solution was cooled to room temperature whereupon crystals were precipitated. The crystals were collected by filtration, washed with a small amount of methanol, and then dried to give the desired N-(2-chloro-5-pyridylmethyl)-N'-(1-mercapto-2-nitrovinyl)ethylenediamine (1.2 g) having a melting point of 136° to 137° C. (decomp.).
Reaction SMILES: [Cl:1][S:2]([OH:5])(=O)=[O:3].[N:6]1[CH:11]=[CH:10][C:9]([C:12]2[C:21]3[C:16](=[CH:17][CH:18]=[C:19]([C:22]4[CH:23]=[CH:24][C:25]([NH2:28])=[N:26][CH:27]=4)[CH:20]=3)[N:15]=[CH:14][CH:13]=2)=[CH:8][CH:7]=1>>[NH2:28][C:25]1[C:24]([S:2]([Cl:1])(=[O:5])=[O:3])=[CH:23][C:22]([C:19]2[CH:20]=[C:21]3[C:16](=[CH:17][CH:18]=2)[N:15]=[CH:14][CH:13]=[C:12]3[C:9]2[CH:10]=[CH:11][N:6]=[CH:7][CH:8]=2)=[CH:27][N:26]=1
Reactant: O=S(=O)(O)Cl
Reactant: Nc1ccc(-c2ccc3nccc(-c4ccncc4)c3c2)cn1
Product: Nc1ncc(-c2ccc3nccc(-c4ccncc4)c3c2)cc1S(=O)(=O)Cl
Temperature: 25 °C
Yield: 47 %

Procedure:
To cold (0° C.) chlorosulfonic acid (15 mL) under vigorous stirring was added 5-[4-(4-pyridinyl)-6-quinolinyl]-2-pyridinamine (4.348 g, 14.57 mmol) portionwise. The reaction mixture was then heated at reflux for 16 hrs. Upon cooling to room temperature, LCMS indicated 47% of the title compound MS(ES)+ m/e 396.9 [M+]+ and 37% of sulfonic acid by-product MS(ES)+ m/e 379.1 [M+]+. A 2 mL aliquot of this 0.456M solution of the title compound was used in the next reaction without further workup.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([OH:8])[CH:5]=[CH:6][CH:7]=1.[NH2:9][C:10]1[CH:11]=[C:12]([NH:16][C:17](=[O:19])[CH3:18])[CH:13]=[CH:14][CH:15]=1.[O:20]=[C:21]1[C:33]2[CH:32]=[C:31]([S:34](Cl)(=[O:36])=[O:35])[CH:30]=[CH:29][C:28]=2[C:27]2[C:22]1=[CH:23][C:24]([S:38](Cl)(=[O:40])=[O:39])=[CH:25][CH:26]=2>N1C=CC=CC=1>[OH:8][C:4]1[CH:3]=[C:2]([NH:1][S:34]([C:31]2[CH:32]=[C:33]3[C:28]([C:27]4[CH:26]=[CH:25][C:24]([S:38]([NH:9][C:10]5[CH:11]=[C:12]([NH:16][C:17](=[O:19])[CH3:18])[CH:13]=[CH:14][CH:15]=5)(=[O:39])=[O:40])=[CH:23][C:22]=4[C:21]3=[O:20])=[CH:29][CH:30]=2)(=[O:35])=[O:36])[CH:7]=[CH:6][CH:5]=1
Reactant: O=C1c2cc(S(=O)(=O)Cl)ccc2-c2ccc(S(=O)(=O)Cl)cc21
Reactant: Nc1cccc(O)c1
Reactant: CC(=O)Nc1cccc(N)c1
Solvent: c1ccncc1
Product: CC(=O)Nc1cccc(NS(=O)(=O)c2ccc3c(c2)C(=O)c2cc(S(=O)(=O)Nc4cccc(O)c4)ccc2-3)c1
Temperature: 25 °C
Reaction time: 1 h
Yield: 38.6 %

Procedure:
3-Aminophenol (0.29 g, 2.65 mmmol) and N-(3-aminophenyl)acetamide (0.49 g, 2.65 mmol) in pyridine were treated with 9-oxo-9H-fluorene-2,7-disulfonyl dichloride (1.00 g, 2.65 mmol) in one portion at 0° C. The mixture was allowed to warm to ambient temperature and stirred for 1 hour after which the volatiles were evaporated under reduced pressure. The residue was partitioned between ethyl acetate and H2O. The separated organic phase was washed with 1N HCl, brine, dried (Na2SO4), filtered, and the filtrate concentrated under reduced pressure. The residue was purified by flash chromatography (85% ethyl acetate/hexanes) to provide the title compound as a yellow solid (577 mg, 39% yield). 1H NMR (300 MHz, DMSO-d6) δ 9.91 (bs, 1H), 9.47 (s, 1H), 7.9-8.1 (m, 6H), 7.48 (m, 1H), 7.26 bd, 1H), 7.12 (t, 1H), 6.99 (t, 1H), 6.75 (m, 1H), 6.58 (t, 1H), 6.52 (dd, 1H), 6.42 (dd, 1H), 1.98 (s, 3H); MS (ESI) 562 (M−H)−.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:18][CH2:17][C:11]2[N:12]=[C:13]([NH2:16])[N:14]=[CH:15][C:10]=2[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].Br[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1.C(=O)([O-])[O-].[Cs+].[Cs+]>CC(O)(C)C.C(Cl)Cl>[NH:16]([C:13]1[N:14]=[CH:15][C:10]2[CH2:9][N:8]([C:6]([O:5][C:1]([CH3:4])([CH3:2])[CH3:3])=[O:7])[CH2:18][CH2:17][C:11]=2[N:12]=1)[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1
Reactant: CC(C)(C)OC(=O)N1CCc2nc(N)ncc2C1
Reactant: Brc1ccccc1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CC(C)(C)O
Solvent: ClCCl
Product: CC(C)(C)OC(=O)N1CCc2nc(Nc3ccccc3)ncc2C1
Temperature: 100 °C
Yield: 59 %

Procedure:
A mixture of 6-t-Butoxycarbonyl-5,6,7,8-tetrahydropyrido[4,3-d]pyrimidin-2-ylamine, Intermediate 3 (996 mg, 3.98 mmol), bromobenzene (0.42 mL, 3.98 mmol), Cl-BrettPhos-Pd/BrettPhos 1 mol/1 mol admixture (133 mg, 0.0995 mmol) and cesium carbonate (1.82 g, 5.57 mmol) in t-BuOH (30 mL) was heated at 100° C. for 16 hours. Upon cooling to ambient temperature, the reaction mixture was diluted with CH2Cl2 and the insolubles were filtered off (celite). The filtrate was concentrated and the residue was eluted through a flash column (silica gel 60, 230-400 mesh, 7:3 hexanes:EtOAc) to obtain a yellow glass (770 mg, 59%).
Reaction SMILES: [C:1]([CH:3]1[CH2:7][CH2:6][N:5]([C:8]([O:10][CH2:11][C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)=[O:9])[CH2:4]1)#[N:2].[N-:18]=[N+:19]=[N-:20].[Na+].C(Cl)Cl.C(O)(=O)C1C(=CC=CC=1)O>C1(C)C=CC=CC=1>[NH:18]1[C:1]([CH:3]2[CH2:7][CH2:6][N:5]([C:8]([O:10][CH2:11][C:12]3[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=3)=[O:9])[CH2:4]2)=[N:2][N:20]=[N:19]1
Reactant: [N-]=[N+]=[N-]
Reactant: N#CC1CCN(C(=O)OCc2ccccc2)C1
Agent: O=C(O)c1ccccc1O
Agent: [Na+]
Solvent: ClCCl
Solvent: Cc1ccccc1
Product: O=C(OCc1ccccc1)N1CCC(c2nnn[nH]2)C1
Temperature: 115 °C
Reaction time: 5 h
Yield: 910 %

Procedure:
To a solution of benzyl 3-cyanopyrrolidine-1-carboxylate (1.0 g) and TEA hydrochloride (2.99 g) in toluene was added sodium azide (1.41 g) at 25° C., followed by stirring at 115° C. for 5 hours. The reaction liquid was left to be cooled and DCM (10 mL) was added thereto. Then, to a 5% aqueous salicylic acid solution (100 mL) was added dropwise the reaction liquid, followed by stirring at 25° C. for 1 hour. The reaction liquid was extracted with EtOAc (30 mL) three times. The organic layer was washed with brine, dried over MgSO4, and then concentrated under reduced pressure. The residue was purified by silica gel column chromatography (automatic purification device, hexane:EtOAc=100:0 to 80:20) to obtain benzyl 3-(1H-tetrazol-5-yl)pyrrolidine-1-carboxylate (10.8 g) as a colorless liquid.
Reaction SMILES: [Br:1][C:2]1[C:10]2[C:9](Cl)=[N:8][C:7]([Cl:12])=[N:6][C:5]=2[NH:4][CH:3]=1.[CH:13]1([NH2:17])[CH2:16][CH2:15][CH2:14]1.C(Cl)Cl.O>C(O)CCC>[Br:1][C:2]1[C:10]2[C:9]([NH:17][CH:13]3[CH2:16][CH2:15][CH2:14]3)=[N:8][C:7]([Cl:12])=[N:6][C:5]=2[NH:4][CH:3]=1
Reactant: NC1CCC1
Reactant: Clc1nc(Cl)c2c(Br)c[nH]c2n1
Solvent: CCCCO
Solvent: ClCCl
Solvent: O
Product: Clc1nc(NC2CCC2)c2c(Br)c[nH]c2n1
Yield: 96.4 %

Procedure:
A solution of 5-bromo-2,4-dichloro-7H-pyrrolo[2,3-d]pyrimidine (142 mg, 0.530 mmol), cyclobutylamine (0.090 mL, 1.06 mmol) and TEA (0.150 mL, 1.08 mmol) in nBuOH (6 mL) was stirred at 70° C. for 18 h. CH2Cl2 and H2O were added. The organic phase was separated, washed with 5% NaHCO3, then with 1N HCl, dried over Na2SO4, concentrated in vacuo to give 5-bromo-2-chloro-N-cyclobutyl-7H-pyrrolo[2,3-d]pyrimidin-4-amine (154 mg).
Reaction SMILES: [CH:1](=[O:7])[CH2:2][CH2:3][CH2:4][CH2:5][CH3:6].[C-]#[C-].[Na+].[Na+].[C:12]1(C)C(C)=CC=C[CH:17]=1>O1CCCC1>[CH:12]#[C:17][CH:1]([OH:7])[CH2:2][CH2:3][CH2:4][CH2:5][CH3:6]
Reactant: CCCCCC=O
Reactant: Cc1ccccc1C
Agent: [C-]#[C-]
Agent: [Na+]
Solvent: C1CCOC1
Product: C#CC(O)CCCCC
Reaction time: 2 h

Procedure:
A 750-mL reactor is loaded with 40.1 g (400 mmoles) i.e. 49.2 mL of hexanal (RN 66-25-1) and 400 mL of anhydrous tetrahydrofuran and 100 g of a suspension of 18% sodium acetylide (RN 1066-26-8) in xylene (375 mmoles) is added by portions accompanied by stirring. An exothermic reaction takes place. Stirring is then continued for another 2 hours at no particular temperature. After hydrolysis, extractions and concentration, fractionation is carried out under reduced pressure.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:12]([S:13]([C:16]3[CH:21]=[CH:20][C:19]([CH3:22])=[CH:18][CH:17]=3)(=[O:15])=[O:14])[CH:11]=[C:10]([CH:23]=O)[CH:9]=2)=[CH:4][CH:3]=1.[Cl-].C[NH3+].[C:28]([BH3-])#[N:29].[Na+]>CO>[F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:12]([S:13]([C:16]3[CH:21]=[CH:20][C:19]([CH3:22])=[CH:18][CH:17]=3)(=[O:15])=[O:14])[CH:11]=[C:10]([CH2:23][NH:29][CH3:28])[CH:9]=2)=[CH:4][CH:3]=1
Reactant: [BH3-]C#N
Reactant: Cc1ccc(S(=O)(=O)n2cc(C=O)cc2-c2ccc(F)cc2)cc1
Agent: C[NH3+]
Agent: [Cl-]
Agent: [Na+]
Solvent: CO
Product: CNCc1cc(-c2ccc(F)cc2)n(S(=O)(=O)c2ccc(C)cc2)c1
Temperature: 25 °C
Reaction time: 18 h
Yield: 82.1 %

Procedure:
5-(4-Fluorophenyl)-1-[(4-methylphenyl)sulfonyl]-1H-pyrrole-3-carbaldehyde (0.49 g) was dissolved in methanol (12 mL), and methylammonium chloride (1.17 g) and sodium cyanoborohydride (0.27 g) were added. After stirring at room temperature for 18 hr, the mixture was concentrated under reduced pressure. The residue was dissolved in water, and the solution was alkalized with a saturated aqueous sodium hydrogencarbonate solution and extracted with ethyl acetate. The extract was washed with saturated brine, dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (eluent: ethyl acetate-methanol=5:1) to give the title compound as a colorless solid (yield 0.42 g, 82%).