Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH:1]([C:9]([O:11][C:12]([CH3:15])([CH3:14])[CH3:13])=[O:10])[C@H:2]([C:6]([OH:8])=O)[CH:3]([CH3:5])[CH3:4].C(N(CC)CC)C.C(OC(Cl)=O)C.[NH2:29][C@H:30]([C:35]([O:37][CH2:38][C:39]1[CH:44]=[CH:43][CH:42]=[CH:41][CH:40]=1)=[O:36])[CH2:31][CH:32]([CH3:34])[CH3:33]>CN(C)C=O>[NH:1]([C:9]([O:11][C:12]([CH3:15])([CH3:14])[CH3:13])=[O:10])[C@H:2]([C:6]([NH:29][C@H:30]([C:35]([O:37][CH2:38][C:39]1[CH:44]=[CH:43][CH:42]=[CH:41][CH:40]=1)=[O:36])[CH2:31][CH:32]([CH3:34])[CH3:33])=[O:8])[CH:3]([CH3:4])[CH3:5]
Reactant: CC(C)[C@H](NC(=O)OC(C)(C)C)C(=O)O
Reactant: CC(C)C[C@H](N)C(=O)OCc1ccccc1
Agent: CCOC(=O)Cl
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: CC(C)C[C@H](NC(=O)[C@@H](NC(=O)OC(C)(C)C)C(C)C)C(=O)OCc1ccccc1
Temperature: 0 °C
Reaction time: 0.17 h

Procedure:
19.9 g (92 mmols) of BOC-Val-OH are dissolved in 200 ml of freshly distilled dimethylformamide, while heating. After cooling to 0°C, 25.9 ml of absolute triethylamine are added and the solution cooled to -10°C before 8.64 ml of chlorocarbonic acid ethyl ester are added. After 10 minutes, a solution of 23.2 g (90 mmols) of H-Leu-OBzl, HCL in 90 ml of dimethylformamide is added at -10°C. The mixture is allowed to stand at -10°C for 30 minutes, at 0°C for 3 hours, and at 20°C for 16 hours. Undissolved matter is then filtered off and the filtrate concentrated to dryness under a high vacuum. The residue is dissolved in ethyl acetate and the solution washed with dilute citric acid solution, water, sodium bicarbonate solution, and water, dried with sodium sulfate, and evaporated. On addition of petroleum ether the product crystallizes overnight. Melting point 88.5° - 89.5°C; [α]D20 -22° (c = 2 in dimethylformamide); Rf2 = 0.73.
Reaction SMILES: C(Cl)(=O)C(Cl)=O.CS(C)=O.[C:11]([CH2:13][C:14]([NH:16][CH:17]1[CH2:22][CH2:21][CH:20]([CH2:23][CH2:24][N:25]2[CH2:30][CH2:29][N:28]([C:31]3[CH:36]=[CH:35][CH:34]=[C:33]([CH:37]([OH:39])[CH3:38])[CH:32]=3)[CH2:27][CH2:26]2)[CH2:19][CH2:18]1)=[O:15])#[N:12].C(N(CC)CC)C>ClCCl.O>[C:37]([C:33]1[CH:32]=[C:31]([N:28]2[CH2:27][CH2:26][N:25]([CH2:24][CH2:23][CH:20]3[CH2:21][CH2:22][CH:17]([NH:16][C:14](=[O:15])[CH2:13][C:11]#[N:12])[CH2:18][CH2:19]3)[CH2:30][CH2:29]2)[CH:36]=[CH:35][CH:34]=1)(=[O:39])[CH3:38]
Reactant: CC(O)c1cccc(N2CCN(CCC3CCC(NC(=O)CC#N)CC3)CC2)c1
Agent: O=C(Cl)C(=O)Cl
Solvent: ClCCl
Solvent: O
Solvent: CS(C)=O
Product: CC(=O)c1cccc(N2CCN(CCC3CCC(NC(=O)CC#N)CC3)CC2)c1
Temperature: 25 °C
Yield: 21 %

Procedure:
A solution of 44 mg (0.35 mmol) of oxalyl chloride in 1 mL of dichloromethane is purged with argon and cooled to a temperature close to −70° C. A solution of 66 mg (0.8 mmol) of dimethyl sulfoxide in 1 mL of dichloromethane is added. Stirring is maintained at a temperature close to −70° C. for 15 minutes and a solution of 120 mg (0.3 mmol) of 2-cyano-N-[4-(2-{4-[3-(1-hydroxyethyl)phenyl]piperazin-1-yl}ethyl)cyclohexyl]acetamide trans/cis 80/20 in 4 mL of dichloromethane is added. After an additional stirring for 15 minutes at a temperature close to −70° C., 110 mg (1.08 mmol) of triethylamine are added. The mixture is allowed to warm to room temperature then stirred overnight at room temperature. The mixture is poured into water and extracted twice with ethyl acetate. The organic phases are combined, washed with water, then brine, dried over magnesium sulfate, filtered and concentrated under reduced pressure. The oily residue is purified over 5 g silica gel (eluant dichloromethane/methanol 98/2 then 95/5). To give 25 mg (21%) of N-(4-{2-[4-(3-acetylphenyl)piperazin-1-yl]ethyl}cyclohexyl)-2-cyanoacetamide trans/cis 80/20 as a white solid.
Reaction SMILES: NS(N)(=O)=O.Cl[CH2:7][CH2:8][CH2:9][S:10]([N:13]1[CH2:18][CH2:17][CH:16]([C:19]2[C:27]3[C:22](=[C:23]([C:34]([NH2:36])=[O:35])[CH:24]=[C:25]([C:28]4[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=4)[CH:26]=3)[NH:21][CH:20]=2)[CH2:15][CH2:14]1)(=[O:12])=[O:11].[CH3:37][CH:38]([NH:40][CH:41]([CH3:43])[CH3:42])[CH3:39].C([O-])([O-])=O.[K+].[K+]>>[CH3:37][CH:38]([N:40]([CH:41]([CH3:43])[CH3:42])[CH2:7][CH2:8][CH2:9][S:10]([N:13]1[CH2:18][CH2:17][CH:16]([C:19]2[C:27]3[C:22](=[C:23]([C:34]([NH2:36])=[O:35])[CH:24]=[C:25]([C:28]4[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=4)[CH:26]=3)[NH:21][CH:20]=2)[CH2:15][CH2:14]1)(=[O:12])=[O:11])[CH3:39]
Reactant: NC(=O)c1cc(-c2ccccc2)cc2c(C3CCN(S(=O)(=O)CCCCl)CC3)c[nH]c12
Reactant: CC(C)NC(C)C
Agent: NS(N)(=O)=O
Agent: O=C([O-])[O-]
Agent: [K+]
Product: CC(C)N(CCCS(=O)(=O)N1CCC(c2c[nH]c3c(C(N)=O)cc(-c4ccccc4)cc23)CC1)C(C)C
Yield: 12.5 %

Procedure:
Following the general procedure for aminosulfonamide formation outlined in example 2, 3-{1-[(3-chloropropyl)sulfonyl]-4-piperidinyl}-5-phenyl-1H-indole-7-carboxamide (100 mg, 0.313 mmol) and N-(1-methylethyl)-2-propanamine (0.22 mL, 1.55 mmol) were allowed to react in the presence of K2CO3 (172.5 mg, 1.28 mmol). The resulting residue was purified by reverse phase HPLC eluting with 10% B to 80% B, where A=H2O (0.1% trifluoroacetic acid) and B=CH3CN (0.1% triflucaroacetic acid) to give the title compound (20.5 mg, 13%).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([C@@H:12]([OH:36])[C@@H:13]([CH2:27][CH2:28][CH2:29][C:30]2[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=2)[CH2:14][N:15]2[CH:19]=[C:18](/[CH:20]=[CH:21]/[C:22]([O:24][CH2:25][CH3:26])=[O:23])[CH:17]=[N:16]2)[CH:6]=[C:7]([O:10][CH3:11])[C:8]=1[CH3:9]>[C].[Pd].CO>[CH2:25]([O:24][C:22](=[O:23])[CH2:21][CH2:20][C:18]1[CH:17]=[N:16][N:15]([CH2:14][C@@H:13]([C@@H:12]([C:5]2[CH:6]=[C:7]([O:10][CH3:11])[C:8]([CH3:9])=[C:3]([O:2][CH3:1])[CH:4]=2)[OH:36])[CH2:27][CH2:28][CH2:29][C:30]2[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=2)[CH:19]=1)[CH3:26]
Reactant: CCOC(=O)/C=C/c1cnn(C[C@H](CCCc2ccccc2)[C@H](O)c2cc(OC)c(C)c(OC)c2)c1
Agent: [Pd]
Solvent: CO
Product: CCOC(=O)CCc1cnn(C[C@H](CCCc2ccccc2)[C@H](O)c2cc(OC)c(C)c(OC)c2)c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 99.6 %

Procedure:
Using the compound produced in Example 34 instead of the compound produced in Example 18, procedures similar to Example 19 were carried out, and to a methanol (5 ml) solution of the resulting ethyl(2E)-3-(1-{(2S)-2-[(S)-(3,5-dimethoxy-4-methylphenyl)(hydroxy)methyl]-5-phenylpentyl}-1H-pyrazol-4-yl)acrylate (39 mg), 10% palladium-carbon (8 mg) was added. The mixture was stirred under hydrogen gas atmosphere at room temperature for 8 hours. The reaction mixture was filtered, and the filtrate was concentrated to give the title compound (39 mg) having the following physical properties.
Reaction SMILES: [O:1]=[C:2]1[N:8]([CH:9]2[CH2:14][CH2:13][N:12]([C:15]([O:17][C@H:18]([CH2:41][C:42]3[CH:47]=[C:46]([C:48]([F:51])([F:50])[F:49])[C:45]([NH2:52])=[C:44]([Cl:53])[CH:43]=3)[C:19]([N:21]3[CH2:26][CH2:25][N:24]([CH:27]4[CH2:32][CH2:31][N:30]([CH2:33][CH2:34][CH2:35][C:36]([O:38]CC)=[O:37])[CH2:29][CH2:28]4)[CH2:23][CH2:22]3)=[O:20])=[O:16])[CH2:11][CH2:10]2)[CH2:7][CH2:6][C:5]2[CH:54]=[CH:55][CH:56]=[CH:57][C:4]=2[NH:3]1.[Li+].[OH-]>>[O:1]=[C:2]1[N:8]([CH:9]2[CH2:10][CH2:11][N:12]([C:15]([O:17][C@H:18]([CH2:41][C:42]3[CH:47]=[C:46]([C:48]([F:50])([F:49])[F:51])[C:45]([NH2:52])=[C:44]([Cl:53])[CH:43]=3)[C:19]([N:21]3[CH2:22][CH2:23][N:24]([CH:27]4[CH2:32][CH2:31][N:30]([CH2:33][CH2:34][CH2:35][C:36]([OH:38])=[O:37])[CH2:29][CH2:28]4)[CH2:25][CH2:26]3)=[O:20])=[O:16])[CH2:13][CH2:14]2)[CH2:7][CH2:6][C:5]2[CH:54]=[CH:55][CH:56]=[CH:57][C:4]=2[NH:3]1
Reactant: CCOC(=O)CCCN1CCC(N2CCN(C(=O)[C@@H](Cc3cc(Cl)c(N)c(C(F)(F)F)c3)OC(=O)N3CCC(N4CCc5ccccc5NC4=O)CC3)CC2)CC1
Agent: [Li+]
Agent: [OH-]
Product: Nc1c(Cl)cc(C[C@@H](OC(=O)N2CCC(N3CCc4ccccc4NC3=O)CC2)C(=O)N2CCN(C3CCN(CCCC(=O)O)CC3)CC2)cc1C(F)(F)F

Procedure:
Prepared analogously to Example 27.1 from 50 mg (0.06 mmol) (R)-1-(4-amino-3-chloro-5-trifluoromethyl-benzyl)-2-{4-[1-(3-ethoxycarbonyl-propyl)-piperidin-4-yl]-piperazin-1-yl}-2-oxo-ethyl 4-(2-oxo-1,2,4,5-tetrahydro-1,3-benzodiazepin-3-yl)-piperidine-1-carboxylate and 2.40 mg (0.10 mmol) LiOH.
Reaction SMILES: [OH:1][C:2]1[CH:13]=[CH:12][C:5]2[S:6][CH:7]=[C:8]([C:9]([OH:11])=[O:10])[C:4]=2[CH:3]=1.O.[C:15](OC(=O)C)(=[O:17])[CH3:16]>N1C=CC=CC=1>[C:15]([O:1][C:2]1[CH:13]=[CH:12][C:5]2[S:6][CH:7]=[C:8]([C:9]([OH:11])=[O:10])[C:4]=2[CH:3]=1)(=[O:17])[CH3:16]
Reactant: CC(=O)OC(C)=O
Reactant: O=C(O)c1csc2ccc(O)cc12
Solvent: O
Solvent: c1ccncc1
Product: CC(=O)Oc1ccc2scc(C(=O)O)c2c1
Reaction time: 3 h
Yield: 97.3 %

Procedure:
A solution of 1,140 mg of the above obtained 5-hydroxybenzo[b]thiophene-3-carboxylic acid (1) in 2 ml of acetic anhydride and 4 ml of pyridine was allowed to stand for 3 hours. After addition of water, the mixture was stirred for 1.5 hours under ice-cooling, and the precipitated crystals were filtered, washed with water, and dried to give 1,349 mg of 5-acetoxybenzo[b]thiophene-3-carboxylic acid (4). Yield 97.3%. mp 239-240° C.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:10]=[CH:9][C:6]([CH2:7][NH2:8])=[CH:5][CH:4]=1.C(N(CC)CC)C.C1COCC1.[C:23](Cl)(=[O:30])[C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1>O>[CH3:1][O:2][C:3]1[CH:10]=[CH:9][C:6]([CH2:7][NH:8][C:23](=[O:30])[C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)=[CH:5][CH:4]=1
Reactant: O=C(Cl)c1ccccc1
Reactant: COc1ccc(CN)cc1
Solvent: O
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: COc1ccc(CNC(=O)c2ccccc2)cc1
Temperature: 7 °C
Reaction time: 3 h
Yield: 80.7 %

Procedure:
To a mixture of p-methoxybenzylamine (181 g, 1.32 mol), triethylamine (185 mL, 134 g, 1.32 mol) and THF (772 mL) was added dropwise benzoyl chloride (185 g, 1.32 mol) at 16° C. or lower. The mixture was stirred at 7° C. or lower for 3 hr, water (400 mL) was added dropwise thereto at 14° C. or lower. The mixture was extracted with ethyl acetate (140 ml), and the aqueous layer was extracted with ethyl acetate (360 ml). The combined organic layers were washed successively with 20% brine (0.15 kg×2) and 20% brine (0.22 kg, once), and dried over magnesium sulfate (50 g). Silica gel (22 g) was added to the solution, and the mixture was filtered (silica gel precoat). The filtrate was concentrated to 0.67 kg under reduced pressure at 60° C. or lower, and the residue was cooled to 5° C. The resulting crystals were collected by filtration, washed with cold ethyl acetate (140 mL), and dried under reduced pressure at 50° C. to give N-(p-methoxybenzyl)benzamide (257 g, yield 80.7%) as white crystals.
Reaction SMILES: [C:1]1([C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=2)[CH:6]=[CH:5][C:4]([CH2:7][C@@H:8]([NH:15][C:16]([O:18][C:19]([CH3:22])([CH3:21])[CH3:20])=[O:17])[CH2:9][C:10](=[CH2:14])[C:11]([OH:13])=[O:12])=[CH:3][CH:2]=1.[H][H]>[Pd].C(O)C>[C:1]1([C:23]2[CH:24]=[CH:25][CH:26]=[CH:27][CH:28]=2)[CH:2]=[CH:3][C:4]([CH2:7][C@@H:8]([NH:15][C:16]([O:18][C:19]([CH3:22])([CH3:20])[CH3:21])=[O:17])[CH2:9][C@@H:10]([CH3:14])[C:11]([OH:13])=[O:12])=[CH:5][CH:6]=1
Reactant: [H][H]
Reactant: C=C(C[C@@H](Cc1ccc(-c2ccccc2)cc1)NC(=O)OC(C)(C)C)C(=O)O
Agent: [Pd]
Solvent: CCO
Product: C[C@H](C[C@@H](Cc1ccc(-c2ccccc2)cc1)NC(=O)OC(C)(C)C)C(=O)O
Temperature: 25 °C

Procedure:
20 mg (R)-5-Biphenyl-4-yl-4-tert-butoxycarbonylamino-2-methylenepentanoic acid (2-a, R1=Boc, R2=H, R3=CO2H) is added to ethanol (400 μl). 10% Palladium on carbon (2 mg, 50% water wet, Degussa type E101 NE/W) is then added. Hydrogen gas at ambient pressure is applied to the mixture. The mixture is stirred at ambient temperature and pressure overnight. The mixture is then filtered over Celite and washed with ethanol (2×0.5 ml). The mixture is then concentrated in vacuo to give (2R,4S)-5-biphenyl-4-yl-4-tert-butoxycarbonylamino-2-methylpentanoic acid (1-a, R1=Boc, R2=H, R3=CO2H) and (2S,4S)-5-biphenyl-4-yl-4-tert-butoxycarbonylamino-2-methylpentanoic acid (1-b, R1=Boc, R2=H, R3=CO2H). 1H NMR (CDCl3): 1.11-1.16, 1.21 and 1.33, 1.39-1.53, 1.70-1.92, 2.32-2.81, 3.72-3.97, 4.44-4.50, 6.41 and 6.56, 7.16-7.49, 10.84.
Reaction SMILES: [Br:1][C:2]1[CH:14]=[CH:13][C:12]2[C:11]3[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=3)[CH2:5][C:4]=2[CH:3]=1.S(=O)(=O)(O)O.II.[I:22](O)(=O)=O>O.C(O)(=O)C>[Br:1][C:2]1[CH:14]=[CH:13][C:12]2[C:11]3[C:6](=[CH:7][C:8]([I:22])=[CH:9][CH:10]=3)[CH2:5][C:4]=2[CH:3]=1
Reactant: [O-][I+2]([O-])O
Reactant: Brc1ccc2c(c1)Cc1ccccc1-2
Agent: II
Agent: O=S(=O)(O)O
Solvent: CC(=O)O
Solvent: O
Product: Brc1ccc2c(c1)Cc1cc(I)ccc1-2
Temperature: 85 °C
Yield: 317 %

Procedure:
A mixture of 2-bromofluorene (12.61 g, 50 mmol), acetic acid (125 mL), water (9 mL), concentrated sulfuric acid (4 mL), iodine (5.1 g, 20.1 mmol) and iodic acid (2.2 g, 12.5 mmol) was heated at 80-90° C. for 2 hours, cooled and filtered. The solids were washed with acetic acid (100 mL) and water (500 mL), to get the product 14.7 g (79% yield), m.p. 179-185° C. Mass Spec. (m/z): 418 (M+ diiodo), 370, 372 (M+iodobromo), 322, 324, 326 (M+ dibromo).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[C:13](=[O:14])[CH:12]=[C:11]([C:15]([F:18])([F:17])[F:16])[N:10]([CH3:19])[C:9]2=[O:20])=[CH:4][C:3]=1[CH:21]=O.[C:23]([CH2:25]P(=O)(OCC)OCC)#[N:24].C(=O)([O-])[O-].[K+].[K+].O>CN(C)C=O>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[C:13](=[O:14])[CH:12]=[C:11]([C:15]([F:18])([F:16])[F:17])[N:10]([CH3:19])[C:9]2=[O:20])=[CH:4][C:3]=1[CH:21]=[CH:25][C:23]#[N:24]
Reactant: Cn1c(C(F)(F)F)cc(=O)n(-c2ccc(Cl)c(C=O)c2)c1=O
Reactant: CCOP(=O)(CC#N)OCC
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: Cn1c(C(F)(F)F)cc(=O)n(-c2ccc(Cl)c(C=CC#N)c2)c1=O
Reaction time: 20 h

Procedure:
3.3 g of 3-(4-chloro-3-formylphenyl)-2,4-dioxo-1-methyl-6-trifluoromethyl-1,2,3,4-tetrahydropyrimidine in 30 ml of dimethylformamide were added dropwise to a suspension of 1.8 g of diethyl cyanomethylphosphonate and 1.5 g of potassium carbonate in 120 ml of dimethylformamide, and stirring was carried out for 20 hours at room temperature. Thereafter, 150 ml of water were added and the precipitate which had separated out was isolated, washed with water and petroleum ether and dried.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5]([Cl:12])=[C:6]([CH:11]=1)[O:7][CH2:8][CH:9]=O>C1C=CC=CC=1>[Br:1][C:2]1[C:11]2[CH:9]=[CH:8][O:7][C:6]=2[C:5]([Cl:12])=[CH:4][CH:3]=1
Reactant: O=CCOc1cc(Br)ccc1Cl
Solvent: c1ccccc1
Product: Clc1ccc(Br)c2ccoc12
Temperature: 90 °C
Yield: 31.6 %

Procedure:
To 80 mL of benzene was added polyphosphoric acid (3.47 g, 36.9 mmol) and commercially available 2-(5-bromo-2-chlorophenoxy)acetaldehyde (9.2 g, 36.9 mmol) and separated into eight 20 mL vials containing equal amounts. The vials were heated with an external temperature of 90° C. for 4 days. Upon cooling of the reaction, the benzene was removed by decanting. Celite (50 g) was added to the organic solution and the solvent was removed using a rotary evaporator. The impregnated Celite was loaded onto a Teledyne-Isco purification system and purified by silica gel chromatography using 0-30% ethyl acetate:hexanes to give 4-bromo-7-chlorobenzofuran as a white solid (2.7 g, 32%): 1H NMR (400 MHz, CDCl3) δ 7.73 (d, J=2.2 Hz, 1H), 7.33 (d, J=8.3 Hz, 1H), 7.18 (d, J=8.3 Hz, 1H), 6.85 (d, J=2.2 Hz, 1H); 13C NMR (101 MHz, CDCl3) δ 150.38 (s), 146.14 (s), 130.27 (s), 126.56 (s), 125.32 (s), 116.44 (s), 112.49 (s), 107.71 (s); ESIMS m/z 232 ([M+H]+), 230 ([M−H]−).
Reaction SMILES: [CH2:1]([NH:8][C:9]1[N:17]=[C:16](F)[N:15]=[C:14]2[C:10]=1[N:11]=[CH:12][N:13]2[CH:19]([CH3:21])[CH3:20])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.CS(C)=O.[NH2:26][C@H:27]([CH2:31][CH3:32])[C@@H:28]([OH:30])[CH3:29]>C(Cl)Cl.CCOCC.CO>[CH2:1]([NH:8][C:9]1[N:17]=[C:16]([NH:26][C@H:27]([CH2:31][CH3:32])[C@@H:28]([OH:30])[CH3:29])[N:15]=[C:14]2[C:10]=1[N:11]=[CH:12][N:13]2[CH:19]([CH3:21])[CH3:20])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CC[C@@H](N)[C@H](C)O
Reactant: CC(C)n1cnc2c(NCc3ccccc3)nc(F)nc21
Solvent: CO
Solvent: CCOCC
Solvent: ClCCl
Product: CC[C@@H](Nc1nc(NCc2ccccc2)c2ncn(C(C)C)c2n1)[C@H](C)O
Temperature: 25 °C
Reaction time: 72 h
Yield: 42.6 %

Procedure:
To a stirred solution of benzyl-(2-fluoro-9-isopropyl-9H-purin-6-yl)-amine (0.20 g, 0.70 mmol) in BunOH/DMSO (5 mL, 4:1) at RT under Ar was added Pri2NEt (1.2 mL, 6.88 mmol) followed by (2S,3R)-3-amino-pentan-2-ol (0.18 g, 1.74 mmol). The reaction mixture was placed in a preheated oil bath at 140° C. and stirred at this temperature for 72 h, when TLC (55:40:5, CH2Cl2/Et2O/MeOH) indicated that the reaction had gone to completion. The reaction mixture was allowed to cool to RT and the solvent was evaporated in vacuo. The residue was partitioned between CH2Cl2 (100 ML) and H2O (200 mL), the aqueous phase was extracted with more CH2Cl2 (3×50 mL), and the combined organic phase was washed with brine (50 mL), dried (MgSO4) and evaporated in vacuo. The residue was purified by gradient column chromatography on silica gel eluted with CH2Cl2/Et2O/MeOH (60:40:0→60:40:2) to afford the title compound as a white solid (0.11 g, 43%, 80% de). Mp 42-44° C. 1H-NMR (d6-DMSO, 250 MHz): δ 0.81 (m, 3H, —NHCH(CH2CH3)CH(CH3)OH), 1.02 (d, 3H, J=6.16 Hz, —NHCH(CH2CH3)CH(CH3)OH) 1.45 (m, 8H, —NHCH(CH2CH3)CH(CH3)OH+—CH(CH3)2), 3.62+3.73 (2×m, 1H, —NHCH(CH2CH3)CH(CH3)OH), 4.49-4.63 (m, 4H, —HNCH2-Bz+—NHCH(CH2CH3)CH(CH3)OH+—CH(CH3)2), 5.59+5.90 ([1.8, 2′R/3′S:2′R/3′S], 2×d, 1H, J=9.00+8.85 Hz, —NHCH(CH2CH3)CH(CH3)OH), 7.19-7.37 (m, 5H, Bz), 7.77 (bs, 2H, —N═CH—N—+—HNCH2-Bz). FAB-MS m/z (relative intensity): 369 ([M+H]+, 100), 323 (70), 134 (15). Accurate Mass (M+H): Actual: 369.2403, Measured: 369.2418.
Reaction SMILES: [NH2:1][C:2]1[CH:22]=[CH:21][C:5]([C:6]([N:8]2[CH2:13][CH2:12][N:11](C(OC(C)(C)C)=O)[CH2:10][CH2:9]2)=[O:7])=[CH:4][C:3]=1[Cl:23].FC(F)(F)C(O)=O>ClCCl>[NH2:1][C:2]1[CH:22]=[CH:21][C:5]([C:6]([N:8]2[CH2:9][CH2:10][NH:11][CH2:12][CH2:13]2)=[O:7])=[CH:4][C:3]=1[Cl:23]
Reactant: CC(C)(C)OC(=O)N1CCN(C(=O)c2ccc(N)c(Cl)c2)CC1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: Nc1ccc(C(=O)N2CCNCC2)cc1Cl
Reaction time: 24 h
Yield: 70.9 %

Procedure:
A mixture of tert-butyl 4-(4-amino-3-chlorobenzoyl)piperazine-1-carboxylate (45.3 mmol, 15.4 g), dichloromethane (50 mL) and 2,2,2-trifluoroacetic acid (136 mmol, 15.50 g) were stirred for 24 hours. The reaction was concentrated under reduced pressure and was then basified with potassium carbonate (aqueous). The aqueous was extracted with ethyl acetate and then dichloromethane to give the title compound (7.7 g).
Reaction SMILES: [S:1]1[CH:8]=[CH:7][C:6]2[C:5]3[NH:9][N:10]=[C:11]([C:12]4[CH:17]=[CH:16][C:15]([NH2:18])=[CH:14][CH:13]=4)[C:4]=3[CH2:3][C:2]1=2.C([O-])([O-])=[O:20].[Cs+].[Cs+]>CN(C=O)C>[NH2:18][C:15]1[CH:16]=[CH:17][C:12]([C:11]2[C:4]3[C:3](=[O:20])[C:2]4[S:1][CH:8]=[CH:7][C:6]=4[C:5]=3[NH:9][N:10]=2)=[CH:13][CH:14]=1
Reactant: O=C([O-])[O-]
Reactant: Nc1ccc(-c2n[nH]c3c2Cc2sccc2-3)cc1
Agent: [Cs+]
Solvent: CN(C)C=O
Product: Nc1ccc(-c2n[nH]c3c2C(=O)c2sccc2-3)cc1
Temperature: 25 °C
Yield: 930 %

Procedure:
A mixture of 4-(4,7-Dihydro-1-thia-4,5-diaza-cyclopenta[a]pentalen-6-yl)-phenylamine (0.25 g, 1.0 mmol) and Cs2CO3 (3.26 g, 10.0 mmol) in DMF (10 mL) was stirred under molecular oxygen at ambient temperature. The reaction mixture was stirred for 12 hr. After poured into ice water, aqueous wash, and evaporation of the solvent provided the corresponding 6-(4-Amino-phenyl)-4H-1-thia-4,5-diaza-cyclopenta[a]pentalen-7-one (2.49 g, 9.3 mmol) as brown solid in 93% yield.
Reaction SMILES: [NH2:1][C:2]1[C:11]([N+:12]([O-:14])=[O:13])=[CH:10][C:5]([C:6]([O:8]C)=[O:7])=[C:4]([O:15][CH2:16][CH3:17])[CH:3]=1.[OH-].[Na+].O>C(O)(=O)C>[NH2:1][C:2]1[C:11]([N+:12]([O-:14])=[O:13])=[CH:10][C:5]([C:6]([OH:8])=[O:7])=[C:4]([O:15][CH2:16][CH3:17])[CH:3]=1
Reactant: CCOc1cc(N)c([N+](=O)[O-])cc1C(=O)OC
Agent: [Na+]
Agent: [OH-]
Solvent: CC(=O)O
Solvent: O
Product: CCOc1cc(N)c([N+](=O)[O-])cc1C(=O)O
Yield: 66.6 %

Procedure:
A mixture of 4.8 parts of methyl 4-amino-2-ethoxy-5-nitrobenzoate, 1.6 parts of sodium hydroxide and 30 parts of water was stirred and refluxed for 30 minutes. The reaction mixture was cooled and 50 parts of water were added. The whole was neutralized by the dropwise addition of glacial acetic acid. The precipitated product was filtered off and crystallized from 2-propanol at 0° C. The product was filtered off, washed with a small amount of 2,2'-oxybispropane and dried, yielding 3 parts (66.6%) of 4-amino-2-ethoxy-5-nitrobenzoic acid; mp. 230° C. (intermediate 34).
Reaction SMILES: [CH2:1]([S:3]([N:6]1[CH2:9][C:8]([N:12]2[CH:16]=[C:15]([C:17]3[C:18]4[CH:25]=[CH:24][N:23](COCC[Si](C)(C)C)[C:19]=4[N:20]=[CH:21][N:22]=3)[CH:14]=[N:13]2)([CH2:10][F:11])[CH2:7]1)(=[O:5])=[O:4])[CH3:2].[C:34]([OH:40])([C:36]([F:39])([F:38])[F:37])=[O:35].C(N)CN>>[CH2:1]([S:3]([N:6]1[CH2:7][C:8]([N:12]2[CH:16]=[C:15]([C:17]3[C:18]4[CH:25]=[CH:24][NH:23][C:19]=4[N:20]=[CH:21][N:22]=3)[CH:14]=[N:13]2)([CH2:10][F:11])[CH2:9]1)(=[O:4])=[O:5])[CH3:2].[C:34]([OH:40])([C:36]([F:39])([F:38])[F:37])=[O:35]
Reactant: CCS(=O)(=O)N1CC(CF)(n2cc(-c3ncnc4c3ccn4COCC[Si](C)(C)C)cn2)C1
Solvent: O=C(O)C(F)(F)F
Solvent: NCCN
Product: CCS(=O)(=O)N1CC(CF)(n2cc(-c3ncnc4[nH]ccc34)cn2)C1

Procedure:
4-{1-[1-(Ethylsulfonyl)-3-(fluoromethyl)azetidin-3-yl]-1H-pyrazol-4-yl}-7-{[2-(trimethylsilyl)ethoxy]methyl}-7H-pyrrolo[2,3-d]pyrimidine (0.060 g, 0.12 mmol) was treated with 2 mL of TFA at rt for 30 min. The reaction mixture was evaporated to dryness. LCMS (M+H) 395.3. The resulting residue was dissolved in 3 mL of methanol and treated with ethylenediamine (0.0811 mL, 1.21 mmol) at rt for 30 min. The mixture was purified on RP-HPLC (XBridge C18 column, eluting with a gradient of acetone/water containing 0.2% TFA) to give the desired product as TFA salt. LCMS calculated for C15H18FN6O2S(M+H)+(free base): m/z=365.1. Found: 365.3. 1H NMR (DMSO-d6, 300 MHz) δ 12.57 (1H, br s), 8.94 (1H, s), 8.81 (1H, s), 8.53 (1H, s), 7.75 (1H, br s), 7.21 (1H, br s), 5.03 (2H, d, J=46.8 Hz), 4.53 (1H, dd, J=9.0 and 2.7 Hz), 4.24 (1H, d, J=9.0 Hz), 3.25 (2H, q, J=7.2 Hz), 1.23 (3H, t, J=7.2 Hz) ppm. 19F NMR (DMSO-d6, 300 MHz) δ −74.98 (3F, s), −225.56 (1F, t, J=48.3 Hz) ppm.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[NH:8][CH:7]([C:12]1[CH:13]=[C:14]([NH2:18])[CH:15]=[CH:16][CH:17]=1)[CH2:6][C:5]2([CH3:20])[CH3:19].[F:21][C:22]1[CH:23]=[C:24]([S:28](Cl)(=[O:30])=[O:29])[CH:25]=[CH:26][CH:27]=1>N1C=CC=CC=1>[Cl:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[NH:8][CH:7]([C:12]1[CH:13]=[C:14]([NH:18][S:28]([C:24]3[CH:25]=[CH:26][CH:27]=[C:22]([F:21])[CH:23]=3)(=[O:30])=[O:29])[CH:15]=[CH:16][CH:17]=1)[CH2:6][C:5]2([CH3:20])[CH3:19]
Reactant: O=S(=O)(Cl)c1cccc(F)c1
Reactant: CC1(C)CC(c2cccc(N)c2)Nc2ccc(Cl)cc21
Solvent: c1ccncc1
Product: CC1(C)CC(c2cccc(NS(=O)(=O)c3cccc(F)c3)c2)Nc2ccc(Cl)cc21
Temperature: 25 °C
Reaction time: 8 h
Yield: 51.7 %

Procedure:
3-(6-Chloro-4,4-dimethyl-1,2,3,4-tetrahydro-quinolin-2-yl)-phenylamine (150 mg, 0.53 mmol) and 3-fluoro-benzenesulfonyl chloride (92 mg, 0.63 mmol) were dissolved in pyridine (5 ml). The mixture was stirred at room temperature overnight. The solvent was removed and the residue was purified on column chromatography using petroleum ether/ethyl acetate=5:1 as eluent to afford N-[3-(6-chloro-4,4-dimethyl-1,2,3,4-tetrahydro-quinolin-2-yl)-phenyl]-3-fluoro-benzenesulfonamide 122 mg (yield: 41%) as yellow solid. MS (ESI+APCI) M+1=445.1.
Reaction SMILES: C([O:8][C:9](=O)[CH:10]([N:14]1[CH:18]=[CH:17][C:16]([C:19]([F:22])([F:21])[F:20])=[N:15]1)[C:11](=O)[CH3:12])C1C=CC=CC=1.[NH2:24][NH2:25].[Cl-].[NH4+]>CCO>[CH3:12][C:11]1[C:10]([N:14]2[CH:18]=[CH:17][C:16]([C:19]([F:22])([F:21])[F:20])=[N:15]2)=[C:9]([OH:8])[NH:24][N:25]=1
Reactant: NN
Reactant: CC(=O)C(C(=O)OCc1ccccc1)n1ccc(C(F)(F)F)n1
Agent: [Cl-]
Agent: [NH4+]
Solvent: CCO
Product: Cc1n[nH]c(O)c1-n1ccc(C(F)(F)F)n1

Procedure:
3-Oxo-2-(3-trifluoromethyl-pyrazol-1-yl)-butyric acid benzyl ester (800 mg, 2.452 mmol), EtOH (12.30 ml) and hydrazine (0.231 ml, 7.36 mmol) are stirred at 50° C. for hour. The volatiles are removed in vacuo yielding a wet solid which is added to ammonium chloride (sat. aq. 100 ml) and the product is extracted into EtOAc (2×100 ml). The combined organic extracts are washed with brine, dried over Na2SO4, and concentrated in vacuo to give a pale yellow solid. The crude product is purified by ISCO combiflash chromatography, eluting with 0 to 100% (EtOAc/Iso-hexane) on a 24 g SiO2-column to afford the title compound as an orange oil; MS: m/z 233.09 [M+H]+.