Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Br:1][C:2]1[C:3]([C:8]2[N:12]=[CH:11][NH:10][N:9]=2)=[C:4]([NH2:7])[S:5][CH:6]=1.[C:13]([C:15]1[CH:16]=[C:17]2[C:22](=[CH:23][CH:24]=1)[N:21]([CH2:25][C:26](O)=[O:27])[C:20](=[O:29])[CH:19]=[CH:18]2)#[N:14]>>[Br:1][C:2]1[C:3]([C:8]2[N:12]=[CH:11][NH:10][N:9]=2)=[C:4]([NH:7][C:26](=[O:27])[CH2:25][N:21]2[C:22]3[C:17](=[CH:16][C:15]([C:13]#[N:14])=[CH:24][CH:23]=3)[CH:18]=[CH:19][C:20]2=[O:29])[S:5][CH:6]=1
Reactant: Nc1scc(Br)c1-c1nc[nH]n1
Reactant: N#Cc1ccc2c(ccc(=O)n2CC(=O)O)c1
Product: N#Cc1ccc2c(ccc(=O)n2CC(=O)Nc2scc(Br)c2-c2nc[nH]n2)c1

Procedure:
The title compound was prepared from 4-bromo-3-(1H-1,2,4-triazol-3-yl)thiophen-2-amine (253 mg, 1.03 mmol) and 2-(6-cyano-2-oxoquinolin-1(2H)-yl)acetic acid (325 mg, 1.42 mmol) according to protocol A. HPLC purification gave N-(4-bromo-3-(1H-1,2,4-triazol-3-yl)thiophen-2-yl)-2-(6-cyano-2-oxoquinolin-1(2H)-yl)acetamide. Method [7] Retention time 4.00 min by HPLC (M+=455 and 457). 1H NMR (300 MHz, DMSO-d6) δ 8.42 (broad s, 1H), 8.37 (s, 1H), 8.13 (d, J=9.9 Hz, 1H), 7.98 (d, J=9.0 Hz, 1H), 7.70 (d, J=9.0 Hz, 1H), 7.27 (s, 1H), 6.87 (d, J=9.3 Hz, 1H), 5.30 (s, 2H).
Reaction SMILES: [CH:1]1([NH:6][C:7]2[C:12]([CH:13]=O)=[CH:11][N:10]=[C:9]([S:15][CH3:16])[N:8]=2)[CH2:5][CH2:4][CH2:3][CH2:2]1.C[Si]([N-][Si](C)(C)C)(C)C.[Li+].CCCCCC.[CH3:33][S:34](Cl)(=[O:36])=[O:35]>C1COCC1>[CH:1]1([N:6]2[C:7]3[C:12](=[CH:11][N:10]=[C:9]([S:15][CH3:16])[N:8]=3)[CH:13]=[CH:33][S:34]2(=[O:36])=[O:35])[CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: CSc1ncc(C=O)c(NC2CCCC2)n1
Reactant: CS(=O)(=O)Cl
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Li+]
Solvent: CCCCCC
Solvent: C1CCOC1
Product: CSc1ncc2c(n1)N(C1CCCC1)S(=O)(=O)C=C2
Temperature: -70 °C
Reaction time: 0.5 h
Yield: 18.7 %

Procedure:
A solution of 4-cyclopentylamino-2-methylsulfanyl-pyrimidine-5-carbaldehyde (prepared as described in WO 98/33798 (incorporated herein by reference)) (30 g, 126 mmol) was suspended in dry THF (700 mL) under argon, and the mixture was cooled to −70° C. A solution of lithium bis(trimethylsilyl) amide, 1.0M in hexane (316 mL, 316 mmol) was added dropwise with stirring over 30 minutes. A solution of methanesulfonylchloride (10.5 ml, 136 mmol) in dry THF (25 mL) was added over 5 minutes, and then the reaction mixture was left to stir at −55° C. for at least 1 hour. An additional portion of methanesulfonylchloride (9 ml, 78 mmol) was added over 2 hours as the temperature was allowed to reach 0° C. The reaction was then cooled to −70° C. and left undisturbed overnight. The reaction mixture was then evaporated in vacuo to an oil and poured into a mixture of diethyl ether (1 L) and 1N citric acid solution (375 ml). The pH of the mixture was adjusted to 8 by addition of 4N NaOH, agitated, and the ether phase was decanted. The aqueous phase was extracted with diethylether, the organic phases were combined, washed with water, brine, and dried over anhydrous magnesium sulfate. After removal of the drying agent and evaporation of the solvent, the crude product was purified by chromatography on 300 g silica gel (10%–20% ethyl acetate in hexanes) to yield 7.01 g (18.7% yield) 1-Cyclopentyl-7-methylsulfanyl-1H-2-thia-1,6,8-triaza-naphthalene 2,2-dioxide as a colorless solid. MS: APCI: M+1: 298.1 (M: 297.4).
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][C:9](=[O:11])[CH3:10])=[CH:4][CH:3]=1.[Br:12][CH2:13][CH2:14][CH:15](Br)C.C(=O)([O-])[O-].[K+].[K+]>CC(CC)=O.C(Cl)(Cl)Cl>[Br:12][CH2:13][CH2:14][CH2:15][O:1][C:2]1[CH:3]=[CH:4][C:5]([NH:8][C:9](=[O:11])[CH3:10])=[CH:6][CH:7]=1
Reactant: CC(Br)CCBr
Reactant: CC(=O)Nc1ccc(O)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: ClC(Cl)Cl
Solvent: CCC(C)=O
Product: CC(=O)Nc1ccc(OCCCBr)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 75.8 %

Procedure:
A solution of N-(4-hydroxyphenyl)acetamide (paracetamol) (1) (1.50 g) and 1,3-dibromobutane (14) (10.0 ml) in ethyl methyl ketone (25.0 ml) containing potassium carbonate (5.0 g) was stirred overnight at room temperature. The reaction mixture was filtered, residue washed with ethyl methyl ketone and solvent evaporated under reduced pressure to get the residue. The residue was dissolved in chloroform (200.0 ml), washed with 5% NaOH solution (3×100 ml), water (3×50 ml), dried, filtered and crystallized from methanol to get the desired product N-[4-(3-Bromo-propoxy)-phenyl]-acetamide (16) (2.01 g, 75.8%), mp 115-118° C.
Reaction SMILES: [CH2:1]([OH:10])[C:2]1[CH:7]=[CH:6][C:5]([O:8][CH3:9])=[CH:4][CH:3]=1.C([O-])(=O)C.[Na+].ClN1C(=O)C(C)(C)N(Cl)C1=O.ClC1C=CC(OC)=CC=1>C(Cl)Cl.CC1(C)N([O])C(C)(C)CCC1>[CH3:9][O:8][C:5]1[CH:4]=[CH:3][C:2]([CH:1]=[O:10])=[CH:7][CH:6]=1
Reactant: COc1ccc(CO)cc1
Agent: CC(=O)[O-]
Agent: CC1(C)C(=O)N(Cl)C(=O)N1Cl
Agent: CC1(C)CCCC(C)(C)N1[O]
Solvent: ClCCl
Product: COc1ccc(C=O)cc1
Temperature: 0 °C
Reaction time: 16 h
Yield: 91.1 %

Procedure:
5 g (36.2 mmol) of anisyl alcohol, 3.0 g (36.6 mmol) of sodium acetate and 4.2 g (21.3 mmol) of dichlorodimethylhydantoin were suspended in 40 ml of methylene chloride in a 100 ml sulphonation flask. The suspension was cooled to 0° C. while stirring and treated with 10 mg (0.06 mmol) of TEMPO, whereupon the mixture was held at 0° C. for 16 hours. Thereafter, the reaction had finished without 4-chloro-anisole being formed in any amount worth mentioning. The white precipitate was filtered off and the filtrate was washed with sodium bicarbonate solution and with sodium chloride solution. Distillation of the crude product gave 4.49 g (91%) of anisaldehyde GC content: 88.8% (area percent).
Reaction SMILES: [N:1]1([CH:7]2[CH2:16][CH2:15][C:14]3[CH:13]=[C:12]([C:17]#[N:18])[CH:11]=[CH:10][C:9]=3[CH2:8]2)[CH2:6][CH2:5][NH:4][CH2:3][CH2:2]1.Br[CH2:20][CH2:21][C:22]1[CH:27]=[CH:26][C:25]([N+:28]([O-:30])=[O:29])=[CH:24][CH:23]=1.CCN(C(C)C)C(C)C.[OH-].[Na+]>CN(C=O)C.C(Cl)Cl>[N+:28]([C:25]1[CH:26]=[CH:27][C:22]([CH2:21][CH2:20][N:4]2[CH2:3][CH2:2][N:1]([CH:7]3[CH2:16][CH2:15][C:14]4[CH:13]=[C:12]([C:17]#[N:18])[CH:11]=[CH:10][C:9]=4[CH2:8]3)[CH2:6][CH2:5]2)=[CH:23][CH:24]=1)([O-:30])=[O:29]
Reactant: N#Cc1ccc2c(c1)CCC(N1CCNCC1)C2
Reactant: O=[N+]([O-])c1ccc(CCBr)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Solvent: ClCCl
Product: N#Cc1ccc2c(c1)CCC(N1CCN(CCc3ccc([N+](=O)[O-])cc3)CC1)C2
Temperature: 60 °C
Reaction time: 21 h

Procedure:
A mixture of 6-piperazin-1-yl-5,6,7,8-tetrahydronaphthalene-2-carbonitrile (generated from treateding tert-Butyl 4-(6-cyano-1,2,3,4-tetrahydronaphthalen-2-yl) piperazine-1-carboxylate (110 mg, 0.32 mmol) with trifluoroacetic acid (2 ml, 26 mmol) at RT), 1-(2-bromoethyl)-4-nitrobenzene (47 mg, 0.21 mmol), and Hunig's Base (0.054 ml, 0.31 mmol in 1 ml DMF was stirred at 60° C. for 21 hours. The reaction was shaken with 1 ml 1 N NaOH and 1 mL DCM. The organic layer was separated and evaporated to dryness. The residue was purified by mass directed HPLC to yield 6-{4-[2-(4-nitrophenyl)ethyl]piperazin-1yl}-5,6,7,8-tetrahydronaphthalene-2-carbonitrile. LC-MS (IE, m/z): 391 [M+1]+. (0.050 μM)
Reaction SMILES: [Br:1][C:2]1[C:20]([CH3:21])=[CH:19][C:5]([O:6][C@@H:7]2[CH2:10][C@H:9]([NH:11]C(=O)OC(C)(C)C)[CH2:8]2)=[CH:4][C:3]=1[CH3:22].FC(F)(F)C(O)=O>ClCCl.C([O-])(O)=O.[Na+]>[Br:1][C:2]1[C:20]([CH3:21])=[CH:19][C:5]([O:6][C@@H:7]2[CH2:10][C@H:9]([NH2:11])[CH2:8]2)=[CH:4][C:3]=1[CH3:22]
Reactant: Cc1cc(O[C@H]2C[C@@H](NC(=O)OC(C)(C)C)C2)cc(C)c1Br
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: Cc1cc(O[C@H]2C[C@@H](N)C2)cc(C)c1Br
Temperature: 0 °C
Reaction time: 5 h

Procedure:
tert-Butyl cis-3-(4-bromo-3,5-dimethylphenoxy)cyclobutylcarbamate (200 mg) and trifluoroacetic acid (0.13 mL) are dissolved in dichloromethane (6 mL). The reaction mixture is stirred at 0° C. for 5 hours, diluted with a saturated aqueous solution of NaHCO3, dried (MgSO4) and concentrated to give the title compound. Yield: 400 mg.
Reaction SMILES: [C:1]1([C:7]2[CH:8]=[C:9]3[C:13](=[C:14]([C:16]([NH2:18])=[O:17])[CH:15]=2)[NH:12][CH:11]=[C:10]3[CH:19]2[CH2:24][CH2:23][NH:22][CH2:21][CH2:20]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[S:25]1[CH:29]=[CH:28][CH:27]=[C:26]1[S:30](Cl)(=[O:32])=[O:31].C(N(CC)CC)C>>[C:1]1([C:7]2[CH:8]=[C:9]3[C:13](=[C:14]([C:16]([NH2:18])=[O:17])[CH:15]=2)[NH:12][CH:11]=[C:10]3[CH:19]2[CH2:24][CH2:23][N:22]([S:30]([C:26]3[S:25][CH:29]=[CH:28][CH:27]=3)(=[O:32])=[O:31])[CH2:21][CH2:20]2)[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: NC(=O)c1cc(-c2ccccc2)cc2c(C3CCNCC3)c[nH]c12
Reactant: O=S(=O)(Cl)c1cccs1
Solvent: CCN(CC)CC
Product: NC(=O)c1cc(-c2ccccc2)cc2c(C3CCN(S(=O)(=O)c4cccs4)CC3)c[nH]c12

Procedure:
Following the general procedure in example 267, 5-(phenyl)-3-(4-piperidinyl)-1H-indole-7-carboxamide (40 mg, 0.12 mmol), 2-thiophenesulfonyl chloride (23 mg, 0.13 mmol) and triethylamine (0.07 mL, 0.5 mmol) were reacted to form the desired product which was purified by Gilson HPLC (CH3CN/Water, 0.1% TFA) (30 mg, 52%).
Reaction SMILES: [CH2:1]=[C:2]([C:4]1[CH:5]=[C:6]([NH2:10])[CH:7]=[N:8][CH:9]=1)[CH3:3]>C(O)C.[Pd]>[CH:2]([C:4]1[CH:5]=[C:6]([NH2:10])[CH:7]=[N:8][CH:9]=1)([CH3:3])[CH3:1]
Reactant: C=C(C)c1cncc(N)c1
Agent: [Pd]
Solvent: CCO
Product: CC(C)c1cncc(N)c1
Reaction time: 18 h
Yield: 134.1 %

Procedure:
To a solution of 5-(prop-1-en-2-yl)pyridin-3-amine (0.773 g, 2.48 mmol) in ethanol (8 mL) was added 10% Pd/C (0.132 g, 0.124 mmol) and the resulting suspension was stirred under a hydrogen atmosphere (1 atm) for 18 h. The reaction was filtered through Celite® and washed forward with EtOH. The filtrate was concentrated, diluted with EtOAc (30 mL) and washed with H2O (1×15 ml) and brine (1×15 ml). The aqueous phase was back-extracted with EtOAc (1×20 ml). The combined organic layers were dried (MgSO4) and concentrated to afford 5-isopropylpyridin-3-amine (0.453 g, 134%) as a light yellow oil. MS (ESI) m/z: 137.1 (M+H+).
Reaction SMILES: C([O:3][C:4](=[O:19])[CH:5]([O:16][CH2:17][CH3:18])[CH2:6][C:7]1[CH:8]=[C:9]2[C:13](=[CH:14][CH:15]=1)[NH:12][CH:11]=[CH:10]2)C.Cl[CH2:21][C:22]1[N:23]=[C:24]([C:28]2[CH:33]=[CH:32][C:31]([CH2:34][CH3:35])=[CH:30][CH:29]=2)[O:25][C:26]=1[CH3:27]>>[CH2:17]([O:16][CH:5]([CH2:6][C:7]1[CH:8]=[C:9]2[C:13](=[CH:14][CH:15]=1)[N:12]([CH2:21][C:22]1[N:23]=[C:24]([C:28]3[CH:29]=[CH:30][C:31]([CH2:34][CH3:35])=[CH:32][CH:33]=3)[O:25][C:26]=1[CH3:27])[CH:11]=[CH:10]2)[C:4]([OH:3])=[O:19])[CH3:18]
Reactant: CCOC(=O)C(Cc1ccc2[nH]ccc2c1)OCC
Reactant: CCc1ccc(-c2nc(CCl)c(C)o2)cc1
Product: CCOC(Cc1ccc2c(ccn2Cc2nc(-c3ccc(CC)cc3)oc2C)c1)C(=O)O
Yield: 41 %

Procedure:
Starting from rac-2-ethoxy-3-(1H-indol-5-yl)-propionic acid ethyl ester and 4-chloromethyl-2-(4-ethyl-phenyl)-5-methyl-oxazole, the title compound was obtained in 41% yield as a yellow solid. MS: (M+H)+ 433.4.
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([N+:8]([O-])=O)[CH:5]=[CH:4][C:3]=1[N:11]1[C:20]2[C:15](=[CH:16][C:17]([F:38])=[C:18]([N:21]3[CH2:26][CH2:25][N:24]([CH2:27][C:28]([C:30]4[CH:35]=[CH:34][C:33]([O:36][CH3:37])=[CH:32][CH:31]=4)=[O:29])[CH2:23][CH2:22]3)[CH:19]=2)[C:14](=[O:39])[C:13]([C:40]([OH:42])=[O:41])=[CH:12]1>C(O)C.[H][H].[Pd]>[NH2:8][C:6]1[CH:5]=[CH:4][C:3]([N:11]2[C:20]3[C:15](=[CH:16][C:17]([F:38])=[C:18]([N:21]4[CH2:22][CH2:23][N:24]([CH2:27][C:28]([C:30]5[CH:31]=[CH:32][C:33]([O:36][CH3:37])=[CH:34][CH:35]=5)=[O:29])[CH2:25][CH2:26]4)[CH:19]=3)[C:14](=[O:39])[C:13]([C:40]([OH:42])=[O:41])=[CH:12]2)=[C:2]([F:1])[CH:7]=1
Reactant: COc1ccc(C(=O)CN2CCN(c3cc4c(cc3F)c(=O)c(C(=O)O)cn4-c3ccc([N+](=O)[O-])cc3F)CC2)cc1
Reactant: [H][H]
Agent: [Pd]
Solvent: CCO
Product: COc1ccc(C(=O)CN2CCN(c3cc4c(cc3F)c(=O)c(C(=O)O)cn4-c3ccc(N)cc3F)CC2)cc1
Yield: 51 %

Procedure:
To a suspension of the 1-(2-fluoro-4-nitrophenyl)-6-fluoro-7-{4-[2-(4-methoxyphenyl)-2-oxoethyl]-1-piperazinyl}-4-oxo-1,4-dihydroquinoline-3-carboxylic acid [example 8] (0.58 g, 1 mmol) in ethanol (20 ml) was hydrogenated overnight in hydrogen in the presence of 10% Pd/C (25 mg) at room temperature. The reaction mixture was filtered and the filtrate was evaporated in vacuo to give a solid, the resulting solid was recrystallized from ethanol to afford 1-(4-amino-2-fluorophenyl)-6-fluoro-7-{4-[2-(4-methoxyphenyl)-2-oxoethyl]-1-piperazinyl}-4-oxo-1,4-dihydroquinoline-3-carboxylic acid (0.28 g, 51%). Mp: 143° C. (dec). 1H NMR (DMSO-d6) δ 2.66 and 3.09 (two m, 8H), 3.85-3.84 (m, 5H), 6.05 (s, 2H), 6.47 (d, 1H, J=7.2), 6.58 (m, 2H), 7.02 (m, 2H), 7.36 (m, 1H), 7.97 (m, 3H), 8.62 (s, 1H), 15.06 (br s, 1H). Anal. Calcd. for C29H26F2N4O5•1.0 H2O: C, 61.48; H, 4.98; N, 9.89. Found: C, 61.81; H, 4.85; N, 9.81.
Reaction SMILES: Cl.C(OC(=O)[NH:8][C@H:9]([C:17](=[O:31])[NH:18][C@H:19]1[CH2:25][CH2:24][C@@H:23]([CH3:26])[N:22]([CH2:27][CH2:28][CH3:29])[CH2:21][C@@H:20]1[OH:30])[CH2:10][CH:11]1[CH2:16][CH2:15][CH2:14][CH2:13][CH2:12]1)(C)(C)C>O1CCOCC1.CO>[NH2:8][C@@H:9]([CH2:10][CH:11]1[CH2:12][CH2:13][CH2:14][CH2:15][CH2:16]1)[C:17]([NH:18][C@H:19]1[CH2:25][CH2:24][C@@H:23]([CH3:26])[N:22]([CH2:27][CH2:28][CH3:29])[CH2:21][C@@H:20]1[OH:30])=[O:31]
Reactant: CCCN1C[C@H](O)[C@@H](NC(=O)[C@H](CC2CCCCC2)NC(=O)OC(C)(C)C)CC[C@H]1C
Agent: Cl
Solvent: C1COCCO1
Solvent: CO
Product: CCCN1C[C@H](O)[C@@H](NC(=O)[C@@H](N)CC2CCCCC2)CC[C@H]1C
Temperature: 25 °C
Reaction time: 2 h

Procedure:
HCl in dioxane (4.0 M, 15 ml) was added to a stirred solution of [(S)-2-Cyclohexyl-1-((3S,4S,7R)-3-hydroxy-7-methyl-1-propyl-azepan-4-ylcarbamoyl)-ethyl]-carbamic acid tert-butyl ester (1.4 g, 3.0 mmol) in MeOH (5 ml). The reaction mixture was stirred for 2 h at RT, then was concentrated in vacuo by rotary evaporation and was used in the next reaction without further purification (1.4 g).
Reaction SMILES: [N+](C1C=CC(COC([NH:12][CH:13]([CH2:24][CH2:25][P:26]([O:35][CH3:36])([O:28][C:29]2[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=2)=[O:27])[C:14]([O:16]CC2C=CC=CC=2)=[O:15])=O)=CC=1)([O-])=O.[H][H]>C(O)(=O)C.[C].[Pd]>[NH2:12][CH:13]([CH2:24][CH2:25][P:26]([O:35][CH3:36])([O:28][C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1)=[O:27])[C:14]([OH:16])=[O:15]
Reactant: [H][H]
Reactant: COP(=O)(CCC(NC(=O)OCc1ccc([N+](=O)[O-])cc1)C(=O)OCc1ccccc1)Oc1ccccc1
Agent: [Pd]
Solvent: CC(=O)O
Product: COP(=O)(CCC(N)C(=O)O)Oc1ccccc1
Yield: 48.8 %

Procedure:
Next, 0.57 g (1.05 mmol) of benzyl 2-(N-4-nitrobenzyloxycarbonylamino)-4-[methyl(phenyl)phosphono]butanoate was dissolved in 20 mL of acetic acid and mixed with 210 mg of 10% palladium-carbon and hydrogen gas was introduced for 2 hours. The palladium-carbon was removed by Celite filtration and the filtrate was concentrated in reduced pressure. The residue was purified by medium pressure reversed-phase column chromatography ODS-S-50B. The column was eluted with a linear gradient of 4 to 50% acetonitrile (12 mL/min flow rate) and the fractions of the compound eluted with 5% acetonitrile were collected and the elution and purity of the compound were confirmed by TLC (BuOH/AcOH/H2O=5:2:2, ninhydrin coloration). After vacuum concentration, freeze drying was carried out to obtain 2-amino-4-[methyl(phenyl)phosphono]butanoic acid (0.14 g, yield 48%) as a colorless solid.
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([I:8])[CH:5]=[CH:4][C:3]=1[NH:9][C:10]1[N:15]2[CH:16]=[N:17][CH:18]=[C:14]2[CH:13]=[N:12][C:11]=1[C:19]([OH:21])=O.[CH3:22][C:23]1([CH3:31])[O:27][C@@H:26]([CH2:28][O:29][NH2:30])[CH2:25][O:24]1.C1C=CC2N(O)N=NC=2C=1.CCN=C=NCCCN(C)C.CN1CCOCC1>CN(C=O)C.C(OCC)(=O)C>[CH3:22][C:23]1([CH3:31])[O:27][C@@H:26]([CH2:28][O:29][NH:30][C:19]([C:11]2[N:12]=[CH:13][C:14]3[N:15]([CH:16]=[N:17][CH:18]=3)[C:10]=2[NH:9][C:3]2[CH:4]=[CH:5][C:6]([I:8])=[CH:7][C:2]=2[F:1])=[O:21])[CH2:25][O:24]1
Reactant: O=C(O)c1ncc2cncn2c1Nc1ccc(I)cc1F
Reactant: CC1(C)OC[C@H](CON)O1
Agent: CCN=C=NCCCN(C)C
Agent: On1nnc2ccccc21
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Solvent: CN1CCOCC1
Product: CC1(C)OC[C@H](CONC(=O)c2ncc3cncn3c2Nc2ccc(I)cc2F)O1
Temperature: 25 °C
Reaction time: 72 h
Yield: 55.1 %

Procedure:
To a solution of 5-(2-fluoro-4-iodo-phenylamino)-imidazo[1,5-a]pyrazine-6-carboxylic acid (100.0 mg, 0.25 mmol) in anhydrous DMF (2.5 mL) was added, in order, (R)—O-((2,2-dimethyl-1,3-dioxolan-4-yl)methyl)hydroxylamine (40.7 mg, 0.28 mmol, 1.1 eq.), HOBt (37.3 mg, 0.27 mmol, 1.1 eq.), EDCI (53.0 mg, 0.27 mmol, 1.1 eq.), and N-methylmorpholine (0.1 mL, 0.91 mmol, 3.6 mmol). The reaction mixture was stirred at room temperature under N2 for 3 days. The reaction mixture was diluted with ethyl acetate, and the organic layer was washed with a saturated solution of sodium bicarbonate, water and brine. The organic phase was isolated, dried (Na2SO4), filtered and concentrated in vacuo. The resultant residue was subjected to flash chromatography (Si-PPC, gradient 80% to 100%, ethyl acetate in hexane, followed by gradient 0 to 20% methanol in ethyl acetate) to give a yellow solid (72.6 mg, 54.8%). LCMS (method D1): RT=0.97 min, [M+H]+=528.
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][C:7]([S:10]([CH3:13])(=[NH:12])=[O:11])=[CH:6][CH:5]=1)([O-])=O.C(OC(C)C)(C)C>C(O)C.[Pd]>[NH2:1][C:4]1[CH:5]=[CH:6][C:7]([S:10]([CH3:13])(=[NH:12])=[O:11])=[CH:8][CH:9]=1
Reactant: CS(=N)(=O)c1ccc([N+](=O)[O-])cc1
Agent: [Pd]
Solvent: CC(C)OC(C)C
Solvent: CCO
Product: CS(=N)(=O)c1ccc(N)cc1

Procedure:
A solution of 2.45 g (12.2 mmol) of (RS)-S-(4-nitrophenyl)-S-methyl sulfoximide in 150 ml of ethanol is hydrogenated at room temperature with use of 0.80 g of Pd/C (10%×50% H2O) under a hydrogen atmosphere at normal pressure over 4 hours. The hydrogen absorption is 920 ml. The batch is filtered and concentrated by evaporation. The residue that is obtained is digested with diisopropyl ether. 1.90 g (11.2 mmol, corresponding to 92% of theory) is obtained.
Reaction SMILES: C[O:2][C:3]1[C:8]2[C:9](=[O:18])[CH2:10][C:11]3([O:17][C:7]=2[CH:6]=[C:5]([O:19]C)[CH:4]=1)[CH2:16][CH2:15][CH2:14][CH2:13][CH2:12]3>Br>[OH:2][C:3]1[C:8]2[C:9](=[O:18])[CH2:10][C:11]3([O:17][C:7]=2[CH:6]=[C:5]([OH:19])[CH:4]=1)[CH2:16][CH2:15][CH2:14][CH2:13][CH2:12]3
Reactant: COc1cc(OC)c2c(c1)OC1(CCCCC1)CC2=O
Agent: Br
Product: O=C1CC2(CCCCC2)Oc2cc(O)cc(O)c21
Yield: 41.9 %

Procedure:
A mixture of 5,7-dimethoxyspiro[2H-1-benzopyran-2,1'-cyclohexan]-4(3H)-one [H.F.Birch, A.Robertson, and T.S.Subramanjam, J.Chem.Soc., 1832 (1936)] (1.3 g, 6.25 mmol) and 48% hydrobromic acid (50 ml) is heated to reflux for one hour. After cooling, the reaction mixture is concentrated under reduced pressure. The concentrate is extracted with diethyl ether and the extract is washed with water, dried, and concentrated. The residue is placed on a silica gel column and eluted with diethyl ether. The eluate is treated with ether to yield the title compound as a crystalline solid (0.65 g, 58%).
Reaction SMILES: [C:1]([C:5]1[CH:10]=[CH:9][C:8]([S:11]([NH:14][C:15]2[N:20]=[C:19]([N:21]3[CH2:26][CH2:25][O:24][CH2:23][CH2:22]3)[N:18]=[C:17]([O:27][CH2:28][CH2:29][C:30]([OH:32])=[O:31])[C:16]=2[O:33][C:34]2[CH:39]=[CH:38][CH:37]=[CH:36][C:35]=2[O:40][CH3:41])(=[O:13])=[O:12])=[CH:7][CH:6]=1)([CH3:4])([CH3:3])[CH3:2].[CH2:42](O)[C:43]1[CH:48]=[CH:47][CH:46]=[CH:45][CH:44]=1>>[C:1]([C:5]1[CH:6]=[CH:7][C:8]([S:11]([NH:14][C:15]2[N:20]=[C:19]([N:21]3[CH2:22][CH2:23][O:24][CH2:25][CH2:26]3)[N:18]=[C:17]([O:27][CH2:28][CH2:29][C:30]([O:32][CH2:42][C:43]3[CH:48]=[CH:47][CH:46]=[CH:45][CH:44]=3)=[O:31])[C:16]=2[O:33][C:34]2[CH:39]=[CH:38][CH:37]=[CH:36][C:35]=2[O:40][CH3:41])(=[O:13])=[O:12])=[CH:9][CH:10]=1)([CH3:4])([CH3:2])[CH3:3]
Reactant: COc1ccccc1Oc1c(NS(=O)(=O)c2ccc(C(C)(C)C)cc2)nc(N2CCOCC2)nc1OCCC(=O)O
Reactant: OCc1ccccc1
Product: COc1ccccc1Oc1c(NS(=O)(=O)c2ccc(C(C)(C)C)cc2)nc(N2CCOCC2)nc1OCCC(=O)OCc1ccccc1

Procedure:
The procedure described in Example 22 was repeated by use of 3-[6-(4-t-butylphenylsulfonylamino)-5-(2-methoxyphenoxy)-2-morpholino-4-pyrimidinyloxy]propionic acid and benzyl alcohol, to thereby obtain the title compound as a colorless oil.
Reaction SMILES: C([N:8]1[CH2:13][CH2:12][CH:11]([N:14]2[C:22]3[C:17](=[CH:18][CH:19]=[C:20]([NH:23][C:24](=[O:40])[C:25]4[CH:30]=[CH:29][CH:28]=[N:27][C:26]=4[NH:31][CH2:32][C:33]4[CH:38]=[CH:37][C:36]([F:39])=[CH:35][CH:34]=4)[CH:21]=3)[C:16]([CH3:42])([CH3:41])[CH2:15]2)[CH2:10][CH2:9]1)(OC(C)(C)C)=O>Cl.CCOC(C)=O>[CH3:41][C:16]1([CH3:42])[C:17]2[C:22](=[CH:21][C:20]([NH:23][C:24](=[O:40])[C:25]3[CH:30]=[CH:29][CH:28]=[N:27][C:26]=3[NH:31][CH2:32][C:33]3[CH:38]=[CH:37][C:36]([F:39])=[CH:35][CH:34]=3)=[CH:19][CH:18]=2)[N:14]([CH:11]2[CH2:12][CH2:13][NH:8][CH2:9][CH2:10]2)[CH2:15]1
Reactant: CC(C)(C)OC(=O)N1CCC(N2CC(C)(C)c3ccc(NC(=O)c4cccnc4NCc4ccc(F)cc4)cc32)CC1
Agent: Cl
Solvent: CCOC(C)=O
Product: CC1(C)CN(C2CCNCC2)c2cc(NC(=O)c3cccnc3NCc3ccc(F)cc3)ccc21
Temperature: 25 °C
Reaction time: 1.5 h

Procedure:
N-[1-(1-Boc-piperidin-4-yl)-3,3-dimethyl-2,3-dihydro-1H-indol-6-yl]-2-(4-fluoro-benzylamino)-nicotinamide (Example 47) was dissolved in a mixture of conc. HCl and EtOAc and stirred at RT for 1.5 h. The mixture was concentrated in vacuo and the residue was partitioned between EtOAc and 1 N NaOH. The organic layer was removed, washed with brine, dried over Na2SO4, filtered and concentrated in vacuo to provide a yellow solid. M+H 474.3. Calc'd for C28H32FN5O: 473.3.
Reaction SMILES: C(O[C:6]([N:8]([C@H:10]1[CH2:15][CH2:14][C@H:13]([C:16]2[CH:21]=[CH:20][C:19]([CH2:22][CH2:23][CH2:24][OH:25])=[CH:18][C:17]=2[CH2:26][NH:27][CH3:28])[CH2:12][CH2:11]1)C)=O)(C)(C)C.FC(F)(F)C(O)=O.[OH-].[Na+]>C(Cl)Cl>[OH:25][CH2:24][CH2:23][CH2:22][C:19]1[CH:20]=[CH:21][C:16]([C@H:13]2[CH2:14][CH2:15][C@H:10]([NH:8][CH3:6])[CH2:11][CH2:12]2)=[C:17]([CH2:26][NH:27][CH3:28])[CH:18]=1
Reactant: CNCc1cc(CCCO)ccc1[C@H]1CC[C@H](N(C)C(=O)OC(C)(C)C)CC1
Agent: [Na+]
Agent: [OH-]
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CNCc1cc(CCCO)ccc1[C@H]1CC[C@H](NC)CC1
Reaction time: 2 h

Procedure:
7.1 g of trans-N-tert.butoxycarbonyl-N-methyl-4-[4-(3-hydroxypropyl)methylaminomethylphenyl]cyclohexylamine are combined with 20 ml of trifluoroacetic acid in 150 ml of methylene chloride at ambient temperature. After 2 hours, ice and 6N sodium hydroxide solution are added, the organic phase is separated off, washed, dried and evaporated down. After the residue has been recrystallised from ether, 3.1 g of the title compound are obtained, melting point 144°-146° C.
Reaction SMILES: C[O:2][C:3](=O)[C:4]([C:13]1[CH:18]=[CH:17][C:16]([N+:19]([O-])=O)=[CH:15][C:14]=1[N+:22]([O-])=[O:23])([C:9]([F:12])([F:11])[F:10])[C:5]([F:8])([F:7])[F:6]>CCO.[Pd]>[NH2:19][C:16]1[CH:15]=[C:14]2[C:13]([C:4]([C:9]([F:12])([F:10])[F:11])([C:5]([F:8])([F:7])[F:6])[C:3](=[O:2])[N:22]2[OH:23])=[CH:18][CH:17]=1
Reactant: COC(=O)C(c1ccc([N+](=O)[O-])cc1[N+](=O)[O-])(C(F)(F)F)C(F)(F)F
Agent: [Pd]
Solvent: CCO
Product: Nc1ccc2c(c1)N(O)C(=O)C2(C(F)(F)F)C(F)(F)F
Reaction time: 8 h

Procedure:
To an argon-degassed solution of 5.13 g (13.64 mmol) 2-(2,4-dinitro-phenyl)-3,3,3-trifluoro-2-trifluoromethyl-propionic acid methyl ester in 300 ml EtOH was added 0.5 g of 10% by weight Pd/C. The reaction was stirred under H2 overnight and filtered through Celite®, concentrated down, and dried under vacuum, yielding the titled compound.