Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:14]=[CH:13][C:12]([N+:15]([O-:17])=[O:16])=[C:11](F)[CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:19]([O:23][C:24]([NH:26][CH2:27][C:28]1[CH:33]=[CH:32][CH:31]=[C:30]([OH:34])[CH:29]=1)=[O:25])([CH3:22])([CH3:21])[CH3:20].C(=O)([O-])[O-].[K+].[K+].CN(C)C=O>O>[C:19]([O:23][C:24](=[O:25])[NH:26][CH2:27][C:28]1[CH:33]=[CH:32][CH:31]=[C:30]([O:34][C:11]2[CH:10]=[C:9]([O:8][CH2:1][C:2]3[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=3)[CH:14]=[CH:13][C:12]=2[N+:15]([O-:17])=[O:16])[CH:29]=1)([CH3:22])([CH3:20])[CH3:21]
Reactant: O=[N+]([O-])c1ccc(OCc2ccccc2)cc1F
Reactant: CC(C)(C)OC(=O)NCc1cccc(O)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)NCc1cccc(Oc2cc(OCc3ccccc3)ccc2[N+](=O)[O-])c1
Temperature: 100 °C
Reaction time: 12 h
Yield: 95.6 %

Procedure:
A mixture of 4-benzyloxy-2-fluoronitrobenzene (6.43 g, 26 mmols), N-tert-butoxycarbonyl-3-hydroxybenzylamine (5.78 g, 26 mmols), potassium carbonate (3.59 g, 26 mmols) and N,N-dimethylformamide (70 ml) was stirred at 100° C. for 12 hours. The reaction mixture was cooled, then poured into water, and extracted with ethyl acetate. The extract was washed with water, and then dried with anhydrous magnesium sulfate, and the solvent was evaporated away to give an yellow oil of tert-butyl[3-(5-benzyloxy-2-nitrophenoxy)benzyl]carbamate (11.2 g, 95.0%).
Reaction SMILES: C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[N:20]([CH2:23][C@@:24]12[CH2:39][O:38][C@@H:26]([C@H:27]([N:29]3[CH:36]=[C:35]([CH3:37])[C:33](=[O:34])[NH:32][C:30]3=[O:31])[O:28]1)[C@@H:25]2[OH:40])=[N+]=[N-].N>N1C=CC=CC=1>[NH2:20][CH2:23][C@@:24]12[CH2:39][O:38][C@@H:26]([C@H:27]([N:29]3[CH:36]=[C:35]([CH3:37])[C:33](=[O:34])[NH:32][C:30]3=[O:31])[O:28]1)[C@@H:25]2[OH:40]
Reactant: Cc1cn([C@@H]2O[C@@]3(CN=[N+]=[N-])CO[C@@H]2[C@@H]3O)c(=O)[nH]c1=O
Agent: N
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: c1ccncc1
Product: Cc1cn([C@@H]2O[C@@]3(CN)CO[C@@H]2[C@@H]3O)c(=O)[nH]c1=O
Temperature: 25 °C
Reaction time: 3 h

Procedure:
In a nitrogen stream, triphenylphosphine (49 mg, 0.19 mmol) was added to a pyridine solution (3.0 ml) of Compound 4 (28 mg, 0.095 mmol), and the mixture was stirred for 3 hours at room temperature. A 28% aqueous solution of ammonia (5.0 ml) was added, and the mixture was stirred further for 14 hours. Then, the solvent was distilled off under reduced pressure to obtain 5′-amino-5′-deoxy-5-methyl-2′-O,4′-C-methyleneuridine (Compound 5) as a crude product.
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[C:9]([Cl:11])[C:8]([C:12]2[C:16]([F:17])=[C:15]([O:18][CH:19](F)[F:20])[N:14]([CH3:22])[N:13]=2)=[CH:7][C:3]=1[C:4](O)=[O:5].C(Cl)(=O)C([Cl:26])=O>>[Cl:1][C:2]1[CH:10]=[C:9]([Cl:11])[C:8]([C:12]2[C:16]([F:17])=[C:15]([O:18][CH2:19][F:20])[N:14]([CH3:22])[N:13]=2)=[CH:7][C:3]=1[C:4]([Cl:26])=[O:5]
Reactant: Cn1nc(-c2cc(C(=O)O)c(Cl)cc2Cl)c(F)c1OC(F)F
Reactant: O=C(Cl)C(=O)Cl
Product: Cn1nc(-c2cc(C(=O)Cl)c(Cl)cc2Cl)c(F)c1OCF

Procedure:
5.8 g (16 mmol) of 2,4-dichloro-5-(5-difluoromethoxy-4-fluoro-1-methyl-1H-pyrazol-3-yl)benzoic acid and 10.4 g (82 mmol) of oxalyl chloride were reacted in the manner described for Precursor 1.1. Yield: 5.2 g.
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4]([CH2:11][S:12]([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][N+:15]=2[O-:20])=[O:13])[CH:5]=[CH:6][C:7]=1[N+:8]([O-:10])=[O:9].C(OO)(=[O:23])C>C(O)(=O)C>[CH3:1][C:2]1[CH:3]=[C:4]([CH2:11][S:12]([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][N+:15]=2[O-:20])(=[O:23])=[O:13])[CH:5]=[CH:6][C:7]=1[N+:8]([O-:10])=[O:9]
Reactant: Cc1cc(CS(=O)c2cccc[n+]2[O-])ccc1[N+](=O)[O-]
Reactant: CC(=O)OO
Solvent: CC(=O)O
Product: Cc1cc(CS(=O)(=O)c2cccc[n+]2[O-])ccc1[N+](=O)[O-]
Temperature: 25 °C

Procedure:
To a mixture of 9.5 g of 2-[[(3-methyl-4-nitrophenyl)methyl]sulfinyl]-pyridine-1-oxide in 50 ml of acetic acid was added, dropwise with stirring at room temperature, 9.17 g of 40% peracetic acid in acetic acid. After addition, a short period of heating was required to complete the reaction. Excess peracetic acid was then destroyed by the addition of sodium bisulfite and this was followed by the addition of 200 ml of water and potassium carbonate to neutralize the acidic solution. The white solid was filtered off and washed with water. Yield 9.7 g, melting point of 160-162° C. Infrared and NMR spectra supported the proposed structure.
Reaction SMILES: [I:1]Cl.[NH2:3][C:4]1[C:12]([C:13]([OH:15])=[O:14])=[CH:11][CH:10]=[CH:9][C:5]=1[C:6]([OH:8])=[O:7].O>CC(O)=O>[NH2:3][C:4]1[C:12]([C:13]([OH:15])=[O:14])=[CH:11][C:10]([I:1])=[CH:9][C:5]=1[C:6]([OH:8])=[O:7]
Reactant: ClI
Reactant: Nc1c(C(=O)O)cccc1C(=O)O
Solvent: O
Solvent: CC(=O)O
Product: Nc1c(C(=O)O)cc(I)cc1C(=O)O
Reaction time: 2 h
Yield: 87.3 %

Procedure:
A solution of iodine monochloride (0.9 g) in glacial AcOH (1.7 ml) was added dropwise over 15 minutes to a stirred solution of 2-aminoisophthalic acid (1 g) in glacial AcOH (6.9 ml) at room temperature. The mixture was stirred for 2 hours and then poured into water (70 ml). The resultant orange solid was isolated by filtration, washed with water, diluted with MeOH and concentrated to yield 2-amino-5-iodoisophthalic acid (1.48 g); Mass Spectrum: M+H+ 308.
Reaction SMILES: Cl[C:2]1[CH:3]=[C:4]2[C:12](=[O:13])[C:11]3[CH:14]=[C:15]([NH:18][S:19]([CH3:22])(=[O:21])=[O:20])[CH:16]=[CH:17][C:10]=3[CH:9]=[CH:8][C:5]2=[N:6][CH:7]=1.C1C=CC(P(C2C(C3C(P(C4C=CC=CC=4)C4C=CC=CC=4)=CC=C4C=3C=CC=C4)=C3C(C=CC=C3)=CC=2)C2C=CC=CC=2)=CC=1.C(=O)([O-])[O-].[Cs+].[Cs+].[CH:75]([N:78]1[CH2:83][CH2:82][NH:81][CH2:80][CH2:79]1)([CH3:77])[CH3:76]>C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd].CN(C)C=O>[CH:75]([N:78]1[CH2:83][CH2:82][N:81]([C:2]2[CH:3]=[C:4]3[C:12](=[O:13])[C:11]4[CH:14]=[C:15]([NH:18][S:19]([CH3:22])(=[O:21])=[O:20])[CH:16]=[CH:17][C:10]=4[CH:9]=[CH:8][C:5]3=[N:6][CH:7]=2)[CH2:80][CH2:79]1)([CH3:77])[CH3:76]
Reactant: CS(=O)(=O)Nc1ccc2ccc3ncc(Cl)cc3c(=O)c2c1
Reactant: CC(C)N1CCNCC1
Agent: [Pd]
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Agent: O=C([O-])[O-]
Solvent: CN(C)C=O
Product: CC(C)N1CCN(c2cnc3ccc4ccc(NS(C)(=O)=O)cc4c(=O)c3c2)CC1
Temperature: 180 °C

Procedure:
N-(3-chloro-5-oxo-5H-benzo[4,5]cyclohepta[1,2-b]pyridin-7-yl)methanesulfonamide (0.100 g, 0.30 mmol), Pd2(dba)3 (6 mg, 0.006 mmol), rac-BINAP (11 mg, 0.018 mmol), and cesium carbonate (0.490 g, 1.50 mmol) combined mixed in a dry tube. Isopropylpiperazine (0.170 mL, 1.20 mmol) and 0.70 mL of dry dimethylformamide were added and the tube was sealed. The reaction contents were heated in the Biotage Initiator series microwave at 180° C. for 15 minutes. The reaction contents were partially concentrated and purified by reverse phase HPLC (10-100% acetonitrile/water gradient, 0.1% trifluoroacetic acid modifier) to afford the title compound.
Reaction SMILES: [NH2:1][CH:2]([C:5]1[CH:10]=[CH:9][C:8]([CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH3:20])=[CH:7][CH:6]=1)[CH2:3][OH:4].C(N(CC)CC)C.[F:28][C:29]1[CH:37]=[CH:36][CH:35]=[C:34]([F:38])[C:30]=1[C:31](Cl)=O.S(Cl)(Cl)=O>O1CCCC1.C1C=CC=CC=1>[F:28][C:29]1[CH:37]=[CH:36][CH:35]=[C:34]([F:38])[C:30]=1[C:31]1[O:4][CH2:3][CH:2]([C:5]2[CH:10]=[CH:9][C:8]([CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH3:20])=[CH:7][CH:6]=2)[N:1]=1
Reactant: CCCCCCCCCCc1ccc(C(N)CO)cc1
Reactant: O=C(Cl)c1c(F)cccc1F
Solvent: O=S(Cl)Cl
Solvent: CCN(CC)CC
Solvent: c1ccccc1
Product: CCCCCCCCCCc1ccc(C2COC(c3c(F)cccc3F)=N2)cc1

Procedure:
To a mixture of 2.77 g (10 millimoles) of 2-amino-2-(4-n-decylphenyl)ethanol, 1.01 g (10 millimoles) of triethylamine and 30 ml of tetrahydrofuran contained in a 100 ml eggplant-shaped (spheroidal) flask, a solution of 1.77 g (10 millimoles) of 2,6-difluorobenzoyl chloride in 15 ml of tetrahydrofuran was added over 30 minutes with stirring at ice-bath temperature. After further continuation of stirring for 3 hours at room temperature, the produced triethylamine hydrochloride was removed by filtration using a glass filter and the filtrate was concentrated under reduced pressure. This concentrate was added with 50 ml of benzene and 3.57 g (30 millimoles) of thionyl chloride, and then refluxed for 3 hours with stirring on an oil bath. The reaction mixture was concentrated under reduced pressure and added with 50 ml of methanol followed by dropwise addition of 2 ml of a 50% aqueous sodium hydroxide solution at 60° C. with stirring. After further continuation of stirring for 30 minutes, the reaction mixture was poured into water and extracted with ethyl acetate followed by desiccation over anhydrous sodium sulfate and concentration under reduced pressure. This concentrate was purified by silica-gel column chromatography using a 8/2 solvent mixture of n-hexane/ethyl acetate as a movable phase to obtain 2-(2,6-difluorophenyl)-4-(4-n-decylphenyl)-2-oxazoline (Compound Number 20).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4](Br)[CH:5]=[CH:6][C:7]=1[O:8][CH2:9][CH2:10][CH3:11].OB(O)[C:15]1[CH:20]=[CH:19][CH:18]=[C:17]([F:21])[CH:16]=1.FC1C=C(Br)C=CC=1.[Mg].COB(OC)OC.Cl.C([O-])([O-])=O.[K+].[K+]>[Pd].CCCCCCC.C1(C)C=CC=CC=1.C1(C)C=CC=CC=1.C(O)C.O>[F:1][C:2]1[CH:3]=[C:4]([C:15]2[CH:20]=[CH:19][CH:18]=[C:17]([F:21])[CH:16]=2)[CH:5]=[CH:6][C:7]=1[O:8][CH2:9][CH2:10][CH3:11]
Reactant: OB(O)c1cccc(F)c1
Reactant: CCCOc1ccc(Br)cc1F
Agent: [Pd]
Agent: COB(OC)OC
Agent: Cl
Solvent: CCO
Solvent: CCCCCCC
Solvent: O
Product: CCCOc1ccc(-c2cccc(F)c2)cc1F
Yield: 85.8 %

Procedure:
A mixture of 22.0 g (94.4 mmol) of 3-fluoro-4-propoxybromobenzene, 22.5 g (141.6 mmol) of dihydroxy(3-fluorophenyl)borane (prepared by reacting a Grignard reagent, which was prepared from 3-fluorobromobenzene and magnesium, with trimethoxyborane, and then hydrolysing with hydrochloric acid), 26.1 g (188.8 mmol) of K2CO3, 2.0 g of 5%Pd—C, and 150 ml of mixed solvent of toluene/ethanol/water (1/1/1) was heated to reflux for 27 hours. Subsequently, the Pd—C was removed by filtration, the mixture was extracted with 150 ml of toluene, the organic layer thus obtained was washed with water thrice, and then dried over anhydrous magnesium sulfate. The solvent was distilled off under a reduced pressure, and the residue thus obtained was subjected to silica gel column chromatography (eluent: heptane/toluene=1/1) to obtain 20.1 g of a crude 3,3′-difluoro-4-propoxybiphenyl. (Yield: 86.1%)
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]2[C:19]3[C@@H:9]([CH2:10][C@@H:11]4[C@@H:16]([C:17]=3[CH:18]=1)[CH2:15][C@H:14]([NH:20][C:21](=[O:27])[N:22]([CH2:25][CH3:26])[CH2:23][CH3:24])[CH2:13][N:12]4[CH2:28]CC)[CH2:8][NH:7]2)([O-:3])=[O:2]>C(Cl)(Cl)Cl>[CH3:28][N:12]1[C@H:11]2[C@@H:16]([C:17]3[CH:18]=[C:4]([N+:1]([O-:3])=[O:2])[CH:5]=[C:6]4[C:19]=3[C@@H:9]([CH2:10]2)[CH2:8][NH:7]4)[CH2:15][C@@H:14]([NH:20][C:21](=[O:27])[N:22]([CH2:25][CH3:26])[CH2:23][CH3:24])[CH2:13]1
Reactant: CCCN1C[C@@H](NC(=O)N(CC)CC)C[C@@H]2c3cc([N+](=O)[O-])cc4c3[C@H](CN4)C[C@H]21
Solvent: ClC(Cl)Cl
Product: CCN(CC)C(=O)N[C@@H]1C[C@@H]2c3cc([N+](=O)[O-])cc4c3[C@H](CN4)C[C@H]2N(C)C1
Yield: 50 %

Procedure:
3-(2,3α-Dihydro-13-nitro-6-n-propyl-8α-ergolinyl)-1,1-diethylurea. Yield: 50%. [α]D =-156° (0.5% in CHCl3).
Reaction SMILES: [H-].[Na+].[C:3]([CH2:5]P(=O)(OCC)OCC)#[N:4].[CH2:14]([N:21]([CH2:32][C:33]1[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=1)[C:22]1[N:27]=[C:26]2[C:28](=O)[CH2:29][CH2:30][C:25]2=[CH:24][CH:23]=1)[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1>O1CCCC1.[Cl-].[NH4+].C(OCC)(=O)C>[CH2:14]([N:21]([CH2:32][C:33]1[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=1)[C:22]1[N:27]=[C:26]2[C:28](=[CH:5][C:3]#[N:4])[CH2:29][CH2:30][C:25]2=[CH:24][CH:23]=1)[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1
Reactant: O=C1CCc2ccc(N(Cc3ccccc3)Cc3ccccc3)nc21
Reactant: CCOP(=O)(CC#N)OCC
Agent: [Cl-]
Agent: [H-]
Agent: [NH4+]
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: N#CC=C1CCc2ccc(N(Cc3ccccc3)Cc3ccccc3)nc21
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 94.5 %

Procedure:
To a suspension of 60% sodium hydride (146 mg, 3.65 mmol) in tetrahydrofuran (20 mL) was added diethyl cyanomethylphosphonate (640 μL, 3.96 mmol), and the mixture was stirred at room temperature for 15 min. A solution of 2-(dibenzylamino)-5,6-dihydro-7H-cyclopenta[b]pyridin-7-one (1.00 g, 3.04 mmol) in tetrahydrofuran (10 mL) was added thereto, and the mixture was further stirred for 15 min. The reaction solution was diluted with saturated aqueous ammonium chloride solution, diluted with ethyl acetate, washed with saturated brine, and dried over anhydrous sodium sulfate. The solvent was evaporated under reduced pressure, and the residue was purified by silica gel column chromatography (ethyl acetate/hexane=10/90→30/70) to give the title compound (1.01 g, yield 95%).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]([O:10][C:11]2[CH:15]=[C:14]([N:16]3[C:24]4[CH:23]=[C:22]([CH2:25][OH:26])[N:21]=[CH:20][C:19]=4[N:18]=[CH:17]3)[S:13][C:12]=2[C:27]([NH2:29])=[O:28])[CH3:9])=[C:4]([C:30]([F:33])([F:32])[F:31])[CH:3]=1.[CH3:34][S:35](Cl)(=[O:37])=[O:36].C(N(CC)CC)C>ClCCl>[CH3:34][S:35]([O:26][CH2:25][C:22]1[N:21]=[CH:20][C:19]2[N:18]=[CH:17][N:16]([C:14]3[S:13][C:12]([C:27](=[O:28])[NH2:29])=[C:11]([O:10][CH:8]([C:5]4[CH:6]=[CH:7][C:2]([F:1])=[CH:3][C:4]=4[C:30]([F:33])([F:31])[F:32])[CH3:9])[CH:15]=3)[C:24]=2[CH:23]=1)(=[O:37])=[O:36]
Reactant: CS(=O)(=O)Cl
Reactant: CC(Oc1cc(-n2cnc3cnc(CO)cc32)sc1C(N)=O)c1ccc(F)cc1C(F)(F)F
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CC(Oc1cc(-n2cnc3cnc(COS(C)(=O)=O)cc32)sc1C(N)=O)c1ccc(F)cc1C(F)(F)F

Procedure:
In a similar manner as described for example 49 (step 1), 120 mg of 3-{1-[4-fluoro-2-(trifluoromethyl)phenyl]ethoxy}-5-[6-(hydroxymethyl)-1H-imidazo[4,5-c]pyridin-1-yl]thiophene-2-carboxamide, 57 mg of methanesulfonyl chloride, and 51 mg of triethylamine in 3 ml dichloromethane give [1-(5-carbamoyl-4-{1-[4-fluoro-2-(trifluoromethyl)phenyl]ethoxy}-2-thienyl)-1H-imidazo[4,5-c]pyridin-6-yl]methyl methanesulfonate as crude material that is used for step 2 without further purification.
Reaction SMILES: [CH3:1][N+:2]1[C:6]([S-:7])=[N:5][N:4]([CH:8]([CH3:11])[CH2:9][CH3:10])[N:3]=1.S(=O)(=O)(O)O.[OH-].[Na+].C(=O)(O)[O-].[Na+].[F:24][B-:25]([F:28])([F:27])[F:26].[Na+]>O>[F:24][B-:25]([F:28])([F:27])[F:26].[CH3:1][N+:2]1[C:6]([S:7][CH:8]([CH3:11])[CH2:9][CH3:10])=[N:5][N:4]([CH:8]([CH3:11])[CH2:9][CH3:10])[N:3]=1
Reactant: CCC(C)n1nc([S-])[n+](C)n1
Agent: F[B-](F)(F)F
Agent: O=C([O-])O
Agent: O=S(=O)(O)O
Solvent: O
Product: CCC(C)Sc1nn(C(C)CC)n[n+]1C
Reaction time: 13 h
Yield: 150 %

Procedure:
1-methyl-3-(1-methylpropyl)tetrazolium-5-thiolate (173.7 mg, 1.0 mmol) was introduced into a recovery flask; concentrated sulfuric acid (1.7 mL) and C2H5(CH3)CHOH (s-BuOH, 92.0 μL, 1.0 mmol) were added to this; and stirring was performed for 13 hours. Then, while on an ice bath, an aqueous sodium hydroxide solution (30.0 mmol, 10 mL) and aqueous sodium bicarbonate (30.0 mmol, 10.0 mL) were added dropwise using a dropping funnel. More aqueous sodium bicarbonate was added to bring to neutrality (pH=6-7). Extraction with methylene chloride, washing with an aqueous sodium carbonate solution, drying over anhydrous sodium sulfate, and distillation of the solvent yielded a yellow liquid. On the other hand, sodium fluoroborate (165.0 mg, 1.5 mmol) was added to the water layer followed by extraction with methylene chloride, drying over anhydrous sodium sulfate, and removal of the solvent by distillation to obtain 1-methyl-3-(1-methylpropyl)-5-(1-methylpropylthio)tetrazolium tetrafluoroborate (yield=237.1 mg, 75%).
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][C:8]=2[NH:10][C:11]2[N:16]3[N:17]=[CH:18][C:19]([C:20](O)=[O:21])=[C:15]3[N:14]=[CH:13][C:12]=2[C:23]([N:25]2[CH2:30][CH2:29][CH:28]([C:31]3[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=3)[CH2:27][CH2:26]2)=[O:24])[CH:3]=[CH:2]1.[CH2:37]([S:39]([NH2:42])(=[O:41])=[O:40])[CH3:38]>>[NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][C:8]=2[NH:10][C:11]2[N:16]3[N:17]=[CH:18][C:19]([C:20]([NH:42][S:39]([CH2:37][CH3:38])(=[O:41])=[O:40])=[O:21])=[C:15]3[N:14]=[CH:13][C:12]=2[C:23]([N:25]2[CH2:30][CH2:29][CH:28]([C:31]3[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=3)[CH2:27][CH2:26]2)=[O:24])[CH:3]=[CH:2]1
Reactant: CCS(N)(=O)=O
Reactant: O=C(O)c1cnn2c(Nc3cccc4cc[nH]c34)c(C(=O)N3CCC(c4ccccc4)CC3)cnc12
Product: CCS(=O)(=O)NC(=O)c1cnn2c(Nc3cccc4cc[nH]c34)c(C(=O)N3CCC(c4ccccc4)CC3)cnc12
Yield: 26.2 %

Procedure:
In the same manner as in Example 1, step 6 and using 7-(7-indolylamino)-6-(4-phenylpiperidine-1-carbonyl)pyrazolo[1,5-a]pyrimidine-3-carboxylic acid (0.05 g, 0.10 mmol) obtained in step 2 and ethanesulfonamide (0.080 g, 0.73 mmol), the title compound (0.015 g, 27%) was obtained.
Reaction SMILES: [NH2:1][CH2:2][C:3]1[N:8]=[CH:7][C:6]([C:9]2[CH:14]=[CH:13][C:12]([C@H:15]3[O:19]C(C)(C)[N:17]([C:22](=[O:26])[CH:23]([F:25])[F:24])[C@@H:16]3[CH2:27][F:28])=[CH:11][CH:10]=2)=[CH:5][CH:4]=1.C(N(CC)CC)C.[CH2:36]([S:40](Cl)(=[O:42])=[O:41])[CH:37]([CH3:39])[CH3:38].FC(F)(F)C(O)=O>C(Cl)Cl.C1(C)C=CC=CC=1>[F:24][CH:23]([F:25])[C:22]([NH:17][C@H:16]([CH2:27][F:28])[C@H:15]([OH:19])[C:12]1[CH:11]=[CH:10][C:9]([C:6]2[CH:7]=[N:8][C:3]([CH2:2][NH:1][S:40]([CH2:36][CH:37]([CH3:39])[CH3:38])(=[O:42])=[O:41])=[CH:4][CH:5]=2)=[CH:14][CH:13]=1)=[O:26]
Reactant: CC(C)CS(=O)(=O)Cl
Reactant: CC1(C)O[C@H](c2ccc(-c3ccc(CN)nc3)cc2)[C@@H](CF)N1C(=O)C(F)F
Solvent: Cc1ccccc1
Solvent: CCN(CC)CC
Solvent: O=C(O)C(F)(F)F
Product: CC(C)CS(=O)(=O)NCc1ccc(-c2ccc([C@@H](O)[C@@H](CF)NC(=O)C(F)F)cc2)cn1
Temperature: 25 °C
Reaction time: 1 h
Yield: 18 %

Procedure:
To a solution of 1-((4S,5R)-5-(4-(6-(aminomethyl)pyridin-3-yl)phenyl)-4-(fluoromethyl)-2,2-dimethyloxazolidin-3-yl)-2,2-difluoroethanone (80 mg, 0.2 mmol) in CH2Cl2 (15 mL) at 0° C. is added triethylamine (804, 0.5 mmol) followed by isobutylsulfonyl chloride (29 mg, 0.2 mmol). The reaction is stirred at room temperature for 1 hour. Next, trifluoroacetic acid (1 mL) is added and the reaction is stirred at room temperature for an additional 1 hour. Toluene (20 mL) is added and the reaction is concentrated under vacuum. The crude reaction is purified using reverse-phase chromatography, free-based with saturated NaHCO3, extracted with ethylacetate, and concentrated under vacuum to afford the title compound (17 mg). 1H NMR (400 MHz, DMSO-d6) δ: 0.99 (d, 6H), 2.05-2.11 (m, 1H), 2.94 (d, 2H), 4.28-4.36 (m, 3.5H), 4.41-4.45 (m, 0.5H), 4.52-4.58 (m, 0.5H), 4.65-4.68 (m, 0.5H), 4.89 (m, 1H), 5.90 (d, 1H), 6.21 (t, 1H), 7.47 (d, 2H), 7.54 (d, 1H), 7.69-7.74 (m, 3H), 8.12 (dd, 1H), 8.81-8.83 (m, 2H); m/z (Cl) 474 [M+H].
Reaction SMILES: [CH3:1][N:2]([C@@H:10]1[CH2:14][CH2:13][N:12]([C:15]2[C:16]3[CH:23]=[CH:22][N:21]([CH2:24][O:25][CH2:26][CH2:27][Si:28]([CH3:31])([CH3:30])[CH3:29])[C:17]=3[N:18]=[CH:19][N:20]=2)[CH2:11]1)[C:3]1[CH:8]=[CH:7][C:6]([NH2:9])=[CH:5][N:4]=1.C([O-])([O-])=O.[K+].[K+].Cl[CH2:39][C:40]1[CH:45]=[CH:44][C:43]([F:46])=[CH:42][CH:41]=1.O>CN(C=O)C>[F:46][C:43]1[CH:44]=[CH:45][C:40]([CH2:39][NH:9][C:6]2[CH:7]=[CH:8][C:3]([N:2]([CH3:1])[C@@H:10]3[CH2:14][CH2:13][N:12]([C:15]4[C:16]5[CH:23]=[CH:22][N:21]([CH2:24][O:25][CH2:26][CH2:27][Si:28]([CH3:30])([CH3:29])[CH3:31])[C:17]=5[N:18]=[CH:19][N:20]=4)[CH2:11]3)=[N:4][CH:5]=2)=[CH:41][CH:42]=1
Reactant: CN(c1ccc(N)cn1)[C@@H]1CCN(c2ncnc3c2ccn3COCC[Si](C)(C)C)C1
Reactant: Fc1ccc(CCl)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: CN(c1ccc(NCc2ccc(F)cc2)cn1)[C@@H]1CCN(c2ncnc3c2ccn3COCC[Si](C)(C)C)C1
Temperature: 80 °C
Reaction time: 18 h
Yield: 30 %

Procedure:
To a solution of (R)—N2-methyl-N2-(1-(7-((2-(trimethylsilyl)ethoxy)methyl)-7H-pyrrolo[2,3-d]pyrimidin-4-yl)pyrrolidin-3-yl)pyridine-2,5-diamine (0.20 mmol) in DMF (5 mL) were added K2CO3 (0.24 mmol) and 1-Chloromethyl-4-fluoro-benzene (0.24 mmol) at room temperature. The mixture was stirred at 80° C. for 18 hours, poured into water and extracted with EtOAc. The organic layer was washed with water and brine sequentially, then concentrated. The residue was purified by preparative TLC to give the title compound in 30% yield.
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[CH:6]2[N:12]([C:13]([O:15][C:16]([CH3:19])([CH3:18])[CH3:17])=[O:14])[CH:9]([CH2:10][CH:11]=1)[CH2:8][CH2:7]2)=[O:4]>C(O)C.[Pd]>[CH3:1][O:2][C:3]([CH:5]1[CH2:11][CH2:10][CH:9]2[N:12]([C:13]([O:15][C:16]([CH3:19])([CH3:18])[CH3:17])=[O:14])[CH:6]1[CH2:7][CH2:8]2)=[O:4]
Reactant: COC(=O)C1=CCC2CCC1N2C(=O)OC(C)(C)C
Agent: [Pd]
Solvent: CCO
Product: COC(=O)C1CCC2CCC1N2C(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 2 h

Procedure:
8-Azabicyclo[3.2.1]oct-2-ene-2,8-dicarboxylic acid 8-tert-butyl ester 2-methyl ester from Step 4 (5.9 g, 22 mmol) was dissolved in ethanol (100 mL), to which palladium (10% on charcoal, 0.59 g) was added. The resulting mixture was shaken under an atmosphere of hydrogen (50 psi) for 2 hours at room temperature, and was then filtered through a bed of Celite, which was washed with ethyl acetate. The filtrate was concentrated under reduced pressure, and the resulting residue was purified by flash chromatography (silica gel, ethyl acetate/hexane) to provide 8-azabicyclo[3.2.1]octane-2,8-dicarboxylic acid 8-tert-butyl ester 2-methyl ester as a mixture of endo and exo isomers as a colorless oil (5.8 g, 97% yield).
Reaction SMILES: C(O)CCC#C.[CH:7]([C:10]1[CH:11]=[C:12]([C:16]#[C:17][CH2:18][CH2:19][CH:20]=[O:21])[CH:13]=[CH:14][CH:15]=1)=[CH:8][CH3:9]>>[CH:7]([C:10]1[CH:11]=[C:12]([C:16]#[C:17][CH2:18][CH2:19][CH2:20][OH:21])[CH:13]=[CH:14][CH:15]=1)=[CH:8][CH3:9]
Reactant: CC=Cc1cccc(C#CCCC=O)c1
Agent: C#CCCCO
Product: CC=Cc1cccc(C#CCCCO)c1

Procedure:
5-(3'-propenylphenyl)-4-pentyn-1-ol was prepared from 4-pentyn-1-ol and 3-(1'-propenyl) iodobenzene as in Example 15 and converted into 5-(3'-propenylphenyl)-4-pentyn-1-al by the method of Example 9.
Reaction SMILES: Cl.[CH3:2][O:3][C:4](=[O:12])[CH:5]([NH2:11])[CH2:6][S:7][CH2:8][CH2:9]Cl>CN(C=O)C>[CH3:2][O:3][C:4]([C@@H:5]1[CH2:6][S:7][CH2:8][CH2:9][NH:11]1)=[O:12]
Reactant: COC(=O)C(N)CSCCCl
Agent: Cl
Solvent: CN(C)C=O
Product: COC(=O)[C@@H]1CSCCN1
Temperature: 92.5 °C
Reaction time: 8 h
Yield: 43.6 %

Procedure:
36.3 g of 2-amino-3-(2-chloro-ethylsulfanyl)-propionic acid methyl ester hydrochloride was dissolved in 700 mL of dry DMF in a 100 ml three neck flask and 125 mL of TEA was added dropwise into the above solution. And then the mixture was stirred for 8 hours at 90-95° C. The white solid was removed and the mother liquid was concentrated to obtain a red oil (10.9 g). The obtained red oil was dissolved in ethyl acetate and washed with saturated aqueous sodium chloride solution (50, 40, 40 ml) and then with water (40 ml) and dried over MgSO4. The drying agent and ethyl acetate were removed to obtain a brown oil (10.9 g). Yield 43.6%.
Reaction SMILES: [N:1]([O-])=O.[Na+].[NH2:5][C:6]1[CH:7]=[N:8][C:9]2[C:14]([C:15]=1[CH3:16])=[CH:13][C:12]([O:17][CH3:18])=[C:11]([O:19][CH3:20])[CH:10]=2>O.C(O)(=O)C>[CH3:20][O:19][C:11]1[C:12]([O:17][CH3:18])=[CH:13][C:14]2[C:15]3[CH:16]=[N:1][NH:5][C:6]=3[CH:7]=[N:8][C:9]=2[CH:10]=1
Reactant: O=N[O-]
Reactant: COc1cc2ncc(N)c(C)c2cc1OC
Agent: [Na+]
Solvent: CC(=O)O
Solvent: O
Product: COc1cc2ncc3[nH]ncc3c2cc1OC
Temperature: 25 °C
Reaction time: 3 h
Yield: 68.4 %

Procedure:
Sodium nitrite (1.28 g, 18.60 mmol), dissolved in water (2.5 ml), is added to a solution of 3-amino-6,7-dimethoxy-4-methylquinoline (2.70 g, 12.39 mmol) in glacial acetic acid (90 ml). The reaction mixture is stirred at room temperature for 3 h. When the reaction is complete, the mixture is evaporated in vacuo. The residue is taken up in water, filtered and rinsed with water. The filtrate is evaporated to dryness in vacuo. The residue obtained is filtered off with suction a number of times through a little flash silica gel in a frit with cyclohexane/ethyl acetate 4:1 (parts by volume) in order to remove impurities. The filtrate is discarded. The filter cake is subsequently washed with ethyl acetate/0-10% by vol. of ethanol, and the filtrate is evaporated to dryness in vacuo, giving 7,8-dimethoxy-3H-pyrazolo[3,4-c]-quinoline (2.29 g, purity 85%, 8.48 mmol) as a solid. MS: 230.0 (M+H+), TLC (HPTLC): Rf=0.45 (ethyl acetate/ethanol 8:1, parts by volume).