Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH:1]1([C:4]2[N:9]=[C:8]([C:10]3[NH:31][C:13]4=[N:14][C:15]([N:18]5[CH2:23][CH2:22][CH2:21][C@@H:20]([C:24]([N:26]6[CH2:30][CH2:29][CH2:28][CH2:27]6)=[O:25])[CH2:19]5)=[CH:16][CH:17]=[C:12]4[N:11]=3)[CH:7]=[CH:6][N:5]=2)[CH2:3][CH2:2]1.[B-](F)(F)(F)[F:33].[B-](F)(F)(F)F.C1[N+]2(CCl)CC[N+](F)(CC2)C1>CN(C)C=O>[CH:1]1([C:4]2[N:9]=[C:8]([C:10]3[NH:31][C:13]4=[N:14][C:15]([N:18]5[CH2:23][CH2:22][CH2:21][C@@H:20]([C:24]([N:26]6[CH2:27][CH2:28][CH2:29][CH2:30]6)=[O:25])[CH2:19]5)=[C:16]([F:33])[CH:17]=[C:12]4[N:11]=3)[CH:7]=[CH:6][N:5]=2)[CH2:3][CH2:2]1
Reactant: O=C([C@@H]1CCCN(c2ccc3nc(-c4ccnc(C5CC5)n4)[nH]c3n2)C1)N1CCCC1
Reactant: F[B-](F)(F)F
Agent: F[N+]12CC[N+](CCl)(CC1)CC2
Solvent: CN(C)C=O
Product: O=C([C@@H]1CCCN(c2nc3[nH]c(-c4ccnc(C5CC5)n4)nc3cc2F)C1)N1CCCC1
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
(R)-(1-(2-(2-Cyclopropylpyrimidin-4-yl)-3H-imidazo[4,5-b]pyridin-5-yl)piperidin-3-yl)(pyrrolidin-1-yl)methanone (Example 95, 100 mg, 0.2 mmol) was dissolved in N,N-dimethylformamide. The solution was cooled to 0° C. and Selectfluor (87 mg, 0.2 mmol) was added. The reaction mixture was stirred at 0° C. for 30 min and then at room temperature for 18 h. The reaction mixture was partitioned between ethyl acetate and water. The organics were washed with brine, dried over magnesium sulfate, filtered, and concentrated under reduced pressure. The residue was purified via HPLC to afford the title compound. MS (ESI+) (M+H) 436.2; HPLC retention time 2.72 min (Method A).
Reaction SMILES: C(N(C(C)C)C(C)C)C.[NH2:10][C@@H:11]1[CH2:15][CH2:14][N:13]([C:16]2[C:25]3[C:20](=[CH:21][C:22]([CH3:26])=[CH:23][CH:24]=3)[N:19]=[C:18]([C:27]3[C:32]([F:33])=[CH:31][CH:30]=[CH:29][C:28]=3[OH:34])[N:17]=2)[CH2:12]1.Cl[C:36]([O:38][C@H:39]1[CH2:43][CH2:42][O:41][CH2:40]1)=[O:37]>C1COCC1>[F:33][C:32]1[CH:31]=[CH:30][CH:29]=[C:28]([OH:34])[C:27]=1[C:18]1[N:17]=[C:16]([N:13]2[CH2:14][CH2:15][C@@H:11]([NH:10][C:36](=[O:37])[O:38][C@H:39]3[CH2:43][CH2:42][O:41][CH2:40]3)[CH2:12]2)[C:25]2[C:20](=[CH:21][C:22]([CH3:26])=[CH:23][CH:24]=2)[N:19]=1
Reactant: O=C(Cl)O[C@H]1CCOC1
Reactant: Cc1ccc2c(N3CC[C@@H](N)C3)nc(-c3c(O)cccc3F)nc2c1
Solvent: CCN(C(C)C)C(C)C
Solvent: C1CCOC1
Product: Cc1ccc2c(N3CC[C@@H](NC(=O)O[C@H]4CCOC4)C3)nc(-c3c(O)cccc3F)nc2c1
Temperature: 25 °C
Yield: 88.4 %

Procedure:
At room temperature, N-ethyl-N-isopropylpropan-2-amine (155 mL, 0.88 mmol) was added to a solution of 2-(4-((R)-3-aminopyrrolidin-1-yl)-7-methylquinazolin-2-yl)-3-fluorophenol (150 mg, 0.40 mmol) in THF. The mixture was cooled in an ice bath, and (S)-tetrahydrofuran-3-yl chloroformate (63 mg, 0.42 mmol) was added slowly over a period of 10 minutes. After warming to room temperature, the reaction was quenched with water and extracted twice with CH2Cl2. The combined organic layers were dried over MgSO4, filtered, and concentrated. Purification via silica gel chromatography using 0-10% EtOAc in CH2Cl2/hexanes (1:1) gave (S)-tetrahydrofuran-3-yl(R)-1-(2-(2-fluoro-6-hydroxyphenyl)-7-methylquinazolin-4-yl)pyrrolidin-3-ylcarbamate (160 mg, 84%). LC/MS: m/z 453.3 (M+H)+ at 2.12 min (10%-99% CH3CN (0.035% TFA)/H2O (0.05% TFA)). 1H NMR (400 MHz, DMSOd6) δ 8.18 (d, J=8.6 Hz, 1H), 7.70 (d, J=6.3 Hz, 1H), 7.58 (s, 1H), 7.29-7.38 (m, 2H), 6.76 (d, J=8.3 Hz, 1H), 6.67-6.72 (m, 1H), 5.14 (s, 1H), 4.23-4.24 (m, 1H), 3.99-4.13 (m, 3H), 3.64-3.85 (m, 5H), 2.50 (s, 3H), 2.07-2.22 (m, 2H), 2.00-2.03 (m, 1H), 1.85-1.90 (m, 1H).
Reaction SMILES: [CH2:1](Br)[CH:2]=[CH2:3].[S:5]([O-:9])([O-:8])(=[O:7])=[S:6].[Na+:10].[Na+].C(O)C>O>[CH2:1]([O:8][S:5]([O-:9])(=[O:7])=[S:6])[CH:2]=[CH2:3].[Na+:10]
Reactant: C=CCBr
Reactant: O=S([O-])([O-])=S
Agent: [Na+]
Solvent: O
Solvent: CCO
Product: C=CCOS(=O)([O-])=S

Procedure:
A mixture of allyl bromide (100 g), sodium thiosulphate (212.5 g), ethanol (90 ml) and water (40 ml) was stirred and heated to reflux for 15 minutes, giving a homogeneous solution. The solution was allowed to cool somewhat, and ethanol and water were then evaporated under vacuum. The solid residue was added to absolute ethanol, and the solvent was then evaporated under vacuum to remove more water. The residue was stirred with hot ethanol (800 ml), and the suspension thus obtained was filtered. On cooling, the filtrate deposited a white solid (109.2 g). The NMR spectrum of the sold showed that it consisted of 80% by weight of sodium allylthiosulphate, 11% by weight of water and 9% by weight of inorganic salt.
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:18]=[C:17]2[C:12]([C:13]([O:19][C:20]3[C:26]([CH3:27])=[CH:25][C:23]([NH2:24])=[C:22]([CH3:28])[CH:21]=3)=[CH:14][CH:15]=[N:16]2)=[CH:11][C:10]=1[O:29][CH3:30])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH3:31][O:32][C:33]1[CH:38]=[CH:37][CH:36]=[CH:35][C:34]=1[N:39]=[C:40]=[O:41]>C(Cl)(Cl)Cl>[CH2:1]([O:8][C:9]1[CH:18]=[C:17]2[C:12]([C:13]([O:19][C:20]3[C:26]([CH3:27])=[CH:25][C:23]([NH:24][C:40]([NH:39][C:34]4[CH:35]=[CH:36][CH:37]=[CH:38][C:33]=4[O:32][CH3:31])=[O:41])=[C:22]([CH3:28])[CH:21]=3)=[CH:14][CH:15]=[N:16]2)=[CH:11][C:10]=1[O:29][CH3:30])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: COc1ccccc1N=C=O
Reactant: COc1cc2c(Oc3cc(C)c(N)cc3C)ccnc2cc1OCc1ccccc1
Solvent: ClC(Cl)Cl
Product: COc1ccccc1NC(=O)Nc1cc(C)c(Oc2ccnc3cc(OCc4ccccc4)c(OC)cc23)cc1C
Temperature: 70 °C
Reaction time: 8 h
Yield: 89 %

Procedure:
4-{[7-(Benzyloxy)-6-methoxy-4-quinolyl]oxy}-2,5-dimethylaniline (300 mg) was dissolved in chloroform (5 ml). 2-Methoxyphenyl isocyanate (0.24 ml) was then added to the solution, and the mixture was stirred at 70° C. overnight. The reaction solution was purified by chromatography on silica gel by development with chloroform/acetone (75/25) to give 365 mg (yield 89%) of the title compound. 1H-NMR (CDCl3, 400 MHz): δ 2.17 (s, 3H), 2.28 (s, 3H), 3.83 (s, 3H), 4.07 (s, 3H), 5.33 (s, 2H), 6.26 (s, 3H), 6.29 (d, J=5.4 Hz, 1H), 6.86-7.06 (m, 4H), 7.12 (s, 1H), 7.30-7.41 (m, 3H), 7.46 (s, 1H), 7.50-7.56 (m, 3H), 7.61 (s, 1H), 8.11-8.16 (m, 1H), 8.43 (d, J=5.4 Hz, 1H)
Reaction SMILES: C([Li])CCC.C[Si](C)(C)[NH:8][Si](C)(C)C.[Br:15][C:16]1[S:17][C:18]([C:29]#[N:30])=[C:19]([C:21]2[CH:26]=[CH:25][C:24]([Cl:27])=[CH:23][C:22]=2[Cl:28])[N:20]=1.Cl>C(OCC)C.C1COCC1>[Br:15][C:16]1[S:17][C:18]([C:29](=[NH:8])[NH2:30])=[C:19]([C:21]2[CH:26]=[CH:25][C:24]([Cl:27])=[CH:23][C:22]=2[Cl:28])[N:20]=1
Reactant: C[Si](C)(C)N[Si](C)(C)C
Reactant: N#Cc1sc(Br)nc1-c1ccc(Cl)cc1Cl
Agent: Cl
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: CCOCC
Product: N=C(N)c1sc(Br)nc1-c1ccc(Cl)cc1Cl
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
2.5 M n-Butyllithium in hexanes (1.20 mL, 2.99 mmol) was added dropwise to a solution of hexamethyldisilazane (0.61 mL, 2.9 mmol) in diethylether (5 mL) at 0° C. The mixture was stirred for 30 mins at 0° C. and 2-bromo-4-(2,4-dichlorophenyl)-1,3-thiazole-5-carbonitrile (400 mg, 1.0 mmol) in THF (50 mL) was added. After stirring at rt for 2 hours LCMS indicated complete conversion. The reaction mixture was poured to a cold 2N HCl (10 ml) and was extracted with diethylether (2×20 mL). The aqueous phase was adjusted to pH˜10 with NH4OH and was extracted with DCM (3×30 mL). Combined DCM extracts were dried over Na2SO4, filtered and evaporated under reduced pressure to afford the title compound which was used directly in the next step (0.360 g, 80%). LCMS: (FA) ES+, 350, 352, 354.
Reaction SMILES: [F:1][C:2]1[CH:9]=[CH:8][C:5]([CH2:6][NH2:7])=[CH:4][CH:3]=1.C([O:14][C:15]([C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=1[C:23]1[CH:28]=[CH:27][C:26]([CH2:29][N:30]2[C:38]3[C:33](=[CH:34][C:35]([C:39](O)=[O:40])=[CH:36][CH:37]=3)[C:32]([CH3:42])=[C:31]2[CH3:43])=[CH:25][CH:24]=1)=[O:16])(C)(C)C>>[F:1][C:2]1[CH:9]=[CH:8][C:5]([CH2:6][NH:7][C:39]([C:35]2[CH:34]=[C:33]3[C:38](=[CH:37][CH:36]=2)[N:30]([CH2:29][C:26]2[CH:25]=[CH:24][C:23]([C:18]4[C:17]([C:15]([OH:16])=[O:14])=[CH:22][CH:21]=[CH:20][CH:19]=4)=[CH:28][CH:27]=2)[C:31]([CH3:43])=[C:32]3[CH3:42])=[O:40])=[CH:4][CH:3]=1
Reactant: NCc1ccc(F)cc1
Reactant: Cc1c(C)n(Cc2ccc(-c3ccccc3C(=O)OC(C)(C)C)cc2)c2ccc(C(=O)O)cc12
Product: Cc1c(C)n(Cc2ccc(-c3ccccc3C(=O)O)cc2)c2ccc(C(=O)NCc3ccc(F)cc3)cc12

Procedure:
The title compound was prepared following the same general protocol as described in Steps 8-9, Example 1, using 4-fluorobenzylamine and 1-((2′-(tert-butoxycarbonyl)biphenyl-4-yl)methyl)-2,3-dimethyl-1H-indole-5-carboxylic acid.
Reaction SMILES: [N-:1]=[N+:2]=[N-:3].[Na+].[F:5][C:6]1[CH:11]=[CH:10][C:9](/[CH:12]=[CH:13]/[N+]([O-])=O)=[CH:8][CH:7]=1>CS(C)=O>[F:5][C:6]1[CH:11]=[CH:10][C:9]([C:12]2[N:1]=[N:2][NH:3][CH:13]=2)=[CH:8][CH:7]=1
Reactant: O=[N+]([O-])/C=C/c1ccc(F)cc1
Reactant: [N-]=[N+]=[N-]
Agent: [Na+]
Solvent: CS(C)=O
Product: Fc1ccc(-c2c[nH]nn2)cc1
Temperature: 25 °C
Reaction time: 14 h
Yield: 30.8 %

Procedure:
Sodium azide (4.28 g, 65.8 mmol) was added to a solution (E)-1-fluoro-4-(2-nitro-vinyl)-benzene (1.00 g, 5.98 mmol) in DMSO (50 mL), the solution was stirred at room temperature for 14 hours and the reaction mixture was poured onto water. The aqueous phase was extracted with AcOEt. The organic phase was washed with saturated solution of NaHCO3, brine, dried over MgSO4, filtered and evaporated to yield 300 mg (1.84 mmol, 31%) of 4-(4-fluoro-phenyl)-1H-[1,2,3]triazole.
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([NH:8][CH2:9][C:10]2[CH:15]=[CH:14][C:13]([Cl:16])=[C:12]([Cl:17])[CH:11]=2)[CH:5]=[N:4][CH:3]=1.[CH3:18][O:19][C:20]1[CH:25]=[C:24](B2OC(C)(C)C(C)(C)O2)[CH:23]=[CH:22][C:21]=1[OH:35]>>[Cl:17][C:12]1[CH:11]=[C:10]([CH:15]=[CH:14][C:13]=1[Cl:16])[CH2:9][NH:8][C:6]1[N:7]=[C:2]([C:24]2[CH:23]=[CH:22][C:21]([OH:35])=[C:20]([O:19][CH3:18])[CH:25]=2)[CH:3]=[N:4][CH:5]=1
Reactant: COc1cc(B2OC(C)(C)C(C)(C)O2)ccc1O
Reactant: Clc1cncc(NCc2ccc(Cl)c(Cl)c2)n1
Product: COc1cc(-c2cncc(NCc3ccc(Cl)c(Cl)c3)n2)ccc1O
Yield: 57 %

Procedure:
In a procedure analogous to Example 22, reaction of 6-chloro-N-(3,4-dichlorobenzyl)pyrazin-2-amine and 2-methoxy-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenol furnished the product (57%).
Reaction SMILES: F[C:2]1[CH:9]=[CH:8][C:5]([C:6]#[N:7])=[C:4]([C:10]([F:13])([F:12])[F:11])[CH:3]=1.[CH3:14][C:15]1([CH3:22])[NH:19][C:18](=[O:20])[NH:17][C:16]1=[O:21].C([O-])([O-])=O.[K+].[K+].O>CN(C=O)C>[CH3:14][C:15]1([CH3:22])[C:16](=[O:21])[N:17]([C:2]2[CH:9]=[CH:8][C:5]([C:6]#[N:7])=[C:4]([C:10]([F:13])([F:12])[F:11])[CH:3]=2)[C:18](=[O:20])[NH:19]1
Reactant: N#Cc1ccc(F)cc1C(F)(F)F
Reactant: CC1(C)NC(=O)NC1=O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: CC1(C)NC(=O)N(c2ccc(C#N)c(C(F)(F)F)c2)C1=O
Yield: 46 %

Procedure:
A mixture of 4-fluoro-2-(trifluoromethyl)benzonitrile (5.67 mg, 30 mmoles), 5,5-dimethyl-hydantoin (7.68 g, 60 mmoles), K2CO3 (8.28 g, 60 mmoles) in DMF (45 ml) is distributed in equal parts into three tubes to be placed in a microwave oven. Under magnetic stirring, each tube is irradiated at 140° C. for 20 minutes. The reaction masses are then combined, poured into water (200 ml) and extracted with AcOEt (2×75 ml). The organic phases are combined, washed with salt water, dried over Na2SO4 and filtered. The filtrate is concentrated under reduced pressure and the residue crystallized from Et20 (25 ml). After recrystallization from EtOH (75 ml), the powder is filtered and dried under vacuum. The expected compound is obtained in the form of a white solid with a yield of 46% (4.1 g). Melting point: 212-213° C.
Reaction SMILES: [CH3:1][C:2]1[O:3][CH2:4][C:5]([CH3:8])([CH3:7])[N:6]=1.[Cl:9][C:10]1[CH:17]=[CH:16][C:13]([CH:14]=O)=[CH:12][CH:11]=1>>[Cl:9][C:10]1[CH:17]=[CH:16][C:13]([CH:14]=[CH:1][C:2]2[O:3][CH2:4][C:5]([CH3:8])([CH3:7])[N:6]=2)=[CH:12][CH:11]=1
Reactant: CC1=NC(C)(C)CO1
Reactant: O=Cc1ccc(Cl)cc1
Product: CC1(C)COC(C=Cc2ccc(Cl)cc2)=N1

Procedure:
2-(2-p-Chlorophenylethenyl)-4,4-dimethyl-2-oxazoline (P-1581) was synthesized from 2,4,4-trimethyl-2-oxazoline and p-chlorobenzaldehyde.
Reaction SMILES: Cl[CH2:2][CH2:3][CH2:4][CH2:5][O:6][CH3:7].[Mg].[CH:9]12[CH2:15][CH:12]([CH:13]=[CH:14]1)[CH2:11][CH:10]2[CH:16]=[O:17].Cl>O1CCCC1.O>[OH:17][CH:16]([CH:10]1[CH2:11][CH:12]2[CH2:15][CH:9]1[CH:14]=[CH:13]2)[CH2:2][CH2:3][CH2:4][CH2:5][O:6][CH3:7]
Reactant: COCCCCCl
Reactant: O=CC1CC2C=CC1C2
Agent: Cl
Agent: [Mg]
Solvent: O
Solvent: C1CCOC1
Product: COCCCCC(O)C1CC2C=CC1C2
Reaction time: 2 h
Yield: 75.4 %

Procedure:
In 300 g of tetrahydrofuran was dissolved 122.6 g of 1-chloro-4-methoxybutane. The solution was added dropwise to 24.3 g of metallic magnesium over 2 hours and below 60° C. Agitation was continued for 2 hours at room temperature. To the solution, 122.2 g of 5-norbornene-2-carbaldehyde was added dropwise over one hour and below 50° C. Agitation was continued for one hour at room temperature to drive the reaction to completion. Then 300 g of water and 44 g of 20% HCl were added to the solution, which was agitated. Extraction with 500 g of hexane gave the organic layer, which was washed with water, dried over anhydrous sodium sulfate, filtered, and concentrated in vacuum. The oily matter thus obtained was distilled in vacuum, obtaining 158.6 g of 5-(1-hydroxy-5-methoxypentyl)-2-norbornene. The yield was 75.4%.
Reaction SMILES: [S:1]([OH:11])(=[O:10])([C:3]1[CH:8]=[CH:7][C:6]([NH2:9])=[CH:5][CH:4]=1)=[O:2].Cl[C:13]1[C:22]2[C:17](=[CH:18][C:19]([C:23]([F:26])([F:25])[F:24])=[CH:20][CH:21]=2)[N:16]=[CH:15][N:14]=1>C(O)C>[F:26][C:23]([F:24])([F:25])[C:19]1[CH:18]=[C:17]2[C:22]([C:13]([NH:9][C:6]3[CH:5]=[CH:4][C:3]([S:1]([OH:11])(=[O:10])=[O:2])=[CH:8][CH:7]=3)=[N:14][CH:15]=[N:16]2)=[CH:21][CH:20]=1
Reactant: Nc1ccc(S(=O)(=O)O)cc1
Reactant: FC(F)(F)c1ccc2c(Cl)ncnc2c1
Solvent: CCO
Product: O=S(=O)(O)c1ccc(Nc2ncnc3cc(C(F)(F)F)ccc23)cc1

Procedure:
0.8 grams of sulphanilic acid and an equimolar quantity of 4-chloro-7-trifluoromethylquinazoline were heated in 20 ml of 50% aqueous ethanol at 100° C. for 2 hours. The suspension was cooled and the solid was filtered off, washed with water and dried to give 1.03 g of the title compound. The sulphonyl chloride hydrochloride derivative for use in part (b) below was prepared in similar manner to Examples 1 and 2.
Reaction SMILES: [F:1][CH2:2][CH2:3][CH2:4]O.CC(OI1(OC(C)=O)(OC(C)=O)OC(=O)C2C=CC=CC1=2)=O.[CH3:28][O:29][C:30]1[CH:49]=[CH:48][C:33]2[N:34]=[C:35]3[N:40]=[C:39]([C:41]4[CH:47]=[CH:46][C:44]([NH2:45])=[CH:43][CH:42]=4)[CH:38]=[CH:37][N:36]3[C:32]=2[CH:31]=1.[BH-](OC(C)=O)(OC(C)=O)OC(C)=O.[Na+]>ClCCCl.C(Cl)Cl>[F:1][CH2:2][CH2:3][CH2:4][NH:45][C:44]1[CH:46]=[CH:47][C:41]([C:39]2[CH:38]=[CH:37][N:36]3[C:32]4[CH:31]=[C:30]([O:29][CH3:28])[CH:49]=[CH:48][C:33]=4[N:34]=[C:35]3[N:40]=2)=[CH:42][CH:43]=1
Reactant: OCCCF
Reactant: COc1ccc2nc3nc(-c4ccc(N)cc4)ccn3c2c1
Agent: CC(=O)OI1(OC(C)=O)(OC(C)=O)OC(=O)c2ccccc21
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: ClCCl
Solvent: ClCCCl
Product: COc1ccc2nc3nc(-c4ccc(NCCCF)cc4)ccn3c2c1
Temperature: 25 °C
Reaction time: 1 h
Yield: 83.9 %

Procedure:
To a stirred solution of 3-fluoropropan-1-ol (5 mg, 0.05 mmol) in 0.3 mL o DCM at rt was added Dess-Martin reagent (42 mg, 0.1 mmol). The mixture was stirred for 1 h at rt and 0.3 mL of DCE was added. It was filtered through a cotton pad into a stirred mixture of 4-(7-methoxybenzo[4,5]imidazo[1,2-a]pyrimidin-2-yl)aniline (5 mg, 0.017 mmol, prepared following General Experiment Procedures Q and R) and NaBH(AcO)3 (42 mg, 0.2 mmol) in 0.3 mL of DCE. The reaction was vigorously stirred for 5 min and quenched by adding Na2CO3 (2 mL, saturated). The mixture was extracted with EtOAc (3×5 mL) and the combined organic phase was washed with water (2×10 mL) and dried over MgSO4 and concentrated under reduced pressure. The crude product was purified by reversed phase HPLC (TFA buffered water/MeCN) to afford the title compound as an orange solid (5 mg, 53%, TFA salt). MS (ESI) m/z [M+H]+351.
Reaction SMILES: [C:1]([C:3]1[C:4]([NH:13][C:14]2[CH:19]=[CH:18][CH:17]=[C:16]([O:20][CH3:21])[CH:15]=2)=[N:5][NH:6][C:7]=1[N:8]=[CH:9]OCC)#[N:2].[Cl:22][C:23]1[CH:24]=[C:25]([CH:27]=[CH:28][CH:29]=1)[NH2:26]>C(O)C>[Cl:22][C:23]1[CH:24]=[C:25]([N:26]2[C:1](=[NH:2])[C:3]3[C:4]([NH:13][C:14]4[CH:19]=[CH:18][CH:17]=[C:16]([O:20][CH3:21])[CH:15]=4)=[N:5][NH:6][C:7]=3[N:8]=[CH:9]2)[CH:27]=[CH:28][CH:29]=1
Reactant: Nc1cccc(Cl)c1
Reactant: CCOC=Nc1[nH]nc(Nc2cccc(OC)c2)c1C#N
Solvent: CCO
Product: COc1cccc(Nc2n[nH]c3ncn(-c4cccc(Cl)c4)c(=N)c23)c1
Temperature: 25 °C

Procedure:
A mixture of 3.85 g (13.49 mmol) of 4-cyano-5-(ethoxy-methyleneamino)-3-(3-methoxy-phenylamino)-pyrazole, 2.84 ml (27.02 mmol) of 3-chloro-aniline and 75 ml of ethanol is heated under reflux for 2 hours. The reaction mixture is then cooled to RT and filtered. Washing the crystals with ethanol and diethyl ether yields the title compound; m.p. 190-192° C.
Reaction SMILES: [C:1]1([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[C:7]([CH3:11])=[CH:8][CH:9]=O.[CH:18]([NH2:21])([CH3:20])[CH3:19]>CO.[Ni]>[CH:18]([NH:21][CH2:9][CH2:8][CH:7]([C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][C:1]=1[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1)[CH3:11])([CH3:20])[CH3:19]
Reactant: CC(=CC=O)c1ccccc1-c1ccccc1
Reactant: CC(C)N
Agent: [Ni]
Solvent: CO
Product: CC(C)NCCC(C)c1ccccc1-c1ccccc1

Procedure:
A solution of 2.22 g of 3-p-biphenylyl-2-buten-1-al (obtainable by reacting 4-acetylbiphenyl with 2,2-diethoxyethylmagnesium bromide and subsequent treatment with p-toluenesulfonic acid) and 0.6 g of isopropylamine in 25 ml of methanol is heated at 200° for 5 hours in a tube. After cooling, 0.5 g of Raney nickel, moist with methanol, is added and the resulting Schiff's base is hydrogenated for one hour at 100 atms. and 80°. The mixture is cooled and filtered and 1-isopropylamino-3-p-biphenylyl-butane is obtained.
Reaction SMILES: [C:1]([N:4]1[C:13]2[C:8](=[CH:9][C:10]([C:14]3[CH:19]=[CH:18][C:17]([CH2:20][NH:21][CH:22]4[CH2:27][CH2:26][N:25](C(OC(C)(C)C)=O)[CH2:24][CH2:23]4)=[CH:16][CH:15]=3)=[CH:11][CH:12]=2)[C@H:7]([NH:35][C:36]([O:38][CH:39]([CH3:41])[CH3:40])=[O:37])[CH2:6][C@@H:5]1[CH3:42])(=[O:3])[CH3:2].C(O)(C(F)(F)F)=O>ClCCl>[CH3:41][CH:39]([O:38][C:36](=[O:37])[NH:35][C@H:7]1[C:8]2[C:13](=[CH:12][CH:11]=[C:10]([C:14]3[CH:19]=[CH:18][C:17]([CH2:20][NH:21][CH:22]4[CH2:27][CH2:26][NH:25][CH2:24][CH2:23]4)=[CH:16][CH:15]=3)[CH:9]=2)[N:4]([C:1](=[O:3])[CH3:2])[C@@H:5]([CH3:42])[CH2:6]1)[CH3:40]
Reactant: CC(=O)N1c2ccc(-c3ccc(CNC4CCN(C(=O)OC(C)(C)C)CC4)cc3)cc2[C@H](NC(=O)OC(C)C)C[C@@H]1C
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CC(=O)N1c2ccc(-c3ccc(CNC4CCNCC4)cc3)cc2[C@H](NC(=O)OC(C)C)C[C@@H]1C
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 84 %

Procedure:
A solution of 1,1-dimethylethyl 4-[({4-[(2S,4R)-1-acetyl-2-methyl-4-({[(1-methylethyl)oxy]carbonyl}amino)-1,2,3,4-tetrahydro-6-quinolinyl]phenyl}methyl)amino]-1-piperidinecarboxylate (for a preparation see Intermediate 109) (605 mg, 1.045 mmol) in dichloromethane (DCM) (5 mL) was treated with TFA (1 mL, 12.98 mmol) and the resulting mixture was stirred at room temperature for 1.5 h then concentrated in vacuo. The residue was loaded on a 20 G SCX column and eluted with MeOH then with 2N NH3 in MeOH). The ammonia fractions were combined and concentrated in vacuo to give 1-methylethyl((2S,4R)-1-acetyl-2-methyl-6-{4-[(4-piperidinylamino)methyl]phenyl}-1,2,3,4-tetrahydro-4-quinolinyl)carbamate (443 mg, 0.879 mmol, 84%) as a white glassy solid.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]([N+:11]([O-])=O)=[C:7]([CH:10]=1)[CH:8]=[O:9].[H][H]>CO.[Ni]>[NH2:11][C:6]1[CH:5]=[CH:4][C:3]([O:2][CH3:1])=[CH:10][C:7]=1[CH2:8][OH:9]
Reactant: COc1ccc([N+](=O)[O-])c(C=O)c1
Reactant: [H][H]
Agent: [Ni]
Solvent: CO
Product: COc1ccc(N)c(CO)c1

Procedure:
A quantity of 181.2 gm (1 mol) of 5-methoxy-2-nitrobenzaldehyde (prepared by methylation of 2-nitro-5-hydroxy-benzaldehyde with methyl iodide/potassium tert.-butoxide in dimethylsulfoxide) is dissolved in 1.8 liters of methanol, mixed with 50 gm of Raney nickel, and hydrogenated at ambient temperature and at 5 bar. After ten hours, the hydrogen uptake has ended. The catalyst is removed by suction filtration, and the methanol is distilled off.
Reaction SMILES: [H-].[Na+].[OH:3][C@:4]1([C:22]2[CH:27]=[CH:26][C:25]([C:28]3[CH:33]=[CH:32][CH:31]=[CH:30][C:29]=3[CH:34]=[CH2:35])=[CH:24][CH:23]=2)[CH2:8][N:7]([C:9]([O:11][CH2:12][CH2:13][Si:14]([CH3:17])([CH3:16])[CH3:15])=[O:10])[C@H:6]([C:18]([O:20][CH3:21])=[O:19])[CH2:5]1.[CH3:36]I>CN(C=O)C>[CH3:36][O:3][C@:4]1([C:22]2[CH:23]=[CH:24][C:25]([C:28]3[CH:33]=[CH:32][CH:31]=[CH:30][C:29]=3[CH:34]=[CH2:35])=[CH:26][CH:27]=2)[CH2:8][N:7]([C:9]([O:11][CH2:12][CH2:13][Si:14]([CH3:17])([CH3:16])[CH3:15])=[O:10])[C@H:6]([C:18]([O:20][CH3:21])=[O:19])[CH2:5]1
Reactant: C=Cc1ccccc1-c1ccc([C@]2(O)C[C@@H](C(=O)OC)N(C(=O)OCC[Si](C)(C)C)C2)cc1
Reactant: CI
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: C=Cc1ccccc1-c1ccc([C@]2(OC)C[C@@H](C(=O)OC)N(C(=O)OCC[Si](C)(C)C)C2)cc1
Temperature: 0 °C
Reaction time: 3 h
Yield: 31.1 %

Procedure:
Sodium hydride (60% in oil) (0.08 g, 1.925 mmol) was added to a solution of (2S,4R)-2-methyl 1-(2-(trimethylsilyl)ethyl) 4-hydroxy-4-(2′-vinylbiphenyl-4-yl)pyrrolidine-1,2-dicarboxylate (0.5 g, 1.069 mmol) and methyl iodide (0.12 mL, 1.925 mmol) at 0° C. in DMF. This was stirred at 0° C. for 3 hrs. The reaction was then quenched with a saturated NH4Cl solution and ether. The ether layer was washed with brine, dried over MgSO4, filtered and evaporated to give crude material. The crude material was purified by flash chromatography on the Biotage (20-40% EtOAc in hexanes) to give (2S,4R)-2-methyl 1-(2-(trimethylsilyl)ethyl) 4-methoxy-4-(2′-vinylbiphenyl-4-yl)pyrrolidine-1,2-dicarboxylate (160 mg, 31% yield) as a clear oil. LCMS: rt=2.11 min. [M+Na]+=504; Phenomenex-Luna C-18 (5μ) (3.0×50 mm); Solvent A=10% acetonitrile—90% water—0.1% TFA, Solvent B=90% acetonitrile—10% water—0.1% TFA; gradient 0% to 100% solvent B over 2 min. and then hold for 1 min.; 4 mL/min; inj. vol.=5 uL; wavelength=220. 1H NMR (500 MHz, CHLOROFORM-d) δ ppm −0.04-0.13 (m, 9H) 0.95-1.02 (m, 1H) 1.03-1.08 (m, 1H) 2.55 (dd, J=13.12, 8.85 Hz, 1H) 2.76-2.89 (m, 1H) 3.00 (s, 3H) 3.68-3.77 (m, 1H) 3.78 (s, 3H) 3.96-4.09 (m, 1H) 4.20-4.31 (m, 2H) 4.64 (dd, J=8.70, 1.98 Hz, 1H) 5.22 (d, J=11.90 Hz, 1H) 5.72 (d, J=17.40 Hz, 1H) 6.69 (ddd, J=17.40, 10.99, 2.44 Hz, 1H) 7.29 (d, J=7.32 Hz, 1H) 7.32-7.45 (m, 6H) 7.66 (d, J=7.32 Hz, 1H).
Reaction SMILES: [NH2:1][S:2]([C:5]1[CH:10]=[CH:9][C:8]([CH2:11][CH2:12][CH2:13][NH2:14])=[CH:7][CH:6]=1)(=[O:4])=[O:3].[CH2:15]1[O:23][C@@H:16]1[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1>C(#N)C>[OH:23][C@H:16]([C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1)[CH2:15][NH:14][CH2:13][CH2:12][CH2:11][C:8]1[CH:7]=[CH:6][C:5]([S:2]([NH2:1])(=[O:3])=[O:4])=[CH:10][CH:9]=1
Reactant: NCCCc1ccc(S(N)(=O)=O)cc1
Reactant: c1ccc([C@@H]2CO2)cc1
Solvent: CC#N
Product: NS(=O)(=O)c1ccc(CCCNC[C@H](O)c2ccccc2)cc1
Yield: 26.6 %

Procedure:
A mixture of 20.0 g of 3-(4-aminosulphonylphenyl)-propylamine, 16.8 g (R)-styrene oxide and 500 ml of acetonitrile was heated under reflux for 40 hours. The solvent was then evaporated in vacuo and the residue was chromatographed on 1 kg of silica gel, using with chloroform/n-propanol/25% ammonia (1600:100:4). There was isolated 8.3 g of pure p-[3-[[(R)-β-hydroxyphenethyl]amino]propyl]-benzenesulphonamide of melting point 165°-166° (from acetonitrile). [α]D20 =-13.4° (c=1.0% in methanol); UV: ε224 =14710.