Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][C:2]1[N:7]=[C:6]([C:8]2[N:13]=[CH:12][C:11]3[CH:14]=[N:15][NH:16][C:10]=3[CH:9]=2)[CH:5]=[N:4][CH:3]=1.Br[C:18]1[N:23]=[C:22]([N:24]2[CH2:29][CH2:28][CH2:27][C@H:26]([NH:30][C:31](=[O:37])[O:32][C:33]([CH3:36])([CH3:35])[CH3:34])[CH2:25]2)[C:21]([Cl:38])=[N:20][CH:19]=1.CC1(C)C2C(=C(P(C3C=CC=CC=3)C3C=CC=CC=3)C=CC=2)OC2C(P(C3C=CC=CC=3)C3C=CC=CC=3)=CC=CC1=2.CC(C)([O-])C.[Na+]>C1(C)C=CC=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.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd]>[Cl:38][C:21]1[C:22]([N:24]2[CH2:29][CH2:28][CH2:27][C@H:26]([NH:30][C:31](=[O:37])[O:32][C:33]([CH3:35])([CH3:34])[CH3:36])[CH2:25]2)=[N:23][C:18]([N:16]2[C:10]3[CH:9]=[C:8]([C:6]4[CH:5]=[N:4][CH:3]=[C:2]([CH3:1])[N:7]=4)[N:13]=[CH:12][C:11]=3[CH:14]=[N:15]2)=[CH:19][N:20]=1
Reactant: CC(C)(C)OC(=O)N[C@H]1CCCN(c2nc(Br)cnc2Cl)C1
Reactant: Cc1cncc(-c2cc3[nH]ncc3cn2)n1
Agent: [Pd]
Agent: CC(C)(C)[O-]
Agent: CC1(C)c2cccc(P(c3ccccc3)c3ccccc3)c2Oc2c(P(c3ccccc3)c3ccccc3)cccc21
Solvent: Cc1ccccc1
Product: Cc1cncc(-c2cc3c(cn2)cnn3-c2cnc(Cl)c(N3CCC[C@H](NC(=O)OC(C)(C)C)C3)n2)n1
Temperature: 110 °C
Yield: 41.3 %

Procedure:
A mixture of 6-(6-methylpyrazin-2-yl)-1H-pyrazolo[4,3-c]pyridine (110 mg, 0.52 mmol), tert-butyl N-[(3S)-1-(6-bromo-3-chloro-pyrazin-2-yl)-3-piperidyl]carbamate (252 mg, 0.62 mmol), tris(dibenzylideneacetone)dipalladium(0) (47 mg, 0.052 mmol), xantphos (62 mg; 0.10 mmol), and sodium tert-butoxide (103 mg, 1.04 mmol) in toluene 5.0 mL was stirred at 110° C. 18 h. The reaction was filtered through celite. The crude product was purified by flash chromatography (EtOAc/Heptane eluted at 75% EtOAc) to give the desired product 112 mg 41% yield. MS (ESI) m/z: 523.2.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[N:4][CH:5]=[C:6]([Cl:20])[C:7]=1[S:8][C:9]1[S:13][C:12]([C:14](Cl)=[O:15])=[CH:11][C:10]=1[N+:17]([O-:19])=[O:18].[NH2:21][CH2:22][CH2:23][CH2:24][N:25]1[CH2:29][CH2:28][CH2:27][C:26]1=[O:30]>>[Cl:1][C:2]1[CH:3]=[N:4][CH:5]=[C:6]([Cl:20])[C:7]=1[S:8][C:9]1[S:13][C:12]([C:14]([NH:21][CH2:22][CH2:23][CH2:24][N:25]2[CH2:29][CH2:28][CH2:27][C:26]2=[O:30])=[O:15])=[CH:11][C:10]=1[N+:17]([O-:19])=[O:18]
Reactant: NCCCN1CCCC1=O
Reactant: O=C(Cl)c1cc([N+](=O)[O-])c(Sc2c(Cl)cncc2Cl)s1
Product: O=C(NCCCN1CCCC1=O)c1cc([N+](=O)[O-])c(Sc2c(Cl)cncc2Cl)s1

Procedure:
Prepared according to the procedure described for example 50 from 5-[(3,5-dichloro-4-pyridyl)sulfanyl]-4-nitro-thiophene-2-carbonyl chloride (150 mg, 0.41 mmol) and 1-(3-amino-propyl)-2-pyrrolidinone (69 mg, 0.49 mmol). The title compound was obtained as a yellow solid (130 mg, 66% yield). 1H NMR (400 MHz, d6-DMSO) δ: 8.98 (2H, s), 8.32(1H, m), 8.40 (1H, s), 3.33 (1H, m), 3.20 (4H, m), 2.21 (2H, m), 1.90 (2H, m), 1.66 (2H, m). MS m/z: 475.03, 477.05 [M+H]+.
Reaction SMILES: C([O:3][C:4]([C:6]1[S:7][C:8]([C:19]2[CH:24]=[CH:23][C:22]([Cl:25])=[CH:21][CH:20]=2)=[C:9]([C:11]2[CH:16]=[CH:15][C:14]([Cl:17])=[CH:13][C:12]=2[Cl:18])[N:10]=1)=[O:5])C.[OH-].[K+].Cl>CO.O>[Cl:25][C:22]1[CH:21]=[CH:20][C:19]([C:8]2[S:7][C:6]([C:4]([OH:5])=[O:3])=[N:10][C:9]=2[C:11]2[CH:16]=[CH:15][C:14]([Cl:17])=[CH:13][C:12]=2[Cl:18])=[CH:24][CH:23]=1
Reactant: CCOC(=O)c1nc(-c2ccc(Cl)cc2Cl)c(-c2ccc(Cl)cc2)s1
Agent: Cl
Agent: [K+]
Agent: [OH-]
Solvent: CO
Solvent: O
Product: O=C(O)c1nc(-c2ccc(Cl)cc2Cl)c(-c2ccc(Cl)cc2)s1
Yield: 67.8 %

Procedure:
40 Part A; Ethyl-5-(4-chlorophenyl)-4-(2,4-dichlorophenyl)thiazole-2-carboxylate (4.10 gram, 9.93 mmol) is suspended in methanol (75 mL). A solution of KOH (1.98 gram, 30 mmol) in water (75 mL) is added and the resulting mixture is heated at reflux temperature for 2 hours. The resulting yellow solution is allowed to attain room temperature, poured into water and acidified with 1N aqueous HCl to give a white precipitate. This precipitate is collected by filtration and twice washed with water. Drying in vacuo gives 5-(4-chlorophenyl)-4-(2,4-dichlorophenyl)thiazole-2-carboxylic acid as a white solid (2.59 gram, 68% yield). 1H-NMR (200 MHz, DMSO-d6): δ 9.25 (s, 1H), 7.65-7.72 (m, 1H), 7.28-7.52 (m, 6H).
Reaction SMILES: Cl[C:2]1[C:11]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][N:13]=2)=[N:10][C:9]2[C:4](=[CH:5][C:6]([Cl:19])=[C:7]([Cl:18])[CH:8]=2)[N:3]=1.Cl.Cl.[C:22]1([CH:28]([NH2:38])[CH2:29][CH2:30][CH2:31][N:32]2[CH2:37][CH2:36][CH2:35][CH2:34][CH2:33]2)[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1.C(N(CC)CC)C>C1(C)C=CC=CC=1>[Cl:18][C:7]1[CH:8]=[C:9]2[C:4](=[CH:5][C:6]=1[Cl:19])[N:3]=[C:2]([NH:38][CH:28]([C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1)[CH2:29][CH2:30][CH2:31][N:32]1[CH2:33][CH2:34][CH2:35][CH2:36][CH2:37]1)[C:11]([C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][N:13]=1)=[N:10]2
Reactant: NC(CCCN1CCCCC1)c1ccccc1
Reactant: Clc1cc2nc(Cl)c(-c3ccccn3)nc2cc1Cl
Agent: Cl
Solvent: Cc1ccccc1
Solvent: CCN(CC)CC
Product: Clc1cc2nc(NC(CCCN3CCCCC3)c3ccccc3)c(-c3ccccn3)nc2cc1Cl
Yield: 63.3 %

Procedure:
To a solution 2,6,7-trichloro-3-pyridin-2-yl-quinoxaline (0.31 g) and alpha-phenyl-1-piperdine-butylamine dihydrochloride (0.31 g) in toluene (25 mL) was added triethylamine (0.50 mL). The resulting mixture was refluxed under nitrogen atmosphere for 36 hours. After refluxing, the reaction mixture was cooled, filtered, and concentrated under vacuum. The residue was purified by flash chromatography (silica gel, 1:9 methanol/dichloromethane) to give a yellow solid. Recrystallization from methanol and water gave the product as a fluffy yellow powder (0.32 g); mp 125-127° C.
Reaction SMILES: O1[C:5]2([CH2:10][CH2:9][CH:8]([N:11]([CH3:18])[C:12](=[O:17])[C:13]([CH3:16])([CH3:15])[CH3:14])[CH2:7][CH2:6]2)[O:4]CC1.[OH-].[Na+]>Cl>[CH3:14][C:13]([CH3:16])([CH3:15])[C:12]([N:11]([CH3:18])[CH:8]1[CH2:9][CH2:10][C:5](=[O:4])[CH2:6][CH2:7]1)=[O:17]
Reactant: CN(C(=O)C(C)(C)C)C1CCC2(CC1)OCCO2
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Product: CN(C(=O)C(C)(C)C)C1CCC(=O)CC1
Temperature: 25 °C
Reaction time: 1 h
Yield: 70.1 %

Procedure:
To N-(1,4-dioxaspiro[4,5]dec-8-yl)-2,2,N-trimethylpropionamide (12.5 g) was added 6 N hydrochloric acid aqueous solution (50 ml), and stirred at room temperature for 1 hour. After completion of the reaction, 12 N aqueous solution of sodium hydroxide (25 ml) was added thereto, and extracted with ethyl acetate. The organic layer was dried over sodium sulfate, and then the solvent was evaporated. To the obtained residue was added diisopropyl ether, the insoluble matter was collected by filtration, and then dried to give the titled compound (7.25 g) as a white solid. MS (ESI) m/z: 212 (M+H)+.
Reaction SMILES: [C:1]12([S:11](Cl)(=[O:13])=[O:12])[CH2:10][CH:5]3[CH2:6][CH:7]([CH2:9][CH:3]([CH2:4]3)[CH2:2]1)[CH2:8]2.[NH2:15][C@H:16]1[CH2:20][CH2:19][N:18]([CH2:21][CH2:22][C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=2)[CH2:17]1>>[C:23]1([CH2:22][CH2:21][N:18]2[CH2:19][CH2:20][C@H:16]([NH:15][S:11]([C:1]34[CH2:10][CH:5]5[CH2:6][CH:7]([CH2:9][CH:3]([CH2:4]5)[CH2:2]3)[CH2:8]4)(=[O:13])=[O:12])[CH2:17]2)[CH:24]=[CH:25][CH:26]=[CH:27][CH:28]=1
Reactant: O=S(=O)(Cl)C12CC3CC(CC(C3)C1)C2
Reactant: N[C@H]1CCN(CCc2ccccc2)C1
Product: O=S(=O)(N[C@H]1CCN(CCc2ccccc2)C1)C12CC3CC(CC(C3)C1)C2

Procedure:
1-Adamantanesulfonyl chloride and (S)-3-amino-1-(2-phenylethyl)pyrrolidine were reacted under the same conditions as in Example 53 to give (S)-N-(1-(2-phenylethyl)pyrrolidin-3-yl)-1-adamantanesulfonamide.
Reaction SMILES: [CH:1]([C:4]1[CH:5]=[CH:6][C:7]2[C:8]3[CH2:16][N:15]([CH3:17])[CH2:14][CH2:13][C:9]=3[NH:10][C:11]=2[CH:12]=1)([CH3:3])[CH3:2].[H-].[Na+].[CH3:20][C:21]1([C:24]2[CH:29]=[CH:28][N:27]=[CH:26][CH:25]=2)[CH2:23][O:22]1>CN(C=O)C>[CH:1]([C:4]1[CH:5]=[CH:6][C:7]2[C:8]3[CH2:16][N:15]([CH3:17])[CH2:14][CH2:13][C:9]=3[N:10]([CH2:20][C:21]([C:24]3[CH:29]=[CH:28][N:27]=[CH:26][CH:25]=3)([OH:22])[CH3:23])[C:11]=2[CH:12]=1)([CH3:3])[CH3:2]
Reactant: CC(C)c1ccc2c3c([nH]c2c1)CCN(C)C3
Reactant: CC1(c2ccncc2)CO1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CC(C)c1ccc2c3c(n(CC(C)(O)c4ccncc4)c2c1)CCN(C)C3
Temperature: 25 °C
Reaction time: 0.17 h

Procedure:
To a solution of 7-isopropyl-2-methyl-2,3,4,5-tetrahydro-1H-pyrido[4,3-b]indole (500 mg, 2.1 mmol) in DMF (10 mL) was added sodium hydride (252 mg, 6.3 mmol). After stirring for 10 min at RT, 4-(2-methyl-oxiranyl)-pyridine (444 mg, 3.2 mmol) was added and stirring continued for another 16 h. The reaction mixture was poured into ice water and extracted with EtOAc. The organic layer was washed with water, dried over sodium sulfate and concentrated to afford crude product which was re-crystallized in ether and hexane to yield 1-(7-isopropyl-2-methyl-3,4-dihydro-1H-pyrido[4,3-b]indol-5(2H)-yl)-2-(pyridin-4-yl)propan-2-ol. 1H NMR (CD3OD, TFA salt) d (ppm): 8.60 (d, 2H), 8.05 (d, 2H), 7.25 (d, 1H), 6.90 (d, 1H), 6.78 (s, 1H), 4.65 (m, 1H), 4.42 (s, 2H), 4.30 (m, 1H), 3.90 (m, 1H), 3.60 (m, 2H), 3.30 (m, 1H), 3.10 (s, 3H), 2.85 (m, 1H), 1.80 (s, 3H), 1.18 (m, 6H).
Reaction SMILES: [O:1]=[C:2]([CH2:44][CH2:45][O:46][CH2:47][CH2:48][O:49][CH2:50][CH2:51][O:52][CH2:53][CH2:54][O:55][CH2:56][CH2:57][NH:58][C:59](=[O:73])[CH2:60][CH2:61][CH2:62][CH2:63][CH:64]1[CH:71]2[CH:67]([NH:68][C:69](=[O:72])[NH:70]2)[CH2:66][S:65]1)[NH:3][CH2:4][CH2:5][CH2:6][O:7][C:8]1[CH:43]=[CH:42][C:11]([C:12]([C:14]2[CH:19]=[CH:18][C:17]([NH:20][CH2:21][CH2:22][CH2:23][O:24][CH2:25][CH2:26][O:27][CH2:28][CH2:29][O:30][CH2:31][CH2:32][CH2:33][NH:34]C(=O)OC(C)(C)C)=[CH:16][CH:15]=2)=[O:13])=[CH:10][CH:9]=1>C(Cl)Cl.C(O)(C(F)(F)F)=O>[NH2:34][CH2:33][CH2:32][CH2:31][O:30][CH2:29][CH2:28][O:27][CH2:26][CH2:25][O:24][CH2:23][CH2:22][CH2:21][NH:20][C:17]1[CH:16]=[CH:15][C:14]([C:12]([C:11]2[CH:42]=[CH:43][C:8]([O:7][CH2:6][CH2:5][CH2:4][NH:3][C:2](=[O:1])[CH2:44][CH2:45][O:46][CH2:47][CH2:48][O:49][CH2:50][CH2:51][O:52][CH2:53][CH2:54][O:55][CH2:56][CH2:57][NH:58][C:59](=[O:73])[CH2:60][CH2:61][CH2:62][CH2:63][CH:64]3[CH:71]4[CH:67]([NH:68][C:69](=[O:72])[NH:70]4)[CH2:66][S:65]3)=[CH:9][CH:10]=2)=[O:13])=[CH:19][CH:18]=1
Reactant: CC(C)(C)OC(=O)NCCCOCCOCCOCCCNc1ccc(C(=O)c2ccc(OCCCNC(=O)CCOCCOCCOCCOCCNC(=O)CCCCC3SCC4NC(=O)NC43)cc2)cc1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: NCCCOCCOCCOCCCNc1ccc(C(=O)c2ccc(OCCCNC(=O)CCOCCOCCOCCOCCNC(=O)CCCCC3SCC4NC(=O)NC43)cc2)cc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 93.7 %

Procedure:
tert-butyl (3-(2-(2-(3-((4-(4-((5,21-dioxo-25-(2-oxohexahydro-1H-thieno[3,4-d]imidazol-4-yl)-8,11,14,17-tetraoxa-4,20-diazapentacosyl)oxy)benzoyl)phenyl)amino)propoxy)ethoxy)ethoxy)propyl)carbamate (16.1 g, 15.92 mmol) was dissolved in a solution of DCM:TFA (2:1, 96 ml) and the reaction mixture was stirred for ca. 1 h at r.t. Upon completion, reaction was then concentrated under reduced pressure, co-evaporated with toluene, and dried on pump for 5 hs to yield 14.13 g (98% yield) of crude N-(3-(4-(4-((3-(2-(2-(3-aminopropoxy)ethoxy)ethoxy)propyl)amino)benzoyl)phenoxy)propyl)-1-(5-(2-oxohexahydro-1H-thieno[3,4-d]imidazol-4-yl)pentanamido)-3,6,9,12-tetraoxapentadecan-15-amide as yellow oil.
Reaction SMILES: C[O:2][C:3]([C:5]1[N:6]([CH3:16])[C:7]2[C:12]([CH:13]=1)=[CH:11][CH:10]=[C:9]([O:14]C)[CH:8]=2)=[O:4].B(Br)(Br)Br.C(=O)(O)[O-].[Na+].Cl>ClCCl.C(OCC)(=O)C>[OH:14][C:9]1[CH:8]=[C:7]2[C:12]([CH:13]=[C:5]([C:3]([OH:4])=[O:2])[N:6]2[CH3:16])=[CH:11][CH:10]=1
Reactant: COC(=O)c1cc2ccc(OC)cc2n1C
Agent: BrB(Br)Br
Agent: Cl
Agent: O=C([O-])O
Solvent: CCOC(C)=O
Solvent: ClCCl
Product: Cn1c(C(=O)O)cc2ccc(O)cc21
Temperature: -60 °C
Reaction time: 0.75 h

Procedure:
To a flask under nitrogen was added 576 mg (2.63 mM) of 6-Methoxy-1-methyl-1H-indole-2-carboxylic acid methyl ester and 30 ml dichloromethane. The mixture was cooled to −60° C. in dry ice acetone bath and 16 ml 1M boron tribromide in dichloromethane (16 mM) was added. After stirring 45 minutes at −60° C. the mixture was allowed to warm to room temperature and stirred for 5 hours. The mixture was poured into 200 ml saturated sodium bicarbonate solution and stirred for 30 minutes. Hydrochloric acid was added till acidic, ethyl acetate was added and the mixture filtered through a celite plug to remove insoluble solids. The ethyl acetate layer was separated and the aqueous was extracted two more time with ethyl acetate. The combined ethyl acetate layers were dried over magnesium sulfate, filtered and stripped to give 6-Hydroxy-1-methyl-1H-indole-2-carboxylic acid (M/S, ES-, 190.2 M-H)
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][CH:6]=[C:5]([O:9][CH3:10])[C:4]=1[F:11].[Br:12]N1C(=O)CCC1=O.Cl(O)(=O)(=O)=O.CCCCCC>C(Cl)(Cl)(Cl)Cl>[CH3:10][O:9][C:5]1[CH:6]=[CH:7][C:8]([Br:12])=[C:3]([O:2][CH3:1])[C:4]=1[F:11]
Reactant: COc1cccc(OC)c1F
Reactant: O=C1CCC(=O)N1Br
Agent: [O-][Cl+3]([O-])([O-])O
Solvent: CCCCCC
Solvent: ClC(Cl)(Cl)Cl
Product: COc1ccc(Br)c(OC)c1F
Temperature: 25 °C
Reaction time: 1 h
Yield: 95.3 %

Procedure:
2-fluoro resorcinol (prepared according to Patrick, T. B., et al., J. Org. Chem (1986), 51, 3242-4) (12.8 g, 100 mmol), potassium carbonate (42 g, 0.3 mol), and methyl iodide (25 mL, 0.4 mol) were mixed with acetone (300 mL) and refluxed for 6 hrs. The reaction was poured into ice-water (500 mL) and extracted in ethyl acetate (500 mL). The ethyl acetate was washed with water (200 mL×2), and brine (200 mL×1), dried over sodium sulfate, filtered, and solvent was removed to yield 14.2 grams (91%) of 1,3-dimethoxy 2-fluoro benzene. This fluoro-benzene intermediate (23.19 g, 148.5 mmoL), N-bromo succinimide (26.52 g, 149 mmol), and 300 uL of 70% aqueous perchloric acid (Aldrich Chemical, 3.4 mmoL) were mixed in carbon tetrachloride (100 mL) and stirred at room temperature for 1 hour. The mixture was filtered, and solvent was removed to obtain a yellow oil. The oil was subjected to silica-gel chromatography (silica gel, hexane mobile phase) to yield 33.28 grams (95%) of the 1,3-dimethoxy-4-bromo-2-fluorobenzene 12 compound as a yellow oil.
Reaction SMILES: [F:1][C:2]1[C:31]([F:32])=[CH:30][CH:29]=[CH:28][C:3]=1[O:4][C:5]1[CH:10]=[CH:9][C:8]([C:11]2[C:19]3[C:14](=[N:15][CH:16]=[N:17][C:18]=3[NH2:20])[N:13]([CH2:21][C@H:22]3[CH2:26][CH2:25][CH2:24][NH:23]3)[N:12]=2)=[C:7]([F:27])[CH:6]=1.[C:33]([CH2:35][C:36](O)=[O:37])#[N:34].CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F>CN(C)C=O>[NH2:20][C:18]1[N:17]=[CH:16][N:15]=[C:14]2[N:13]([CH2:21][C@H:22]3[CH2:26][CH2:25][CH2:24][N:23]3[C:36](=[O:37])[CH2:35][C:33]#[N:34])[N:12]=[C:11]([C:8]3[CH:9]=[CH:10][C:5]([O:4][C:3]4[CH:28]=[CH:29][CH:30]=[C:31]([F:32])[C:2]=4[F:1])=[CH:6][C:7]=3[F:27])[C:19]=12
Reactant: N#CCC(=O)O
Reactant: Nc1ncnc2c1c(-c1ccc(Oc3cccc(F)c3F)cc1F)nn2C[C@H]1CCCN1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Product: N#CCC(=O)N1CCC[C@@H]1Cn1nc(-c2ccc(Oc3cccc(F)c3F)cc2F)c2c(N)ncnc21
Yield: 78.8 %

Procedure:
A solution of 3-(4-(2,3-difluorophenoxy)-2-fluorophenyl)-1-((R)-pyrrolidin-2-ylmethyl)-1H-pyrazolo[3,4-d]pyrimidin-4-amine (50 mg, 0.12 mmol, 1.00 equiv), 2-cyanoacetic acid (14 mg, 0.18 mmol, 1.50 equiv), HATU (52 mg, 0.18 mmol, 1.5 equiv) and TEA (42 mg, 0.40 mmol, 5.00 equiv) in N,N-dimethylformamide (10 mL) was stirred overnight at 25° C. It was quenched with water (50 mL), which was extracted with EA. The organic layers were combined, washed with brine, dried over sodium sulfate, filtrated and concentrated. The residue was submitted to flash chromatography (SiO2, PE:EtOAc=2:1 to 1:1) to give 48 mg (83%) of 3-((R)-2-((4-amino-3-(4-(2,3-difluorophenoxy)-2-fluorophenyl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl)methyl)pyrrolidin-1-yl)-3-oxopropanenitrile as a yellow solid.
Reaction SMILES: [OH:1][CH:2]1[CH2:6][CH2:5][NH:4][CH2:3]1.C[Si]([N:11]=[C:12]=[O:13])(C)C>C(O)(C)C>[OH:1][CH:2]1[CH2:6][CH2:5][N:4]([C:12]([NH2:11])=[O:13])[CH2:3]1
Reactant: OC1CCNC1
Reactant: C[Si](C)(C)N=C=O
Solvent: CC(C)O
Product: NC(=O)N1CCC(O)C1
Reaction time: 8 h
Yield: 59.6 %

Procedure:
To a stirred solution of 3-hydroxypyrrolidine (1.0 g, 11.48 mmol) in isopropanol (27 mL) at rt was added trimethylsilylisocyanate (2.14 mL, 16.07 mmol) and the resulting solution stirred overnight. The resulting suspension was filtered and the residue washed with isopropanol and dried to give 3-hydroxy-pyrrolidine-1-carboxylic acid amide (0.89 g, 60%); 1H-NMR (300 MHz, d6-DMSO) 5.64 (2H, s), 4.85 (1H, d), 4.21-4.22 (1H, m), 3.22-3.28 (3H, m), 3.06-3.10 (1H, m), 1.79-1.90 (1H, m), 1.67-1.76 (1H, m).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:7]=[CH:8][CH:9]=1)[NH2:6].[N:10]1[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=1[C:16](O)=[O:17].CCN=C=NCCCN(C)C.Cl.CCN(CC)CC.OC1C2N=NNC=2C=CC=1>C(Cl)Cl>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([NH:6][C:16](=[O:17])[C:11]2[CH:12]=[CH:13][CH:14]=[CH:15][N:10]=2)[CH:7]=[CH:8][CH:9]=1
Reactant: COc1cccc(N)c1
Reactant: O=C(O)c1ccccn1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: Oc1cccc2[nH]nnc12
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: COc1cccc(NC(=O)c2ccccn2)c1
Temperature: 50 °C
Reaction time: 12 h
Yield: 90.1 %

Procedure:
According to Scheme 1 Method B: 3-Methoxyaniline (1.62 mmol, 0.18 mL) was added to a solution of picolinic acid (1.62 mmol, 0.20 g), EDCI.HCl (2.44 mmol, 0.47 g), Et3N (3.25 mmol, 0.45 mL), hydroxybenzotriazole (1.95 mmol, 0.30 g) in DCM (6 mL) at room temperature. The reaction mixture was stirred at 50° C. for 12 hours. The organic phase was washed with a saturated solution of NaHCO3 and with brine, was dried over MgSO4, was filtered and was concentrated under reduced pressure. The crude product was purified by flash chromatography over silica gel using cyclohexane/AcOEt (90:10) as eluent to afford N-(3-methoxyphenyl)picolinamide (1.46 mmol, 0.33 g, 90%) as an orange liquid.
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]([C:10]2[O:11][CH:12]=[C:13]([CH2:15][CH2:16][C:17]([C:19]3[C:24]([CH3:25])=[CH:23][CH:22]=[CH:21][N:20]=3)=[O:18])[N:14]=2)[CH:5]=[CH:6][C:7]=1[O:8][CH3:9].N12CCCN=[C:32]1[CH2:31][CH2:30][CH2:29][CH2:28]C2.BrCC1CCC1.O>C(O)C.C(OCC)(=O)C>[CH:29]1([CH2:28][O:1][C:2]2[CH:3]=[C:4]([C:10]3[O:11][CH:12]=[C:13]([CH2:15][CH2:16][C:17]([C:19]4[C:24]([CH3:25])=[CH:23][CH:22]=[CH:21][N:20]=4)=[O:18])[N:14]=3)[CH:5]=[CH:6][C:7]=2[O:8][CH3:9])[CH2:30][CH2:31][CH2:32]1
Reactant: COc1ccc(-c2nc(CCC(=O)c3ncccc3C)co2)cc1O
Reactant: C1CCC2=NCCCN2CC1
Agent: BrCC1CCC1
Solvent: CCOC(C)=O
Solvent: CCO
Solvent: O
Product: COc1ccc(-c2nc(CCC(=O)c3ncccc3C)co2)cc1OCC1CCC1

Procedure:
A 0.15 g quantity of 3-[2-(3-hydroxy-4-methoxy phenyl)oxazol-4-yl]-1-(3-methylpyridin-2-yl)propan-1-one obtained in Example 136 and 0.15 ml of 1,8-diazabicyclo[5,4,0]undec-7-ene were dissolved in 5 ml of ethanol, 0.13 g of (bromomethyl)cyclobutane was added thereto, and the mixture was heated and refluxed overnight. After standing to cool, water was added to the reaction mixture, and ethyl acetate extraction was performed. The extract was washed twice with water, the organic layer was then concentrated under reduced pressure, and the obtained residue was purified by silica gel column chromatography (n-hexane:ethyl acetate=2:1), thereby yielding 90 mg of white powdery 3-[2-(3-cyclobutylmethoxy-4-methoxyphenyl)oxazol-4-yl]-1-(3-methylpyridin-2-yl)propan-1-one.
Reaction SMILES: [I:1][C:2]1[CH:3]=[C:4]2[C:9]3=[C:10]([O:12][CH2:13][N:14]([CH3:15])[N:8]3[CH:7]=[C:6]([C:16]([OH:18])=O)[C:5]2=[O:19])[CH:11]=1.C(N1C=CN=C1)(N1C=CN=C1)=O.[Cl:32][C:33]1[CH:40]=[CH:39][C:36]([CH2:37][NH2:38])=[CH:35][CH:34]=1>O1CCCC1.CCOCC>[Cl:32][C:33]1[CH:40]=[CH:39][C:36]([CH2:37][NH:38][C:16]([C:6]2[C:5](=[O:19])[C:4]3[C:9]4=[C:10]([O:12][CH2:13][N:14]([CH3:15])[N:8]4[CH:7]=2)[CH:11]=[C:2]([I:1])[CH:3]=3)=[O:18])=[CH:35][CH:34]=1
Reactant: NCc1ccc(Cl)cc1
Reactant: CN1COc2cc(I)cc3c(=O)c(C(=O)O)cn1c23
Agent: O=C(n1ccnc1)n1ccnc1
Solvent: CCOCC
Solvent: C1CCOC1
Product: CN1COc2cc(I)cc3c(=O)c(C(=O)NCc4ccc(Cl)cc4)cn1c23
Temperature: 25 °C
Yield: 57 %

Procedure:
A solution of 9-iodo-3-methyl-7-oxo-2,3-dihydro-7H-[1,3,4]oxadiazino[6,5,4-ij]quinoline-6-carboxylic acid (Preparation 31, 0.900 g) in tetrahydrofuran (25 mL) is refluxed with 1,1′-carbonyldiimidazole (0.631 g) for 5 h. The reaction mixture is cooled to room temperature and treated with 4-chlorobenzylamine (0.828 g). The reaction mixture is diluted with ether (75 mL), filtered, and the filtrate is concentrated at reduced pressure. The crude product is purified by chromatography, using 75 g of silica gel packed and eluted with EtOAc/CH2Cl2/heptane (1/4/5), to afford a 57% yield of the title compound. Physical characteristics: 1H NMR (DMSO-d6) δ10.15, 8.67, 8.12, 7.75, 7.37, 5.29, 4.54, 2.98; MS (EI) m/z 495 (M+); HRMS (FAB) m/z 495.9935 (C19H15ClIN3O3+H). Anal. Found: C, 45.97; H, 3.14; N, 8.39.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:53])[C@@H:4]([NH:20][C:21]([CH:23]1[CH2:32][C:31]2[CH:30]=[C:29]3[O:33][CH2:34][C@H:35]([C:37]4[CH:42]=[CH:41][C:40]([O:43][CH2:44][C:45]5[CH:50]=[CH:49][C:48]([Cl:51])=[C:47]([Cl:52])[CH:46]=5)=[CH:39][CH:38]=4)[O:36][C:28]3=[CH:27][C:26]=2[CH2:25][NH:24]1)=[O:22])[CH2:5][C:6]1[CH:11]=[CH:10][C:9]([C:12]2[CH:17]=[CH:16][C:15]([C:18]#[N:19])=[CH:14][CH:13]=2)=[CH:8][CH:7]=1.[C:54]([O:58][C:59](=[O:74])[NH:60][C:61]1[S:62][C:63]2[CH:69]=[C:68]([S:70](Cl)(=[O:72])=[O:71])[CH:67]=[CH:66][C:64]=2[N:65]=1)([CH3:57])([CH3:56])[CH3:55]>>[CH3:1][O:2][C:3](=[O:53])[C@@H:4]([NH:20][C:21]([CH:23]1[CH2:32][C:31]2[CH:30]=[C:29]3[O:33][CH2:34][C@H:35]([C:37]4[CH:42]=[CH:41][C:40]([O:43][CH2:44][C:45]5[CH:50]=[CH:49][C:48]([Cl:51])=[C:47]([Cl:52])[CH:46]=5)=[CH:39][CH:38]=4)[O:36][C:28]3=[CH:27][C:26]=2[CH2:25][N:24]1[S:70]([C:68]1[CH:67]=[CH:66][C:64]2[N:65]=[C:61]([NH:60][C:59]([O:58][C:54]([CH3:55])([CH3:56])[CH3:57])=[O:74])[S:62][C:63]=2[CH:69]=1)(=[O:72])=[O:71])=[O:22])[CH2:5][C:6]1[CH:11]=[CH:10][C:9]([C:12]2[CH:13]=[CH:14][C:15]([C:18]#[N:19])=[CH:16][CH:17]=2)=[CH:8][CH:7]=1
Reactant: CC(C)(C)OC(=O)Nc1nc2ccc(S(=O)(=O)Cl)cc2s1
Reactant: COC(=O)[C@H](Cc1ccc(-c2ccc(C#N)cc2)cc1)NC(=O)C1Cc2cc3c(cc2CN1)O[C@@H](c1ccc(OCc2ccc(Cl)c(Cl)c2)cc1)CO3
Product: COC(=O)[C@H](Cc1ccc(-c2ccc(C#N)cc2)cc1)NC(=O)C1Cc2cc3c(cc2CN1S(=O)(=O)c1ccc2nc(NC(=O)OC(C)(C)C)sc2c1)O[C@@H](c1ccc(OCc2ccc(Cl)c(Cl)c2)cc1)CO3

Procedure:
(S)-3-(4′-Cyano-biphenyl-4-yl)-2-({(S)-3-[4-(3,4-dichloro-benzyloxy)-phenyl]-2,3,6,7,8,9-hexahydro-[1,4]dioxino[2,3-g]isoquinoline-8-carbonyl}-amino)-propionic acid methyl ester (25 mg) was reacted with (6-chlorosulfonyl-benzothiazol-2-yl)-carbamic acid tert-butyl ester to give (S)-2-({(S)-7-(2-tert-butoxycarbonylamino-benzothiazole-6-sulfonyl)-3-[4-(3,4-dichloro-benzyloxy)-phenyl]-2,3,6,7,8,9-hexahydro-[1,4]dioxino[2,3-g]isoquinoline-8-carbonyl}-amino)-3-(4′-cyano-biphenyl-4-yl)-propionic acid methyl ester according to General Procedure E. This product (25 mg) was deprotected and hydrolysed according to General Procedure C and B to give the title compound. LCMS (m/z): 947.