Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C[O:2][C:3]([C:5]1[NH:9][N:8]=[C:7]([C:10]2[CH:29]=[CH:28][C:27]([O:30][CH2:31][C:32]3[CH:33]=[N:34][CH:35]=[CH:36][CH:37]=3)=[CH:26][C:11]=2[O:12][C@@H:13]([C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][C:20]=2[CH3:25])[CH2:14][CH2:15][C:16]([OH:18])=[O:17])[CH:6]=1)=O.[NH3:38]>CO>[C:3]([C:5]1[NH:9][N:8]=[C:7]([C:10]2[CH:29]=[CH:28][C:27]([O:30][CH2:31][C:32]3[CH:33]=[N:34][CH:35]=[CH:36][CH:37]=3)=[CH:26][C:11]=2[O:12][C@@H:13]([C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][C:20]=2[CH3:25])[CH2:14][CH2:15][C:16]([OH:18])=[O:17])[CH:6]=1)(=[O:2])[NH2:38]
Reactant: COC(=O)c1cc(-c2ccc(OCc3cccnc3)cc2O[C@H](CCC(=O)O)c2ccccc2C)n[nH]1
Reactant: N
Solvent: CO
Product: Cc1ccccc1[C@@H](CCC(=O)O)Oc1cc(OCc2cccnc2)ccc1-c1cc(C(N)=O)[nH]n1
Reaction time: 8 h

Procedure:
(R)-4-[2-(5-methoxycarbonylpyrazol-3-yl)-5-(3-pyridylmethoxy)phenoxy]-4-(2-methylphenyl)butanoic acid (0.2 g) is dissolved in methanol (20 mL) and concentrated aqueous ammonia (20 mL). After standing at room temperature overnight .the solution is evaporated to dryness and the residue triturated successively with ether and ethyl acetate to give (R)-4-[2-(5-carbamoylpyrazol-3-yl)-5-(3-pyridylmethoxy)-phenoxy]-4-(2-methylphenyl)butanoic acid (0.035 g) as a white powder, mp 180-192° C.
Reaction SMILES: CC(C[AlH]CC(C)C)C.C[O:11][C:12](=O)[C:13]1[CH:18]=[CH:17][CH:16]=[C:15]([O:19][CH:20]([C:24]2[CH:25]=[N:26][C:27]([C:33]3[C:38]([CH2:39][CH3:40])=[CH:37][CH:36]=[CH:35][C:34]=3[CH2:41][CH3:42])=[CH:28][C:29]=2[O:30][CH2:31][CH3:32])[CH2:21][CH2:22][CH3:23])[CH:14]=1>C1COCC1.CCOCC>[CH2:41]([C:34]1[CH:35]=[CH:36][CH:37]=[C:38]([CH2:39][CH3:40])[C:33]=1[C:27]1[N:26]=[CH:25][C:24]([CH:20]([O:19][C:15]2[CH:14]=[C:13]([CH2:12][OH:11])[CH:18]=[CH:17][CH:16]=2)[CH2:21][CH2:22][CH3:23])=[C:29]([O:30][CH2:31][CH3:32])[CH:28]=1)[CH3:42]
Reactant: CCCC(Oc1cccc(C(=O)OC)c1)c1cnc(-c2c(CC)cccc2CC)cc1OCC
Agent: CC(C)C[AlH]CC(C)C
Solvent: CCOCC
Solvent: C1CCOC1
Product: CCCC(Oc1cccc(CO)c1)c1cnc(-c2c(CC)cccc2CC)cc1OCC
Reaction time: 2 h

Procedure:
DIBAL-H (1.5 M in Toluene, 0.3 mL) is added dropwise to a solution of 3-{1-[6-(2,6-diethyl-phenyl)-4-ethoxy-pyridin-3-yl]-butoxy}-benzoic acid methyl ester (80 mg, 0.17 mmol) in THF (3 mL) at room temperature. The reaction mixture is stirred for 2 hours, then diluted with ether (5 mL) and treated with Na2SO4.10H2O. The resulting mixture is stirred for one hour and filtered through Celite. Concentration of the filtrate at reduced pressure gives (3-{1-[6-(2,6-diethyl-phenyl)-4-ethoxy-pyridin-3-yl]-butoxy}-phenyl)-methanol. 1H NMR (CDCl3) 8.53 (s, 1H), 7.10-7.30 (m, 4H), 6.74-6.90 (m, 4H), 5.60 (m, 1H), 4.51 (s, 2H), 4.13 (, 21), 2.47 (s, 1H), 2.24-2.37 (m, 4H), 1.80-2.10 (m, 2H), 1.4-1.6 (m, 1H), 0.90-1.05 (m, 9H).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([NH2:20])[CH:5]=[C:6]([Cl:19])[C:7]=1[CH2:8][C:9]1[CH:18]=[CH:17][C:16]2[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=2)[N:10]=1.[Cl:21][C:22]1[CH:27]=[C:26]([C:28]([F:31])([F:30])[F:29])[CH:25]=[CH:24][C:23]=1[S:32](Cl)(=[O:34])=[O:33]>N1C=CC=CC=1>[Cl:21][C:22]1[CH:27]=[C:26]([C:28]([F:30])([F:29])[F:31])[CH:25]=[CH:24][C:23]=1[S:32]([NH:20][C:4]1[CH:5]=[C:6]([Cl:19])[C:7]([CH2:8][C:9]2[CH:18]=[CH:17][C:16]3[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=3)[N:10]=2)=[C:2]([Cl:1])[CH:3]=1)(=[O:34])=[O:33]
Reactant: O=S(=O)(Cl)c1ccc(C(F)(F)F)cc1Cl
Reactant: Nc1cc(Cl)c(Cc2ccc3ccccc3n2)c(Cl)c1
Solvent: c1ccncc1
Product: O=S(=O)(Nc1cc(Cl)c(Cc2ccc3ccccc3n2)c(Cl)c1)c1ccc(C(F)(F)F)cc1Cl

Procedure:
2-Chloro-N-(3,5-dichloro-4-quinolin-2-ylmethyl-phenyl)4-trifluoromethyl-benzenesulfonamide was synthesized (84%) from 3,5-dichloro-4-quinolin-2-ylmethyl-phenylamine (223), 2-chloro-4-trifluromethylbenzenesulfonyl chloride (Maybridge) and pyridine (EM) in a similar manner as described in Examples 70-91. 1H NMR (400 MHz, DMSO-d6) δ 11.45 (br s, 1H), 8.34 (d, J=8.3 Hz, 1H), 8.24 (d, J=8.5 Hz, 1H), 8.19 (s, 1H), 8.00 (d, J=8.3 Hz, 1H), 7.91 (d, J=8.0 Hz, 1H), 7.76 (d, J=8.3 Hz, 1H), 7.67 (td, J=7.8, 1.3 Hz, 1H), 7.54 (td, J=7.8, 1.0 Hz, 1H), 7.23 (d, J=8.5 Hz, 1H), 7.22 (s, 2H), 4.48 (s, 2H). MS (EI): m/z 543 (M−H).
Reaction SMILES: [CH:1]([Li])([CH2:3][CH3:4])[CH3:2].[F:6][C:7]1[C:12](F)=[C:11]([F:14])[C:10]([F:15])=[C:9]([F:16])[C:8]=1[F:17].C(=O)=O.CC(C)=O>C1CCCCC1>[CH:1]([C:12]1[C:11]([F:14])=[C:10]([F:15])[C:9]([F:16])=[C:8]([F:17])[C:7]=1[F:6])([CH2:3][CH3:4])[CH3:2]
Reactant: Fc1c(F)c(F)c(F)c(F)c1F
Reactant: [Li]C(C)CC
Agent: O=C=O
Solvent: CC(C)=O
Solvent: C1CCCCC1
Product: CCC(C)c1c(F)c(F)c(F)c(F)c1F

Procedure:
A solution of sec-butyl lithium (350 ml; 12% in cyclohexane) was added over a period of 1 hour to a stirred mixture of hexafluorobenzene (80 g) in cyclohexane (750 ml) at a temperature of 0° C. On warming the reaction mixture above 0° C. a violently exothermic reaction took place which was brought under control by external cooling (Cardice-acetone). The reaction mixture was subsequently brought to room temperature (no further reaction occurred) and was quenched with water (600 ml). The organic layer was separated, washed with dilute hydrochloric acid (2N; 2×200 ml) and water (2×200 ml) and dried over anhydrous magnesium sulphate, and afterwards distilled through a 15 cm vigreux column. The fraction distilling at 160°-170° C. was collected to give sec-butylpentafluorobenzene (50.3 g), b.p. 162°-164° C. (760 mm), in the form of a colourless liquid.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]2[O:10][C:9](B(O)O)=[CH:8][C:7]=2[CH:14]=1.I[C:16]1[CH:17]=[CH:18][C:19](=[O:22])[NH:20][CH:21]=1.CCN(CC)CC>CCO.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>[CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]2[O:10][C:9]([C:16]3[CH:17]=[CH:18][C:19]([OH:22])=[N:20][CH:21]=3)=[CH:8][C:7]=2[CH:14]=1
Reactant: O=c1ccc(I)c[nH]1
Reactant: COc1ccc2oc(B(O)O)cc2c1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Solvent: CCO
Solvent: CCN(CC)CC
Product: COc1ccc2oc(-c3ccc(O)nc3)cc2c1
Temperature: 140 °C
Reaction time: 0.17 h
Yield: 8.3 %

Procedure:
5-methoxybenzofuran boronic acid (230 mg, 1.2 mmol), 5-iodo-2-pyridone (221 mg, 1.0 mmol), Pd(PPh3)2Cl2 (17 mg, 0.024 mmol) and NEt3 (317 μL, 2.4 mmol) were mixed in EtOH (10 mL) in a 20 mL microwave vial. The mixture was stirred at 140° C. for 10 min in a microwave reactor. The solvent was removed under vacuum, water was added and the solution was extracted with EtOAc. The organic layer was dried over Na2SO4, filtered and the solvent removed under vacuum. The crude substance was purified by preparative HPLC to afford the title compound as a white solid (20 mg). 1H NMR δ ppm 11.95 (br. s., 1 H) 7.94 (dd, 1 H) 7.88 (s, 1 H) 7.44 (d, 1 H) 7.00-7.20 (m, 2 H) 6.84 (dd, 1 H) 6.48 (d, 1H) 3.78 (s, 3 H); MS m/z 242 (M+H).
Reaction SMILES: [F:1][C:2]([F:18])([F:17])[C:3]1[CH:8]=[CH:7][C:6]([C:9]2[N:14]=[C:13]([CH:15]=[O:16])[CH:12]=[CH:11][CH:10]=2)=[CH:5][CH:4]=1.[CH2:19]([Mg]Br)[CH2:20][CH2:21][CH2:22][CH3:23]>C1(C)C=CC=CC=1.CCOCC>[F:18][C:2]([F:17])([F:1])[C:3]1[CH:4]=[CH:5][C:6]([C:9]2[N:14]=[C:13]([CH:15]([OH:16])[CH2:19][CH2:20][CH2:21][CH2:22][CH3:23])[CH:12]=[CH:11][CH:10]=2)=[CH:7][CH:8]=1
Reactant: O=Cc1cccc(-c2ccc(C(F)(F)F)cc2)n1
Reactant: CCCCC[Mg]Br
Solvent: Cc1ccccc1
Solvent: CCOCC
Product: CCCCCC(O)c1cccc(-c2ccc(C(F)(F)F)cc2)n1
Temperature: 0 °C
Reaction time: 2 h

Procedure:
A solution of 6-[4-(trifluoromethyl)phenyl]-2-pyridinecarbaldehyde (300 mg, 1.19 mmol) in dry toluene (12 mL) under nitrogen was cooled to 0° C. (ice/water bath) and treated with n-pentylmagnesium bromide (0.66 mL of a 2M solution in Et2O, 1.31 mmol) and the resulting mixture was stirred at 0° C. for 2 hours. The reaction was then quenched by the cautious addition of aqueous HCl (2M, 2 mL) and the solvent was removed under vacuum and the residue partitioned between EtOAc (2×50 mL) and aqueous HCl (2M, 50 mL). The organic solution was washed with water (60 mL) then brine (60 mL), dried (MgSO4) and reduced. Purification by SPE (silica, 20 g cartridge) eluting with cyclohexane:EtOAc (gradient 99:1 to 19:1) afforded the title compound as a colourless oil (131 mg).
Reaction SMILES: [CH3:1][S:2]([NH:5][C:6]1[CH:11]=[CH:10][C:9]([N+:12]([O-])=O)=[CH:8][N:7]=1)(=[O:4])=[O:3].[H][H]>CCO.[Pd]>[NH2:12][C:9]1[CH:10]=[CH:11][C:6]([NH:5][S:2]([CH3:1])(=[O:4])=[O:3])=[N:7][CH:8]=1
Reactant: [H][H]
Reactant: CS(=O)(=O)Nc1ccc([N+](=O)[O-])cn1
Agent: [Pd]
Solvent: CCO
Product: CS(=O)(=O)Nc1ccc(N)cn1
Yield: 33.2 %

Procedure:
A solution of the product from Step 2 (0.374 g, 1.72 mmol) in 95% EtOH (90 ml) was treated with 0.5 g of 10% palladium-on-carbon catalyst and hydrogenated at atmospheric pressure. The reaction was stopped when the theoretical amount of hydrogen had been consumed. The mixture was filtered through celite and the solid was extracted with warm (2:1) MeOH--CH2 cl2. The combined extracts and filtrate were concentrated and the residue was crystallized from MeOH to give 0.107 g of the titled product, mp 199°-202° C.
Reaction SMILES: [Cl:1][C:2]1[CH:11]=[C:10]2[C:5]([CH:6]=[CH:7][C:8]([CH3:12])=[N:9]2)=[CH:4][CH:3]=1.C([N-]C(C)C)(C)C.[Li+].[C:21]([C:23]1[CH:24]=[C:25]([CH:28]=[CH:29][CH:30]=1)[CH2:26]Br)#[N:22]>C1COCC1>[Cl:1][C:2]1[CH:11]=[C:10]2[C:5]([CH:6]=[CH:7][C:8]([CH2:12][CH2:26][C:25]3[CH:24]=[C:23]([CH:30]=[CH:29][CH:28]=3)[C:21]#[N:22])=[N:9]2)=[CH:4][CH:3]=1
Reactant: N#Cc1cccc(CBr)c1
Reactant: Cc1ccc2ccc(Cl)cc2n1
Agent: CC(C)[N-]C(C)C
Agent: [Li+]
Solvent: C1CCOC1
Product: N#Cc1cccc(CCc2ccc3ccc(Cl)cc3n2)c1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a solution of 7-chloroquinaldine (17.7 g) in THF (80 mL) at -78° was added a solution of 100 mL lithium diisopropyl amide (LDA) (1M) dropwise. After addition the solution was warmed to -20° and added dropwise to 3-cyanobenzyl bromide (20 g) in THF (80 mL) at 0°. The reaction mixture was stirred 1 hr at 0° and warmed to room temperature (30 min). The mixture was partitioned between pH 7 buffer (25% NH4OAc) and ethyl acetate. The organic layer was dried and evaporated. Flash chromatography of the residue using 30% ether in hexane afforded the title compound.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[C:17]2[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=2)[CH:11]=[C:10]([C:18](O)=[O:19])[N:9]=1.ClC(OCC)=O.[CH:27]([NH:30][CH:31]([CH3:33])[CH3:32])([CH3:29])[CH3:28]>C(N(CC)CC)C>[CH3:28][CH:27]([N:30]([CH:31]([CH3:33])[CH3:32])[C:18]([C:10]1[N:9]=[C:8]([C:3]2[CH:4]=[CH:5][CH:6]=[CH:7][C:2]=2[Cl:1])[C:17]2[C:12]([CH:11]=1)=[CH:13][CH:14]=[CH:15][CH:16]=2)=[O:19])[CH3:29]
Reactant: O=C(O)c1cc2ccccc2c(-c2ccccc2Cl)n1
Reactant: CC(C)NC(C)C
Agent: CCOC(=O)Cl
Solvent: CCN(CC)CC
Product: CC(C)N(C(=O)c1cc2ccccc2c(-c2ccccc2Cl)n1)C(C)C
Yield: 23.2 %

Procedure:
Operations are carried out as for Example 7, starting from 2.83 g of 1-(2-chloro phenyl) isoquinoline 3-carboxylic acid, 1.17 g of triethylamine, 1.25 g of ethyl chloroformate and 1.31 g of di-isopropylamine in 100 ml of chlorofom. 0.85 g of N,N-di(1-methyl ethyl) 1-(2-chloro phenyl) isoquinoline 3-carboxamide, melting at 161° C., is obtained.
Reaction SMILES: [F:1][C:2]([F:30])([F:29])[C:3]1[CH:4]=[C:5]([CH:22]=[C:23]([C:25]([F:28])([F:27])[F:26])[CH:24]=1)[CH2:6][N:7]([CH2:18][CH2:19][CH2:20][OH:21])[C:8](=[O:17])[C:9]1[C:14]([I:15])=[CH:13][CH:12]=[N:11][C:10]=1Cl.[H-].[Na+].O>O1CCCC1>[F:1][C:2]([F:30])([F:29])[C:3]1[CH:4]=[C:5]([CH:22]=[C:23]([C:25]([F:28])([F:27])[F:26])[CH:24]=1)[CH2:6][N:7]1[CH2:18][CH2:19][CH2:20][O:21][C:10]2[N:11]=[CH:12][CH:13]=[C:14]([I:15])[C:9]=2[C:8]1=[O:17]
Reactant: O=C(c1c(I)ccnc1Cl)N(CCCO)Cc1cc(C(F)(F)F)cc(C(F)(F)F)c1
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: O
Product: O=C1c2c(I)ccnc2OCCCN1Cc1cc(C(F)(F)F)cc(C(F)(F)F)c1
Reaction time: 0.5 h
Yield: 41.9 %

Procedure:
N-[3,5-Bis(trifluoromethyl)benzyl]-2-chloro-N-(3-hydroxypropyl)-4-iodonicotinamide (compound of Reference Example 2; 6.86 g) was dissolved in tetrahydrofuran (60 mL). While the resulting solution was chilled on an ice bath, sodium hydride (581 mg, 60% oil suspension) was added, and the mixture was stirred for 30 minutes. The temperature of the mixture was then allowed to rise to room temperature, and the mixture was further stirred for 1 hour. While the reaction mixture was chilled on an ice bath, water was added, and then the resulting mixture was subjected to extraction with ethyl acetate. The resulting extract was washed with a saturated aqueous solution of sodium chloride, and was then dried on anhydrous sodium sulfate. The solvent was removed by distillation to obtain a residue, and then the residue was purified on a silica gel column chromatography (ethyl acetate:n-hexane=2:1) to obtain 5-[3,5-bis(trifluoromethyl)benzyl]-7-iodo6-oxo-2,3,4,5-tetrahydro-6H-pyrido[2,3-b][1,5]oxazocine (2.69 g, 42%).
Reaction SMILES: [OH-].[Na+].Cl.[CH3:4][S:5]([N:8]1[C:21]2[C:16](=[CH:17][CH:18]=[CH:19][CH:20]=2)[C:10]2([CH2:15][CH2:14][NH:13][CH2:12][CH2:11]2)[CH2:9]1)(=[O:7])=[O:6].[S:22]1[C:26]2[CH:27]=[CH:28][CH:29]=[CH:30][C:25]=2[N:24]=[C:23]1[NH:31][C:32](=O)[O:33]C1C=CC=CC=1>CS(C)=O.O>[S:22]1[C:26]2[CH:27]=[CH:28][CH:29]=[CH:30][C:25]=2[N:24]=[C:23]1[NH:31][C:32]([N:13]1[CH2:12][CH2:11][C:10]2([C:16]3[C:21](=[CH:20][CH:19]=[CH:18][CH:17]=3)[N:8]([S:5]([CH3:4])(=[O:6])=[O:7])[CH2:9]2)[CH2:15][CH2:14]1)=[O:33]
Reactant: CS(=O)(=O)N1CC2(CCNCC2)c2ccccc21
Reactant: O=C(Nc1nc2ccccc2s1)Oc1ccccc1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CS(C)=O
Product: CS(=O)(=O)N1CC2(CCN(C(=O)Nc3nc4ccccc4s3)CC2)c2ccccc21
Temperature: 25 °C
Reaction time: 20 h
Yield: 85.2 %

Procedure:
10 M aqueous NaOH solution (75 uL,) was added to a solution of 1-methylsulfonylspiro[indoline-3,4′-piperidine]hydrochloride 2-1(225 mg, 0.74 mmol) in DMSO (2.5 mL). Phenyl N-(2-benzothiazolyl)carbamate 2-2 (200 mg, 0.74 mmol) was added to the mixture, and the resulting mixture was stirred at room temperature for 20 h. The mixture was diluted with water and extracted with EtOAc. The organic extract was washed with dil. NaOH and brine, and dried over Na2SO4. The solvent was evaporated, and the residue was purified by silica gel column chromatography to give 200 (279 mg, 85%) as a colorless amorphous solid.
Reaction SMILES: Br[C:2]1[C:3]([O:8][CH:9]2[CH2:12][CH:11]([NH:13][S:14]([C:17]3[CH:22]=[CH:21][C:20]([CH3:23])=[CH:19][CH:18]=3)(=[O:16])=[O:15])[CH2:10]2)=[N:4][CH:5]=[CH:6][CH:7]=1.CC1(C)C(C)(C)OB([C:32]2[CH2:37][CH2:36][N:35]([C:38]([O:40][C:41]([CH3:44])([CH3:43])[CH3:42])=[O:39])[CH2:34][CH:33]=2)O1>O1CCOCC1.O.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.Cl[Pd]Cl.[Fe+2]>[CH3:23][C:20]1[CH:21]=[CH:22][C:17]([S:14]([NH:13][CH:11]2[CH2:12][CH:9]([O:8][C:3]3[C:2]([C:32]4[CH2:37][CH2:36][N:35]([C:38]([O:40][C:41]([CH3:44])([CH3:43])[CH3:42])=[O:39])[CH2:34][CH:33]=4)=[CH:7][CH:6]=[CH:5][N:4]=3)[CH2:10]2)(=[O:16])=[O:15])=[CH:18][CH:19]=1
Reactant: Cc1ccc(S(=O)(=O)NC2CC(Oc3ncccc3Br)C2)cc1
Reactant: CC(C)(C)OC(=O)N1CC=C(B2OC(C)(C)C(C)(C)O2)CC1
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: c1ccc(P(c2ccccc2)[c-]2cccc2)cc1
Solvent: O
Solvent: C1COCCO1
Product: Cc1ccc(S(=O)(=O)NC2CC(Oc3ncccc3C3=CCN(C(=O)OC(C)(C)C)CC3)C2)cc1
Temperature: 110 °C
Reaction time: 8 h
Yield: 70 %

Procedure:
To a solution of N-(3-((3-bromopyridin-2-yl)oxy)cyclobutyl)-4-methylbenzenesulfonamide (397 mg, 1 mmol), tert-butyl 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-5,6-dihydropyridine-1(2H)-carboxylate (335 mg, 1.1 mmol) and NaCO3 (212 mg, 2 mmol) in 1,4-dioxane (60 mL) and H2O (6 mL) was added Pd(dppf)Cl2 (36.6 mg, 0.05 mmol). The reaction mixture was stirred at 110° C. under N2 overnight. The reaction mixture was filtered through CELITE® and washed with CH2Cl2. The organic layer was concentrated and the crude product was purified by silica gel column to give tert-butyl 2-(3-(4-methylphenylsulfonamido)cyclobutoxy)-5′,6′-dihydro-[3,4′-bipyridine]-1′(2′H)-carboxylate (351 mg, 0.7 mmol, yield 70%). ESI-MS (M+1): 500 calc. for C26H33N3O5S 499.
Reaction SMILES: [CH2:1]=[CH:2][C:3]([N:5]1[CH2:10][C@H:9]([N:11]2[N:15]=[C:14]([C:16]3[CH:17]=[CH:18][C:19]([O:22][C:23]4[CH:24]=[CH:25][CH:26]=[CH:27][CH:28]=4)=[CH:20][CH:21]=3)[C:13]3=[C:29]([NH2:33])[N:30]=[CH:31][N:32]=[C:12]23)[CH2:8][CH2:7][CH2:6]1)=[O:4].[C:34]([O:37][CH2:38][O:39][C:40](ON1C(=O)CCC1=O)=[O:41])(=[O:36])[CH3:35].C([O-])(O)=O.[Na+].O>C(#N)C>[C:34]([O:37][CH2:38][O:39][C:40](=[O:41])[NH:33][C:29]1[N:30]=[CH:31][N:32]=[C:12]2[N:11]([C@@H:9]3[CH2:8][CH2:7][CH2:6][N:5]([C:3](=[O:4])[CH:2]=[CH2:1])[CH2:10]3)[N:15]=[C:14]([C:16]3[CH:17]=[CH:18][C:19]([O:22][C:23]4[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=4)=[CH:20][CH:21]=3)[C:13]=12)(=[O:36])[CH3:35]
Reactant: CC(=O)OCOC(=O)ON1C(=O)CCC1=O
Reactant: C=CC(=O)N1CCC[C@@H](n2nc(-c3ccc(Oc4ccccc4)cc3)c3c(N)ncnc32)C1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Solvent: CC#N
Product: C=CC(=O)N1CCC[C@@H](n2nc(-c3ccc(Oc4ccccc4)cc3)c3c(NC(=O)OCOC(C)=O)ncnc32)C1
Temperature: 20 °C
Reaction time: 8 h

Procedure:
A mixture of ibrutinib (15 mg, 1.0 eq), (2,5-dioxopyrrolidin-1-yl)oxycarbonyloxymethyl acetate (1.5 eq), and NaHCO3 (3.0 eq) in 1:1 water and acetonitrile (0.5 mL) was stirred at 20° C. overnight. The reaction was then purified by reverse-phase (C-18) liquid chromatography using water and acetonitrile as eluents to yield compound (1). MS (ESI): m/z 557.2 (M+H)+.
Reaction SMILES: C(OC(=O)[N:7]([C:17]1[C:22]([O:23][CH3:24])=[CH:21][C:20]([CH:25](O)[C:26]2[C:34]3[C:29](=[N:30][CH:31]=[C:32]([CH3:35])[CH:33]=3)[NH:28][CH:27]=2)=[CH:19][N:18]=1)CC1C=CC(OC)=CC=1)(C)(C)C.C([SiH](CC)CC)C.FC(F)(F)C(O)=O>C(#N)C>[CH3:24][O:23][C:22]1[C:17]([NH2:7])=[N:18][CH:19]=[C:20]([CH2:25][C:26]2[C:34]3[C:29](=[N:30][CH:31]=[C:32]([CH3:35])[CH:33]=3)[NH:28][CH:27]=2)[CH:21]=1
Reactant: COc1ccc(CN(C(=O)OC(C)(C)C)c2ncc(C(O)c3c[nH]c4ncc(C)cc34)cc2OC)cc1
Agent: CC[SiH](CC)CC
Solvent: O=C(O)C(F)(F)F
Solvent: CC#N
Product: COc1cc(Cc2c[nH]c3ncc(C)cc23)cnc1N
Temperature: 25 °C
Reaction time: 18 h

Procedure:
In a round bottom flask, {5-[hydroxy-(5-methyl-1H-pyrrolo[2,3-b]pyridin-3-yl)-methyl]-3-methoxy-pyridin-2-yl}-(4-methoxy-benzyl)-carbamic acid tert-butyl ester (127, 1 equivalent) is combined with 100 mL of acetonitrile, triethylsilane (18 equivalents), and trifluoroacetic acid (18 equivalents). The reaction is heated at reflux for 24 hours, then concentrated under vacuum. The resulting material is dissolved in 40 mL of trifluoroacetic acid and stirred at room temperature for 18 hours. This is concentrated under vacuum and combined with water and sodium bicarbonate, then extracted with ethyl acetate. The organic layer is washed with sodium bicarbonate, water, brine, then dried with magnesium sulfate, filtered and the filtrate is concentrated under vacuum. The resulting material is purified by silica gel column chromatography eluting with ethyl acetate and hexane. Appropriate fractions are combined and concentrated under vacuum to provide the desired compound.
Reaction SMILES: [C:1]([N:4]1[C:13]2[C:8](=[CH:9][C:10]([C:14]3[CH:22]=[CH:21][C:17]([C:18](O)=[O:19])=[CH:16][N:15]=3)=[CH:11][CH:12]=2)[C@H:7]([NH:23][C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][N:25]=2)[CH2:6][C@@H:5]1[CH3:30])(=[O:3])[CH3:2].CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C.[CH3:64][N:65]([CH3:69])[CH2:66][CH2:67][NH2:68]>CN(C=O)C>[C:1]([N:4]1[C:13]2[C:8](=[CH:9][C:10]([C:14]3[CH:22]=[CH:21][C:17]([C:18]([NH:68][CH2:67][CH2:66][N:65]([CH3:69])[CH3:64])=[O:19])=[CH:16][N:15]=3)=[CH:11][CH:12]=2)[C@H:7]([NH:23][C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][N:25]=2)[CH2:6][C@@H:5]1[CH3:30])(=[O:3])[CH3:2]
Reactant: CC(=O)N1c2ccc(-c3ccc(C(=O)O)cn3)cc2[C@H](Nc2ccccn2)C[C@@H]1C
Reactant: CN(C)CCN
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: CC(=O)N1c2ccc(-c3ccc(C(=O)NCCN(C)C)cn3)cc2[C@H](Nc2ccccn2)C[C@@H]1C
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
To a flask charged with 6-((2S,4R)-1-acetyl-2-methyl-4-(pyridin-2-ylamino)-1,2,3,4-tetrahydroquinolin-6-yl)nicotinic acid (for a preparation see Intermediate 28)(50 mg, 0.124 mmol) and HATU (56.7 mg, 0.149 mmol) was added DMF (2 mL) and the resulting mixture was treated with DIPEA (0.065 mL, 0.373 mmol) then after 5 min with N1,N1-dimethylethane-1,2-diamine (21.90 mg, 0.248 mmol. The resulting solution was stirred at room temperature for 30 min then partitioned between EtOAc and saturated NaHCO3. The organic phase was separated and aqueous layer extracted with EtOAc (×2). The combined organic layers were washed with saturated NaHCO3, dried over MgSO4 and concentrated in vacuo. The residue divided into 2 portions and each was purified by MDAP (HpH). The appropriate fractions were collected and concentrated in vacuo. The residue was dissolved in MeOH and concentrated again, then co-evaporated with toluene. The residue were then dissolved in 1,4-dioxane (2 mL) and treated with hydrogen chloride in 1,4-dioxane (4N, 0.5 mL). After 2 min the solvent was evaporated in vacuo and the precipitate formed triturated with Et2O then dried under house vacuum to give 6-((2S,4R)-1-acetyl-2-methyl-4-(pyridin-2-ylamino)-1,2,3,4-tetrahydroquinolin-6-yl)-N-(2-(dimethylamino)ethyl)nicotinamide, as the d-hydrochloride salt (37 mg, 0.068 mmol, 54.6% yield) as a yellow solid. LCMS (HpH, 2 min), Rt=0.81 min, MH+=473.
Reaction SMILES: I.CS[C:4](=[N:18][CH2:19][CH2:20][CH2:21][CH3:22])[NH:5][C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][C:7]=1[N:12]1[CH2:17][CH2:16][O:15][CH2:14][CH2:13]1.[CH3:23][NH2:24]>C(O)C>[CH2:19]([NH:18][C:4]([NH:24][CH3:23])=[N:5][C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][C:7]=1[N:12]1[CH2:17][CH2:16][O:15][CH2:14][CH2:13]1)[CH2:20][CH2:21][CH3:22]
Reactant: CCCCN=C(Nc1ccccc1N1CCOCC1)SC
Reactant: CN
Agent: I
Solvent: CCO
Product: CCCCNC(=Nc1ccccc1N1CCOCC1)NC
Reaction time: 504 h

Procedure:
A mixture of 2-methyl-3-(n-butyl)-1-(2-morpholinophenyl)-2-thiopseudourea hydroiodide (4.0 g) and 33% methylamine in absolute ethanol solution (200 ml) was heated initially for 24 hours at 45° and then left at room temperature for 21 days to yield 1-(n-butyl)-2-(2-morpholinophenyl)-3-methylguanidine as an oil; a solution of which in methanol (25 ml) on treatment with fumaric acid (0.7 g) gave a colourless solid which was recrystallised from a 1:1 mixture of methanol and ether to give 1-(n-butyl)-2-(2-morpholinophenyl)-3-methylguanidine monofumarate (m.p. 170°-172° C.).
Reaction SMILES: [CH2:1]([N:4]1[C:13](=[O:14])[C:12]2[C:7](=[N:8][C:9]([N:15]3[CH:19]=CN=C3)=[N:10][CH:11]=2)[N:6]([CH:20]([CH3:22])[CH3:21])[C:5]1=[O:23])[CH:2]=[CH2:3].NC1[CH:30]=[CH:29][C:28]([N:31]2[CH2:36][CH2:35][N:34]([CH3:37])[CH2:33][CH2:32]2)=[CH:27][CH:26]=1>C(Cl)(Cl)Cl>[CH2:1]([N:4]1[C:13](=[O:14])[C:12]2[C:7](=[N:8][C:9]([NH:15][C:19]3[CH:30]=[CH:29][C:28]([N:31]4[CH2:36][CH2:35][N:34]([CH3:37])[CH2:33][CH2:32]4)=[CH:27][CH:26]=3)=[N:10][CH:11]=2)[N:6]([CH:20]([CH3:22])[CH3:21])[C:5]1=[O:23])[CH:2]=[CH2:3]
Reactant: CN1CCN(c2ccc(N)cc2)CC1
Reactant: C=CCn1c(=O)c2cnc(-n3ccnc3)nc2n(C(C)C)c1=O
Solvent: ClC(Cl)Cl
Product: C=CCn1c(=O)c2cnc(Nc3ccc(N4CCN(C)CC4)cc3)nc2n(C(C)C)c1=O
Temperature: 180 °C
Yield: 60 %

Procedure:
A mixture of 300 mg (0.96 mmol) of 3-allyl-7-(imidazol-1-yl)-1-isopropyl-1H-pyrimido[4,5-d]pyrimidine-2,4-dione and 551 mg (2.88 mmol) of 1-(4-aminophenyl)-4-methylpiperazine is heated at 180° C. for 2 hours. The reaction mixture is cooled, dissolved into chloroform, and chromatographed on silica eluting with 4:96 methanol/chloroform. The resulting material is crystallized from methanol/water to give 251 mg (60%) of the title compound: mp 176-177° C.