Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([NH:15][C:16]2[C:25]3[C:20](=[CH:21][C:22](F)=[C:23]([O:26][CH2:27][CH2:28][O:29][CH3:30])[CH:24]=3)[N:19]=[CH:18][C:17]=2[C:32]#[N:33])[CH:5]=[CH:6][C:7]=1[S:8][C:9]1[N:10]([CH3:14])[CH:11]=[CH:12][N:13]=1.[CH2:34]([N:36]1[CH2:41][CH2:40][N:39]([CH2:42][CH2:43][CH2:44][OH:45])[CH2:38][CH2:37]1)[CH3:35]>>[Cl:1][C:2]1[CH:3]=[C:4]([NH:15][C:16]2[C:25]3[C:20](=[CH:21][C:22]([O:45][CH2:44][CH2:43][CH2:42][N:39]4[CH2:38][CH2:37][N:36]([CH2:34][CH3:35])[CH2:41][CH2:40]4)=[C:23]([O:26][CH2:27][CH2:28][O:29][CH3:30])[CH:24]=3)[N:19]=[CH:18][C:17]=2[C:32]#[N:33])[CH:5]=[CH:6][C:7]=1[S:8][C:9]1[N:10]([CH3:14])[CH:11]=[CH:12][N:13]=1
Reactant: CCN1CCN(CCCO)CC1
Reactant: COCCOc1cc2c(Nc3ccc(Sc4nccn4C)c(Cl)c3)c(C#N)cnc2cc1F
Product: CCN1CCN(CCCOc2cc3ncc(C#N)c(Nc4ccc(Sc5nccn5C)c(Cl)c4)c3cc2OCCOC)CC1
Yield: 39.3 %

Procedure:
Following the procedure of Example 15, 4-({3-chloro-4-[(1-methyl-1H-imidazol-2-yl)sulfanyl]phenyl}amino)-7-fluoro-6-(2-methoxyethoxy)-3-quinolinecarbonitrile (300 mg, 0.62 mmol) and 1-ethyl-4-(3-hydroxypropyl)piperazine (540 mg, 3.1 mmol) provides 155 mg of 4-({3-chloro-4-[(1-methyl-1H-imidazol-2-yl)sulfanyl]phenyl}amino)-7-[3-(4-ethyl-1-piperazinyl)propoxy]-6-(2-methoxyethoxy)-3-quinolinecarbonitrile, mp 188-190° C.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:29]=[C:28]([O:30][CH3:31])[CH:27]=[CH:26][C:4]=1[CH2:5][N:6]1[C:9](=[O:10])[C@@H:8]([NH:11][C:12](=[O:21])[O:13][CH2:14][C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)[C@H:7]1/[CH:22]=[CH:23]/[O:24]C.[H-].[Na+].[CH3:34][O:35][C:36]1[CH:43]=[CH:42][C:39]([CH2:40]Cl)=[CH:38][CH:37]=1>CN(C=O)C>[CH3:1][O:2][C:3]1[CH:29]=[C:28]([O:30][CH3:31])[CH:27]=[CH:26][C:4]=1[CH2:5][N:6]1[C@H:7]([CH2:22][CH:23]=[O:24])[C@H:8]([N:11]([CH2:40][C:39]2[CH:42]=[CH:43][C:36]([O:35][CH3:34])=[CH:37][CH:38]=2)[C:12](=[O:21])[O:13][CH2:14][C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)[C:9]1=[O:10]
Reactant: COc1ccc(CCl)cc1
Reactant: CO/C=C/[C@@H]1[C@H](NC(=O)OCc2ccccc2)C(=O)N1Cc1ccc(OC)cc1OC
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: COc1ccc(CN(C(=O)OCc2ccccc2)[C@@H]2C(=O)N(Cc3ccc(OC)cc3OC)[C@@H]2CC=O)cc1
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 38 %

Procedure:
To a solution of benzyl ((2R,3S)-1-(2,4-dimethoxybenzyl)-2-((E)-2-methoxyvinyl)-4-oxoazetidin-3-yl)carbamate (example 82, step 1, 1.44 g, 3.38 mmol) in DMF (33.8 ml) at −10° C. (salt-ice bath) was addeds sodium hydride (60%, 162 mg, 4.05 mmol). After stirring for 30 min, p-methoxybenzylchloride (506, μL, 3.71 mmol) was added. After warming to 0° C. and stirring for an additional 30 min, it was quenched with NH4Cl (aq, satd) then diluted with EtOAc and LiCl (5% aq). The layers were separated and aqueous layer was extracted with EtOAc (2×). The combined organic layers washed with LiCl (5% aq), brine, dried over Na2SO4 and concd in vacuo. The crude material was subjected to conditions described in example 82, step 2 then purified via silica gel chromatography (EtOAc-Hept, 0-70%) to afford the title compound (684 mg, 38%). LCMS: Rt=0.97 min, m/z=533.2 (M+1) Method 2m_acidic.
Reaction SMILES: [NH2:1][C:2]([CH3:40])([CH3:39])[CH:3]=[C:4]([C:7]([N:9]1[CH2:13][CH2:12][CH2:11][C@H:10]1[CH2:14][N:15]1[C:19]2=[N:20][CH:21]=[N:22][C:23]([NH2:24])=[C:18]2[C:17]([C:25]2[CH:30]=[CH:29][C:28]([O:31][C:32]3[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=3)=[CH:27][C:26]=2[F:38])=[N:16]1)=[O:8])[C:5]#[N:6].C(=O)([O-])[O-].[K+].[K+].Br[CH2:48][CH2:49][O:50][CH3:51]>CC#N>[NH2:24][C:23]1[N:22]=[CH:21][N:20]=[C:19]2[N:15]([CH2:14][C@@H:10]3[CH2:11][CH2:12][CH2:13][N:9]3[C:7]([C:4](=[CH:3][C:2]([NH:1][CH2:48][CH2:49][O:50][CH3:51])([CH3:40])[CH3:39])[C:5]#[N:6])=[O:8])[N:16]=[C:17]([C:25]3[CH:30]=[CH:29][C:28]([O:31][C:32]4[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=4)=[CH:27][C:26]=3[F:38])[C:18]=12
Reactant: CC(C)(N)C=C(C#N)C(=O)N1CCC[C@H]1Cn1nc(-c2ccc(Oc3ccccc3)cc2F)c2c(N)ncnc21
Reactant: COCCBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: COCCNC(C)(C)C=C(C#N)C(=O)N1CCC[C@H]1Cn1nc(-c2ccc(Oc3ccccc3)cc2F)c2c(N)ncnc21
Temperature: 50 °C
Reaction time: 8 h
Yield: 3.7 %

Procedure:
To a suspension of 4-amino-2-((S)-2-((4-amino-3-(2-fluoro-4-phenoxyphenyl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl)methyl)pyrrolidine-1-carbonyl)-4-methylpent-2-enenitrile (210 mg, 0.39 mmol, 1.0 equiv), KI (130 mg, 0.78 mmol, 2.0 equiv) and potassium carbonate (166 mg, 1.17 mmol, 3.0 equiv) in CH3CN (15 mL) was added 1-bromo-2-methoxyethane (160 mg, 1.17 mmol, 3.0 equiv). The resulting suspension was stirred at 50° C. overnight. The solvent was removed under reduced pressure and then water (20 mL) was added to the residue. The resulting mixture was extracted with ethyl acetate (30 mL*3). The organic layers were combined, washed with brine, dried over sodium sulfate and concentrated. The residue was purified on Prep-HPLC. Conditions: (1#-Pre-HPLC-001(SHIMADZU)): Column, SunFire Prep C18, 19*150 mm 5 um; mobile phase, WATER WITH 0.5% NH4OH and CH3CN (40% CH3CN up to 100% in 20 min); Detector, 254 nm. This resulted in 8.7 mg (3.7%) of the title compound as an off-white solid. MS (ESI, pos. ion) m/z: 599 (M+1) H-NMR (400 MHz, CDCl3, ppm): 8.38 (s, 1H), 7.54 (t, J=8.4, 7.2 Hz, 1H), 7.45 (t, J=7.6, 8.0 Hz, 2H), 7.28-7.25 (m, 1H), 7.13 (d, J=8.0 Hz, 2H), 6.95 (dd, J=8.4, 2.0 Hz, 1H), 6.87 (dd, J=11.2, 2.4 Hz, 1H), 6.77 (s, 1H), 5.42 (brs, 2H), 4.93-4.90 (m, 1H), 4.83-4.82 (m, 1H), 4.70-4.65 (m, 1H), 3.67-3.65 (m, 5H), 3.36 (s, 3H), 3.36-3.31 (m, 1H), 2.20-2.89 (m, 3H), 1.88-1.71 (m, 1H), 1.61-1.51 (m, 4H), 1.35 (s, 3H), 1.33 (s, 3H).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[O:9][CH:10]=[CH:11][CH:12]=2)=[CH:4][CH:3]=1.[C:13]([C:19]([O:21][CH3:22])=[O:20])#[C:14][C:15]([O:17][CH3:18])=[O:16].C(OCC)(=O)C>O>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]23[O:9][CH:10]([CH:11]=[CH:12]2)[C:14]([C:15]([O:17][CH3:18])=[O:16])=[C:13]3[C:19]([O:21][CH3:22])=[O:20])=[CH:6][CH:7]=1
Reactant: COC(=O)C#CC(=O)OC
Reactant: Clc1ccc(-c2ccco2)cc1
Solvent: CCOC(C)=O
Solvent: O
Product: COC(=O)C1=C(C(=O)OC)C2(c3ccc(Cl)cc3)C=CC1O2
Reaction time: 8 h

Procedure:
A mixture of 2-(4-chlorophenyl)furan (prepared according to A.W. Johnson, J. of Chem. Soc. 1946, p 895-99) (0.105 g), and dimethyl acetylenedicarboxylate (0.07 mL) in distilled water (0.25 mL) was placed in a closed vial and subjected to ultrasonic vibration overnight. The reaction temperature at the end of the reaction was between 40 and 50° C. After cooling the Diels-Alder adduct was isolated by extraction with ethyl acetate. The ethyl acetate extract was dried (Na2SO4) and evaporated to dryness in-vacuo to provide almost pure product which was further purified by chromatography on silica gel using 5-10% acetone in n-hexane. The title compound (0.16 g) m.p. 84° C. was isolated from some of the combined fractions: PMR δH (CDCl3): 3.7(s,3H), 3.84 (s, 3H), 5.76 (d, 1H, J=1.2Hz), 7.58-7.29 (m, 5H).
Reaction SMILES: C([O:8][C:9]1[CH:10]=[C:11]([CH:21]=[C:22]([O:24][C@@H:25]([CH3:38])[CH2:26][O:27][Si:28]([CH:35]([CH3:37])[CH3:36])([CH:32]([CH3:34])[CH3:33])[CH:29]([CH3:31])[CH3:30])[CH:23]=1)[C:12]([NH:14][C:15]1[CH:19]=[CH:18][N:17]([CH3:20])[N:16]=1)=[O:13])C1C=CC=CC=1>[Pd].C1COCC1>[OH:8][C:9]1[CH:10]=[C:11]([CH:21]=[C:22]([O:24][C@@H:25]([CH3:38])[CH2:26][O:27][Si:28]([CH:35]([CH3:37])[CH3:36])([CH:29]([CH3:31])[CH3:30])[CH:32]([CH3:33])[CH3:34])[CH:23]=1)[C:12]([NH:14][C:15]1[CH:19]=[CH:18][N:17]([CH3:20])[N:16]=1)=[O:13]
Reactant: CC(C)[Si](OC[C@H](C)Oc1cc(OCc2ccccc2)cc(C(=O)Nc2ccn(C)n2)c1)(C(C)C)C(C)C
Agent: [Pd]
Solvent: C1CCOC1
Product: CC(C)[Si](OC[C@H](C)Oc1cc(O)cc(C(=O)Nc2ccn(C)n2)c1)(C(C)C)C(C)C
Reaction time: 16 h
Yield: 100.6 %

Procedure:
10% Palladium on carbon was added to 3-(benzyloxy)-N-(1-methyl-1H-pyrazol-3-yl)-5-{(1S)-1-methyl-2-[(triisopropylsilyl)oxy]ethoxy}benzamide (21.7 g, 40.4 mmol) in dry THF (480 mL) under argon. The reaction mixture was degassed and placed under a hydrogen balloon and stirred for 16 hours. The atmosphere was replaced with argon and mixture was filtered through diatomaceous earth then the filtrate evaporated and dried under high vacuum for 1 hour to give the title compound (18.2 g). 1H NMR δ (CDCl3): 1.05 (s, 18H), 1.05-1.1 (m, 3H), 1.3 (d, 3H), 3.7 (m, 1H), 3.8 (s, 3H), 3.9 (m, 1H), 4.5 (m, 1H), 6.6 (s, 1H), 6.8 (s, 1H), 7.0 (m, 2H), 7.20 (s, 1H), 7.3 (s, 1H), 8.7 (s, 1H). m/z 448 (M+H)+, 446 (M−H)−
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[CH2:13][CH2:12][N:11](C(OC(C)(C)C)=O)[CH2:10][CH2:9]2)=[CH:4][C:3]=1[NH:21][S:22]([C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1)(=[O:24])=[O:23].[F:31][C:32]1[CH:33]=[CH:34][C:35]([CH3:42])=[C:36]([S:38](Cl)(=[O:40])=[O:39])[CH:37]=1>>[F:31][C:32]1[CH:33]=[CH:34][C:35]([CH3:42])=[C:36]([S:38]([NH:1][C:2]2[CH:7]=[CH:6][C:5]([N:8]3[CH2:13][CH2:12][NH:11][CH2:10][CH2:9]3)=[CH:4][C:3]=2[NH:21][S:22]([C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=2)(=[O:24])=[O:23])(=[O:40])=[O:39])[CH:37]=1
Reactant: Cc1ccc(F)cc1S(=O)(=O)Cl
Reactant: CC(C)(C)OC(=O)N1CCN(c2ccc(N)c(NS(=O)(=O)c3ccccc3)c2)CC1
Product: Cc1ccc(F)cc1S(=O)(=O)Nc1ccc(N2CCNCC2)cc1NS(=O)(=O)c1ccccc1

Procedure:
5-Fluoro-2-methyl-N-[2-[(phenylsulfonyl)amino]-4-(1-piperazinyl)-phenyl]benzenesulfonamide was synthesized from N-{2-amino-5-(4-t-butyloxycarbonyl-piperazinyl)-phenyl}benzenesulfonamide and 5-fluoro-2-methylbenzenesulfonylchloride (50 mg, 0.239 mmol) according to general method 3 to give 60 mg of a purple solid. MS (posES-FIA) m/z=Found: 505.2. Calcd 505.13. 1H-NMR δ 7.73-7.17 (m, 8H), 6.83 (d, 1H), 6.68 (dd, 1H), 6.50 (dd, 1H), 3.27-3.17 (m, 8H), 2.55 (s, 3H).
Reaction SMILES: [NH2:1][C:2]([NH:4][C:5]1[CH:9]=[C:8]([C:10]2[CH:15]=[CH:14][C:13]([O:16][CH2:17][CH2:18][N:19]([CH3:21])[CH3:20])=[CH:12][CH:11]=2)[S:7][C:6]=1[C:22]([NH2:24])=[O:23])=[O:3].ClCCN1CC[CH2:31][CH2:30][CH2:29]1>>[NH2:1][C:2]([NH:4][C:5]1[CH:9]=[C:8]([C:10]2[CH:11]=[CH:12][C:13]([O:16][CH2:17][CH2:18][N:19]3[CH2:21][CH2:31][CH2:30][CH2:29][CH2:20]3)=[CH:14][CH:15]=2)[S:7][C:6]=1[C:22]([NH2:24])=[O:23])=[O:3]
Reactant: CN(C)CCOc1ccc(-c2cc(NC(N)=O)c(C(N)=O)s2)cc1
Reactant: ClCCN1CCCCC1
Product: NC(=O)Nc1cc(-c2ccc(OCCN3CCCCC3)cc2)sc1C(N)=O

Procedure:
Prepared by the method of Example 9(b) using the product of Example 10 (a) and N-(2-chloroethyl)piperidine.
Reaction SMILES: [Br:1][C:2]1[CH:11]=[CH:10][CH:9]=[C:8]2[C:3]=1[CH:4]=[CH:5][C:6](Cl)=[N:7]2.[CH3:13][C:14]1[O:18][C:17]([CH2:19][NH2:20])=[CH:16][CH:15]=1>>[Br:1][C:2]1[CH:11]=[CH:10][CH:9]=[C:8]2[C:3]=1[CH:4]=[CH:5][C:6]([NH:20][CH2:19][C:17]1[O:18][C:14]([CH3:13])=[CH:15][CH:16]=1)=[N:7]2
Reactant: Clc1ccc2c(Br)cccc2n1
Reactant: Cc1ccc(CN)o1
Product: Cc1ccc(CNc2ccc3c(Br)cccc3n2)o1

Procedure:
(5-Bromo-quinolin-2-yl)-(5-methyl-furan-2-ylmethyl)-amine was prepared from 5-bromo-2-chloroquinoline and 5-methyl-2-furanmethanamine as described in example 1 step A.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([C:8]([OH:10])=[O:9])[NH:5][C:6]=1[CH3:7].[F:11][C:12]1[C:17](O)=[C:16]([F:19])[C:15]([F:20])=[C:14]([F:21])[C:13]=1[F:22].C(Cl)CCl>C1COCC1>[Br:1][C:2]1[CH:3]=[C:4]([C:8]([O:10][C:17]2[C:16]([F:19])=[C:15]([F:20])[C:14]([F:21])=[C:13]([F:22])[C:12]=2[F:11])=[O:9])[NH:5][C:6]=1[CH3:7]
Reactant: Oc1c(F)c(F)c(F)c(F)c1F
Reactant: Cc1[nH]c(C(=O)O)cc1Br
Solvent: C1CCOC1
Solvent: ClCCCl
Product: Cc1[nH]c(C(=O)Oc2c(F)c(F)c(F)c(F)c2F)cc1Br
Temperature: 25 °C
Reaction time: 6 h

Procedure:
4-Bromo-5-methyl-1H-pyrrole-2-carboxylic acid (Intermediate 18, 2.16 g, 10.59 mmol) was dissolved an THF (10 ml). Pentafluorophenol and EDC (2.03 g, 10.59 mmol) were added and the mixture was stirred at room temperature for 6 h. The solvent was removed under vacuum and EtOAc (50 ml) was added. The organic phase was washed with water, 10% Na2CO3 (2×25 ml), water (50 ml) and brine (50 ml), dried over Na2SO4 and concentrated in vacuo to give the title compound as an off white solid (2.23 g).
Reaction SMILES: [Cl:1][C:2]1[C:10]([N+:11]([O-])=O)=[CH:9][CH:8]=[C:7]([Cl:14])[C:3]=1[C:4]([OH:6])=[O:5].[NH4+].[Cl-]>C1COCC1.[Zn]>[NH2:11][C:10]1[C:2]([Cl:1])=[C:3]([C:7]([Cl:14])=[CH:8][CH:9]=1)[C:4]([OH:6])=[O:5]
Reactant: O=C(O)c1c(Cl)ccc([N+](=O)[O-])c1Cl
Agent: [Cl-]
Agent: [NH4+]
Agent: [Zn]
Solvent: C1CCOC1
Product: Nc1ccc(Cl)c(C(=O)O)c1Cl
Temperature: 25 °C
Reaction time: 24 h
Yield: 75.5 %

Procedure:
2,6-Dichloro-3-nitrobenzoic acid (2.13 g, 9.03 mmol) was dissolved in 2:1 THF:saturated aqueous NH4Cl and cooled to 0° C. The mixture was treated with zinc (11.8 g, 181 mmol). The reaction mixture was allowed to warm to ambient temperature and stir for 24 hours. The reaction mixture was filtered through GF/F paper while rinsing with THF. The mixture was acidified to a pH of 1 using 1.0M HCl and extracted with 15% 2-propanol:DCM (3×). The extracts were washed with water and brine, dried over sodium sulfate and concentrated to afford 3-amino-2,6-dichlorobenzoic acid (1.40 g, 6.82 mmol, 75.5% yield). MS (APCI-neg) m/z=203.6 (M-H).
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:16])[CH2:5][N:6]1[C:14]2[C:9](=[C:10]([OH:15])[CH:11]=[CH:12][CH:13]=2)[CH:8]=[CH:7]1)[CH3:2].[F:17][C:18]([F:33])([F:32])[O:19][C:20]1[CH:25]=[CH:24][C:23]([C:26]#[C:27][CH2:28][CH2:29][CH2:30]O)=[CH:22][CH:21]=1.CN(C)C(N=NC(N(C)C)=O)=O.C(P(CCCC)CCCC)CCC>>[CH2:1]([O:3][C:4](=[O:16])[CH2:5][N:6]1[C:14]2[C:9](=[C:10]([O:15][CH2:30][CH2:29][CH2:28][C:27]#[C:26][C:23]3[CH:24]=[CH:25][C:20]([O:19][C:18]([F:17])([F:32])[F:33])=[CH:21][CH:22]=3)[CH:11]=[CH:12][CH:13]=2)[CH:8]=[CH:7]1)[CH3:2]
Reactant: OCCCC#Cc1ccc(OC(F)(F)F)cc1
Reactant: CCOC(=O)Cn1ccc2c(O)cccc21
Agent: CCCCP(CCCC)CCCC
Agent: CN(C)C(=O)N=NC(=O)N(C)C
Product: CCOC(=O)Cn1ccc2c(OCCCC#Cc3ccc(OC(F)(F)F)cc3)cccc21

Procedure:
In analogy to the procedure described for example 1 d], (4-hydroxy-indol-1-yl)-acetic acid ethyl ester was reacted with 5-(4-trifluoromethoxy-phenyl)-pent-4-yn-1-ol in the presence of N,N,N′,N′-tetramethyl azodicarboxamide and tributylphosphine to give the title compound as colorless crystals.
Reaction SMILES: [C:1]([C:3]1[CH:8]=[CH:7][C:6]([NH:9][C:10](=[O:18])[CH2:11][CH:12]([CH3:17])[CH2:13][C:14](O)=[O:15])=[CH:5][CH:4]=1)#[N:2].B.C1COCC1.O>C1COCC1>[C:1]([C:3]1[CH:4]=[CH:5][C:6]([NH:9][C:10](=[O:18])[CH2:11][CH:12]([CH3:17])[CH2:13][CH2:14][OH:15])=[CH:7][CH:8]=1)#[N:2]
Reactant: CC(CC(=O)O)CC(=O)Nc1ccc(C#N)cc1
Agent: B
Solvent: O
Solvent: C1CCOC1
Product: CC(CCO)CC(=O)Nc1ccc(C#N)cc1
Temperature: 25 °C
Reaction time: 14 h
Yield: 46.9 %

Procedure:
To a solution of 5-(4-cyanophenylamino)-3-methyl-5-oxopentanoic acid (1.00 g, 4.06 mmol) in THF (15 mL) was added borane-THF complex (1.2M, THF solution 6.77 mL, 8.12 mmol) under ice-cooling. The mixture was stirred at room temperature for 14 hr, and the reaction mixture was poured into water. The mixture was extracted with ethyl acetate, the organic layer was washed with water and saturated brine, and dried, and the solvent was evaporated under reduced pressure. The obtained residue was purified by silica gel column chromatography (solvent gradient; 10 to 100% ethyl acetate/hexane) to give N-(4-cyanophenyl)-5-hydroxy-3-methylpentanamide (0.442 g, 1.904 mmol, 46.9%) as a colorless oil.
Reaction SMILES: Cl[CH2:2][C@H:3]([CH3:15])[CH2:4][O:5][C:6]1[CH:11]=[C:10]([F:12])[C:9]([F:13])=[CH:8][C:7]=1[F:14].[CH3:16][CH:17]([CH3:33])[C:18]([NH:20][C:21]1[CH:26]=[CH:25][CH:24]=[C:23]([CH:27]2[CH2:32][CH2:31][NH:30][CH2:29][CH2:28]2)[CH:22]=1)=[O:19]>>[CH3:16][CH:17]([CH3:33])[C:18]([NH:20][C:21]1[CH:26]=[CH:25][CH:24]=[C:23]([CH:27]2[CH2:32][CH2:31][N:30]([CH2:2][C@H:3]([CH3:15])[CH2:4][O:5][C:6]3[CH:11]=[C:10]([F:12])[C:9]([F:13])=[CH:8][C:7]=3[F:14])[CH2:29][CH2:28]2)[CH:22]=1)=[O:19]
Reactant: C[C@@H](CCl)COc1cc(F)c(F)cc1F
Reactant: CC(C)C(=O)Nc1cccc(C2CCNCC2)c1
Product: CC(C)C(=O)Nc1cccc(C2CCN(C[C@H](C)COc3cc(F)c(F)cc3F)CC2)c1

Procedure:
Prepared by Procedure G and Scheme B1 using 1-{[(2R)-3-chloro-2-methylpropyl]oxy}-2,4,5-trifluorobenzene and 2-methyl-N-[3-(4-piperidinyl)phenyl]propanamide: ESMS m/e: 449.2 (M+H)+.
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][C:8]=2[O:10][CH2:11][CH2:12][OH:13])[CH:3]=[CH:2]1.O1CCOCC1.[H-].[Na+].Cl[C:23]1[C:28]([N:29]2[CH2:34][CH2:33][NH:32][CH2:31][CH2:30]2)=[N:27][CH:26]=[CH:25][N:24]=1>O>[N:29]1([C:28]2[C:23]([O:13][CH2:12][CH2:11][O:10][C:8]3[CH:7]=[CH:6][CH:5]=[C:4]4[C:9]=3[NH:1][CH:2]=[CH:3]4)=[N:24][CH:25]=[CH:26][N:27]=2)[CH2:34][CH2:33][NH:32][CH2:31][CH2:30]1
Reactant: Clc1nccnc1N1CCNCC1
Reactant: OCCOc1cccc2cc[nH]c12
Agent: [H-]
Agent: [Na+]
Solvent: C1COCCO1
Solvent: O
Product: c1cc(OCCOc2nccnc2N2CCNCC2)c2[nH]ccc2c1
Temperature: 100 °C
Reaction time: 3 h
Yield: 81 %

Procedure:
The product obtained in Step 1 above (0.200 g, 1 .13 mmol) and dioxane (4 mL) was placed in a reaction tube and NaH (60% in oil; 0.060 g, 1.50 mmol) was added. When the gas evolution had ceased, 2-chloro-3-(1-piperazinyl)pyrazine (0.228 g, 1.15 mmol. from Example 90, Step 1) was added and the tube sealed. The mixture was stirred at 100° C. for 3 h. After cooling, the reaction mixture was poured into water and extracted with EtOAc. The organic layer was extracted with 0.5 M aqueous HCl. The pH of the aqueous phase was adjusted to pH 11 with NaOH and extracted with EtOAc. The organic layer was dried (MgSO4) and concentrated to give 0.31 g (81%) of the title product. Pos-EI-MS shows M+ and 9 ions supporting the stated structure HRMS m/z calcd for C18H21N5O2 (M)+ 339.1695, found 339 1696.
Reaction SMILES: [O:1]=[C:2]([CH3:27])[CH:3]=C1CCP(C2C=CC=CC=2)C1(C1C=CC=CC=1)C1C=CC=CC=1.[CH:28]([C:30]1[C:31]([CH3:44])=[C:32]([CH:37]=[CH:38][C:39]=1[S:40]([CH3:43])(=[O:42])=[O:41])[C:33]([O:35][CH3:36])=[O:34])=O>C1C=CC=CC=1>[CH3:43][S:40]([C:39]1[CH:38]=[CH:37][C:32]([C:33]([O:35][CH3:36])=[O:34])=[C:31]([CH3:44])[C:30]=1[CH:28]=[CH:3][C:2](=[O:1])[CH3:27])(=[O:42])=[O:41]
Reactant: CC(=O)C=C1CCP(c2ccccc2)C1(c1ccccc1)c1ccccc1
Reactant: COC(=O)c1ccc(S(C)(=O)=O)c(C=O)c1C
Solvent: c1ccccc1
Product: COC(=O)c1ccc(S(C)(=O)=O)c(C=CC(C)=O)c1C
Reaction time: 1 h

Procedure:
30 ml of benzene and then 3.85 g (0.012 mol) of 2-oxopropylidenetri phenylphospholane were added to 3.1 g (0.012 mol) of methyl 3-formyl-4-methanesulfonyl-2-methylbenzoate, followed by stirring for 1 hour under heating reflux. After the solution was allowed to cool, insoluble substance was removed by filtration, and the solvent was concentrated under reduced pressure to obtain methyl 4-methanesulfonyl-3-(3-oxo-1-butenyl)-2-methylbenzoate. Methyl 4-methanesulfonyl-3-(3-oxo-1-butenyl)-2-methylbenzoate thus obtained was dissolved in a solvent of 10 ml of ethanol and 10 ml of pyridine, and 1.1 g (0.016 mol) of hydroxyamine hydrochloride was added, followed by stirring for 1 hour under heating reflux. The resulting reaction mixture was poured into ice water, and extraction was carried out with ethyl acetate. Afterward, the resulting ethyl acetate layer was washed with 1N hydrochloric acid and subsequently with saturated sodium chloride solution, and then dried over anhydrous magnesium sulfate. Next, the solvent was distilled off under reduced pressure. The thus obtained methyl 4-methanesulfonyl-3-(3-hydroxyimino-1-butenyl)-2-methylbenzoate was dissolved in 15 ml of THF, and 15 ml of water containing 1.4 g (0.017 mol) of sodium hydrogencarbonate was added to the solution. Next, an aqueous solution obtained by dissolving 2.5 g (0.015 mol) of potassium iodide and 1.1 g (0.05 mol) of iodine in 12 ml of water was added, and the solution was heated under reflux for 3 hours under a condition that light was blocked. The reaction mixture was poured into ice water, and sodium hydrogen sulfite was then added, followed by extraction with ethyl acetate. The resulting organic layer was washed with a saturated sodium chloride solution, and then dried over anhydrous magnesium sulfate. Next, the solvent was distilled off under reduced pressure. The resulting residue was purified through silica gel column chromatography to obtain 0.84 g of methyl 4-methanesulfonyl-2-methyl-3-(3-methyl-1,2-isoxazol-5-yl)benzoate. Yield=23%.
Reaction SMILES: [CH3:1][C:2]1[C:3](=O)[NH:4][N:5]=[C:6]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)[CH:7]=1.P(Cl)(Cl)([Cl:17])=O>>[Cl:17][C:3]1[N:4]=[N:5][C:6]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)=[CH:7][C:2]=1[CH3:1]
Reactant: Cc1cc(-c2ccccc2)n[nH]c1=O
Reactant: O=P(Cl)(Cl)Cl
Product: Cc1cc(-c2ccccc2)nnc1Cl

Procedure:
A mixture of 13.2 g. of 4-methyl-6-phenyl-3(2H)-pyridazinone and 200 ml. of phosphorus oxychloride is heated on a steam bath for 18 hours. The reaction mixture is filtered. The filtrate is concentrated free of excess phosphorus oxychloride. The residue is stirred with ice water and filtered. The solid is washed with water and air dried giving 3-chloro-4-methyl-6-phenylpyridazine as a cream colored solid.
Reaction SMILES: [NH2:1][C:2]1[S:3][C:4]([CH3:10])=[C:5]([CH3:9])[C:6]=1[C:7]#[N:8].[C:11]1([CH:17]([C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)[C:18](Cl)=[O:19])[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1.C(N(CC)CC)C>C(Cl)Cl>[C:7]([C:6]1[C:5]([CH3:9])=[C:4]([CH3:10])[S:3][C:2]=1[NH:1][C:18](=[O:19])[CH:17]([C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1)[C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1)#[N:8]
Reactant: Cc1sc(N)c(C#N)c1C
Reactant: O=C(Cl)C(c1ccccc1)c1ccccc1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: Cc1sc(NC(=O)C(c2ccccc2)c2ccccc2)c(C#N)c1C
Reaction time: 1.5 h
Yield: 46.8 %

Procedure:
To a stirred solution of 2-Amino-3-cyano-4,5-dimethylthiophene (152 mg; 1.0 mmol) and diphenylacetyl chloride (300 mg; 1.3 mmol) in dry methylene chloride (10 mL) under nitrogen at room temperature was added triethylamine (0.42 mL; 3.0 mmol) dropwise. After 1.5 h, the mixture was washed with 1N HCl. The organic layer was dried over sodium sulfate, filtered and concentrated in vacuo. The crude product was triturated with cold 30% ethylacetate/hexanes and filtered to give 162 mg (47%) of N-(3-Cyano-4,5-dimethyl-thiophen-2-yl)-2,2-diphenyl-acetamide as a white solid. ES-HRMS m/e calcd for C21H18N2OS (M+H+) 347.1213, found 347.1217.
Reaction SMILES: I[C:2]1[CH:7]=[CH:6][C:5]([NH:8][CH2:9][CH2:10][N:11]2[CH2:15][CH2:14][CH2:13][CH2:12]2)=[CH:4][CH:3]=1.[Cl:16][C:17]1[CH:22]=[CH:21][C:20]([C:23]2[CH:24]=[CH:25][C:26]([C:29]#[CH:30])=[N:27][CH:28]=2)=[CH:19][CH:18]=1>>[Cl:16][C:17]1[CH:18]=[CH:19][C:20]([C:23]2[CH:24]=[CH:25][C:26]([C:29]#[C:30][C:2]3[CH:7]=[CH:6][C:5]([NH:8][CH2:9][CH2:10][N:11]4[CH2:15][CH2:14][CH2:13][CH2:12]4)=[CH:4][CH:3]=3)=[N:27][CH:28]=2)=[CH:21][CH:22]=1
Reactant: Ic1ccc(NCCN2CCCC2)cc1
Reactant: C#Cc1ccc(-c2ccc(Cl)cc2)cn1
Product: Clc1ccc(-c2ccc(C#Cc3ccc(NCCN4CCCC4)cc3)nc2)cc1

Procedure:
Prepared according to general working method I from (4-iodo-phenyl)-(2-pyrrolidin-1-yl-ethyl)-amine (450 mg, 1.42 mmol) and 5-(4-chloro-phenyl)-2-ethynyl-pyridine (450 mg, 2.11 mmol).
Reaction SMILES: FC(F)(F)C(O)=O.[CH:8]1([CH2:11][CH2:12][O:13][C:14]2[NH:15][C:16]([NH2:25])=[C:17]3[C:21]([N:22]=2)=[N:20][C:19]([O:23][CH3:24])=[N:18]3)[CH2:10][CH2:9]1.Br[CH2:27][CH2:28][C@H:29]1[CH2:33][CH2:32][O:31][CH2:30]1>>[CH:8]1([CH2:11][CH2:12][O:13][C:14]2[N:22]=[C:21]3[C:17]([N:18]=[C:19]([O:23][CH3:24])[N:20]3[CH2:27][CH2:28][C@H:29]3[CH2:33][CH2:32][O:31][CH2:30]3)=[C:16]([NH2:25])[N:15]=2)[CH2:10][CH2:9]1
Reactant: COc1nc2nc(OCCC3CC3)[nH]c(N)c-2n1
Reactant: BrCC[C@H]1CCOC1
Solvent: O=C(O)C(F)(F)F
Product: COc1nc2c(N)nc(OCCC3CC3)nc2n1CC[C@H]1CCOC1

Procedure:
Prepared similarly to Intermediate 215 from 2-[(2-cyclopropylethyl)oxy]-8-(methyloxy)-1H-purin-6-amine trifluoroacetate and (3R)-3-(2-bromoethyl)tetrahydrofuran.