Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([CH:3]1[CH2:5][CH2:4]1)#[CH:2].C([Li])CCC.[C:11]([O:15][C:16](=[O:37])[NH:17][C:18]1[CH:23]=[CH:22][C:21]([O:24][CH2:25][O:26][CH2:27][CH2:28][O:29][CH3:30])=[CH:20][C:19]=1[C:31](=[O:36])[C:32]([F:35])([F:34])[F:33])([CH3:14])([CH3:13])[CH3:12].[Cl-].[NH4+]>ClCCl.C(O)(C)C.C1COCC1>[C:11]([O:15][C:16](=[O:37])[NH:17][C:18]1[CH:23]=[CH:22][C:21]([O:24][CH2:25][O:26][CH2:27][CH2:28][O:29][CH3:30])=[CH:20][C:19]=1[C:31]([OH:36])([C:32]([F:35])([F:34])[F:33])[C:2]#[C:1][CH:3]1[CH2:5][CH2:4]1)([CH3:14])([CH3:12])[CH3:13]
Reactant: C#CC1CC1
Reactant: COCCOCOc1ccc(NC(=O)OC(C)(C)C)c(C(=O)C(F)(F)F)c1
Agent: [Cl-]
Agent: [Li]CCCC
Agent: [NH4+]
Solvent: C1CCOC1
Solvent: ClCCl
Solvent: CC(C)O
Product: COCCOCOc1ccc(NC(=O)OC(C)(C)C)c(C(O)(C#CC2CC2)C(F)(F)F)c1
Temperature: -40 °C
Reaction time: 0.17 h
Yield: 61 %

Procedure:
A solution of 200 μL (2.3 mmol) of ethynyl-cyclopropane in 2 mL of freshly distilled THF was cooled to −40° C. and 1 mL (2.5 mmol) of n-butyl lithium (2.5M in hexane) was added under argon atmosphere. The reaction mixture was allowed to stir at −40° C. for 10 minutes. To the reaction mixture a solution of 400 mg (1.0 mmol) of 6 in 4 mL of freshly distilled THF was added, and the reaction was allowed to stir at −40° C. for 15 minutes. To the reaction mixture 2 mL of isopropanol were added followed by 20 mL of saturated ammonium chloride solution at −40° C. The reaction mixture was warmed up to room temperature, and 30 mL of dichloromethane was added. The organic layer was separated, and the aqueous layer was extracted with 3×30 mL of dichloromethane. The organic layers were combined, dried (anhydrous Na2SO4), and concentrated under reduced pressure. The residue was purified by silica gel flash column chromatography using 20% ethyl acetate in hexane to give 280 mg (0.61 mmol, 60%) of 7 [LC-MS; M+Na 482.2].
Reaction SMILES: [F:1][C:2]([F:17])([O:7][C:8]1[CH:13]=[CH:12][C:11]([C:14](=O)[CH3:15])=[CH:10][CH:9]=1)[C:3]([F:6])([F:5])[F:4].[CH3:18][C:19]([S@:22]([NH2:24])=[O:23])([CH3:21])[CH3:20]>>[CH3:18][C:19]([S@:22]([NH:24][CH:14]([C:11]1[CH:12]=[CH:13][C:8]([O:7][C:2]([F:17])([F:1])[C:3]([F:6])([F:5])[F:4])=[CH:9][CH:10]=1)[CH3:15])=[O:23])([CH3:21])[CH3:20]
Reactant: CC(C)(C)[S@](N)=O
Reactant: CC(=O)c1ccc(OC(F)(F)C(F)(F)F)cc1
Product: CC(N[S@](=O)C(C)(C)C)c1ccc(OC(F)(F)C(F)(F)F)cc1
Yield: 78 %

Procedure:
The title compound is prepared in 78% yield (812 mg, a yellow oil) from 1-(4-(perfluoroethoxy)phenyl)ethanone (737 mg, 2.90 mmol, Step-2) and (R)-2-methylpropane-2-sulfinamide by the similar manner in Step-4 of Amine-1.
Reaction SMILES: F[B-](F)(F)F.[CH3:6][N+:7]1[C:11](SC(C)CC)=[N:10][N:9]([CH:17]([CH3:20])[CH2:18][CH3:19])[N:8]=1.[OH-:21].[Na+]>O>[CH3:6][N+:7]1[C:11]([O-:21])=[N:10][N:9]([CH:17]([CH3:20])[CH2:18][CH3:19])[N:8]=1
Reactant: [OH-]
Reactant: CCC(C)Sc1nn(C(C)CC)n[n+]1C
Agent: F[B-](F)(F)F
Agent: [Na+]
Solvent: O
Product: CCC(C)n1nc([O-])[n+](C)n1
Reaction time: 0.5 h
Yield: 100 %

Procedure:
Thus, 1-methyl-3-(1-methylpropyl)-5-(1-methylpropylthio)tetrazolium tetrafluoroborate (137 mg, 0.43 mmol) was introduced into a recovery flask; an aqueous sodium hydroxide solution (prepared by the dissolution of sodium hydroxide (24 mg, 0.60 mmol) in water (10 mL)) was added to the recovery flask; and stirring was carried out for 30 minutes. Extraction with methylene chloride, drying over anhydrous sodium sulfate, and distillation of the solvent yielded 1-methyl-3-(1-methylpropyl)tetrazolium-5-olate (yield=65 mg, 100%).
Reaction SMILES: [CH3:1][N:2]1[C:6]([C:7]2[S:8][C:9]3[N:10]=[CH:11][N:12]=[C:13]([NH2:16])[C:14]=3[N:15]=2)=[C:5]([C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[N:4]=[C:3]1[C:23]#[C:24][Si](C)(C)C.O.C(=O)([O-])[O-].[K+].[K+].Cl>CO>[C:23]([C:3]1[N:2]([CH3:1])[C:6]([C:7]2[S:8][C:9]3[N:10]=[CH:11][N:12]=[C:13]([NH2:16])[C:14]=3[N:15]=2)=[C:5]([C:17]2[CH:18]=[CH:19][CH:20]=[CH:21][CH:22]=2)[N:4]=1)#[CH:24]
Reactant: Cn1c(C#C[Si](C)(C)C)nc(-c2ccccc2)c1-c1nc2c(N)ncnc2s1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CO
Product: C#Cc1nc(-c2ccccc2)c(-c2nc3c(N)ncnc3s2)n1C
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 25.4 %

Procedure:
2-{1-Methyl-4-phenyl-2-[(trimethylsilyl)ethynyl]-1H-imidazol-5-yl}[1,3]thiazolo[5,4-d]pyrimidin-7-amine (Intermediate 45) (48 mg) was dissolved/suspended in MeOH (3 mL)/water (1 mL) and potassium carbonate (50 mg) added, then stirred for 90 minutes at ambient temperature. The reaction mixture was neutralised with 2M HCl, concentrated in vacuo, the residue diluted with water (10 mL) and extracted with DCM (3×10 mL). The organic extracts were dried (MgSO4), filtered, concentrated in vacuo then purified by flash chromatography on silica eluting with 4% MeOH/DCM to give the title compound as a yellow solid (10 mg, 25%);
Reaction SMILES: C([O:3][C:4]([C:6]1([S:16]([C:19]2[CH:24]=[CH:23][C:22]([O:25][CH3:26])=[CH:21][CH:20]=2)(=[O:18])=[O:17])[CH2:11][CH2:10][N:9]([C:12]([CH3:15])([CH3:14])[CH3:13])[CH2:8][CH2:7]1)=[O:5])C>CO.[OH-].[Na+]>[C:12]([N:9]1[CH2:8][CH2:7][C:6]([S:16]([C:19]2[CH:24]=[CH:23][C:22]([O:25][CH3:26])=[CH:21][CH:20]=2)(=[O:18])=[O:17])([C:4]([OH:5])=[O:3])[CH2:11][CH2:10]1)([CH3:15])([CH3:14])[CH3:13]
Reactant: CCOC(=O)C1(S(=O)(=O)c2ccc(OC)cc2)CCN(C(C)(C)C)CC1
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: COc1ccc(S(=O)(=O)C2(C(=O)O)CCN(C(C)(C)C)CC2)cc1

Procedure:
1-tert-Butyl-4-(4-methoxy-benzenesulfonyl)-piperidine-4-carboxylic acid was prepared starting from 1-tert-butyl-4-(4-methoxy-benzenesulfonyl)-piperidine-4-carboxylic acid ethyl ester (5.37 g 14 mmol) dissolved in methanol (300 ml) and 10 N NaOH (23 ml). The resulting reaction mixture was worked up as outlined in example 83. Yield 1.52 g (30.6%); white powder; mp 204° C.; MS: 356 (M+H)+.
Reaction SMILES: Cl[C:2]1[C:3]2[C:10]3[CH:11]=[CH:12][N:13]=[CH:14][C:9]=3[NH:8][C:4]=2[N:5]=[CH:6][N:7]=1.[NH:15]1[CH2:20][CH2:19][O:18][CH2:17][CH2:16]1.C(N(CC)CC)C>CN1C(=O)CCC1>[N:15]1([C:2]2[C:3]3[C:10]4[CH:11]=[CH:12][N:13]=[CH:14][C:9]=4[NH:8][C:4]=3[N:5]=[CH:6][N:7]=2)[CH2:20][CH2:19][O:18][CH2:17][CH2:16]1
Reactant: Clc1ncnc2[nH]c3cnccc3c12
Reactant: C1COCCN1
Solvent: CCN(CC)CC
Solvent: CN1CCCC1=O
Product: c1cc2c(cn1)[nH]c1ncnc(N3CCOCC3)c12
Yield: 33.1 %

Procedure:
A mixture of 4-chloro-9H-pyrido[4′,3′:4,5]pyrrolo[2,3-d]pyrimidine (18 mg, 0.09 mmol), morpholine (23 μL, 0.26 mmol) and triethylamine (62 μL, 0.44 mmol) in 1 mL of NMP was irradiated in a microwave reactor at 150° C. for 20 minutes. The reaction mixture was evaporated to dryness and the residue purified by prep HPLC to give 7.6 mg of a white solid. 1H NMR (DMSO, 6, ppm) δ 3.65-3.75 (8H, m), 7.70 (1H, d, J=5.5 Hz), 8.45 (1H, d, J=5.5 Hz), 8.55 (1H, s), 8.85 (1H, s), 12.50 (1H, br s); LC-MS (2) Rt 1.46 min; m/z (ES+) 256.
Reaction SMILES: N#N.[CH3:3][C:4]([CH3:22])([O:6][C@H:7]1[C@@:15]2([CH3:16])[C@@H:10]([CH2:11][C:12]([OH:21])=[C:13]([C:17]([O:19][CH3:20])=[O:18])[CH2:14]2)[CH2:9][CH2:8]1)[CH3:5].[CH2:23]=[CH:24][C:25](=[O:31])[CH2:26][CH2:27][CH2:28][CH:29]=[CH2:30]>C(Cl)Cl>[CH3:5][C:4]([CH3:22])([O:6][C@H:7]1[C@@:15]2([CH3:16])[C@@H:10]([CH2:11][C:12](=[O:21])[C:13]([CH2:23][CH2:24][C:25](=[O:31])[CH2:26][CH2:27][CH2:28][CH:29]=[CH2:30])([C:17]([O:19][CH3:20])=[O:18])[CH2:14]2)[CH2:9][CH2:8]1)[CH3:3]
Reactant: C=CCCCC(=O)C=C
Reactant: COC(=O)C1=C(O)C[C@H]2CC[C@@H](OC(C)(C)C)[C@]2(C)C1
Agent: N#N
Solvent: ClCCl
Product: C=CCCCC(=O)CCC1(C(=O)OC)C[C@]2(C)[C@H](CC[C@H]2OC(C)(C)C)CC1=O
Temperature: 180 °C
Reaction time: 16 h
Yield: 90.7 %

Procedure:
Neutral alumina (15 g) was heated in a flask at 180° C. under high vacuum for 4 h. After cooling down to room temperature, the flask was filled with N2. Compound 31 (7.2 g, 25.5 mmol), 1,7-octadien-3-one (4.3 g, 30 mmol), and CH2Cl2 (30 mL) were added to the anhydrous alumina at room temperature. The mixture was stirred at room temperature for 16 h. The suspension was filtered through Celite® 545 which was washed with CH2Cl2 (100 mL×3). The solvent was removed under reduced pressure and the residue was purified by flash column chromatography (silica gel eluted with 10% EtOAc in hexanes) to afford compound 32 (9.4 g, 91%). The compound is a mixture of diastereomers at position C-5 in a 3 to 1 ratio. The major diastereomer had: 1H NMR (CDCl3) δ 5.72-5.60 (m, 1H), 4.95-4.86 (m, 2H), 3.64 (s, 3H), 3.35 (t, J=7.1 Hz, 1H), 1.05 (s, 9H), 0.75 (s, 3H); 13C NMR (CDCl3) δ 209.5, 208.0, 173.7, 137.8, 115.0, 79.9, 72.4, 56.2, 52.2, 46.9, 45.5, 42.4, 42.1, 41.7, 38.1, 32.9, 31.3, 30.5, 28.6, 28.4, 25.5, 22.6; IR νmax 1714, 1641, 1435 cm−1. Anal. Calcd for (C24H38O5): C, 70.90; H, 9.42. Found: C, 71.16; H, 9.70.
Reaction SMILES: CCOCC.[H-].[Al+3].[Li+].[H-].[H-].[H-].[CH2:12]1[O:20][C:19]2[CH:18]=[CH:17][C:16]([CH:21]([CH2:25][CH2:26][CH2:27][CH2:28]C)[C:22](O)=[O:23])=[CH:15][C:14]=2[O:13]1>O>[CH2:12]1[O:20][C:19]2[CH:18]=[CH:17][C:16]([CH:21]([CH2:25][CH2:26][CH2:27][CH3:28])[CH2:22][OH:23])=[CH:15][C:14]=2[O:13]1
Reactant: CCCCCC(C(=O)O)c1ccc2c(c1)OCO2
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: O
Solvent: CCOCC
Product: CCCCC(CO)c1ccc2c(c1)OCO2
Temperature: 25 °C
Yield: 99.8 %

Procedure:
To 40 ml of ether suspension containing 1.74 g (46 mmol) of lithium aluminum hydride, was added dropwise under cooling with ice 40 ml of ether solution containing 10.9 g (46 mmol) of (-)-2-(3,4-methylenedioxyphenyl)-heptanoic acid obtained in Reference Example 2. After 2-hour reflux, the reaction mixture was cooled to room temperature and was treated with water under cooling with ice to obtain 10.2 g of oily 2-(3,4-methylenedioxyphenyl)hexyl alcohol.
Reaction SMILES: Br[C:2]1[C:7]([N:8]([CH2:23][O:24][CH3:25])[S:9]([C:12]2[CH:17]=[CH:16][C:15]([Cl:18])=[C:14]([C:19]([F:22])([F:21])[F:20])[CH:13]=2)(=[O:11])=[O:10])=[CH:6][C:5]([Cl:26])=[CH:4][N:3]=1.C([Mg]Cl)(C)C.[CH3:32][O:33][C:34]1[N:45]=[CH:44][CH:43]=[CH:42][C:35]=1[C:36](N(OC)C)=[O:37]>C1COCC1>[Cl:18][C:15]1[CH:16]=[CH:17][C:12]([S:9]([N:8]([C:7]2[C:2]([C:36]([C:35]3[C:34]([O:33][CH3:32])=[N:45][CH:44]=[CH:43][CH:42]=3)=[O:37])=[N:3][CH:4]=[C:5]([Cl:26])[CH:6]=2)[CH2:23][O:24][CH3:25])(=[O:11])=[O:10])=[CH:13][C:14]=1[C:19]([F:22])([F:21])[F:20]
Reactant: COCN(c1cc(Cl)cnc1Br)S(=O)(=O)c1ccc(Cl)c(C(F)(F)F)c1
Reactant: COc1ncccc1C(=O)N(C)OC
Agent: CC(C)[Mg]Cl
Solvent: C1CCOC1
Product: COCN(c1cc(Cl)cnc1C(=O)c1cccnc1OC)S(=O)(=O)c1ccc(Cl)c(C(F)(F)F)c1
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 29.3 %

Procedure:
To a solution of N-(2-bromo-5-chloro-pyridin-3-yl)-4-chloro-N-methoxymethyl-3-trifluoromethyl-benzenesulfonamide (612 mg, 1.24 mmol) in THF (5 mL) under nitrogen atmosphere at 0° C. was added dropwise isopropylmagnesium chloride (2 M solution in THF, 1.55 mL, 3.1 mmol). The mixture was then stirred for 30 min at 0° C. followed by the addition of a solution of 2,N-dimethoxy-N-methyl-nicotinamide (487 mg, 2.48 mmol) in THF (2 mL) at 0° C. The mixture was stirred at room temperature for 6 hours, quenched with saturated aqueous NH4Cl solution (5 mL) and extracted with EtOAc (2×25 mL). The combined organic layers were washed with saturated aqueous NH4Cl solution (25 mL), brine (25 mL), dried (anhydrous Na2SO4) and concentrated under reduced pressure. The obtained residue was purified via column chromatography (SiO2, 50% EtOAc-hexanes) to obtain 4-chloro-N-[5-chloro-2-(2-methoxy-pyridine-3-carbonyl)-pyridin-3-yl]-N-methoxymethyl-3-trifluoromethyl-benzenesulfonamide (200 mg) in 29.2% yield. ESMS m/z (relative intensity): 550 (M+H)+ (100), 571.9 (M+Na)+ (80).
Reaction SMILES: [CH:1]1[C:11]2[CH2:10][CH2:9][C:8]3[CH:12]=[CH:13][CH:14]=[CH:15][C:7]=3[C:6](=[CH:16][C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=3[NH2:23])[C:5]=2[CH:4]=[CH:3][CH:2]=1.[C:24](Cl)(=[O:26])[CH3:25]>>[CH:1]1[C:11]2[CH2:10][CH2:9][C:8]3[CH:12]=[CH:13][CH:14]=[CH:15][C:7]=3[C:6](=[CH:16][C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=3[NH:23][C:24](=[O:26])[CH3:25])[C:5]=2[CH:4]=[CH:3][CH:2]=1
Reactant: CC(=O)Cl
Reactant: Nc1ccccc1C=C1c2ccccc2CCc2ccccc21
Product: CC(=O)Nc1ccccc1C=C1c2ccccc2CCc2ccccc21
Yield: 70 %

Procedure:
Following procedures essentially as described in Example 90, 2-(10,11-dihydro-dibenzo[a,d]cyclohepten-5-ylidenemethyl)-phenylamine and acetyl chloride give the title compound in 70% yield as a yellow solid, mp 189.7° C. 1H NMR (CDCl3) δ 2.16 (s, 3H), 3.26 (br s, 4H), 6.78 (s, 1H), 6.84-7.50 (m, 111), 7.82 (d, 1H); MS (ES) 340 (M+H) 338 (M−H). HPLC shows 94% purity.
Reaction SMILES: [OH:1][C:2]1[C:11]([CH2:12][C:13]([CH3:15])=[CH2:14])=[CH:10][C:9]([CH3:16])=[C:8]2[C:3]=1[CH2:4][C:5]([CH3:19])([CH3:18])[C:6](=[O:17])[NH:7]2.[Br:20]N1C(=O)CCC1=O>C(Cl)(Cl)Cl.CCCCCC>[Br:20][CH2:14][C:13]1([CH3:15])[O:1][C:2]2=[C:3]3[C:8](=[C:9]([CH3:16])[CH:10]=[C:11]2[CH2:12]1)[NH:7][C:6](=[O:17])[C:5]([CH3:19])([CH3:18])[CH2:4]3
Reactant: C=C(C)Cc1cc(C)c2c(c1O)CC(C)(C)C(=O)N2
Reactant: O=C1CCC(=O)N1Br
Solvent: ClC(Cl)Cl
Solvent: CCCCCC
Product: Cc1cc2c(c3c1NC(=O)C(C)(C)C3)OC(C)(CBr)C2
Yield: 74.2 %

Procedure:
Using 5-hydroxy-6-(2-methyl-2-propenyl)-3,3,8-trimethyl-3,4-dihydrocarbostyril (1.35 g, 5.18 mmol) and N-bromosuccinimide (968 mg, 5.44 mmol), the procedure of Example 299 was followed (reaction, post-treatment, and recrystallization from chloroform-hexane) to obtain 1.30 g of the title compound as colorless needles (74%).
Reaction SMILES: [NH2:1][CH2:2][CH:3]([C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1)[OH:4].[F:11][C:12]1[CH:17]=[CH:16][C:15]([NH:18][C:19]([C:21]2[C:22](Cl)=[N:23][C:24]([S:27][CH3:28])=[N:25][CH:26]=2)=[O:20])=[CH:14][CH:13]=1.O>CO>[F:11][C:12]1[CH:17]=[CH:16][C:15]([NH:18][C:19]([C:21]2[C:22]([NH:1][CH2:2][CH:3]([OH:4])[C:5]3[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=3)=[N:23][C:24]([S:27][CH3:28])=[N:25][CH:26]=2)=[O:20])=[CH:14][CH:13]=1
Reactant: CSc1ncc(C(=O)Nc2ccc(F)cc2)c(Cl)n1
Reactant: NCC(O)c1ccccc1
Solvent: O
Solvent: CO
Product: CSc1ncc(C(=O)Nc2ccc(F)cc2)c(NCC(O)c2ccccc2)n1
Temperature: 25 °C
Reaction time: 16 h
Yield: 76.5 %

Procedure:
To a solution of 2-amino-1-phenyl-ethanol (140 mg, 1.01 mmol) in methanol (5 mL) was added 4-chloro-2-methylsulfanylpyrimidine-5-carboxylic acid (4-fluorophenyl)amide (100 mg, 0.34 mmol). The mixture was stirred for 16 h at an ambient temperature and the resulting mixture was poured into water. Solids were collected by filtration and were dried in vacuo to afford 103.7 mg (0.26 mmol, 78% yield) of the titled compound as a solid. 1H NMR (300 MHz, DMSO-d6) δ 10.22(s, 1H), 8.85 (m, 1H), 8.60 (s, 1H), 7.65(m, 2H), 7.40–7.05 (m, 7H), 5.67 (m, 1H), 4.78 (m, 1H), 3.78 (m, 1H), 3.41 (m, 1H), 2.44 (s, 31H); MS (EI) m/z 397.18 (M−H)−.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[N:4][CH:5]=[C:6]([F:9])[C:7]=1I.[CH3:10][N:11]1[CH2:16][CH:15]=[C:14](B2OC(C)(C)C(C)(C)O2)[CH2:13][CH2:12]1.C([O-])([O-])=O.[Na+].[Na+]>COCCOC.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>[Cl:1][C:2]1[CH:3]=[N:4][CH:5]=[C:6]([F:9])[C:7]=1[C:14]1[CH2:15][CH2:16][N:11]([CH3:10])[CH2:12][CH:13]=1
Reactant: CN1CC=C(B2OC(C)(C)C(C)(C)O2)CC1
Reactant: Fc1cncc(Cl)c1I
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: COCCOC
Product: CN1CC=C(c2c(F)cncc2Cl)CC1
Temperature: 80 °C
Yield: 85.9 %

Procedure:
3-chloro-5-fluoro-4-iodo-pyridine (500 mg, 1.942 mmol), 1-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-3,6-dihydro-2H-pyridine (476.6 mg, 2.136 mmol) and Pd(PPh3)2Cl2 (68.15 mg, 0.09710 mmol) in DME (10.00 mL) were degassed using 3×vacuum/nitrogen cycles. Na2CO3 (2.913 mL of 2 M, 5.826 mmol) was added followed by further degassing and the reaction heated at 80° C. for 18 hours. The reaction was cooled to ambient temperature and diluted with EtOAc/water. The layers were separated and the aqueous layer extracted with EtOAc (×3). The combined organic extracts were washed with brine (×1), dried (MgSO4), filtered and concentrated in vacuo. The residue was passed through a 10 g SCX-2 cartridge and washed with MeOH/DCM mixtures. The product was eluted by washing the cartridge with 2M NH3 in MeOH/DCM mixtures and concentrated in vacuo. The residue was purified by column chromatography (ISCO Companion, 40 g column, eluting with 0 to 10% MeOH/DCM+1% NH4OH, loaded in DCM) to give 3′-chloro-5′-fluoro-1-methyl-1,2,3,6-tetrahydro-4,4′-bipyridine as a red solid (378 mg, 86% Yield). MS (ES+) 227.1.
Reaction SMILES: Cl.[NH2:2][C:3]1[CH:4]=[C:5]([C:9]2[CH:10]=[C:11]3[C:16](=[CH:17][CH:18]=2)[N:15]([CH3:19])[C:14](=[O:20])[CH2:13][CH2:12]3)[CH:6]=[N:7][CH:8]=1.[C:21]([O:24][CH2:25][C:26](Cl)=[O:27])(=[O:23])[CH3:22].C([O-])(O)=O.[Na+]>C(Cl)Cl>[CH3:19][N:15]1[C:16]2[C:11](=[CH:10][C:9]([C:5]3[CH:4]=[C:3]([NH:2][C:26]([CH2:25][O:24][C:21](=[O:23])[CH3:22])=[O:27])[CH:8]=[N:7][CH:6]=3)=[CH:18][CH:17]=2)[CH2:12][CH2:13][C:14]1=[O:20]
Reactant: CN1C(=O)CCc2cc(-c3cncc(N)c3)ccc21
Reactant: CC(=O)OCC(=O)Cl
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Product: CC(=O)OCC(=O)Nc1cncc(-c2ccc3c(c2)CCC(=O)N3C)c1
Temperature: 25 °C
Reaction time: 2 h
Yield: 57.1 %

Procedure:
To a solution of 6-(5-amino-pyridin-3-yl)-1-methyl-3,4-dihydro-1H-quinolin-2-one hydrochloride (intermediate A-2, 0.045 g, 0.155 mmol) in DCM (1.5 mL) was added TEA (0.039 g, 0.388 mmol) followed by 2-chloro-2-oxoethyl acetate (0.017 g, 0.124 mmol) in DCM (1 mL) and the reaction mixture was stirred at room temperature for 2 h. The mixture was diluted with DCM, poured into aq. NaHCO3 (10 mL) and the aqueous layer was extracted with DCM (2×25 mL). Combined organics were washed with brine, dried over Na2SO4, filtered and evaporated to dryness. The residue was purified by silica gel flash chromatography eluting with a 0 to 5% MeOH-DCM gradient to give the title compound (0.025 g, 46%) as a light brown solid. MS: 354.2 (M+H+).
Reaction SMILES: [C:1]([Si:5]([O:8]/[C:9](/[C:12]1[CH:17]=[CH:16][CH:15]=[C:14](Cl)[CH:13]=1)=[CH:10]\[CH3:11])([CH3:7])[CH3:6])([CH3:4])([CH3:3])[CH3:2].[CH3:19]CCC(C1C=CC=CC=1)=O.[Si](OS(C(F)(F)F)(=O)=O)(C(C)(C)C)(C)C.CCN(CC)CC>C(Cl)Cl>[C:1]([Si:5]([O:8]/[C:9](/[C:12]1[CH:13]=[C:14]([CH3:19])[CH:15]=[CH:16][CH:17]=1)=[CH:10]\[CH3:11])([CH3:7])[CH3:6])([CH3:4])([CH3:3])[CH3:2]
Reactant: CCCC(=O)c1ccccc1
Reactant: C/C=C(\O[Si](C)(C)C(C)(C)C)c1cccc(Cl)c1
Agent: CC(C)(C)[Si](C)(C)OS(=O)(=O)C(F)(F)F
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: C/C=C(\O[Si](C)(C)C(C)(C)C)c1cccc(C)c1
Yield: 84 %

Procedure:
Compound 9e was synthesized by a procedure similar to that described for 9a using commercially available 3-methylpropiophenone (8e, 5.0 g, 0.033 mol), TBDMSOTf (8.5 mL, 36.1 mmol), and Et3N (7.5 mL) in CH2Cl2 (50 mL). After purification by column chromatography on silica gel, 7.45 g (84%) of 9e was isolated as colorless oil: 1H NMR (CDCl3) δ 7.31-7.24 (m, 2H), 7.23-7.17 (m, 1H), 7.10-7.05 (m, 1H), 5.22 (q, 1H, J=6.9 Hz), 2.37 (s, 3H), 1.76 (d, 3H, J=6.9 Hz), 1.03 (s, 9H), −0.03 (s, 6H); 13C NMR (CDCl3) δ 150.7, 140.1, 137.7, 128.4, 127.9, 126.8, 123.2, 105.9, 26.3, 21.8, 18.7, 12.1, −3.6. C16H26OSi.
Reaction SMILES: FC(F)(F)S(O[C:7]1[C:18]([CH3:19])=[N:17][C:10]2[N:11]=[C:12]([NH:15][CH3:16])[N:13]=[CH:14][C:9]=2[CH:8]=1)(=O)=O.[F:22][C:23]1[CH:29]=[C:28]([CH3:30])[C:27](B2OC(C)(C)C(C)(C)O2)=[CH:26][C:24]=1[NH2:25].C([O-])(O)=O.[Na+]>O1CCOCC1.O.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[NH2:25][C:24]1[C:23]([F:22])=[CH:29][C:28]([CH3:30])=[C:27]([C:7]2[C:18]([CH3:19])=[N:17][C:10]3[N:11]=[C:12]([NH:15][CH3:16])[N:13]=[CH:14][C:9]=3[CH:8]=2)[CH:26]=1
Reactant: Cc1cc(F)c(N)cc1B1OC(C)(C)C(C)(C)O1
Reactant: CNc1ncc2cc(OS(=O)(=O)C(F)(F)F)c(C)nc2n1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: C1COCCO1
Solvent: O
Product: CNc1ncc2cc(-c3cc(N)c(F)cc3C)c(C)nc2n1
Temperature: 60 °C
Yield: 88.6 %

Procedure:
Combine 7-methyl-2-(methylamino)pyrido[2,3-d]pyrimidin-6-yl trifluoromethanesulfonate (1.15 g, 3.57 mmol), 2-fluoro-4-methyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)aniline (0.896 g, 3.57 mmol), and NaHCO3 (0.899 g, 10.71 mmol) in dioxane (24 mL) and H2O (6 mL), sparge with argon, treat with Pd(PPh3)4 (0.206 g, 0.178 mmol) and heat to 60° C. overnight. Add additional 7-methyl-2-(methylamino)pyrido[2,3-d]pyrimidin-6-yl trifluoromethanesulfonate (120 mg, 0.37 mmol) and Pd(PPh3)4 (80 mg, 0.07 mmol), sparge the mixture with argon, and heat at 60° C. overnight. Cool the mixture to RT, treat with brine and extract with EtOAc (3×). Wash the combined organics with brine, dry over Na2SO4, concentrate to dryness and purify via silica gel chromatography (50-100% EtOAc/Hexanes) to afford the title compound (940 mg, 89% yield). MS (m/z): 298.1 (M+1).
Reaction SMILES: [CH2:1]([N:8]1[C:12]([CH3:13])=[CH:11][CH:10]=[C:9]1[CH:14]=[O:15])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.O=P(Cl)(Cl)Cl.C(N1C=CC=C1C)C1C=CC=CC=1.C([O:36][C:37]([C:39]1[NH:49][C:42]2=[N:43][CH:44]=[CH:45][C:46]([O:47][CH3:48])=[C:41]2[CH:40]=1)=O)C>O1CCCC1.CN(C)C=O>[CH2:1]([N:8]1[C:12]([CH3:13])=[CH:11][CH:10]=[C:9]1[CH:14]=[O:15])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1.[CH3:48][O:47][C:46]1[CH:45]=[CH:44][N:43]=[C:42]2[NH:49][C:39]([CH2:37][OH:36])=[CH:40][C:41]=12
Reactant: CCOC(=O)c1cc2c(OC)ccnc2[nH]1
Agent: Cc1ccc(C=O)n1Cc1ccccc1
Agent: Cc1cccn1Cc1ccccc1
Solvent: O=P(Cl)(Cl)Cl
Solvent: C1CCOC1
Solvent: CN(C)C=O
Product: COc1ccnc2[nH]c(CO)cc12
Reaction time: 1.5 h

Procedure:
1-Benzyl-5-methyl-1H-pyrrole-2-carbaldehyde, 4: POCl3 (23.46 mL, 246 mmol) was added dropwise to a stirred N,N-dimethyformamide (204 mL) at 0° C. After addition the mixture was stirred for additional 90 minutes. To the mixture was added dropwise the solution of 1-benzyl-2-methyl-1H-pyrrole, 3 (2.71 g, 45 mmol) in tetrahydrofuran (1150 mL). The reaction mixture was allowed to be stirred for 18 h from 0° C. to room temperature. The mixture was concentrated and redissolved in ethyl acetate (2 L). The mixture was washed with saturated Na2CO3 (2×500 mL). The Na2CO3 solution was extracted with ethyl acetate (7×1 L). The organic layers were combined and concentrated. The crude product was purified by silica gel chromatography (hexane to hexane:ethyl acetate, 7:1) to afford 1-benzyl-5-methyl-1H-pyrrole-2-carbaldehyde, 4 as a light yellow liquid. Yield: 30.8 g (81%).
Reaction SMILES: [N:1]12[CH2:9][CH:5]([CH2:6][CH2:7][CH2:8]1)[CH:4]([NH:10][C:11]1[CH:16]=[CH:15][C:14](Br)=[CH:13][N:12]=1)[CH2:3][CH2:2]2.[NH:18]1[C:26]2[C:21](=[CH:22][C:23](B(O)O)=[CH:24][CH:25]=2)[CH:20]=[CH:19]1>C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[N:1]12[CH2:9][CH:5]([CH2:6][CH2:7][CH2:8]1)[CH:4]([NH:10][C:11]1[CH:16]=[CH:15][C:14]([C:23]3[CH:22]=[C:21]4[C:26](=[CH:25][CH:24]=3)[NH:18][CH:19]=[CH:20]4)=[CH:13][N:12]=1)[CH2:3][CH2:2]2
Reactant: OB(O)c1ccc2[nH]ccc2c1
Reactant: Brc1ccc(NC2CCN3CCCC2C3)nc1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Product: c1cc2cc(-c3ccc(NC4CCN5CCCC4C5)nc3)ccc2[nH]1
Yield: 43.9 %

Procedure:
A microwave vial containing a stirring bar is loaded with 148 mg (0.5 mmol) of (4SR, 5RS)-(1-aza-bicyclo[3.3.1]non-4-yl)-(5-bromo-pyridin-2-yl)-amine, 98 mg (0.61 mmol) of indole-5-boronic acid and 29.7 mg of tetrakis(triphenylphosphine)palladium, capped and after evacuation purged with argon. After addition of 9 ml of toluene, 1 ml of EtOH and 1 ml of 2 M Na2CO3 soln. the mixture is irradiated at 120° C. for 45 min in a microwave reactor (Initiator Exp. Biotage). The reaction mixture is filtered over hyflo and diluted with AcOEt. The aq. phase is extracted with AcOEt, the combined organic phases are washed with water and brine, dried over Na2SO4 and evaporated. The residue is purified by medium pressure chromatography on silica gel with AcOEt/MeOH/NEt3 50:45:5 affording a foam which after trituration with pentane yields 73 mg of (4SR,5RS)-(1-aza-bicyclo[3.3.1]non-4-yl)-[5-(1H-indol-5-yl)-pyridin-2-yl]-amine as beige powder.