Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br[CH:2]1[CH2:6][CH2:5][CH2:4][CH2:3]1.[OH:7][N:8]1[C:12](=[O:13])[C:11]2=[CH:14][CH:15]=[CH:16][CH:17]=[C:10]2[C:9]1=[O:18].C(N(CC)CC)C.CN(C)C=O>O>[CH:2]1([O:7][N:8]2[C:9](=[O:18])[C:10]3=[CH:17][CH:16]=[CH:15][CH:14]=[C:11]3[C:12]2=[O:13])[CH2:6][CH2:5][CH2:4][CH2:3]1
Reactant: O=C1c2ccccc2C(=O)N1O
Reactant: BrC1CCCC1
Solvent: O
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: O=C1c2ccccc2C(=O)N1OC1CCCC1
Reaction time: 16 h
Yield: 49.2 %

Procedure:
A mixture of bromocyclopentane (14.9 g), N-hydroxyphthalimide (16.3 g), triethylamine (15 ml), and dimethylformamide (30 ml) was stirred for 16 hours, then poured into water (500 ml). The oily mixture was extracted with ethyl acetate, and the combined extracts, after washing (water), drying, and removal of solvent gave a white solid. This solid was recrystallised from ethanol to give N-cyclopentyloxyphthalimide (11.37 g, 49%); m.p. 81.2°-82.5°; νmax. (CHBr3) include 1780, 1720 cm-1 (CO-N-CO), 970 cm-1 ##STR72## τ values (DMSO-d6) 2.08 (4 Ar-H), 5.12 (cyclopentyl 1-H), 8.18 (4-CH2).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:21])[C:4]1[CH:9]=[CH:8][CH:7]=[C:6]([C:10]2[S:11][CH:12]=[C:13]([C@H:15]3[CH2:20][CH2:19][CH2:18][CH2:17][NH:16]3)[N:14]=2)[CH:5]=1.C(N(CC)CC)C.CN(C1C=CC=CN=1)C.[O:38]([CH2:45][C:46](Cl)=[O:47])[C:39]1[CH:44]=[CH:43][CH:42]=[CH:41][CH:40]=1>ClCCl>[CH3:1][O:2][C:3](=[O:21])[C:4]1[CH:9]=[CH:8][CH:7]=[C:6]([C:10]2[S:11][CH:12]=[C:13]([C@H:15]3[CH2:20][CH2:19][CH2:18][CH2:17][N:16]3[C:46](=[O:47])[CH2:45][O:38][C:39]3[CH:44]=[CH:43][CH:42]=[CH:41][CH:40]=3)[N:14]=2)[CH:5]=1
Reactant: COC(=O)c1cccc(-c2nc([C@H]3CCCCN3)cs2)c1
Reactant: O=C(Cl)COc1ccccc1
Agent: CN(C)c1ccccn1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: COC(=O)c1cccc(-c2nc([C@H]3CCCCN3C(=O)COc3ccccc3)cs2)c1
Temperature: 25 °C
Reaction time: 4 h

Procedure:
A solution of 3-((R)-4-piperidin-2-yl-thiazol-2-yl)-benzoic acid methyl ester (0.048 g, 0.16 mmol) in dry dichloromethane (2 mL) under argon was treated with triethylamine (0.064 g, 0.09 ml.), dimethylaminopyridine (0.002 g, 0.020 mmol) and phenoxyacetyl chloride (0.027 g, 0.16 mmol). The mixture was stirred at room temperature for 4 h. The mixture was washed with water and saturated sodium chloride. The organic phase was dried over sodium sulphate and evaporated. The residual oil was purified by preparative HPLC: Column: YMC-Pack Pro C18 RS, 20×50 mm, S-5 um, 8 nm, No200504707(W); Gradient: 0-0.4 min: 30% acetonitrile in (water+0.1% HCO2H), 0.4-2.4 min: increse of acetonitrile fraction from 30% to 95%, 2.4-4.7 min: 95% acetonitrile, 4.7-4.8 min: decrease of acetonitrile fraction from 95% to 30%; Program end at 4.87 min; Flow: 30 ml/min. 3-{4-[(R)-1-(2-Phenoxy-acetyl)-piperidin-2-yl]-thiazol-2-yl}-benzoic acid methyl ester was obtained after lyophilization as a light yellow oil (0.033 g, 48%), MS (ISP): 437.3 (M+H)+..
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[CH:14]=[CH:13][C:12]2[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=2)[C:6]=1[OH:15])=[O:4].[O:16]([CH2:23][CH:24](O)[CH3:25])[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.CC(OC(/N=N/C(OC(C)C)=O)=O)C>C1COCC1>[CH3:1][O:2][C:3]([C:5]1[CH:14]=[CH:13][C:12]2[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=2)[C:6]=1[O:15][CH:24]([CH3:25])[CH2:23][O:16][C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1)=[O:4]
Reactant: COC(=O)c1ccc2ccccc2c1O
Reactant: CC(O)COc1ccccc1
Agent: CC(C)OC(=O)/N=N/C(=O)OC(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: COC(=O)c1ccc2ccccc2c1OC(C)COc1ccccc1

Procedure:
To a solution of 1.00 g 1-hydroxy-naphthalene-2-carboxylic acid methyl ester, 0.75 g 1-phenoxy-propan-2-ol and 3.89 g triphenyl phosphine in 60 ml dry THF at 0° C. 3.00 g diisopropylazodicarboxylate were added. After 48 h at room temperature the reaction was concentrated in vacuo, the residue was taken up in ethyl acetate, washed with sat. sodium hydrogen carbonate solution and dryed over magnesium sulphate. The solvent was removed in vacuo and after chromatography on silica (ethyl acetate/heptane) 0.47 g 1-(1-methyl-2-phenoxy-ethoxy)-naphthalene-2-carboxylic acid methyl ester were obtained.
Reaction SMILES: [CH2:1]([Li])CCC.C(NC(C)C)(C)C.[C:13]([CH:18]1[CH2:22][S:21][C:20]([C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=2)=[N:19]1)([O:15][CH2:16][CH3:17])=[O:14].CI.Cl>CC(OC)(C)C>[C:13]([C:18]1([CH3:1])[CH2:22][S:21][C:20]([C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=2)=[N:19]1)([O:15][CH2:16][CH3:17])=[O:14]
Reactant: CCOC(=O)C1CSC(c2ccccc2)=N1
Reactant: [Li]CCCC
Agent: Cl
Solvent: COC(C)(C)C
Solvent: CI
Solvent: CC(C)NC(C)C
Product: CCOC(=O)C1(C)CSC(c2ccccc2)=N1
Temperature: -15 °C
Reaction time: 0.5 h

Procedure:
152.2 g (0.594 mol, 1.10 eq) of butyllithium solution (25% strength in heptane) were added dropwise under nitrogen in the course of 30 min to a solution of 90.8 ml (65.6 g, 0.648 mol, 1.20 eq) of diisopropylamine in 800 ml of absolute MTBE at −15° C. This solution was stirred at −15° C. for 30 min. 400 ml of the MTBE solution containing the 4-carbethoxy-2-phenyl-thiazoline were added dropwise at −15° C. in the course of 30 min and the mixture was stirred at −15° C. for 1 h, whereby a brown solution resulted. 115.0 g (50.4 ml, 0.81 mol, 1.50 eq) of methyl iodide were added and the reaction mixture was warmed to 23° C. and stirred at this temperature for a further 3 h. 300 ml of 2 M HCl were then slowly added with vigorous stirring, then the mixture was adjusted to pH 2-3 so that the temperature did not exceed 30° C. The two-phase mixture obtained thereby was stirred for a further 30 min. The organic phase was then separated off. This MTBE solution, containing 4-carbethoxy-4-methyl-2-phenylthiazoline, was employed in stage 3.
Reaction SMILES: [Cl:1][C:2]1[C:7]([O:8][C:9]2[CH:14]=[CH:13][C:12]([Cl:15])=[CH:11][CH:10]=2)=[CH:6][N:5]=[C:4]([N:16]=CN(C(C)C)C(C)C)[N:3]=1.[NH2:25][C:26]1[CH:31]=[CH:30][C:29]([OH:32])=[CH:28][CH:27]=1>CO>[ClH:1].[NH2:16][C:4]1[N:3]=[C:2]([NH:25][C:26]2[CH:31]=[CH:30][C:29]([OH:32])=[CH:28][CH:27]=2)[C:7]([O:8][C:9]2[CH:10]=[CH:11][C:12]([Cl:15])=[CH:13][CH:14]=2)=[CH:6][N:5]=1
Reactant: CC(C)N(C=Nc1ncc(Oc2ccc(Cl)cc2)c(Cl)n1)C(C)C
Reactant: Nc1ccc(O)cc1
Solvent: CO
Product: Cl
Product: Nc1ncc(Oc2ccc(Cl)cc2)c(Nc2ccc(O)cc2)n1
Temperature: 24 °C
Reaction time: 20 h
Yield: 85.6 %

Procedure:
Nitrogen was bubbled through a suspension of 10.11 g (27.5 mmol) of 4-chloro-5-(4-chlorophenoxy)-2-(diisopropylaminomethyleneamino)pyrimidine (see Example 2) in 205 ml of methanol for 10 minutes. Then 3.18 g (29.1 mmol) of 4-aminophenol was added and nitrogen bubbled through the suspension for 5 minutes. The solution was then tightly sealed and stirred at 24° C. for 20 hours. Then 50 ml of concentrated hydrochloric acid was added to the mixture and refluxed for 140 minutes. The mixture was cooled and spin evaporated to one-half the original volume and then stored at 3° C. After 3 hours, a large precipitate had formed which was collected by filtration and washed quickly with cold methanol. The filter cake was suspended in 79 ml of CH2Cl2 and the suspension was boiled for 5 minutes. The solids were collected by filtration, washed with CH2Cl2 and dried in vacuo at 100° C. 8.6 g (86%) of product as a pale yellow powder was obtained, mp 288-289° C.
Reaction SMILES: I[C:2]1[C:7]([O:8][CH3:9])=[CH:6][CH:5]=[CH:4][C:3]=1[O:10][CH3:11].[Li]CCCC.[C:17]([S:21]([N:23]=[CH:24][CH2:25][CH2:26][CH2:27][C:28]([O:30][CH3:31])=[O:29])=[O:22])([CH3:20])([CH3:19])[CH3:18].[NH4+].[Cl-]>C1COCC1.O.CCOCC>[CH3:11][O:10][C:3]1[CH:4]=[CH:5][CH:6]=[C:7]([O:8][CH3:9])[C:2]=1[CH:24]([NH:23][S:21]([C:17]([CH3:20])([CH3:19])[CH3:18])=[O:22])[CH2:25][CH2:26][CH2:27][C:28]([O:30][CH3:31])=[O:29]
Reactant: COc1cccc(OC)c1I
Reactant: COC(=O)CCCC=NS(=O)C(C)(C)C
Agent: [Cl-]
Agent: [Li]CCCC
Agent: [NH4+]
Solvent: CCOCC
Solvent: O
Solvent: C1CCOC1
Product: COC(=O)CCCC(NS(=O)C(C)(C)C)c1c(OC)cccc1OC
Temperature: -78 °C
Reaction time: 0.25 h

Procedure:
A cooled (−78° C.) yellow solution of commercially available 2-iodo-1,3-dimethoxybenzene (9.930 g; 37.60 mmol) in anh. THF (170 ml), under nitrogen, was treated dropwise with a solution of 1.6 M n-BuLi in hexanes (23.5 ml; 37.60 mmol). The resulting slightly yellow solution was further stirred at −78° C. for 15 min. A yellow solution of methyl 5-((tert-butylsulfinyl)imino)pentanoate (5.850 g; 25.07 mmol) in anh. THF (12 ml) was then added dropwise to the cooled reaction mixture, and stirring at −78° C. was continued for 45 min. The resulting yellow reaction mixture was treated successively with aq. sat. NH4Cl (80 ml), Et2O (250 ml) and water (75 ml). The separated yellow organic layer was then washed with brine (75 ml), dried over anh. MgSO4, filtered, and concentrated to dryness under reduced pressure. Purification by FC (DCM/MeOH=25/1) afforded methyl 5-(2,6-dimethoxyphenyl)-5-(1,1-dimethylethylsulfinamido)pentanoate as a yellow oil. LC-MS (conditions B): tR=0.85 min.; [M+H]+: 372.34 g/mol.
Reaction SMILES: [F:1][C:2]([F:9])([F:8])/[CH:3]=[CH:4]/[C:5](O)=[O:6].C(Cl)(=O)C(Cl)=O.Cl.Cl.[CH2:18]([N:20]([C:24]1[CH:29]=[C:28]([CH3:30])[CH:27]=[CH:26][N:25]=1)[CH2:21][CH2:22][NH2:23])[CH3:19].CCOP(O)N(C(C)C)C(C)C>ClCCl>[CH2:18]([N:20]([C:24]1[CH:29]=[C:28]([CH3:30])[CH:27]=[CH:26][N:25]=1)[CH2:21][CH2:22][NH:23][C:5](=[O:6])/[CH:4]=[CH:3]/[C:2]([F:9])([F:8])[F:1])[CH3:19]
Reactant: O=C(O)/C=C/C(F)(F)F
Reactant: CCN(CCN)c1cc(C)ccn1
Agent: CCOP(O)N(C(C)C)C(C)C
Agent: Cl
Agent: O=C(Cl)C(=O)Cl
Solvent: ClCCl
Product: CCN(CCNC(=O)/C=C/C(F)(F)F)c1cc(C)ccn1
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 64 %

Procedure:
(E)-4,4,4-Trifluorobut-2-enoic acid (32 mg, 0.23 mmol) was dissolved in dichloromethane (0.5 ml containing one drop of dimethyl formamide), oxalyl chloride was added (20 μl, 0.23 mmol) and the solution was stirred at room temperature for 15 minutes. This solution was added to a solution of N-ethyl-N-(4-methyl-2-pyridyl)ethane-1,2-diamine dihydrochloride (38 mg, 0.15 mmol) and EDIPA (128 μl, 0.8 mmol) in anhydrous dichloromethane (2 ml) and the resulting mixture was stirred at room temperature overnight. The reaction mixture was concentrated under reduced pressure and the resulting residue was purified by preparative HPLC (Waters XBridge, gradient of water containing 0.1% NH3 and 10% to 100% acetonitrile) to yield 29 mg of a solid (0.096 mmol, 64% yield).
Reaction SMILES: C(=O)([O-])[O-].[K+].[K+].[CH3:7][C@@:8]([S:36]([CH3:39])(=[O:38])=[O:37])([CH2:19][CH2:20][C:21]1[CH:26]=[CH:25][C:24](B2OC(C)(C)C(C)(C)O2)=[CH:23][CH:22]=1)[C:9]([NH:11][O:12][CH:13]1[CH2:18][CH2:17][CH2:16][CH2:15][O:14]1)=[O:10].Br[C:41]1[CH:53]=[CH:52][C:44]([O:45][CH:46]2[CH2:51][CH2:50][CH2:49][CH2:48][O:47]2)=[CH:43][CH:42]=1.O>O1CCOCC1.C(Cl)Cl.[Pd+2]>[CH3:7][C@@:8]([S:36]([CH3:39])(=[O:37])=[O:38])([CH2:19][CH2:20][C:21]1[CH:22]=[CH:23][C:24]([C:41]2[CH:53]=[CH:52][C:44]([O:45][CH:46]3[CH2:51][CH2:50][CH2:49][CH2:48][O:47]3)=[CH:43][CH:42]=2)=[CH:25][CH:26]=1)[C:9]([NH:11][O:12][CH:13]1[CH2:18][CH2:17][CH2:16][CH2:15][O:14]1)=[O:10]
Reactant: CC1(C)OB(c2ccc(CC[C@](C)(C(=O)NOC3CCCCO3)S(C)(=O)=O)cc2)OC1(C)C
Reactant: Brc1ccc(OC2CCCCO2)cc1
Agent: [Pd+2]
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: C1COCCO1
Solvent: ClCCl
Solvent: O
Product: C[C@@](CCc1ccc(-c2ccc(OC3CCCCO3)cc2)cc1)(C(=O)NOC1CCCCO1)S(C)(=O)=O

Procedure:
Palladium (II) EnCat (575 mg, 0.22 mmol) was added to a mixture of potassium carbonate (892 mg, 3.1 mmol), (2R)-2-methyl-2-(methylsulfonyl)-N-(tetrahydro-2H-pyran-2-yloxy)-4-[4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl]butanamide (1.01 g, 2.1 mmol), (i.e. compound VIIa, which was prepared as in Preparation 8) and 2-(4-bromophenoxy)tetrahydro-2H-pyran (819 mg, 3.18 mmol) in dioxane:water (20 mL, 1:1) in a 50 mL flask and the reaction was heated at 90° C. overnight. The reaction was filtered and the resin was washed with ethyl acetate (50 mL) and water (50 mL). The organic layer was separated and aqueous layer extracted with ethyl acetate (2×100 mL). The combined organics were washed with saturated aqueous sodium bicarbonate (100 mL), dried (MgSO4), filtered and concentrated in vacuo to furnish the crude product. The material was dissolved in a minimum amount of DCM and loaded onto an Analogix SF25-40 g column and eluted with 100% heptane (500 mL) followed by increasing EtOAc in heptane 20%-30%-50% over 500 mL volumes. The title compound was obtained as a white solid (830 mg, 74.4%) LC-MS m/z 530.8 (M−1).
Reaction SMILES: [H-].[Na+].[Cl:3][C:4]1[CH:26]=[CH:25][C:24]([C:27]([F:30])([F:29])[F:28])=[CH:23][C:5]=1[NH:6][C:7]1[C:12]([N+:13]([O-:15])=[O:14])=[CH:11][C:10]([N+:16]([O-:18])=[O:17])=[CH:9][C:8]=1[C:19]([F:22])([F:21])[F:20].Cl[S:32][N:33]([CH3:44])[S:34]([C:37]1[CH:42]=[CH:41][C:40]([CH3:43])=[CH:39][CH:38]=1)(=[O:36])=[O:35]>C1COCC1>[Cl:3][C:4]1[CH:26]=[CH:25][C:24]([C:27]([F:28])([F:29])[F:30])=[CH:23][C:5]=1[N:6]([C:7]1[C:8]([C:19]([F:22])([F:21])[F:20])=[CH:9][C:10]([N+:16]([O-:18])=[O:17])=[CH:11][C:12]=1[N+:13]([O-:15])=[O:14])[S:32][N:33]([CH3:44])[S:34]([C:37]1[CH:42]=[CH:41][C:40]([CH3:43])=[CH:39][CH:38]=1)(=[O:36])=[O:35]
Reactant: O=[N+]([O-])c1cc([N+](=O)[O-])c(Nc2cc(C(F)(F)F)ccc2Cl)c(C(F)(F)F)c1
Reactant: Cc1ccc(S(=O)(=O)N(C)SCl)cc1
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: Cc1ccc(S(=O)(=O)N(C)SN(c2cc(C(F)(F)F)ccc2Cl)c2c([N+](=O)[O-])cc([N+](=O)[O-])cc2C(F)(F)F)cc1
Reaction time: 0.5 h
Yield: 66.6 %

Procedure:
To a suspension of 0.25 g sodium hydride in 20 ml anhydrous THF was added 3.2 g of 2-[2'-chloro-5'-(trifluoromethyl)anilino]-3,5-dinitrobenzotrifluoride, in portions, at 10° to 20° C. After stirring for 30 minutes, a solution of 2 g of N-chlorothio-N-methyl-p-toluenesulfonamide in 20 ml dry THF was added rapidly at a temperature below -20° C. The mixture was stirred in an ice bath for 30 minutes, then quenched by careful addition of ether and water. The organic phase was washed once with water, dried over anhydrous magnesium sulfate and filtered. The filtrate was concentrated in vacuo. The resultant oil was crystallized from a mixture of hexane and chlorobutane to give 3.2 g of N-[N-[2-chloro-5-(trifluoromethyl)-phenyl]-N-[2,4-dinitro-6-(trifluoromethyl)phenyl]-aminothio]-N,4-dimethylbenzenesulfonamide, mp 142.5°-144° C.
Reaction SMILES: [Cl:1][C:2]1[N:7]=[N:6][C:5]([NH:8][NH2:9])=[C:4]([CH3:10])[CH:3]=1.[CH3:11][C:12](O)=O.C([O-])(O)=O.[Na+]>C(Cl)Cl>[Cl:1][C:2]1[CH:3]=[C:4]([CH3:10])[C:5]2[N:6]([C:11]([CH3:12])=[N:9][N:8]=2)[N:7]=1
Reactant: CC(=O)O
Reactant: Cc1cc(Cl)nnc1NN
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Product: Cc1cc(Cl)nn2c(C)nnc12
Temperature: 115 °C
Reaction time: 1 h
Yield: 85.9 %

Procedure:
6-chloro-3-hydrazinyl-4-methylpyridazine (Step 111.1) (721 mg, 4.55 mmol) was dissolved in AcOH (15 mL, 262 mmol) and the resulting mixture was heated up and stirred at 115° C. for 1 hr. The reaction was cooled down to RT, diluted with CH2Cl2 and poured into a saturated aq. NaHCO3 solution. The aq. layer was extracted with CH2Cl2. The combined organic layers were dried over Na2SO4, filtered and concentrated under reduced pressure to afford the title product (752 mg, 3.91 mmol, 84% yield) as grey solid. tR: 0.59 min (LC-MS 2); ESI-MS: 183 [M+H]+ (LC-MS 2).
Reaction SMILES: [CH2:1]([N:8]1[C:12]2=[C:13]([O:17][CH2:18][C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=3)[N:14]=[N:15][CH:16]=[C:11]2[C:10](Br)=[C:9]1[CH3:26])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C([Li])CCC.CN(C)[CH:34]=[O:35]>CCCCCC.O1CCCC1>[CH2:1]([N:8]1[C:12]2=[C:13]([O:17][CH2:18][C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=3)[N:14]=[N:15][CH:16]=[C:11]2[C:10]([CH:34]=[O:35])=[C:9]1[CH3:26])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CN(C)C=O
Reactant: Cc1c(Br)c2cnnc(OCc3ccccc3)c2n1Cc1ccccc1
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: CCCCCC
Product: Cc1c(C=O)c2cnnc(OCc3ccccc3)c2n1Cc1ccccc1
Yield: 32 %

Procedure:
5.0 g (12.2 mmol) of 1-benzyl-7-benzyloxy-3-bromo-2-methylpyrrolo[2,3-d]pyridazine, 9 ml (14.7 mmol) of a 15% strength solution of n-butyllithium in hexane and 2.4 ml (29.4 mmol) of dimethylformamide are reacted in 125 ml of anhydrous tetrahydrofuran as described for Example 2a. Yield: 32%, m.p.: 147°-149° C.
Reaction SMILES: [NH2:1][C:2]1[C:11]([I:12])=[CH:10][C:5]([C:6]([O:8][CH3:9])=[O:7])=[C:4]([Cl:13])[CH:3]=1.C([O-])([O-])=O.[Ca+2].I[Cl:20]>CO.C(Cl)Cl>[NH2:1][C:2]1[C:11]([I:12])=[CH:10][C:5]([C:6]([O:8][CH3:9])=[O:7])=[C:4]([Cl:13])[CH:3]=1.[NH2:1][C:2]1[CH:3]=[CH:4][C:5]([C:6]([O:8][CH3:9])=[O:7])=[C:10]([Cl:20])[C:11]=1[I:12]
Reactant: ClI
Agent: COC(=O)c1cc(I)c(N)cc1Cl
Agent: O=C([O-])[O-]
Agent: [Ca+2]
Solvent: ClCCl
Solvent: CO
Product: COC(=O)c1ccc(N)c(I)c1Cl
Temperature: 25 °C
Reaction time: 1.5 h

Procedure:
Methyl 4-amino-2-chloro-5-iodo-benzoate, 23c. To a suspension of compound 23b (1.18 g, 6.38 mmol) and CaCO3 (12.8 mmol, 1.28 g) in MeOH (13 mL) was added a solution of iodine monochloride (6.70 mmol, 1.09 g) in CH2Cl2 (6 mL) dropwise at room temperature. The resulting reaction mixture was stirred at room temperature for 1.5 h. The reaction mixture was concentrated and then partitioned between EtOAc and water. The organic layer was concentrated and purified by flash column chromatography (silica gel, 20-25% EtOAc/hexanes) to provide methyl 4-amino-2-chloro-5-iodo-benzoate 23c as the major the product and methyl 4-amino-2-chloro-3-iodo-benzoate 23d as the minor product.
Reaction SMILES: Br[C:2]1[C:3]([C:11]2[CH:16]=[CH:15][N:14]=[CH:13][CH:12]=2)=[N:4][N:5]2[CH:10]=[CH:9][CH:8]=[N:7][C:6]=12.[CH3:17][O:18]/[N:19]=[C:20]1\[CH2:21][CH2:22][C:23]2[C:28]\1=[CH:27][CH:26]=[C:25](B(O)O)[CH:24]=2.C(N(CC)CC)C>COCCOC.[Pd](Cl)Cl.C1(P(C2C=CC=CC=2)[C-]2C=CC=C2)C=CC=CC=1.[C-]1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=C1.[Fe+2].C(OCC)(=O)C>[CH3:17][O:18][N:19]=[C:20]1[C:28]2[C:23](=[CH:24][C:25]([C:2]3[C:3]([C:11]4[CH:16]=[CH:15][N:14]=[CH:13][CH:12]=4)=[N:4][N:5]4[CH:10]=[CH:9][CH:8]=[N:7][C:6]=34)=[CH:26][CH:27]=2)[CH2:22][CH2:21]1
Reactant: Brc1c(-c2ccncc2)nn2cccnc12
Reactant: CO/N=C1\CCc2cc(B(O)O)ccc21
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: c1ccc(P(c2ccccc2)[c-]2cccc2)cc1
Solvent: COCCOC
Solvent: CCN(CC)CC
Solvent: CCOC(C)=O
Product: CON=C1CCc2cc(-c3c(-c4ccncc4)nn4cccnc34)ccc21
Temperature: 60 °C
Yield: 48.5 %

Procedure:
To 3-bromo-2-(pyridin-4-yl)pyrazolo[1.5-a]pyrimidine (0.150 g; Example 7, step 4) and (E)-1-(methoxyimino)-2,3-dihydro-1H-inden-5-ylboronic acid (0.224 g; Example 1, Step 5) in 5.5 mL 1,2-dimethoxyethane, was added 0.167 mL triethylamine and 27 mg 1,1′-bis(diphenylphosphino)ferrocene palladium (II) chloride catalyst. The mixture was heated at 60° C. for 16 hours, diluted with ethyl acetate, and washed with 10% aqueous potassium carbonate, dried over sodium sulfate, filtered, and evaporated to yield 94 mg (49% yield) product as a yellow solid. 1H NMR (CDCl3) was consistent with the desired structure. MS showed a M+1 molecular ion of m/z 356.2 by positive APCI.
Reaction SMILES: C[O:2][C:3](=[O:32])[CH2:4][CH2:5][CH2:6][N:7]1[CH2:11][CH2:10][CH2:9][C@@H:8]1[CH2:12][O:13][C:14]1[CH:19]=[CH:18][C:17]([CH2:20][C:21]2[CH:26]=[CH:25][C:24]([C:27]3[CH:31]=[CH:30][S:29][CH:28]=3)=[CH:23][CH:22]=2)=[CH:16][CH:15]=1.O.[ClH:34]>>[ClH:34].[S:29]1[CH:30]=[CH:31][C:27]([C:24]2[CH:23]=[CH:22][C:21]([CH2:20][C:17]3[CH:18]=[CH:19][C:14]([O:13][CH2:12][C@H:8]4[CH2:9][CH2:10][CH2:11][N:7]4[CH2:6][CH2:5][CH2:4][C:3]([OH:32])=[O:2])=[CH:15][CH:16]=3)=[CH:26][CH:25]=2)=[CH:28]1
Reactant: COC(=O)CCCN1CCC[C@@H]1COc1ccc(Cc2ccc(-c3ccsc3)cc2)cc1
Agent: Cl
Solvent: O
Product: O=C(O)CCCN1CCC[C@@H]1COc1ccc(Cc2ccc(-c3ccsc3)cc2)cc1
Temperature: 25 °C
Reaction time: 24 h
Yield: 75 %

Procedure:
To a 20 mL vial which contained a solution of the product from step 1 (155 mg, 0.35 mmol) in HCl (4 N in dioxane 4 mL) was added water (0.5 mL) at 0° C. The mixture was allowed to warm to rt and stir at rt for 24 h. The solvent was removed to yield the crude which was purified by recrystallization from THF-ether to afford the title product (125 mg, 75%); LCMS; 100%, APCI+, Calcd: 435.6. Found m/z: 436.5, (M+1). 1H NMR (400 MHz, DMSO-d6); δ 1.74-2.08 (m, 5H), 2.15-2.26 (m, 1H), 2.31-2.40 (m, 2H), 3.05-3.20 (m, 2H), 3.40-3.49 (m, 1H), 3.53-3.63 (m, 1H), 3.83-3.93 (m, 1H), 3.90 (s, 2H), 4.15-4.19 (m, 1H), 4.27 (dd, J1=10.8 Hz, J2=3.6 Hz, 1H), 6.93 (d, J=8.8 Hz, 2H), 7.20 (d, J=8.8 Hz, 2H), 7.23 (d, J=8.4 Hz, 2H), 7.51 (dd, J1=4.8 Hz, J2=1.6 Hz, 1H), 7.60-7.63 (m, 3H), 7.79 (dd, J=2.8 Hz, J2=1.2 Hz, 1H):
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([CH2:9][CH2:10][CH2:11][OH:12])=[CH:5][CH:4]=1.Cl[C:14]1[NH:19][C:18]2[N:20]=[CH:21][CH:22]=[CH:23][C:17]=2[C:16](=[O:24])[N:15]=1.CC([O-])(C)C.[K+].CC#N>CS(C)=O.C(O)(C(F)(F)F)=O>[CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([CH2:9][CH2:10][CH2:11][O:12][C:14]2[NH:15][C:16](=[O:24])[C:17]3[CH:23]=[CH:22][CH:21]=[N:20][C:18]=3[N:19]=2)=[CH:5][CH:4]=1
Reactant: COc1ccc(CCCO)cc1
Reactant: O=c1nc(Cl)[nH]c2ncccc12
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: CS(C)=O
Solvent: O=C(O)C(F)(F)F
Solvent: CC#N
Product: COc1ccc(CCCOc2nc3ncccc3c(=O)[nH]2)cc1
Temperature: 120 °C

Procedure:
In a screw-capped glass tube, 3-(4-methoxyphenyl)-1-propanol ([5406-18-8], 137 mg, 0.826 mmol) was added to a mixture of 2-chloropyrido[2,3-d]pyrimidin-4(1H)-one ([93049-38-8], 50 mg, 0.28 mmol) and KOtBu (62 mg, 0.55 mmol) in DMSO (2 ml). The mixture was heated (3 days, 120° C.) and the title compound was isolated from the product mixture by reversed-phase, preparative HPLC (Agilent Zorbax XdB C18 column, solvent gradient 5-95% CH3CN in 0.1% TFA(aq) over 7 min, flow rate 30 ml/min). MS: m/e=310.5 [M−H−], 1H NMR (d6-DMSO): δ 2.02 (dd, 2H), 3.36 (d, 2H), 3.71 (s, 3H), 4.42 (d, 2H), 6.86 (d, 2H), 7.15 (d, 2H), 7.36 (dd, 1H), 8.38 (d, 1H), 8.79 (d, 1H).
Reaction SMILES: Br[C:2]1[CH:10]=[CH:9][C:8]2[C:4](=[CH:5][NH:6][N:7]=2)[CH:3]=1.[Li]CCCC.CN([CH:19]=[O:20])C.O>C1COCC1.CCCCCC>[N:7]1[NH:6][CH:5]=[C:4]2[C:8]=1[CH:9]=[CH:10][C:2]([CH:19]=[O:20])=[CH:3]2
Reactant: Brc1ccc2n[nH]cc2c1
Reactant: CN(C)C=O
Agent: [Li]CCCC
Solvent: CCCCCC
Solvent: O
Solvent: C1CCOC1
Product: O=Cc1ccc2n[nH]cc2c1
Temperature: 25 °C
Reaction time: 0.25 h

Procedure:
5-Bromo-2H-indazole (2 g, 9.85 mmol) was dissolved in THF (50 mL) and cooled down to −40° C. n-BuLi in n-hexane (1.6 M, 15.4 mL) was added dropwise. After 15 min stirring, DMF (1.53 mL, 19.7 mmol) was added and the RM was stirred 30 min at −40° C. before warming up to rt. After 1 h, water was added (60 mL) and the mixture was extracted 3 times with EtOAc. Combined organic layers were washed with brine and dried on Na2SO4. After evaporation of the solvent the crude was purified by flash chromatography (CombiFlash® Companion System®, with 12 g RediSep® silica gel column, n-hexane/EtOAc=100:0->50:50) to afford the title compound (tR 3.63 min (conditions 3), MH−=145).
Reaction SMILES: [S:1]1[CH:5]=[CH:4][CH:3]=[CH:2]1.C([Li])(C)(C)C.CCCCC.[CH3:16][Sn:17](Cl)([CH3:19])[CH3:18]>C1COCC1>[CH3:16][Sn:17]([CH3:19])([CH3:18])[C:2]1[S:1][CH:5]=[CH:4][CH:3]=1
Reactant: C[Sn](C)(C)Cl
Reactant: c1ccsc1
Agent: [Li]C(C)(C)C
Solvent: CCCCC
Solvent: C1CCOC1
Product: C[Sn](C)(C)c1cccs1
Temperature: -38 °C
Reaction time: 1 h

Procedure:
To a solution of thiophene (2.1 g, 25.0 mmol) in anhydrous THF (50 mL) was added dropwise over 30 minutes at −38° C. t-butyllithium in pentane (1.6 M, 16.0 mL, 25.6 mmol). The solution was stirred for 1 h at −38° C. and then cooled to −78° C. Trimethyltin chloride in THF (1 M, 25.3 mL, 25.3 mmol) was added dropwise over 30 min. The reaction was then stirred for 2 h at −78° C. and then for 15 h at r.t. The solvent was evaporated and the resulting yellow solid was taken up in other, washed with water and dried Na2SO4 and then evaporated to give a light brown liquid which solidified on standing.