Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Br:1]N1C(=O)CCC1=O.[CH3:9][C:10]1[CH:19]=[CH:18][C:17]2[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=2)[C:11]=1[C:20]([O:22][CH3:23])=[O:21].C(OOC(=O)C1C=CC=CC=1)(=O)C1C=CC=CC=1.C(OCC)(=O)C>C(#N)C>[Br:1][CH2:9][C:10]1[CH:19]=[CH:18][C:17]2[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=2)[C:11]=1[C:20]([O:22][CH3:23])=[O:21]
Reactant: O=C1CCC(=O)N1Br
Reactant: COC(=O)c1c(C)ccc2ccccc12
Agent: O=C(OOC(=O)c1ccccc1)c1ccccc1
Solvent: CCOC(C)=O
Solvent: CC#N
Product: COC(=O)c1c(CBr)ccc2ccccc12
Yield: 54.2 %

Procedure:
N-Bromosuccinimide (0.748 g) was added to a solution of methyl 2-methylnapthalene-1-carboxylate (0.7 g) in acetonitrile (30 ml) and the mixture was heated to reflux. Benzoyl peroxide (0.093 g) was added and the reaction mixture was heated at reflux for 4 hours. After cooling, ethyl acetate was added and the solution was washed with water, dried (MgSO4) and filtered. The filtrate was evaporated to dryness and the residue was purified by chromatography on silica, eluting with a mixture of DCM and pentane with a gradient of 7.5-25% to give methyl 2-bromomethylnaphthalene-1-carboxylate (0.529 g) as a yellow solid.
Reaction SMILES: C(OC(=O)[NH:7][C:8]1[CH:13]=[CH:12][C:11]([C:14]2[CH:19]=[C:18]([Cl:20])[N:17]=[CH:16][N:15]=2)=[CH:10][CH:9]=1)(C)(C)C.C(Cl)Cl.Cl>O>[Cl:20][C:18]1[N:17]=[CH:16][N:15]=[C:14]([C:11]2[CH:12]=[CH:13][C:8]([NH2:7])=[CH:9][CH:10]=2)[CH:19]=1
Reactant: CC(C)(C)OC(=O)Nc1ccc(-c2cc(Cl)ncn2)cc1
Agent: Cl
Solvent: ClCCl
Solvent: O
Product: Nc1ccc(-c2cc(Cl)ncn2)cc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A mixture of [4-(6-chloro-pyrimidin-4-yl)-phenyl]-carbamic acid tert-butyl ester (918 mg, 3.00 mmol), CH2Cl2 (30 mL) and HCl (4 N in dioxane; 3.80 mL) was stirred overnight at rt and the solid isolated by filtration. The resultant solid was taken up in water, treated with satd. aq. NaHCO3 and extracted with CH2Cl2. The extract was dried, filtered, and concentrated. The material was used directly in Step C.
Reaction SMILES: [CH:1]12[CH:6]([CH2:7][N:8]([C:16]3[CH:21]=[CH:20][C:19]([N:22]4[CH2:27][CH2:26][O:25][CH2:24][CH2:23]4)=[C:18]([F:28])[CH:17]=3)[C:9]([C:11]3[S:12][CH:13]=[CH:14][CH:15]=3)=[O:10])[CH:5]1[CH2:4][NH:3][CH2:2]2.CCN(C(C)C)C(C)C.[CH2:38]([C:40]1[CH:48]=[CH:47][C:43]([C:44](Cl)=[O:45])=[CH:42][CH:41]=1)[CH3:39]>C(Cl)Cl>[CH2:38]([C:40]1[CH:48]=[CH:47][C:43]([C:44]([N:3]2[CH2:4][CH:5]3[CH:1]([CH:6]3[CH2:7][N:8]([C:16]3[CH:21]=[CH:20][C:19]([N:22]4[CH2:27][CH2:26][O:25][CH2:24][CH2:23]4)=[C:18]([F:28])[CH:17]=3)[C:9]([C:11]3[S:12][CH:13]=[CH:14][CH:15]=3)=[O:10])[CH2:2]2)=[O:45])=[CH:42][CH:41]=1)[CH3:39]
Reactant: O=C(c1cccs1)N(CC1C2CNCC21)c1ccc(N2CCOCC2)c(F)c1
Reactant: CCc1ccc(C(=O)Cl)cc1
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: CCc1ccc(C(=O)N2CC3C(C2)C3CN(C(=O)c2cccs2)c2ccc(N3CCOCC3)c(F)c2)cc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 72.1 %

Procedure:
To a stirring solution of thiophene-2-carboxylic acid (3-aza-bicyclo[3.1.0]hex-6-ylmethyl)-(3-fluoro-4-morpholin-4-yl-phenyl)-amide (50 mg, 0.13 mmol) in 3 mL of anhydrous CH2Cl2, was added DIEA (0.065 mL, 0.37 mmol), followed by 4-ethylbenzoyl chloride (0.02 mL, 0.14 mmol). The reaction was stirred at room temperature for 1 hour, quenched with saturated NaHCO3, and extracted with CH2Cl2. The combined extracts were dried over anhydrous MgSO4, filtered and concentrated. The resulting crude material was purified via flash chromatography with 75% EtOAc/hexanes. The product containing fractions were collected and concentrated to yield 50 mg of a clear colorless oil. 400 MHz 1H NMR (CDCl3) δ 7.25-7.28 (m, 3H), 7.14-7.16 (m, 2H), 6.82-6.92 (m, 4H), 6.76-6.78 (m, 1H), 4.02-4.09 (m, 1H), 3.84-3.91 (m, 5H), 3.48-3.54 (m, 2H), 3.37-3.44 (m, 2H), 3.08-3.11 (m, 4H), 2.60 (q, 2H), 1.45 (s, 2H), 1.16-1.19 (m, 3H), 0.82-0.85 (m, 1H); MS (M+1) 534.2.
Reaction SMILES: [CH3:1][O:2][CH:3]([O:6][CH3:7])[CH2:4][NH2:5].[CH:8](=O)/[CH:9]=[CH:10]/[CH3:11]>C(O)C>[CH2:8]([NH:5][CH2:4][CH:3]([O:6][CH3:7])[O:2][CH3:1])[CH:9]=[CH:10][CH3:11]
Reactant: COC(CN)OC
Reactant: C/C=C/C=O
Solvent: CCO
Product: CC=CCNCC(OC)OC
Temperature: 0 °C
Reaction time: 8 h

Procedure:
200 g of molecular sieve are initially introduced into 1,000 ml of ethanol and 105 g (1 mol) of aminoacetaldehyde dimethyl acetal and 70 g (1 mol) of crotonaldehyde are added. The mixture is allowed to stand at room temperature overnight, decanted off from molecular sieve and cooled to 0° C., and 40 g of sodium borohydride are added in 1 g portions. The mixture is then stirred overnight at room temperature and concentrated, the residue is taken up in 500 ml of water and potassium carbonate is added until an organic phase separates. This is extracted using chloroform, dried over potassium carbonate and concentrated, and the residue is distilled.
Reaction SMILES: Br[C:2]1[C:3]([NH:9][CH:10]([CH:20]([CH3:22])[CH3:21])[CH2:11][NH:12][C:13](=[O:19])[O:14][C:15]([CH3:18])([CH3:17])[CH3:16])=[N:4][C:5]([Cl:8])=[N:6][CH:7]=1.ClC1N=C(NCCNC(=O)OC(C)(C)C)C([C:41]#[C:42][CH:43]([O:47][CH2:48][CH3:49])[O:44][CH2:45][CH3:46])=CN=1.CCCC[N+](CCCC)(CCCC)CCCC.[F-].ClC1N=CC2C=C(C(OCC)OCC)N(CCNC(=O)OC(C)(C)C)C=2N=1>>[Cl:8][C:5]1[N:6]=[CH:7][C:2]2[CH:41]=[C:42]([CH:43]([O:47][CH2:48][CH3:49])[O:44][CH2:45][CH3:46])[N:9]([CH:10]([CH:20]([CH3:22])[CH3:21])[CH2:11][NH:12][C:13](=[O:19])[O:14][C:15]([CH3:18])([CH3:17])[CH3:16])[C:3]=2[N:4]=1
Reactant: CC(C)C(CNC(=O)OC(C)(C)C)Nc1nc(Cl)ncc1Br
Reactant: CCOC(C#Cc1cnc(Cl)nc1NCCNC(=O)OC(C)(C)C)OCC
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: CCOC(OCC)c1cc2cnc(Cl)nc2n1CCNC(=O)OC(C)(C)C
Agent: [F-]
Product: CCOC(OCC)c1cc2cnc(Cl)nc2n1C(CNC(=O)OC(C)(C)C)C(C)C

Procedure:
tert-butyl N-[2-[2-chloro-6-(diethoxymethyl)pyrrolo[2,3-d]pyrimidin-7-yl]-3-methyl-butyl]carbamate was synthesized by subjecting tert-butyl N-[2-[(5-bromo-2-chloro-pyrimidin-4-yl)amino]-3-methyl-butyl]carbamate to Sonogoshira conditions as described for tert-butyl N-[2-[[2-chloro-5-(3,3-diethoxyprop-1-ynyl)pyrimidin-4-yl]amino]ethyl]carbamate followed by subsequent treatment with TBAF as described in the synthesis of tert-butyl N-[2-[2-chloro-6-(diethoxymethyl)pyrrolo[2,3-d]pyrimidin-7-yl]ethyl]carbamate. 1H NMR (600 MHz, DMSO-d6) δ ppm 1.11 (d, J=6.44 Hz, 3H) 1.18 (t, J=7.03 Hz, 6H) 1.21-1.26 (m, 12H) 2.88 (br. s., 1H) 3.43-3.78 (m, 6H) 3.97-4.08 (m, 1H) 5.61 (s, 1H) 6.65 (s, 1H) 6.71-6.78 (m, 1H) 8.87 (s, 1H). LCMS (ESI) 441 (M+H).
Reaction SMILES: C(=O)([O-])[O-].[K+].[K+].[CH3:7][O:8][CH:9]([O:12][CH3:13])[CH2:10][NH2:11].[Br:14][C:15]1[CH:23]=[CH:22][C:18]([C:19](Cl)=[O:20])=[CH:17][CH:16]=1>O.CC(C)=O>[Br:14][C:15]1[CH:23]=[CH:22][C:18]([C:19]([NH:11][CH2:10][CH:9]([O:12][CH3:13])[O:8][CH3:7])=[O:20])=[CH:17][CH:16]=1
Reactant: COC(CN)OC
Reactant: O=C(Cl)c1ccc(Br)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Solvent: O
Product: COC(CNC(=O)c1ccc(Br)cc1)OC
Temperature: 25 °C

Procedure:
Potassium carbonate (8.0 g) was added to a solution of 2,2-dimethoxyethylamine in water (90 ml) and acetone (40 ml) at rt. The reaction mixture was cooled in an ice-water bath and 4-bromobenzoyl chloride (16.4 g) dissolved in acetone (70 ml) was added drop-wise over 90 min. The stirred reaction mixture was allowed to warm to rt. After a further 2 h the reaction mixture was extracted into EtOAc (3×75 ml), the combined organics were washed with saturated aqueous sodium hydrogen carbonate, dried (MgSO4) and evaporated to give the amide as an off white solid (18.5 g). LCMS electrospray (+ve) 289 (MH+).
Reaction SMILES: C[O:2][C:3]1[C:4]([CH3:33])=[C:5]([C:24]([O:31]C)=[C:25]([O:29][CH3:30])[C:26]=1[O:27][CH3:28])[CH2:6][C:7]1[CH:8]=[CH:9][C:10]([C:16]2[CH:21]=[CH:20][CH:19]=[C:18]([O:22][CH3:23])[CH:17]=2)=[C:11]([CH:15]=1)[C:12]([OH:14])=[O:13].O=[N+]([O-])[O-].[O-][N+](=O)[O-].[O-][N+](=O)[O-].[O-][N+](=O)[O-].[O-][N+](=O)[O-].[O-][N+](=O)[O-].[Ce+4].[NH4+].[NH4+]>C(#N)C.O>[CH3:28][O:27][C:26]1[C:3](=[O:2])[C:4]([CH3:33])=[C:5]([CH2:6][C:7]2[CH:8]=[CH:9][C:10]([C:16]3[CH:21]=[CH:20][CH:19]=[C:18]([O:22][CH3:23])[CH:17]=3)=[C:11]([CH:15]=2)[C:12]([OH:14])=[O:13])[C:24](=[O:31])[C:25]=1[O:29][CH3:30]
Reactant: COc1cccc(-c2ccc(Cc3c(C)c(OC)c(OC)c(OC)c3OC)cc2C(=O)O)c1
Agent: O=[N+]([O-])[O-]
Agent: [Ce+4]
Agent: [NH4+]
Solvent: O
Solvent: CC#N
Product: COC1=C(OC)C(=O)C(Cc2ccc(-c3cccc(OC)c3)c(C(=O)O)c2)=C(C)C1=O
Temperature: 25 °C
Reaction time: 3 h
Yield: 85 %

Procedure:
5-(3,4,5,6-Tetramethoxy-2-methylbenzyl)-2-(3-methoxy-phenyl)benzoic acid (1.03 g, 2.2787 mmol) was dissolved in a mixed solvent of acetonitrile (30 ml) and water (10 ml), then CAN (3.12 g, 5.6934 mmol) was added thereto at room temperature and the mixture was stirred for 3 hour. The reaction solution was poured into water and extracted with ether. The extract was washed with water and dried and the solvent was evaporated therefrom. The residue was purified by silica gel column chromatography (5% methanol-methylene chloride) to give the title compound (817 mg, 1.9360 mmol, 85%).
Reaction SMILES: [C:1]([N:11]1[CH2:16][CH2:15][NH:14][C@@H:13]([C:17]([OH:19])=[O:18])[CH2:12]1)([O:3][CH2:4][C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1)=[O:2].[Cl:20][C:21]1[CH:26]=[C:25]([N+:27]([O-:29])=[O:28])[CH:24]=[C:23](F)[C:22]=1[Cl:31].O.CN(C)C=O>C(N(CC)CC)C>[C:1]([N:11]1[CH2:16][CH2:15][N:14]([C:24]2[CH:23]=[C:22]([Cl:31])[C:21]([Cl:20])=[CH:26][C:25]=2[N+:27]([O-:29])=[O:28])[C@@H:13]([C:17]([OH:19])=[O:18])[CH2:12]1)([O:3][CH2:4][C:5]1[CH:6]=[CH:7][CH:8]=[CH:9][CH:10]=1)=[O:2]
Reactant: O=[N+]([O-])c1cc(F)c(Cl)c(Cl)c1
Reactant: O=C(O)[C@H]1CN(C(=O)OCc2ccccc2)CCN1
Solvent: CN(C)C=O
Solvent: O
Solvent: CCN(CC)CC
Product: O=C(O)[C@H]1CN(C(=O)OCc2ccccc2)CCN1c1cc(Cl)c(Cl)cc1[N+](=O)[O-]
Temperature: 50 °C
Yield: 94.2 %

Procedure:
To a slurry containing 5.0 g of (R)-4-carbobenzyloxypiperazine-2-carboxylic acid, 4.2 g of 1,2-dichloro-fluoro-5-nitrobenzene, 85 mL of water and 170 mL of dimethylformamide is added slowly 5.3 mL of triethylamine. The solution is heated to 50° C. for 5 hours, then at ambient temperature overnight. The dark orange solution is concentrated under reduced pressure (1-2 mm, <50° C.) to an orange oily residue. This oil is dissolved in 400 mL of ethyl acetate and washed with 100 mL of 1 N HCl (2×), with 150 mL of water (2×), and 100 mL of brine. The organic layer is dried over MgSO4, filtered and concentrated to give 8.1 g (94.2%) of title compound as an orange solid foam.
Reaction SMILES: ClC1[CH:10]=[CH:9][C:5](C(O)=O)=[CH:4][N:3]=1.O(C1C=CC(CCN)=CC=1)C1C=CC=CC=1.Cl[C:28]1[CH:51]=[CH:50][C:31]([C:32]([NH:34][CH2:35][CH2:36][C:37]2[CH:42]=[CH:41][C:40]([O:43][C:44]3[CH:49]=[CH:48][CH:47]=[CH:46][CH:45]=3)=[CH:39][CH:38]=2)=[O:33])=[CH:30][N:29]=1.N1CCCCC1>>[O:43]([C:40]1[CH:41]=[CH:42][C:37]([CH2:36][CH2:35][NH:34][C:32](=[O:33])[C:31]2[CH:50]=[CH:51][C:28]([N:3]3[CH2:4][CH2:5][CH2:9][CH2:10]3)=[N:29][CH:30]=2)=[CH:38][CH:39]=1)[C:44]1[CH:49]=[CH:48][CH:47]=[CH:46][CH:45]=1
Reactant: O=C(NCCc1ccc(Oc2ccccc2)cc1)c1ccc(Cl)nc1
Reactant: O=C(O)c1ccc(Cl)nc1
Agent: NCCc1ccc(Oc2ccccc2)cc1
Solvent: C1CCNCC1
Product: O=C(NCCc1ccc(Oc2ccccc2)cc1)c1ccc(N2CCCC2)nc1

Procedure:
In analogy to example 21, 6-chloro-nicotinic acid was coupled with 4-phenoxyphenethylamine. The intermediate 6-chloro-N-[2-(4-phenoxy-phenyl)-ethyl]-nicotinamide was reacted with piperidine. White solid. MS (ISP): 388.3 ([M+H]+)
Reaction SMILES: [NH2:1][C@H:2]1[CH2:7][CH2:6][CH2:5][CH2:4][C@H:3]1[NH:8][C:9]1[N:14]=[C:13]([NH:15][C:16]2[CH:21]=[CH:20][C:19](C3ON=CC=3)=[CH:18][CH:17]=2)[C:12]([C:27]([NH2:29])=[O:28])=[CH:11][N:10]=1.[N:30]1(C2C=C(C=CC=2)N)[CH:34]=[N:33][N:32]=[N:31]1>>[N:30]1([C:20]2[CH:21]=[C:16]([NH:15][C:13]3[C:12]([C:27]([NH2:29])=[O:28])=[CH:11][N:10]=[C:9]([NH:8][C@@H:3]4[CH2:4][CH2:5][CH2:6][CH2:7][C@@H:2]4[NH2:1])[N:14]=3)[CH:17]=[CH:18][CH:19]=2)[CH:34]=[N:33][N:32]=[N:31]1
Reactant: NC(=O)c1cnc(N[C@@H]2CCCC[C@@H]2N)nc1Nc1ccc(-c2ccno2)cc1
Reactant: Nc1cccc(-n2cnnn2)c1
Product: NC(=O)c1cnc(N[C@@H]2CCCC[C@@H]2N)nc1Nc1cccc(-n2cnnn2)c1

Procedure:
This compound was synthesised using the synthetic scheme described for the synthesis of compound 122, and using 3-(1H-tetrazol-1-yl)aniline in step 1. MS: 395.5 (M+H).
Reaction SMILES: C(C1C=C2C(CC(=O)N2)=CC=1)(=O)C1C=CC=CC=1.CN1C2C(=CC=C(C(=O)C3C=CC=CC=3)C=2)CC1=O.[CH2:38]([N:41]1[C:49]2[C:44](=[CH:45][CH:46]=[C:47]([C:50](=[O:57])[C:51]3[CH:56]=[CH:55][CH:54]=[CH:53][CH:52]=3)[CH:48]=2)[CH2:43][C:42]1=[O:58])[CH2:39]C.C(N1C2C(=CC=C(C(=O)C3C=CC=CC=3)C=2)CC1=O)(C)C>>[CH2:38]([N:41]1[C:49]2[C:44](=[CH:45][CH:46]=[C:47]([C:50](=[O:57])[C:51]3[CH:56]=[CH:55][CH:54]=[CH:53][CH:52]=3)[CH:48]=2)[CH2:43][C:42]1=[O:58])[CH3:39]
Reactant: CCCN1C(=O)Cc2ccc(C(=O)c3ccccc3)cc21
Agent: CC(C)N1C(=O)Cc2ccc(C(=O)c3ccccc3)cc21
Agent: CN1C(=O)Cc2ccc(C(=O)c3ccccc3)cc21
Agent: O=C1Cc2ccc(C(=O)c3ccccc3)cc2N1
Product: CCN1C(=O)Cc2ccc(C(=O)c3ccccc3)cc21

Procedure:
Starting with 6-benzoyloxindole and the appropriate dialkyl sulfate and employing the procedure of Preparation G6, 1-methyl-6-benzoyloxindole, 1-n-propyl-6-benzoyloxindole and 1-i-propyl-6-benzoyloxindole are prepared.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][N:3]=1.[CH:8]#[C:9][CH2:10][CH3:11]>C(NCC)C.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.[Cu](I)I>[C:8]([C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][N:3]=1)#[C:9][CH2:10][CH3:11]
Reactant: Brc1ccccn1
Reactant: C#CCC
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: I[Cu]I
Solvent: CCNCC
Product: CCC#Cc1ccccn1
Temperature: 25 °C
Reaction time: 4 h
Yield: 84.3 %

Procedure:
To a solution of 2-bromopyridine (50 g) dissolved in diethylamine (500 mL) was added dichlorobis(triphenylphosphine)palladium(II) (2.2 g) and copper iodide (0.3 g), and the reaction mixture was stirred for 4 hours at room temperature while introducing 1-butyne (100 g) as a gas. The resulting reaction mixture was bubbled with nitrogen, and then ethyl acetate was added. After the reaction mixture was filtered through celite to remove insoluble residue, the filtrate was washed with water and brine. The obtained organic extract was dried over anhydrous magnesium sulfate and filtered, the solvent was evaporated under reduced pressure, the residue was purified by silica gel column chromatography and the title compound (35 g) was obtained as a brown oil from the n-hexane:ethyl acetate (5:1) fraction.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([CH:8]=[C:9]([S:19](=[O:22])(=[O:21])[NH2:20])[C:10]=1[NH:11][C:12]1[N:17]=[C:16]([CH3:18])[CH:15]=[CH:14][CH:13]=1)[C:5]([OH:7])=[O:6].[OH-].[Li+].[CH2:25](Br)[C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1>O>[CH2:25]([NH:1][C:2]1[CH:3]=[C:4]([CH:8]=[C:9]([S:19](=[O:21])(=[O:22])[NH2:20])[C:10]=1[NH:11][C:12]1[N:17]=[C:16]([CH3:18])[CH:15]=[CH:14][CH:13]=1)[C:5]([OH:7])=[O:6])[C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1
Reactant: Cc1cccc(Nc2c(N)cc(C(=O)O)cc2S(N)(=O)=O)n1
Reactant: BrCc1ccccc1
Agent: [Li+]
Agent: [OH-]
Solvent: O
Product: Cc1cccc(Nc2c(NCc3ccccc3)cc(C(=O)O)cc2S(N)(=O)=O)n1

Procedure:
A suspension of 3-amino-4-(2-methyl-6-pyridylamino)-5-sulphamyl-benzoic acid (0.5 g) in water (25 ml) was adjusted to a pH of 8 by addition of 1n lithium hydroxide. To the resulting solution, benzyl bromide (0.2 g) was added while, under stirring, the pH was kept at 8 by automatic titration with 1N lithium hydroxide. After the base consumpton had become negligible, the crude 3-benzylamino-4-(2-methyl-6-pyridylamino)-5-sulphamyl-benzoic acid was precipitated from the reaction mixture by adjusting the pH to 5 by means of 1N hydrochloric acid. The compound was collected by suction, recrystallized from aqueous ethanol, and dried. The melting point of the compound was 168°-170°C.
Reaction SMILES: [C:1]([C:5]1[CH:10]=[C:9]([Cl:11])[CH:8]=[C:7]([Cl:12])[N:6]=1)(OC)=[O:2].CC(C[AlH]CC(C)C)C>C1(C)C=CC=CC=1>[CH:1]([C:5]1[CH:10]=[C:9]([Cl:11])[CH:8]=[C:7]([Cl:12])[N:6]=1)=[O:2]
Reactant: COC(=O)c1cc(Cl)cc(Cl)n1
Agent: CC(C)C[AlH]CC(C)C
Solvent: Cc1ccccc1
Product: O=Cc1cc(Cl)cc(Cl)n1
Reaction time: 0.75 h

Procedure:
To a solution of 2-carbomethoxy-4,6-dichloropyridine (206 mg, 1 mmol) in 4 mL of dry toluene at -78° in a 25 mL round bottomed flask fitted with a stirrer bar and rubber septum, prepared by the procedure of D. G. Markees (vide supra) was slowly added 1.33 mL of 1.5M DIBAL (2 equivalents) in toluene. The mixture was stirred at -78° for 45 minutes, then at -50° for 30 minutes. The mixture was quenched with saturated ammonium chloride. After the effervescence ceased, the mixture was poured into 10 mL of water and extracted with 2×20 mL of methylene chloride. The organic layer was dried over anhydrous MgSO4, filtered and the solvent volume reduced. The residue was purifed by flash chromatography (85/15 hexane/ethyl acetate). Recovered 75 mg of product. NMR (CDCl3 200 Mhz): δ 7.59 (d, 1H, J=2 Hz), 7.87 (d, 1H, J=2 Hz), 9.97 (s, 1H).
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]2[C@@:15]3([CH2:20][CH2:19][O:18]/[C:17](=[N:21]\[C:22](=[O:29])[C:23]4[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=4)/[NH:16]3)[C:14]3[CH:13]=[C:12]([Cl:30])[N:11]=[C:10]([F:31])[C:9]=3[O:8][C:5]2=[CH:6][CH:7]=1.C1CCC(P(C2C(C3C=CC=CC=3)=CC=CC=2)C2CCCCC2)CC1.C[Si]([N-:61][Si](C)(C)C)(C)C.[Li+]>C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].C1COCC1>[NH2:61][C:2]1[CH:3]=[C:4]2[C@@:15]3([CH2:20][CH2:19][O:18]/[C:17](=[N:21]\[C:22](=[O:29])[C:23]4[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=4)/[NH:16]3)[C:14]3[CH:13]=[C:12]([Cl:30])[N:11]=[C:10]([F:31])[C:9]=3[O:8][C:5]2=[CH:6][CH:7]=1
Reactant: C[Si](C)(C)[N-][Si](C)(C)C
Reactant: O=C(/N=C1/N[C@@]2(CCO1)c1cc(Br)ccc1Oc1c2cc(Cl)nc1F)c1ccccc1
Agent: [Pd]
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Agent: [Li+]
Solvent: C1CCOC1
Product: Nc1ccc2c(c1)[C@@]1(CCO/C(=N\C(=O)c3ccccc3)N1)c1cc(Cl)nc(F)c1O2
Temperature: 65 °C

Procedure:
A microwave vial was charged with (S,Z)—N-(7-bromo-3-chloro-1-fluorospiro[chromeno[2,3-c]pyridine-5,4′-[1,3]oxazinan]-2′-ylidene)benzamide (2.0 g, 3.98 mmol), Pd(dba)2 (0.073 g, 0.080 mmol) and (2-biphenyl)dicyclohexylphosphine (0.067 g, 0.191 mmol), sealed and purged with N2 followed by the addition of THF (2 mL) and lithium bis(trimethylsilyl)amide, 1.0 m solution in tetrahydrofuran (8.75 ml, 8.75 mmol). The resulting mixture was heated at 65° C. for 17 h, quenched with saturated NH4Cl. The mixture was diluted with EtOAc, washed with water, brine, and dried over Na2SO4. The solution was concentrated and chromatographed on silica gel using 0-100% EtOAc/hexanes to afford a yellow oil as (S,Z)—N-(7-amino-3-chloro-1-fluorospiro[chromeno[2,3-c]pyridine-5,4′-[1,3]oxazinan]-2′-ylidene)benzamide.
Reaction SMILES: [F:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]([NH:10][C:11](=[O:13])[CH3:12])=[CH2:9])=[N:6][CH:7]=1>CO>[F:1][C:2]1[CH:3]=[CH:4][C:5]([C@@H:8]([NH:10][C:11](=[O:13])[CH3:12])[CH3:9])=[N:6][CH:7]=1
Reactant: C=C(NC(C)=O)c1ccc(F)cn1
Solvent: CO
Product: CC(=O)N[C@@H](C)c1ccc(F)cn1
Temperature: 25 °C
Yield: 88 %

Procedure:
To a solution of N-(1-(5-fluoropyridin-2-yl)vinyl)acetamide (Intermediate 2, 11.0 g, 61.1 mmol) in MeOH (120 ml) under N2 was added (+)-1,2-bis((2S,5S)-2,5-diethylphospholano)benzene(cyclooctadiene)rhodium(I)trifluoromethanesulfonate (0.441 g, 0.611 mmol). The solution was transferred to a high pressure bomb and charged 150 psi H2. The reaction stirred at room temperature and maintained inside pressure between 120-150 psi for 7 hours. The solvent was removed and the resulted residue was purified by column chromatography (EtOAc) to give the title compound as a white solid (9.8 g, 88%). 1H NMR (400 MHz) δ 8.49 (d, J=2.4 Hz, 1H), 8.32 (d, J=7.6 Hz, 1H), 7.66 (m, 1H), 7.39 (dd, J=4.4 and 8.8 Hz, 1H), 4.95 (m, 1H), 1.85 (s, 3H), 1.34 (d, J=7.2 Hz, 3H). MS: Calculated: 182. Found: [M+H]+ 183. Enantiomeric excess determined by HPLC (Chiralpak IA; 70:30 CO2/MeOH), 95.3% ee.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([F:8])[C:3]=1[C:9]1[CH:10]=[C:11]2[C:15](=[CH:16][CH:17]=1)[N:14](C1CCCCO1)[N:13]=[C:12]2[C:24]1[CH:25]=[C:26]([N:30]2[CH2:35][CH2:34][CH:33]([NH:36]C(=O)OC(C)(C)C)[CH2:32][CH2:31]2)[CH:27]=[N:28][CH:29]=1.Cl>O1CCOCC1>[F:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([F:8])[C:3]=1[C:9]1[CH:10]=[C:11]2[C:15](=[CH:16][CH:17]=1)[NH:14][N:13]=[C:12]2[C:24]1[CH:25]=[C:26]([N:30]2[CH2:35][CH2:34][CH:33]([NH2:36])[CH2:32][CH2:31]2)[CH:27]=[N:28][CH:29]=1
Reactant: CC(C)(C)OC(=O)NC1CCN(c2cncc(-c3nn(C4CCCCO4)c4ccc(-c5c(F)cccc5F)cc34)c2)CC1
Agent: Cl
Solvent: C1COCCO1
Product: NC1CCN(c2cncc(-c3n[nH]c4ccc(-c5c(F)cccc5F)cc34)c2)CC1
Temperature: 85 °C
Reaction time: 1 h

Procedure:
A solution of tert-butyl 1-(5-(5-(2,6-difluorophenyl)-1-(tetrahydro-2H-pyran-2-yl)-1H-indazol-3-yl)pyridin-3-yl)piperidin-4-ylcarbamate (120 mg, 0.204 mmol) in dioxane (5 mL) was treated with concentrated HCl (0.113 mL, 2.035 mmol). The reaction was heated to 85° C. After 1 h, the reaction was cooled to 23° C. and concentrated. The residue (as HCl salt) was free-based using a Silicycle Si-propylsulfonic acid ion exchange column (catalog # R51230B). The compound was diluted in MeOH and added to a pad of the resin (wetted and flushed with 10 mL MeOH). It was flushed with MeOH (50 mL), and then the product was “released” using 2.0 M NH3 in MeOH solution (50 ml). The final filtrate was concentrated, affording 1-(5-(5-(2,6-difluorophenyl)-1H-indazol-3-yl)pyridin-3-yl)piperidin-4-amine. MS (ESI, pos. ion) m/z: 406.2 (M+1).
Reaction SMILES: [CH3:1][O:2][C:3]1[C:4]([C:21]([OH:23])=O)=[CH:5][C:6]2[C:11]([CH:12]=1)=[CH:10][CH:9]=[C:8]([C:13]1[CH:18]=[CH:17][CH:16]=[C:15]([O:19][CH3:20])[CH:14]=1)[CH:7]=2.C[CH2:25][N:26]=C=NCCCN(C)C.OC1C2N=NNC=2C=CC=1.CN.C(N(CC)CC)C.Cl>ClCCl>[CH3:1][O:2][C:3]1[C:4]([C:21]([NH:26][CH3:25])=[O:23])=[CH:5][C:6]2[C:11]([CH:12]=1)=[CH:10][CH:9]=[C:8]([C:13]1[CH:18]=[CH:17][CH:16]=[C:15]([O:19][CH3:20])[CH:14]=1)[CH:7]=2
Reactant: COc1cccc(-c2ccc3cc(OC)c(C(=O)O)cc3c2)c1
Reactant: CCN=C=NCCCN(C)C
Agent: CN
Agent: Cl
Agent: Oc1cccc2[nH]nnc12
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CNC(=O)c1cc2cc(-c3cccc(OC)c3)ccc2cc1OC
Temperature: 0 °C
Yield: 74 %

Procedure:
3-Methoxy-7-(3-methoxyphenyl)-2-naphthoic acid (323 mg, 1.05 mmol, 1 eq), EDCI (1 eq) and hydroxybenzotriazole (1 eq) are dissolved in 50 ml of dichloromethane. To this solution, cooled at 0° C., are added dropwise methylamine (1 eq) and triethylamine (1 eq) in 40 ml of dry dichloromethane. The reaction mixture is boiled under reflux for 1.5 h, and after cooling, the reaction is stopped by adding 20 ml of 0.1 M HCl. The organic phase is separated, washed with saturated sodium carbonate and chloride solutions, dried over magnesium sulfate, filtered and concentrated in vacuum on a rotary evaporator. Purification by column chromatography with hexane/ethyl acetate 8/2 as the eluent yielded the desired product in a yield of 74%, 250 mg.
Reaction SMILES: [Na].[CH:2]1[C:7]([OH:8])=[CH:6][CH:5]=[C:4]([CH3:9])[CH:3]=1.Cl[CH:11](Cl)[C:12]([O:14][CH2:15][CH3:16])=[O:13]>C(O)C.C(OCC)C>[CH3:9][C:4]1[CH:5]=[CH:6][C:7]([O:8][CH:11]([O:8][C:7]2[CH:2]=[CH:3][C:4]([CH3:9])=[CH:5][CH:6]=2)[C:12]([O:14][CH2:15][CH3:16])=[O:13])=[CH:2][CH:3]=1
Reactant: Cc1ccc(O)cc1
Reactant: CCOC(=O)C(Cl)Cl
Agent: [Na]
Solvent: CCO
Solvent: CCOCC
Product: CCOC(=O)C(Oc1ccc(C)cc1)Oc1ccc(C)cc1
Temperature: 20 °C
Reaction time: 1 h
Yield: 77.3 %

Procedure:
Sodium (5.7 g) is dissolved in ethanol (160 cc), and a solution of para-cresol (27 g) in ethanol (20 cc) is added. The mixture is stirred for 1 hour at 20° C. and ethyl dichloroacetate (20 g) in solution in ethanol (20 cc) is then added. The mixture is heated under reflux for 20 hours and then allowed to cool. The white precipitate obtained is filtered off and the filtrate is concentrated to dryness under reduced pressure (20 mmHg) at 40° C. The oil thus obtained is taken up in diethyl ether (300 cc) and washed twice with N sodium hydroxide solution (100 cc each time) and twice with distilled water (100 cc each time). The ethereal phase is then dried over anhydrous sodium sulphate, filtered, and concentrated to dryness under reduced pressure (20 mmHg) at 40° C. Ethyl 2,2-bis(4-methylphenoxy)acetate (29 g) is thus obtained as a yellow oil.