Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[CH:4][C:5]2[CH2:11][CH2:10][CH:9]([NH:12][CH2:13][CH2:14][OH:15])[CH2:8][CH2:7][C:6]=2[C:16]=1[O:17][CH3:18].Cl[C:20]1[N:25]=[C:24]([NH:26][C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][C:28]=2[S:33]([N:36]2[CH2:40][CH2:39][CH:38]([OH:41])[CH2:37]2)(=[O:35])=[O:34])[C:23]([Cl:42])=[CH:22][N:21]=1>>[Cl:42][C:23]1[C:24]([NH:26][C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][C:28]=2[S:33]([N:36]2[CH2:40][CH2:39][CH:38]([OH:41])[CH2:37]2)(=[O:34])=[O:35])=[N:25][C:20]([NH:1][C:2]2[CH:3]=[CH:4][C:5]3[CH2:11][CH2:10][CH:9]([NH:12][CH2:13][CH2:14][OH:15])[CH2:8][CH2:7][C:6]=3[C:16]=2[O:17][CH3:18])=[N:21][CH:22]=1
Reactant: O=S(=O)(c1ccccc1Nc1nc(Cl)ncc1Cl)N1CCC(O)C1
Reactant: COc1c(N)ccc2c1CCC(NCCO)CC2
Product: COc1c(Nc2ncc(Cl)c(Nc3ccccc3S(=O)(=O)N3CCC(O)C3)n2)ccc2c1CCC(NCCO)CC2
Yield: 26 %

Procedure:
In an analogous manner to Experimental 691, part c, 2-(2-Amino-1-methoxy-6,7,8,9-tetrahydro-5H-benzocyclohepten-7-ylamino)-ethanol and 1-[2-(2,5-Dichloro-pyrimidin-4-ylamino)-benzenesulfonyl]-pyrrolidin-3-ol were combined to yield 1-(2-{5-Chloro-2-[7-(2-hydroxy-ethylamino)-1-methoxy-6,7,8,9-tetrahydro-5H-benzocyclohepten-2-ylamino]-pyrimidin-4-ylamino}-benzenesulfonyl)-pyrrolidin-3-ol (45.15 mg, 26% yield) as an off white foam. 1H-NMR (CDCl3) δ 9.37 (s, 1H), 8.50 (d, J=8.2 Hz, 1H), 8.15 (s, 1H), 7.95 (m, 2H), 7.70-7.57 (m, 2H), 7.47 (s, 1H), 6.81-6.73 (m, 2H), 5.02 (br s, 1H), 4.35 (br s, 1H), 3.72 (s, 3H), 3.63 (s, 2H), 3.41 (m, 4H), 3.27 (m, 2H), 2.83 (m, 4H), 2.68 (m, 1H), 2.47 (m, 1H), 2.13 (m, 2H), 1.95 (m, 2H), 1.26 (m, 2H). LC/MS (ESI+)=603 (M+H).
Reaction SMILES: [ClH:1].O1CCOCC1.[Br:8][C:9]1[O:13][C:12]([C:14]([N:16]2[CH2:21][CH2:20][N:19](C(OC(C)(C)C)=O)[CH2:18][CH:17]2[CH2:29][O:30][C:31]2[CH:32]=[N:33][CH:34]=[CH:35][CH:36]=2)=[O:15])=[CH:11][CH:10]=1>CO>[ClH:1].[ClH:1].[Br:8][C:9]1[O:13][C:12]([C:14]([N:16]2[CH2:21][CH2:20][NH:19][CH2:18][CH:17]2[CH2:29][O:30][C:31]2[CH:32]=[N:33][CH:34]=[CH:35][CH:36]=2)=[O:15])=[CH:11][CH:10]=1
Reactant: CC(C)(C)OC(=O)N1CCN(C(=O)c2ccc(Br)o2)C(COc2cccnc2)C1
Agent: Cl
Solvent: C1COCCO1
Solvent: CO
Product: O=C(c1ccc(Br)o1)N1CCNCC1COc1cccnc1
Reaction time: 8 h
Yield: 94 %

Procedure:
4 M HCl in 1,4-dioxane (6 mL, 24 mmol) was added to a solution of tert-butyl 4-(5-bromofuran-2-carbonyl)-3-((pyridin-3-yloxy)methyl)piperazine-1-carboxylate (75 mg, 0.16 mmol) in MeOH (1 mL). After stirring overnight, the reaction mixture was concentrated under reduced pressure and purified by HPLC (5 to 50% MeCN/0.1% TFA in H2O/0.1% TFA gradient). The desired chromatography fractions were concentrated under reduced pressure, dissolved in MeOH (1 mL), and treated with 4 M HCl in 1,4-dioxane (6 mL). This was concentrated under reduced pressure, yielding 66 mg (94%) of the desired product as a white solid. LC-MS: RT=3.54 min, [M+H]+=366.0.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:31]=[CH:32][CH:33]=1)[CH2:5][NH:6][C:7]([C:9]1[CH:22]=[CH:21][C:20]2[S:19][C:18]3[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=3)[N:12]([CH:23]([CH3:30])[CH2:24][N:25]3[CH2:29][CH2:28][CH2:27][CH2:26]3)[C:11]=2[CH:10]=1)=S.C(O)(=O)/C=C/C(O)=[O:38]>C(O)(=O)C.C(O)C>[F:1][C:2]1[CH:3]=[C:4]([CH:31]=[CH:32][CH:33]=1)[CH2:5][NH:6][C:7]([C:9]1[CH:22]=[CH:21][C:20]2[S:19][C:18]3[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=3)[N:12]([CH:23]([CH3:30])[CH2:24][N:25]3[CH2:29][CH2:28][CH2:27][CH2:26]3)[C:11]=2[CH:10]=1)=[O:38]
Reactant: O=C(O)/C=C/C(=O)O
Reactant: CC(CN1CCCC1)N1c2ccccc2Sc2ccc(C(=S)NCc3cccc(F)c3)cc21
Solvent: CCO
Solvent: CC(=O)O
Product: CC(CN1CCCC1)N1c2ccccc2Sc2ccc(C(=O)NCc3cccc(F)c3)cc21
Temperature: 20 °C
Reaction time: 20 h
Yield: 70.4 %

Procedure:
Mercuric acetate (0.80 g) is added to a solution of N-(3-fluorobenzyl)-10-[(2RS)-1-(1-pyrrolidinyl)-2-propyl]-2-phenothiazinecarbothioamide neutral fumarate (1.30 g) in acetic acid (20 cc), and the mixture obtained is stirred for 20 hours at a temperature in the region of 20° C. The black suspension obtained is filtered on sintered glass plugged with celite and the yellow filtrate is concentrated under reduced pressure (30 mm Hg; 4 kPa) at 40° C. The residue is taken up with ethyl acetate (100 cc) and the organic phase is washed successively with normal sodium hydroxide (2×20 cc) and distilled water (2×20 cc) and with aqueous sodium chloride solution (20 cc) and dried over magnesium sulphate. After filtration, the yellow filtrate is concentrated under reduced pressure (30 mm Hg; 4 kPa) at 40° C. and a crude yellow oil (0.90 g) is thereby obtained. This residue is dissolved in hot ethanol (3 cc) and treated with fumaric acid (0.25 g) dissolved in ethanol (2 cc). After 4 hours' cooling to 4° C., the crystallized solid is separated by filtration, washed with cold ethanol (2×5 cc) and then dried at 50° C. under reduced pressure (5 mm Hg; 0.7 kPa) to give N-(3-fluorobenzyl)-10-[(2RS)-1-(1-pyrrolidinyl)-2-propyl]-2-phenothiazinecarboxamide neutral fumarate (0.7 g), m.p. 165° C.
Reaction SMILES: Cl.[CH:2]1([CH2:5][O:6][C:7]2[CH:12]=[C:11]([O:13][CH3:14])[CH:10]=[CH:9][C:8]=2[C:15]2[CH:20]=[CH:19][N:18]=[C:17]3[C:21]([C:25]([NH:27][CH:28]4[CH2:33][CH2:32][NH:31][CH2:30][CH2:29]4)=[O:26])=[C:22]([CH3:24])[NH:23][C:16]=23)[CH2:4][CH2:3]1.[C:34](Cl)(=[O:37])[CH2:35][CH3:36]>>[CH:2]1([CH2:5][O:6][C:7]2[CH:12]=[C:11]([O:13][CH3:14])[CH:10]=[CH:9][C:8]=2[C:15]2[CH:20]=[CH:19][N:18]=[C:17]3[C:21]([C:25]([NH:27][CH:28]4[CH2:29][CH2:30][N:31]([C:34](=[O:37])[CH2:35][CH3:36])[CH2:32][CH2:33]4)=[O:26])=[C:22]([CH3:24])[NH:23][C:16]=23)[CH2:4][CH2:3]1
Reactant: COc1ccc(-c2ccnc3c(C(=O)NC4CCNCC4)c(C)[nH]c23)c(OCC2CC2)c1
Reactant: CCC(=O)Cl
Agent: Cl
Product: CCC(=O)N1CCC(NC(=O)c2c(C)[nH]c3c(-c4ccc(OC)cc4OCC4CC4)ccnc23)CC1

Procedure:
Starting from 7-[2-(cyclopropylmethoxy)-4-methoxyphenyl]-2-methyl-N-(piperidin-4-yl)-1H-pyrrolo[3,2-b]pyridine-3-carboxamide hydrochloride (example D.f11) and commercially propionyl chloride the title compound is obtained as colorless solid.
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:10]=[C:11]([N+:16]([O-])=O)[CH:12]=[CH:13][C:14]=1[CH3:15])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[BH4-].[Na+]>O1CCCC1.CO.O.O.O.O.C([O-])(=O)C.[Ni+2].C([O-])(=O)C>[CH2:1]([O:8][C:9]1[CH:10]=[C:11]([CH:12]=[CH:13][C:14]=1[CH3:15])[NH2:16])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: Cc1ccc([N+](=O)[O-])cc1OCc1ccccc1
Agent: [Ni+2]
Agent: CC(=O)[O-]
Agent: [BH4-]
Solvent: CO
Solvent: C1CCOC1
Solvent: O
Product: Cc1ccc(N)cc1OCc1ccccc1
Temperature: 0 °C
Yield: 95.9 %

Procedure:
To a stirred solution of 3-benzyloxy-4-methylnitrobenzene (1.1 g, 4.4 mmol) in tetrahydrofuran (25 mL) and methanol (50 mL) was added nickel acetate tetrahydrate (2.2 g, 8.7 mmol). The solution was cooled to 0° C. and sodium borohydride (0.66 g, 17.4 mmol) was added in small portions. After gas evolution had ceased, the solvents were removed in vacuo and the residue was partitioned between ethyl acetate and concentrated ammonium hydroxide. The layers were separated and the organic phase was washed with ammonium hydroxide followed by saturated aqueous sodium chloride solution, dried (magnesium sulfate), filtered, and concentrated In vacuo to give 0.9 g (97%) of the title product as an off-white solid.
Reaction SMILES: [Br:1][C:2]([Br:29])=[CH:3][C:4]1[CH:9]=[CH:8][C:7]([N:10]2[CH2:14][C@H:13]([CH2:15][N:16]3C(=O)C4[C:18](=CC=CC=4)[C:17]3=[O:26])[O:12][C:11]2=[O:27])=[CH:6][C:5]=1[F:28].O.NN>C1COCC1.C(O)C>[Br:29][C:2]([Br:1])=[CH:3][C:4]1[CH:9]=[CH:8][C:7]([N:10]2[CH2:14][C@H:13]([CH2:15][NH:16][C:17](=[O:26])[CH3:18])[O:12][C:11]2=[O:27])=[CH:6][C:5]=1[F:28]
Reactant: O=C1c2ccccc2C(=O)N1C[C@H]1CN(c2ccc(C=C(Br)Br)c(F)c2)C(=O)O1
Agent: NN
Solvent: O
Solvent: C1CCOC1
Solvent: CCO
Product: CC(=O)NC[C@H]1CN(c2ccc(C=C(Br)Br)c(F)c2)C(=O)O1
Temperature: 25 °C
Reaction time: 0.08 h

Procedure:
A suspension of Example 1D (2.45 g) in 1:1 THF/ethanol (36 mL) was heated to 70° C., treated with hydrazine monohydrate (3×227 μL) at 1 hour intervals, cooled to 25 ° C., and filtered. The filtrate was concentrated, dissolved in a mixture of pyridine (10 mL) and dichloromethane (25 mL), cooled to −5° C., treated with acetic anhydride (880 μL), warmed to room temperature, stirred for 5 minutes, and concentrated to provide the desired product. mp 177-179° C.; MS (ESI(+)) m/e 437 (M+H)+; 1H NMR (300 MHz, CDCl3) δ 7.81 (t, 1H), 7.50 (s, 1H), 7.47 (dd, 1H), 7.20 (dd, 1H), 5.92 (br t, 1H), 4.80 (m, 1H), 4.06 (t, 1H), 3.77 (dd, 1H), 3.75-3.55 (m, 2H), 2.02 (s, 3H).
Reaction SMILES: [CH3:1][C:2]1([CH3:26])[CH2:11][CH2:10][C:9]([CH3:13])([CH3:12])[C:8]2[CH:7]=[C:6]([C:14]3[N:15]=[C:16]([N:19]4[CH2:24][CH2:23][CH:22]([NH2:25])[CH2:21][CH2:20]4)[S:17][CH:18]=3)[CH:5]=[CH:4][C:3]1=2.C(OC([N:34]1[CH2:38][CH2:37][C@H:36]([OH:39])[C@H:35]1[C:40](O)=[O:41])=O)(C)(C)C.Cl>O1CCOCC1>[CH3:1][C:2]1([CH3:26])[CH2:11][CH2:10][C:9]([CH3:12])([CH3:13])[C:8]2[CH:7]=[C:6]([C:14]3[N:15]=[C:16]([N:19]4[CH2:24][CH2:23][CH:22]([NH:25][C:40]([C@@H:35]5[C@@H:36]([OH:39])[CH2:37][CH2:38][NH:34]5)=[O:41])[CH2:21][CH2:20]4)[S:17][CH:18]=3)[CH:5]=[CH:4][C:3]1=2
Reactant: CC1(C)CCC(C)(C)c2cc(-c3csc(N4CCC(N)CC4)n3)ccc21
Reactant: CC(C)(C)OC(=O)N1CC[C@H](O)[C@H]1C(=O)O
Agent: Cl
Solvent: C1COCCO1
Product: CC1(C)CCC(C)(C)c2cc(-c3csc(N4CCC(NC(=O)[C@H]5NCC[C@@H]5O)CC4)n3)ccc21

Procedure:
The preparation was carried out analogously starting from 244 mg (0.50 mmol) of 1-[4-(5,5,8,8-tetramethyl-5,6,7,8-tetrahydronaphthalen-2-yl)thiazol-2-yl]piperidin-4-ylamine and 116 mg (0.50 mmol) of (2S,3S)-3-hydroxypyrrolidine-1,2-dicarboxylic acid 1-tert-butyl ester. The protecting group was cleaved off analogously using HCl in dioxane. The product was purified by means of flash chromatography on silica gel.
Reaction SMILES: [C:1]([N:3]=[C:4]([O:8][CH3:9])[CH2:5][C:6]#[N:7])#[N:2].CCOCC.[ClH:15].C(=O)(O)[O-].[Na+]>C(O)(=O)C.O>[Cl:15][C:1]1[N:3]=[C:4]([O:8][CH3:9])[CH:5]=[C:6]([NH2:7])[N:2]=1
Reactant: COC(CC#N)=NC#N
Reactant: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCOCC
Solvent: CC(=O)O
Solvent: O
Product: COc1cc(N)nc(Cl)n1
Yield: 83.1 %

Procedure:
After 1.23 g of methyl N-cyanocyanoacetimidate was dissolved in 10 ml of glacial acetic acid, 10.7 g of a 20% ether solution of hydrogen chloride was added dropwise at 15°-25°C to the solution. Then, the solution was made to react for 6 hours at room temperature. After the reaction, the solvent was distilled off to give a residue. The residue was dissolved in 10 ml of water and the solution was neutralized with sodium bicarbonate solution to give precipitates. Then, the precipitates were collected by filtration, washed with water and dried to give 1.47 g of crude crystals. The crystals were recrystallized from diluted hydrochloric acid to give 1.33 g of 2-chloro-4-methoxy-6-aminopyrimidine (yield 83.1%), mp 186°-187°C.
Reaction SMILES: [Cl:1][C:2]1[N:9]=[C:8]([NH:10][C:11]2[CH:15]=[C:14]([CH3:16])[NH:13][N:12]=2)[CH:7]=[C:6]([CH3:17])[C:3]=1[C:4]#[N:5].Cl.[CH3:19][O:20][C:21]1[CH:30]=[CH:29][C:24]([O:25][CH2:26][CH2:27][NH2:28])=[CH:23][CH:22]=1.C(=O)([O-])O.[Na+].CS(C)=O>O>[ClH:1].[CH3:19][O:20][C:21]1[CH:30]=[CH:29][C:24]([O:25][CH2:26][CH2:27][NH:28][C:2]2[N:9]=[C:8]([NH:10][C:11]3[CH:15]=[C:14]([CH3:16])[NH:13][N:12]=3)[CH:7]=[C:6]([CH3:17])[C:3]=2[C:4]#[N:5])=[CH:23][CH:22]=1
Reactant: Cc1cc(Nc2cc(C)c(C#N)c(Cl)n2)n[nH]1
Reactant: COc1ccc(OCCN)cc1
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CS(C)=O
Solvent: O
Product: COc1ccc(OCCNc2nc(Nc3cc(C)[nH]n3)cc(C)c2C#N)cc1
Temperature: 100 °C
Reaction time: 27 h
Yield: 19.4 %

Procedure:
Compound A (300 mg, 1.22 mmol), 2-(4-methoxyphenoxy)ethylamine hydrochloride (489 mg) and sodium hydrogencarbonate (1.37 g) were added to DMSO (10 ml), and the mixture was stirred at 100° C. for 27 hr. After stirring, the reaction mixture was added dropwise to cold water, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine, and concentrated, and the residue was washed by suspending in ethyl acetate. This was converted to hydrochloride to give the object compound of 2-(2-(4-methoxyphenoxy)ethylamino)-6-(5-methyl-1H-pyrazol-3-ylamino)-4-methylnicotinonitrile hydrochloride (98 mg).
Reaction SMILES: Cl[CH2:2][C:3]1[CH:8]=[CH:7][C:6]([CH2:9][CH2:10][C:11]2[N:12]=[C:13]([NH:27][C:28](=[O:30])[CH3:29])[S:14][C:15]=2[CH2:16][C:17]2[CH:22]=[CH:21][C:20]([S:23]([CH3:26])(=[O:25])=[O:24])=[CH:19][CH:18]=2)=[CH:5][CH:4]=1.[NH3:31]>CC#N>[NH2:31][CH2:2][C:3]1[CH:8]=[CH:7][C:6]([CH2:9][CH2:10][C:11]2[N:12]=[C:13]([NH:27][C:28](=[O:30])[CH3:29])[S:14][C:15]=2[CH2:16][C:17]2[CH:22]=[CH:21][C:20]([S:23]([CH3:26])(=[O:25])=[O:24])=[CH:19][CH:18]=2)=[CH:5][CH:4]=1
Reactant: N
Reactant: CC(=O)Nc1nc(CCc2ccc(CCl)cc2)c(Cc2ccc(S(C)(=O)=O)cc2)s1
Solvent: CC#N
Product: CC(=O)Nc1nc(CCc2ccc(CN)cc2)c(Cc2ccc(S(C)(=O)=O)cc2)s1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
N-{4-{2-[4-(Chloromethyl)phenyl]ethyl}-5-[4-(methylsulfonyl)benzyl]-1,3-thiazol-2-yl}acetamide (150 mg) was suspended in CH3CN (6 ml), and then 28% ammonia solution (0.4 ml) was added to the suspension at 0° C. The reaction mixture was stirred at r.t. for 16 hours, and concentrated in vacuo. The residual solid was washed with water, and purified by preparative silica gel chromatography with CHCl3/MeOH (10:1) as an eluent to give N-{4-{2-[4-(aminomethyl)phenyl]ethyl}-5-[4-(methylsulfonyl)benzyl]-1,3-thiazol-2-yl}acetamide (32.1 mg) as a pale yellow amorphous substance.
Reaction SMILES: [CH3:1][C:2]([CH3:6])([CH3:5])[CH2:3][OH:4].CS(C)=O.[H-].[Na+].[Br:13][C:14]1[CH:15]=[C:16]2[C@:27]3([N:32]=[C:31]([NH2:33])[CH2:30][O:29][CH2:28]3)[C:26]3[CH:25]=[C:24](Cl)[N:23]=[CH:22][C:21]=3[O:20][C:17]2=[CH:18][CH:19]=1>O.CCOC(C)=O.[Cl-].[Na+].O>[Br:13][C:14]1[CH:15]=[C:16]2[C@:27]3([N:32]=[C:31]([NH2:33])[CH2:30][O:29][CH2:28]3)[C:26]3[CH:25]=[C:24]([O:4][CH2:3][C:2]([CH3:6])([CH3:5])[CH3:1])[N:23]=[CH:22][C:21]=3[O:20][C:17]2=[CH:18][CH:19]=1
Reactant: CC(C)(C)CO
Reactant: NC1=N[C@@]2(COC1)c1cc(Br)ccc1Oc1cnc(Cl)cc12
Agent: [Cl-]
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CS(C)=O
Solvent: CCOC(C)=O
Product: CC(C)(C)COc1cc2c(cn1)Oc1ccc(Br)cc1[C@@]21COCC(N)=N1
Temperature: 25 °C

Procedure:
A vial was charged with 2,2-dimethylpropan-1-ol (100 mg, 1.130 mmol) and DMSO (1130 μL) to give a clear solution. Sodium hydride (60% in mineral oil; 45.2 mg, 1.130 mmol) was added and the vial was placed in a 100° C. oil bath for 5 min, then was removed from the heat and cooled to RT. (S)-7-bromo-3-chloro-2′,6′-dihydrospiro[chromeno[2,3-c]pyridine-5,3′-[1,4]oxazin]-5′-amine (Intermediate 1B, 86 mg, 0.226 mmol) was added to give an orange solution. The vial was sealed and heated in a 100° C. oil bath for 2 h. The mixture was cooled to room temperature, then diluted with water and EtOAc. Brine was added and the layers were separated. The aq. layer was extracted with EtOAc (2×). The combined organic extracts were dried over sodium sulfate, filtered, and concentrated. The residue was purified by chromatography on silica gel (0-100% EtOAc/Hexane) to give (S)-7-bromo-3-(neopentyloxy)-2′,6′-dihydrospiro[chromeno[2,3-c]pyridine-5,3′-[1,4]oxazin]-5′-amine as a light-yellow solid. Step 2: A vial was charged with (S)-7-bromo-3-(neopentyloxy)-2′,6′-dihydrospiro[chromeno[2,3-c]pyridine-5,3′-[1,4]oxazin]-5′-amine (74.0 mg, 0.171 mmol) 4,4-difluoropiperidine hydrochloride (31.1 mg, 0.257 mmol), and chloro(2-dicyclohexylphosphino-2′,4′,6′-tri-1-propyl-1,1′-biphenyl)[2-(2-aminoethyl)phenyl]palladium(II) methyl-t-butylether adduct (12.02 mg, 0.017 mmol). The vial was flushed with Argon and sealed. Lithium bis(trimethylsilyl)amide (1M in THF) (599 μL, 0.599 mmol) was added in one portion. The resulting mixture was sonicated for 1 min, then stirred for 30 min at rt. The reaction mixture was diluted with saturated aq ammonium chloride solution and extracted with EtOAc (3×). The combined organic extracts were dried over sodium sulfate, filtered, and concentrated. The residue was purified by chromatography (0-10% MeOH/DCM) to give (S)-7-(4,4-difluoropiperidin-1-yl)-3-(neopentyloxy)-2′,6′-dihydrospiro[chromeno[2,3-c]pyridine-5,3′-[1,4]oxazin]-5′-amine as an off-white solid. [M+H]+=473.2.
Reaction SMILES: Br[C:2]1[CH:10]=[CH:9][C:8]2[C:4](=[C:5]([CH3:14])[N:6]([CH2:11][CH2:12][CH3:13])[N:7]=2)[CH:3]=1.[Cl:15][C:16]1[CH:30]=[CH:29][C:19]([CH2:20][O:21][C:22]2[CH:27]=[CH:26][NH:25][C:24](=[O:28])[CH:23]=2)=[CH:18][CH:17]=1.C(=O)([O-])[O-].[K+].[K+].CN[C@@H]1CCCC[C@H]1NC>O1CCOCC1.[Cu]I>[Cl:15][C:16]1[CH:30]=[CH:29][C:19]([CH2:20][O:21][C:22]2[CH:27]=[CH:26][N:25]([C:2]3[CH:10]=[CH:9][C:8]4[C:4](=[C:5]([CH3:14])[N:6]([CH2:11][CH2:12][CH3:13])[N:7]=4)[CH:3]=3)[C:24](=[O:28])[CH:23]=2)=[CH:18][CH:17]=1
Reactant: CCCn1nc2ccc(Br)cc2c1C
Reactant: O=c1cc(OCc2ccc(Cl)cc2)cc[nH]1
Agent: [Cu]I
Agent: CN[C@@H]1CCCC[C@H]1NC
Agent: O=C([O-])[O-]
Solvent: C1COCCO1
Product: CCCn1nc2ccc(-n3ccc(OCc4ccc(Cl)cc4)cc3=O)cc2c1C
Temperature: 110 °C
Reaction time: 16 h
Yield: 42.3 %

Procedure:
To a solution of 5-bromo-3-methyl-2-propyl-2H-indazole (110 mg), 4-[(4-chlorobenzyl)oxy]pyridin-2(1H)-one (82 mg) and potassium carbonate (179 mg) in 1,4-dioxane (5 ml) were added copper(I) iodide (32 mg) and trans-N,N′-dimethylcyclohexane-1,2-diamine (24 mg), and the mixture was stirred at 110° C. for 16 hr. The reaction mixture was cooled to room temperature, and concentrated under reduced pressure. To the residue were added dichloromethane and water, and the organic layer was washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (dichloromethane/methanol) to give the title compound (60 mg).
Reaction SMILES: [CH:1]([N:4](CC)C(C)C)(C)[CH3:2].BrCC#N.[N:14]([CH2:17][CH2:18][CH2:19][C@H:20]([NH:24][C:25]([O:27][C:28]([CH3:31])([CH3:30])[CH3:29])=[O:26])[C:21]([OH:23])=[O:22])=[N+:15]=[N-:16]>C(#N)C>[N:14]([CH2:17][CH2:18][CH2:19][C@H:20]([NH:24][C:25]([O:27][C:28]([CH3:31])([CH3:30])[CH3:29])=[O:26])[C:21]([O:23][CH2:2][C:1]#[N:4])=[O:22])=[N+:15]=[N-:16]
Reactant: CC(C)(C)OC(=O)N[C@@H](CCCN=[N+]=[N-])C(=O)O
Reactant: CCN(C(C)C)C(C)C
Agent: N#CCBr
Solvent: CC#N
Product: CC(C)(C)OC(=O)N[C@@H](CCCN=[N+]=[N-])C(=O)OCC#N
Reaction time: 4 h
Yield: 107.1 %

Procedure:
N,N-Diisopropylethylamine (111 μL, 0.639 mmol) and subsequently bromoacetonitrile (203 μL, 2.90 mmol) were added to a solution of (S)-5-azido-2-((tert-butoxycarbonyl)amino)pentanoic acid (Compound tk69) (150 mg, 0.581 mmol) in acetonitrile (0.8 mL) at room temperature under a nitrogen atmosphere. The reaction mixture was stirred at the same temperature for 4 hours and then concentrated under reduced pressure, and the resulting crude product was purified by normal-phase silica gel column chromatography (hexane/ethyl acetate) to afford (S)-cyanomethyl 5-azido-2-((tert-butoxycarbonyl)amino)pentanoate (Compound tk70) (185 mg, quant.).
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([C:8]2[C:9](=[O:31])[N:10]([CH3:30])[C:11]([N:20]3[CH2:24][CH2:23][CH2:22][CH:21]3[CH2:25][NH:26][CH:27]([CH3:29])[CH3:28])=[N:12][C:13]=2[C:14]2[CH:19]=[CH:18][N:17]=[CH:16][CH:15]=2)[CH:5]=[CH:6][CH:7]=1.[C:32]1(C)C(C)=CC=C[CH:37]=1.CN(C=O)C.[F-].[K+]>ClCCl>[CH:27]([NH:26][CH2:25][CH:21]1[CH2:22][CH2:23][CH2:24][N:20]1[C:11]1[N:10]([CH3:30])[C:9](=[O:31])[C:8]([C:4]2[CH:5]=[CH:6][CH:7]=[C:2]([CH:32]=[CH2:37])[CH:3]=2)=[C:13]([C:14]2[CH:19]=[CH:18][N:17]=[CH:16][CH:15]=2)[N:12]=1)([CH3:29])[CH3:28]
Reactant: CC(C)NCC1CCCN1c1nc(-c2ccncc2)c(-c2cccc(Br)c2)c(=O)n1C
Reactant: Cc1ccccc1C
Agent: [F-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: ClCCl
Product: C=Cc1cccc(-c2c(-c3ccncc3)nc(N3CCCC3CNC(C)C)n(C)c2=O)c1
Temperature: 140 °C
Reaction time: 1 h

Procedure:
To a 250 mL RBF, was added 5-(3-bromo-phenyl)-2-[2-(isopropylamino-methyl)-pyrrolidin-1-yl]-3-methyl-6-pyridin-4-yl-3H-pyrimidin-4-one (0.48 g, 1.0 mmol), 50 mL xylene, 5 mL DMF and 0.58 mL tributhyl(vinyl)tin. The mixture was degassed by nitrogen bubbled through for 1 h. After added Pd(PPh)4 (58 mg, 0.05 mmol), the mixture was warmed up to 140° C. and stirred for 1 h under nitrogen. The mixture was cooled down to rt, 20 mL 10% KF solution was added and stirred for 30 min. The mixture was diluted with 200 mL dichloromethane, washed with sat. NaHCO3 and brine. After purified by flash chromatography, the title compound was obtained in 0.28 g as pale yellow solid. MS (ES+): 430 (M+H)+; (ES−): 428 (M−H).
Reaction SMILES: [NH2:1][C:2]1[CH:10]=[C:9]2[C:5]([C:6]([F:14])([F:13])[O:7][C:8]2([F:12])[F:11])=[CH:4][C:3]=1[OH:15].[F:16][C:17]1[CH:25]=[N:24][CH:23]=[CH:22][C:18]=1[C:19](O)=[O:20].CCN=C=NCCCN(C)C.N1C=CC=CC=1>O>[F:16][C:17]1[CH:25]=[N:24][CH:23]=[CH:22][C:18]=1[C:19]([NH:1][C:2]1[CH:10]=[C:9]2[C:5](=[CH:4][C:3]=1[OH:15])[C:6]([F:14])([F:13])[O:7][C:8]2([F:11])[F:12])=[O:20]
Reactant: Nc1cc2c(cc1O)C(F)(F)OC2(F)F
Reactant: O=C(O)c1ccncc1F
Agent: CCN=C=NCCCN(C)C
Solvent: c1ccncc1
Solvent: O
Product: O=C(Nc1cc2c(cc1O)C(F)(F)OC2(F)F)c1ccncc1F
Temperature: 80 °C
Yield: 62.7 %

Procedure:
A mixture of 1.5 g of 6-amino-1,1,3,3-tetrafluoro-5-hydroxy-1,3-dihydroisobenzofuran, 0.95 g of 3-fluoroisonicotinic acid, 1.68 g of WSC and 13 ml of pyridine was stirred while heating at 80° C. for two hours. The reaction mixture was cooled to room temperature, and then water was added, followed by extraction with ethyl acetate three times. The combined organic layers were washed with water and a saturated sodium chloride solution, dried over anhydrous magnesium sulfate, and then concentrated under reduced pressure. The residue was subjected to silica gel column chromatography to give 1.46 g of 3-fluoro-N-(1,1,3,3-tetrafluoro-6-hydroxy-1,3-dihydroisobenzofuran-5-yl)isonicotinamide.
Reaction SMILES: [F:1][C:2]1[CH:3]=[CH:4][CH:5]=[C:6]2[C:11]=1[NH:10][C:9](=[O:12])[N:8]([CH:13]1[CH2:18][CH2:17][N:16]([C:19]([O:21][CH:22]([C:34]3[CH:39]=[CH:38][CH:37]=[C:36](Br)[N:35]=3)[CH2:23][C:24]3[CH:25]=[C:26]4[C:30](=[C:31]([CH3:33])[CH:32]=3)[NH:29][N:28]=[CH:27]4)=[O:20])[CH2:15][CH2:14]1)[CH2:7]2.[Br-].[CH2:42]([Zn+])[CH:43]([CH3:45])[CH3:44]>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>[F:1][C:2]1[CH:3]=[CH:4][CH:5]=[C:6]2[C:11]=1[NH:10][C:9](=[O:12])[N:8]([CH:13]1[CH2:18][CH2:17][N:16]([C:19]([O:21][CH:22]([C:34]3[CH:39]=[CH:38][CH:37]=[C:36]([CH2:42][CH:43]([CH3:45])[CH3:44])[N:35]=3)[CH2:23][C:24]3[CH:25]=[C:26]4[C:30](=[C:31]([CH3:33])[CH:32]=3)[NH:29][N:28]=[CH:27]4)=[O:20])[CH2:15][CH2:14]1)[CH2:7]2
Reactant: CC(C)C[Zn+]
Reactant: Cc1cc(CC(OC(=O)N2CCC(N3Cc4cccc(F)c4NC3=O)CC2)c2cccc(Br)n2)cc2cn[nH]c12
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: [Br-]
Product: Cc1cc(CC(OC(=O)N2CCC(N3Cc4cccc(F)c4NC3=O)CC2)c2cccc(CC(C)C)n2)cc2cn[nH]c12
Temperature: 110 °C
Yield: 73.2 %

Procedure:
A microwave tube was charged with (±)-1-(6-bromopyridin-2-yl)-2-(7-methyl-1H-indazol-5-yl)ethyl 4-(8-fluoro-2-oxo-1,2-dihydroquinazolin-3(4H)-yl)piperidine-1-carboxylate (13.9 mg, 0.0229 mmol, 1.0 equiv) and Pd(PPh3)4 (ca. 2 mg). Isobutylzinc bromide (0.5 M in tetrahydrofuran, 0.46 mL, 0.23 mmol, 10 equiv) was then added via syringe under nitrogen. The vial was sealed and heated by microwave at 110° C. for 4 h. Tetrahydrofuran was removed in vacuo and the residue was partitioned between ethyl acetate and 0.5 N sodium hydroxide solution. The organic layer was separated and washed with brine, dried and concentrated. Flash column chromatography 10% methanol/methylene chloride) afforded the desired product (9.8 mg, 73.3%) as a glassy solid. MS (ESI) [M+H]+=585. 1H-NMR (400 MHz, CDCl3) δ 7.94 (s, 1H), 7.60-7.28 (m, 2H), 7.15-6.68 (m, 7H), 6.01 (br., 1H), 4.60-4.40 (m, 1H), 4.40-4.15 (m, 2H), 4.15-3.90 (m, 1H), 3.85-3.15 (m, 2H), 3.03-2.60 (m, 4H), 2.70 (s, 3H), 2.20-2.02 (m, 1H), 1.82-1.40 (m, 4H), 1.40-1.12 (m, 2H), 1.00-0.90 (m, 6H). HPLC tR=1.44 min.