Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]([CH:10]=[CH:11][CH:12]=1)[C:7](Cl)=[O:8])([O-:3])=[O:2].C(N(CC)CC)C.[CH2:20]([NH2:23])[CH:21]=[CH2:22]>ClCCl>[CH2:20]([NH:23][C:7](=[O:8])[C:6]1[CH:10]=[CH:11][CH:12]=[C:4]([N+:1]([O-:3])=[O:2])[CH:5]=1)[CH:21]=[CH2:22]
Reactant: C=CCN
Reactant: O=C(Cl)c1cccc([N+](=O)[O-])c1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: C=CCNC(=O)c1cccc([N+](=O)[O-])c1
Temperature: 2 °C
Reaction time: 16.5 h
Yield: 90.8 %

Procedure:
Step 1′ A 2-L, three-necked, round-bottomed flask equipped with a magnetic stirring bar, a 24/40 adapter fitted with a thermometer, an argon inlet adapter, and a 250-mL pressure-equalizing addition funnel fitted with a glass stopper was purged with argon. The flask was charged with 3-nitrobenzoyl chloride (J) 112.0 g (0.6035 mol) and 850 mL of dichloromethane, and then cooled with an ice-water bath. The addition funnel was charged with triethylamine 93.0 mL (0.667 mol) and allylamine (K) 50.0 mL (0.666 mol), and this solution was then added dropwise to the reaction mixture over ca. 2.5 h while the reaction temperature was maintained at 0-4° C. The addition funnel was then rinsed with two 5-mL portions of dichloromethane. The resulting turbid pale orange-pink reaction mixture was allowed to slowly warm to and stir at room temperature. After 16.5 h, 600 mL of 1N HCL was added to the turbid bright yellow solution over 30 sec and the biphasic mixture was transferred to a separatory funnel. The reaction flask was rinsed with three 100-mL portions of 1:1 CH2Cl2: 1N HCl and the organic phase was separated and washed with 500 mL of saturated sodium chloride solution, dried over sodium sulfate, filtered, and concentrated under reduced pressure to afford 122 g (98% crude yield) of a pale yellow solid. The crude product was recrystallized from 450 mL of toluene to afford 113 g (91 % yield) of N-allyl-3-nitrobenzamide (L) as a powdery pale yellow solid.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([Mg]Br)=[CH:4][CH:3]=1.[C:10]([N:15]1[C@@H:19]([C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)[CH2:18][O:17][C:16]1=[O:26])(=[O:14])/[CH:11]=[CH:12]/[CH3:13]>C1COCC1.CSC>[F:1][C:2]1[CH:7]=[CH:6][C:5]([C@H:12]([CH3:13])[CH2:11][C:10]([N:15]2[C@@H:19]([C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=3)[CH2:18][O:17][C:16]2=[O:26])=[O:14])=[CH:4][CH:3]=1
Reactant: Fc1ccc([Mg]Br)cc1
Reactant: C/C=C/C(=O)N1C(=O)OC[C@@H]1c1ccccc1
Solvent: C1CCOC1
Solvent: CSC
Product: C[C@H](CC(=O)N1C(=O)OC[C@@H]1c1ccccc1)c1ccc(F)cc1
Temperature: -10 °C
Reaction time: 12 h

Procedure:
To a stirred solution of copper(II)bromide dimethylsulfide complex (6.85 g, 33.3 mmol) in anhydrous THF (60 mL) and dimethylsulfide (30 mL) was added 4-fluorophenylmagnesium bromide (30.0 mL, 1.0 M in THF, 30.0 mmol) at −40° C. The resultant mixture was stirred at −40° C. for 30 min, then warmed to −10° C. The product from Step A (1.18 g, 5.10 mmol) in THF (30 mL) was added to the above reaction mixture over 1 h at −10° C. The resultant mixture was stirred at −10° C. for 2 h, then slowly warmed to room temperature and stirred at room temperature for 12 h. The reaction was quenched by slow addition of saturated aqueous ammonium chloride solution. The organic phase was separated and the aqueous phase was extracted with two portions of ethyl acetate. The combined organic layers were washed with brine and concentrated in vacuo. Purification by flash chromatography (silica gel, 80:20 hexanes/ethyl acetate) afforded the desired product.
Reaction SMILES: [F:1][C:2]1[CH:12]=[CH:11][C:10]([F:13])=[CH:9][C:3]=1[CH:4]=[CH:5][C:6]([OH:8])=[O:7]>C(O)C.[Pd]>[F:1][C:2]1[CH:12]=[CH:11][C:10]([F:13])=[CH:9][C:3]=1[CH2:4][CH2:5][C:6]([OH:8])=[O:7]
Reactant: O=C(O)C=Cc1cc(F)ccc1F
Agent: [Pd]
Solvent: CCO
Product: O=C(O)CCc1cc(F)ccc1F
Reaction time: 3 h

Procedure:
2,5-Difluorocinnamic acid (5.0 g, 27.2 mmol) was dissolved in 25 ml of ethanol and a catalytic amount of 10% Pd on carbon was added. The reaction mixture was hydrogenated at normal pressure for a period of 3 hrs. Filtration through celite and evaporation of the solvent afforded crude 3-(2,5-difluorophenyl)-propionic acid. This acid was dissolved in 75 ml of toluene and 5 ml of thionyl chloride was added. The reaction mixture was heated at +110° C. for a period of 2 hrs. Evaporation of the solvent afforded crude 3-(2,5-difluorophenyl)-propionyl chloride, which was dissolved in 25 ml of carbon disulfide and added drop wise to a suspension of 4 g of aluminium chloride in 100 ml of carbon disulfide. The reaction mixture was refluxed for 2 hrs and gave after work up and re-crystallization from ethanol 975 mg (22%) of 4,7-difluoro-1-indanone.
Reaction SMILES: NN.[CH3:3][CH:4]([N:6]1[CH2:11][CH:10]=[C:9]([C:12]2[CH:17]=[CH:16][C:15]([N+:18]([O-])=O)=[C:14]([O:21][CH3:22])[CH:13]=2)[CH2:8][CH2:7]1)[CH3:5]>>[CH3:5][CH:4]([N:6]1[CH2:7][CH:8]=[C:9]([C:12]2[CH:17]=[CH:16][C:15]([NH2:18])=[C:14]([O:21][CH3:22])[CH:13]=2)[CH2:10][CH2:11]1)[CH3:3]
Reactant: COc1cc(C2=CCN(C(C)C)CC2)ccc1[N+](=O)[O-]
Agent: NN
Product: COc1cc(C2=CCN(C(C)C)CC2)ccc1N
Yield: 90.6 %

Procedure:
In a manner analgous to the hydrazine-mediated reduction of Intermediate B1, 4-[1-(1-methylethyl)-1,2,3,6-tetrahydro-4-pyridinyl]-2-(methyloxy)aniline (1.60 g, 90% yield) was prepared from 1-(1-methylethyl)-4-[3-(methyloxy)-4-nitrophenyl]-1,2,3,6-tetrahydropyridine (2.0 g, 7.17 mmol). 1H NMR (400 MHz, CDCl3) δ ppm 1.12 (d, J=6.6 Hz, 6 H), 2.54 (s, 2 H), 2.73 (t, J=5.5 Hz, 2 H), 2.79 (dt, J=12.9, 6.6 Hz, 1 H), 3.24 (d, J=3.3 Hz, 2 H), 3.77 (s, 2 H), 3.85 (s, 3 H), 5.94 (s, 1 H), 6.65 (d, J=8.1 Hz, 1H), 6.80-6.86 (m, 2 H).
Reaction SMILES: [CH2:1]([NH2:4])[CH2:2][CH3:3].C(N(CC)CC)C.Cl[C:13]([O:15][CH2:16][C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1)=[O:14]>C(Cl)Cl>[CH2:1]([NH:4][C:13](=[O:14])[O:15][CH2:16][C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1)[CH2:2][CH3:3]
Reactant: O=C(Cl)OCc1ccccc1
Reactant: CCCN
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CCCNC(=O)OCc1ccccc1
Temperature: 0 °C
Reaction time: 1 h

Procedure:
Cbz Protection A solution of propylamine (9.0 g, 152.4 mmol) and triethylamine (15.4 g, 152.4 mmol) in methylene chloride (350 mL) was cooled to 0° C. and treated with benzyl chloroformate (20.0 g, 117.2 mmol). Upon stirring at 0° C. for 1 hour the reaction was warmed to ambient temperature and quenched with 1N HCl. The reaction was partitioned between 1N HCl and methylene chloride. The organics were washed with 1N HCl, water and brine. The combined organics were dried over sodium sulfate, filtered and evaporated in vacuo to give benzyl propylcarbamate as a clear oil. 1H NMR (400 MHz, CDCl3) δ 7.37 (m, 5H), 5.10 (s, 2H), 4.77 (bs, 1H), 3.16 (q, J=6.5 Hz, 2H), 1.52 (m, 2H), 0.92 (t, J=7.5 Hz, 3H). Step B: Alkylation A solution of benzyl propylcarbamate (20.8 g, 107.9 mmol) in DMF (200 mL) was cooled to 0° C. and treated with sodium hydride (4.6 g, 194.2 mmol). The reaction was stirred to 0° C. for 15 minutes and subsequently treated with crotyl bromide (17.5 g, 129.5 mmol). The reaction was warmed to ambient temperature and stirred for 16 hours. The reaction was quenched with ammonium chloride solution and partitioned between water and ether. The organics were washed with water (4×) and brine, dried over sodium sulfate, filtered and evaporated in vacuo. Flash chromatography (silica, 0-10% EtOAc/hexanes) gave benzyl (2E)-but-2-enyl(propyl)carbamate as a clear oil. 1H NMR (400 MHz, CDCl3) δ 7.35 (m, 5H), 5.57 (bt, 1H), 5.42 (bs, 1H), 5.13 (s, 2H), 3.82 (bm, 2H), 3.19 (bs, 2H), 1.68 (bs, 3H), 1.54 (bs, 2H), 0.87 (bs, 3H). Step C: Cyclopropanation A solution of benzyl (2E)-but-2-enyl(propyl)carbamate (5.0 g, 20.2 mmol) in methylene chloride (120 mL) was cooled to 0° C. and treated with diethylzinc (12.48 g, 101 mmol) followed by diiodomethane (54.1 g, 202 mmol). The reaction was warmed to ambient temperature and stirred for 16 hours. The reaction was quenched with saturated ammonium chloride solution and partitioned between methylene chloride and saturated sodium bicarbonate solution. The organics were dried over sodium sulfate, filtered and evaporated in vacuo. Flash chromatography (10% EtOAc/hexanes) gave 5.16 g (96%) of benzyl (2-methylcyclopropyl)methyl(propyl)carbamate as a yellow oil. 1H NMR (400 MHz, CDCl3) δ 7.35 (m, 5H), 5.13 (s, 2H), 3.16 (bm, 4H), 1.59 (bm, 2H), 1.01 (bs, 3H), 0.88 (bs, 3H), 0.68 (bs, 2H), 0.34 (bd, 1H), 0.22 (bs, 2H). Step D: Hydrogenation
Reaction SMILES: [NH2:1][C:2]1[C:5](=O)[C:4](=[O:7])[C:3]=1[O:8]C.[CH3:10][N:11]([CH2:13][C:14]1[CH:19]=[CH:18][N:17]=[C:16]([O:20][CH2:21][CH2:22][CH2:23][NH2:24])[CH:15]=1)[CH3:12]>C(O)C>[CH3:10][N:11]([CH2:13][C:14]1[CH:19]=[CH:18][N:17]=[C:16]([O:20][CH2:21][CH2:22][CH2:23][NH:24][C:5]2[C:4](=[O:7])[C:3](=[O:8])[C:2]=2[NH2:1])[CH:15]=1)[CH3:12]
Reactant: COc1c(N)c(=O)c1=O
Reactant: CN(C)Cc1ccnc(OCCCN)c1
Solvent: CCO
Product: CN(C)Cc1ccnc(OCCCNc2c(N)c(=O)c2=O)c1
Yield: 66 %

Procedure:
1-Amino-2-methoxy-cyclobut-1-ene-3,4-dione (0.5 g) and 3-[4-(dimethylaminomethyl)pyrid-2-yloxy]prop-1-yl-amine (0.85 g) were refluxed in ethanol in a similar manner to Example 1. The solid obtained was recrystallised from ethanol to give the title product, (0.79 g), m.p. 212°-4° C.
Reaction SMILES: C(OC(=O)[NH:7][CH2:8][C:9]([N:11]1[CH2:15][CH2:14][CH2:13][CH:12]1[C:16]#[N:17])=[O:10])(C)(C)C.[ClH:19]>CCOCC.O>[ClH:19].[NH2:7][CH2:8][C:9]([N:11]1[CH2:15][CH2:14][CH2:13][CH:12]1[C:16]#[N:17])=[O:10]
Reactant: CC(C)(C)OC(=O)NCC(=O)N1CCCC1C#N
Agent: Cl
Solvent: O
Solvent: CCOCC
Product: N#CC1CCCN1C(=O)CN
Reaction time: 1 h
Yield: 98 %

Procedure:
[2-(2-Cyano-pyrrolidin-1-yl)-2-oxo-ethyl]-carbamic acid tert-butyl ester 1e (13.7 g, 54.2 mmol) was dissolved in the solvent mixture of 140 mL of ether and 40 mL of water, and 37% hydrochloride acid (90 mL) were then added dropwise to the solution. Upon completion of the addition, the reaction mixture was stirred for 1 hour in an ice-water bath, the solvent was evaporated, and ether was added to the residue to centrifuge to give 1-(2-amino-acetyl)-pyrrolidine-2-carbonitrile hydrochloride 1d (10 g, yield 98%) as a white powder.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[CH2:8][CH:9]([CH2:13][CH2:14][CH3:15])[C:10](O)=[O:11].S(Cl)([Cl:18])=O>>[Br:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[CH2:8][CH:9]([CH2:13][CH2:14][CH3:15])[C:10]([Cl:18])=[O:11]
Reactant: CCCC(Cc1ccccc1Br)C(=O)O
Reactant: O=S(Cl)Cl
Product: CCCC(Cc1ccccc1Br)C(=O)Cl

Procedure:
A 500-ml three-necked round flask equipped with a stirring bar, a Dimroth condenser, a thermometer and a NaOH trap was charged with 277 mmol of 3-(2-bromophenyl)-2-propylpropionic acid and 200 ml of thionyl chloride, and the mixture was heated under reflux for 2 hours. Then, the excess thionyl chloride was removed by a single distillation, and the distillation of the residue under reduced pressure gave 77.4 g of a crude product having a boiling point of 130° to 135° C./1 mmHg as a pale brown transparent liquid. This acid chloride was used in the next reaction without further purification.
Reaction SMILES: Cl[C:2]1[C:7]([C:8]([O:10][CH2:11][CH3:12])=[O:9])=[CH:6][N:5]=[C:4]([Cl:13])[CH:3]=1.[CH:14]([NH2:17])([CH3:16])[CH3:15].CCN(C(C)C)C(C)C>CC(N(C)C)=O>[Cl:13][C:4]1[CH:3]=[C:2]([NH:17][CH:14]([CH3:16])[CH3:15])[C:7]([C:8]([O:10][CH2:11][CH3:12])=[O:9])=[CH:6][N:5]=1
Reactant: CC(C)N
Reactant: CCOC(=O)c1cnc(Cl)cc1Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: CC(=O)N(C)C
Product: CCOC(=O)c1cnc(Cl)cc1NC(C)C

Procedure:
A stirred solution of ethyl 4,6-dichloronicotinate (1) (10 g, 43.4 mmol), isopropyl amine (8 mL) and DIPEA (8 mL) in DMA (50 mL) were heated at 120° C. in a sealed tube for 3 h. The reaction mixture was concentrated to dryness to remove excess of DMA from the reaction mass. The crude material obtained was purified by column chromatography through silica gel and EtOAC: pet. Ether as eluent to obtain the title compound (2). LC/MS: Acquity BEH C18 2.1×50 mm, 1.8 micron; Solvent A=0.1% TFA in water; Solvent B=0.1% TFA in ACN; gradient 0-100% B over 2 min; retention time: 0.90 min; LCMS (ES-API), m/z 243.7 (M+H).
Reaction SMILES: [Cl:1][C:2]1[CH:11]=[C:10]2[C:5]([CH:6]=[CH:7][C:8](/[CH:12]=[CH:13]/[C:14]3[CH:15]=[C:16]([C@@H:20](O)[CH2:21][CH2:22][C:23]4[CH:32]=[CH:31][CH:30]=[CH:29][C:24]=4[C:25]([O:27][CH3:28])=[O:26])[CH:17]=[CH:18][CH:19]=3)=[N:9]2)=[CH:4][CH:3]=1.C(#N)C.[I-:37].[Na+].C[Si](C)(C)Cl>CO.C(Cl)Cl.O.C(OCC)(=O)C.C1COCC1>[Cl:1][C:2]1[CH:11]=[C:10]2[C:5]([CH:6]=[CH:7][C:8](/[CH:12]=[CH:13]/[C:14]3[CH:15]=[C:16]([C@@H:20]([I:37])[CH2:21][CH2:22][C:23]4[CH:32]=[CH:31][CH:30]=[CH:29][C:24]=4[C:25]([O:27][CH3:28])=[O:26])[CH:17]=[CH:18][CH:19]=3)=[N:9]2)=[CH:4][CH:3]=1
Reactant: COC(=O)c1ccccc1CC[C@H](O)c1cccc(/C=C/c2ccc3ccc(Cl)cc3n2)c1
Reactant: [I-]
Agent: C[Si](C)(C)Cl
Agent: [Na+]
Solvent: CO
Solvent: CCOC(C)=O
Solvent: O
Product: COC(=O)c1ccccc1CC[C@H](I)c1cccc(/C=C/c2ccc3ccc(Cl)cc3n2)c1

Procedure:
Adding anhydrous methyl 2-[(3S)-[3-[(2E)-(7-chloro quinolin-2-yl)ethenyl]phenyl]-3-hydroxypropyl]benzoate (1) solution in organic polar solvent such as acetonitrile, THF to a solution of sodium iodide at temperature of about 10° C. to about 25° C. followed by addition of trimethylchloro silane to the mass, raising the temperature to about 35° C. to about 55° C., maintaining the reaction mass at temperature of 35° C. to 55° C. for about 10 hrs to 24 hrs, isolation, slurring the wet cake with mixture of ethyl acetate, water gives the crude iodo derivative (IV, X═I). The crude on dissolution in mixture of methylene chloride, methanol followed by washing with sodium bicarbonate solution, water, drying over dehydrating agents such as anhydrous sodium sulphate, anhydrous magnesium sulphate, removal of solvent under reduced pressure at temperature below 50° C. followed by purification with column chromatography gives the pure methyl 2-[(3S)-[3-[(2E)-(7-chloro quinolin-2-yl)ethenyl]phenyl]-3-iodopropyl]benzoate (IV, X═I).
Reaction SMILES: Br[CH2:2][CH2:3][CH2:4][CH2:5]Br.[NH2:7][C:8]1[C:17]2[C:12](=[C:13]([O:18][CH3:19])[CH:14]=[CH:15][CH:16]=2)[CH:11]=[CH:10][CH:9]=1.C(=O)([O-])[O-].[Na+].[Na+]>C1COCC1>[CH3:19][O:18][C:13]1[CH:14]=[CH:15][CH:16]=[C:17]2[C:12]=1[CH:11]=[CH:10][CH:9]=[C:8]2[N:7]1[CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: BrCCCCBr
Reactant: COc1cccc2c(N)cccc12
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: C1CCOC1
Product: COc1cccc2c(N3CCCC3)cccc12

Procedure:
1,4-Dibromobutane (220 g) is added dropwise to a stirred suspension of 1-amino-5-methoxynaphthalene (170 g) and sodium carbonate (200 g) in THF (300 ml), while maintaining the reaction temperature at less than 10° C. When the addition is complete, the stirred mixture is allowed to reach RT and refluxed overnight.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([NH:11][CH:12]2[CH2:20][C:19]3[C:14](=[CH:15][CH:16]=[C:17]([O:21][CH2:22][C:23]([NH:25][CH2:26][CH2:27][C:28]([O:30]C)=[O:29])=[O:24])[CH:18]=3)[CH2:13]2)(=[O:10])=[O:9])=[CH:4][CH:3]=1>CO.[OH-].[Na+]>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([NH:11][CH:12]2[CH2:20][C:19]3[C:14](=[CH:15][CH:16]=[C:17]([O:21][CH2:22][C:23]([NH:25][CH2:26][CH2:27][C:28]([OH:30])=[O:29])=[O:24])[CH:18]=3)[CH2:13]2)(=[O:10])=[O:9])=[CH:4][CH:3]=1
Reactant: COC(=O)CCNC(=O)COc1ccc2c(c1)CC(NS(=O)(=O)c1ccc(Cl)cc1)C2
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: O=C(O)CCNC(=O)COc1ccc2c(c1)CC(NS(=O)(=O)c1ccc(Cl)cc1)C2
Temperature: 25 °C
Reaction time: 3 h
Yield: 94.5 %

Procedure:
818 mg of methyl 3-{[2-[(4-chlorophenyl)sulfonylamino]indan-5-yl]oxyacetylamino}propionate are dissolved in 10 ml of methanol, and an aqueous In sodium hydroxide solution is added to the solution. The mixture is stirred at room temperature for 3 hours. The reaction mixture is evaporated to remove methanol and the residue is acidified with an aqueous 10% hydrochloric acid solution. The mixture is extracted with ethyl acetate. The extract is washed successively with an aqueous saturated sodium hydrochloride solution, dried and evaporated to remove solvent. The residue is recrystallized from a mixture of tetrahydrofuran and isopropyl ether to give 750 mg of 3-{[2-[(4-chlorophenyl)sulfonylamino]indan-5-yl]oxyacetylamino}propionic acid as colorless prisms. Yield: 92%
Reaction SMILES: [C:1]1([S:7]([O:10][C:11]2[CH:12]=[CH:13][CH:14]=[C:15]3[C:20]=2[O:19][C:18](=[O:21])[C:17]([NH:22]C(=O)C)=[CH:16]3)(=[O:9])=[O:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.S(=O)(=O)(O)O.O>C(O)(=O)C>[C:1]1([S:7]([O:10][C:11]2[CH:12]=[CH:13][CH:14]=[C:15]3[C:20]=2[O:19][C:18](=[O:21])[C:17]([NH2:22])=[CH:16]3)(=[O:8])=[O:9])[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: CC(=O)Nc1cc2cccc(OS(=O)(=O)c3ccccc3)c2oc1=O
Agent: O=S(=O)(O)O
Solvent: CC(=O)O
Solvent: O
Product: Nc1cc2cccc(OS(=O)(=O)c3ccccc3)c2oc1=O
Temperature: 50 °C
Yield: 83.5 %

Procedure:
To a solution of the compound produced in the above (1) (3.0 g, 8.3 mmol) in acetic acid (30 mL) was added 50 vol % sulfuric acid (30 mL) followed by stirring at 50° C. After the crystals were completely dissolved, the reaction mixture was allowed to cool and added to water. The crystals separated out therefrom were filtered and dried to give 2.2 g (83%) of the title compound.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][C:6](=[O:11])[CH2:5]2.[CH2:12]=[O:13].C1(C)C=CC=CC=1>CCOCC>[Cl:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[N:7]([CH2:12][OH:13])[C:6](=[O:11])[CH2:5]2
Reactant: C=O
Reactant: O=C1Cc2cc(Cl)ccc2N1
Solvent: CCOCC
Solvent: Cc1ccccc1
Product: O=C1Cc2cc(Cl)ccc2N1CO
Temperature: 25 °C

Procedure:
In an high pressure autoclave, 5-chloro-1,3-dihydro-indol-2-one (5 g, 0.029 mol), paraformaldehyde (1.07 g) and toluene (60 ml) are heated up to 120° C. for 4 h. The mixture is cooled down to room temperature, diluted with ether and filtrated to give 5-chloro-1-hydroxymethyl-1,3-dihydro-indol-2-one a22 as white crystals (4.03 g, 70%). 1H NMR δH (250 MHz, C2D6SO): 3.61 (2H, s); 5.04 (2H, d); 6.26 (1H, t); 7.08 (1H, d); 7.29-7.34 (2H, m).
Reaction SMILES: Cl.[Cl:2][C:3]1[C:7]([NH2:8])=[CH:6][NH:5][N:4]=1.O1CCCC1.C(=O)(O)[O-].[Na+].[Cl:19][CH2:20][CH2:21][C:22](Cl)=[O:23]>C(OCC)(=O)C.O>[Cl:19][CH2:20][CH2:21][C:22]([NH:8][C:7]1[C:3]([Cl:2])=[N:4][NH:5][CH:6]=1)=[O:23]
Reactant: O=C(Cl)CCCl
Reactant: Nc1c[nH]nc1Cl
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: C1CCOC1
Solvent: O
Solvent: CCOC(C)=O
Product: O=C(CCCl)Nc1c[nH]nc1Cl
Temperature: 5 °C

Procedure:
A 250-mL 3-neck flask was charged with 3-chloro-1H-pyrazol-4-amine.hydrochloride (10.0 g, 64.9 mmol), tetrahydrofuran (50 mL), and water (50 mL). The resulting suspension was cooled to 5° C. and sodium bicarbonate (17.6 g, 210 mmol) was added, followed by dropwise addition of 3-chloropropanoyl chloride (7.33 g, 57.7 mmol) at <5° C. The reaction was stirred at <10° C. for 1 hour, at which point thin layer chromatography (TLC) [Eluent: 1:1 ethyl acetate (EtOAc)/hexane]analysis indicated the starting material was consumed and the desired product was formed. It was diluted with water (50 mL) and ethyl acetate (50 mL) and the layers separated. The aqueous layer was extracted with ethyl acetate (20 mL) and the combined organic layers were concentrated to dryness to afford a pale brown solid, which was purified by flash column chromatography using ethyl acetate as eluent. The pure fractions were concentrated to afford a white solid (9.20 g, 77%): mp: 138-140° C.; 1H NMR (400 MHz, DMSO-d6) δ 12.91 (s, 1 H), 9.68 (s, 1 H), 8.03 (d, J=1.7 Hz, 1 H), 3.85 (t, J=6.3 Hz, 2 H), 2.85 (t, J=6.3 Hz, 2 H); 13C NMR (101 MHz, DMSO-d6) δ 167.52, 130.05, 123.59, 116.48, 40.75, 37.91; EIMS m/z 207 (m+).
Reaction SMILES: [C:1]([O:5][C:6](=[O:38])[NH:7][C:8]1([C:12]2[CH:17]=[CH:16][C:15]([C:18]3[C:27]([C:28]4[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=4)=[CH:26][C:25]4[C:24]5=[N:34][N:35]=[C:36]([OH:37])[N:23]5[CH:22]=[CH:21][C:20]=4[N:19]=3)=[CH:14][CH:13]=2)[CH2:11][CH2:10][CH2:9]1)([CH3:4])([CH3:3])[CH3:2].Br[CH2:40][CH3:41]>[Ag]=O.CN1C(=O)CCC1>[C:1]([O:5][C:6](=[O:38])[NH:7][C:8]1([C:12]2[CH:17]=[CH:16][C:15]([C:18]3[C:27]([C:28]4[CH:29]=[CH:30][CH:31]=[CH:32][CH:33]=4)=[CH:26][C:25]4[C:24]5=[N:34][N:35]=[C:36]([O:37][CH2:40][CH3:41])[N:23]5[CH:22]=[CH:21][C:20]=4[N:19]=3)=[CH:14][CH:13]=2)[CH2:9][CH2:10][CH2:11]1)([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)NC1(c2ccc(-c3nc4ccn5c(O)nnc5c4cc3-c3ccccc3)cc2)CCC1
Reactant: CCBr
Agent: O=[Ag]
Solvent: CN1CCCC1=O
Product: CCOc1nnc2c3cc(-c4ccccc4)c(-c4ccc(C5(NC(=O)OC(C)(C)C)CCC5)cc4)nc3ccn12
Temperature: 80 °C

Procedure:
To a microwave vial was added tert-butyl{1-[4-(3-hydroxy-9-phenyl[1,2,4]triazolo[3,4-f]-1,6-naphthyridin-8-yl)phenyl]cyclobutyl}carbamate (1-5e) (113 mg, 0.223 mmol), silver oxide (310 mg, 1.336 mmol), bromoethane (0.062 mL, 0.826 mmol), and finally NMP (1 mL). The reaction mixture was then heated to 80° C. under microwave irradiation for 10 minutes. Upon completion the reaction mixture was filtered and then purified by reverse phase column chromatography (Sunfire C18) eluting with 20 to 100% acetonitrile/(0.1% TFA/water) gradient. The appropriate fractions were then combined, suspended in ethyl acetate, washed with a saturated solution of sodium bicarbonate, water and brine, dried over sodium sulfate, filtered and concentrated in vacuo to give tert-butyl{1-[4-(3-ethoxy-9-phenyl[1,2,4]triazolo[3,4-f]-1,6-naphthyridin-8-yl)phenyl]cyclobutyl}carbamate (9-1) as a tan solid. MS (M+H)+: observed=536.4, calculated=536.64.
Reaction SMILES: I[C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[N:7]([CH2:11][CH2:12][N:13]1[CH2:17][CH2:16][CH2:15][CH2:14]1)[CH2:6][CH2:5]2.[Cl:18][C:19]1[CH:24]=[CH:23][C:22]([C:25]2[CH:26]=[CH:27][C:28]([C:31]#[CH:32])=[N:29][CH:30]=2)=[CH:21][CH:20]=1>>[Cl:18][C:19]1[CH:20]=[CH:21][C:22]([C:25]2[CH:26]=[CH:27][C:28]([C:31]#[C:32][C:2]3[CH:3]=[C:4]4[C:8](=[CH:9][CH:10]=3)[N:7]([CH2:11][CH2:12][N:13]3[CH2:17][CH2:16][CH2:15][CH2:14]3)[CH2:6][CH2:5]4)=[N:29][CH:30]=2)=[CH:23][CH:24]=1
Reactant: Ic1ccc2c(c1)CCN2CCN1CCCC1
Reactant: C#Cc1ccc(-c2ccc(Cl)cc2)cn1
Product: Clc1ccc(-c2ccc(C#Cc3ccc4c(c3)CCN4CCN3CCCC3)nc2)cc1

Procedure:
Prepared according to general working method I from 5-iodo-1-(2-pyrrolidin-1-yl-ethyl)-2,3-dihydro-1H-indole (142 mg, 0.42 mmol) and 5-(4-chloro-phenyl)-2-ethynyl-pyridine (89 mg, 0.42 mmol).
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]([CH:8]=[CH:9][C:10]=1[N+:11]([O-:13])=[O:12])[C:5]([OH:7])=[O:6].OS(O)(=O)=O.[CH3:19]O>>[CH3:19][O:6][C:5](=[O:7])[C:4]1[CH:8]=[CH:9][C:10]([N+:11]([O-:13])=[O:12])=[C:2]([OH:1])[CH:3]=1
Reactant: CO
Reactant: O=C(O)c1ccc([N+](=O)[O-])c(O)c1
Agent: O=S(=O)(O)O
Product: COC(=O)c1ccc([N+](=O)[O-])c(O)c1
Temperature: 60 °C

Procedure:
3-Hydroxy-4-nitro-benzoic acid (10 g) was dissolved in MeOH (500 ml). 96% H2SO4 (2 ml) was added, and the mixture was heated to 60° C. for 18 hours. The reaction mixture was concentrated to approx. 200 ml, diluted with EtOAc (200 ml) and washed with an aqueous saturated solution of NaHCO3 (2×20 ml). The organic layer was dried over Na2SO4 and the solvent was removed by evaporation to yield 10.5 g of the desired intermediate.