Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: O=[C:2]1[C:6]2[CH:7]=[CH:8][CH:9]=[CH:10][C:5]=2[S:4](=[O:12])(=[O:11])[NH:3]1.O.[NH2:14][NH2:15]>C(O)CCC>[NH:14]([CH:2]1[C:6]2[CH:7]=[CH:8][CH:9]=[CH:10][C:5]=2[S:4](=[O:12])(=[O:11])[NH:3]1)[NH2:15]
Reactant: NN
Reactant: O=C1NS(=O)(=O)c2ccccc21
Solvent: CCCCO
Solvent: O
Product: NNC1NS(=O)(=O)c2ccccc21
Yield: 93.4 %

Procedure:
36,6 g (0.2 mol) of 3-keto-2H,3H-1,2-benzisothiazole 1,1-dioxide and 70 g (1,4 mol) of hydrazine hydrate in 250 ml of n-butanol are boiled under reflux for about 25 hours. Further 250 ml n-butanol are added and the solution is then evaporated down in vacuo, and the hemicrystalline residue is stirred with 50 ml of glacial acetic acid. The crystal slurry is filtered under suction. 37,2 g (94% of theory) of 3-hydrazino-2H,3H-1,2-benzisothiazole 1,1-dioxide of melting point 262° C. are obtained.
Reaction SMILES: N[C@@H]1C2C(=CC=CC=2)C[C@@H]1O.[CH:12]1([C:17]2[C:26]([CH2:27][C:28]3[CH:33]=[CH:32][C:31]([C:34]([F:37])([F:36])[F:35])=[CH:30][CH:29]=3)=[C:25]([CH:38]([CH3:40])[CH3:39])[CH:24]=[C:23]3[C:18]=2[C:19](=[O:43])[CH2:20][C:21]([CH3:42])([CH3:41])[O:22]3)[CH2:16][CH2:15][CH2:14][CH2:13]1.CO>O1CCCC1>[CH:12]1([C:17]2[C:26]([CH2:27][C:28]3[CH:29]=[CH:30][C:31]([C:34]([F:35])([F:36])[F:37])=[CH:32][CH:33]=3)=[C:25]([CH:38]([CH3:39])[CH3:40])[CH:24]=[C:23]3[C:18]=2[C@@H:19]([OH:43])[CH2:20][C:21]([CH3:41])([CH3:42])[O:22]3)[CH2:13][CH2:14][CH2:15][CH2:16]1
Reactant: CC(C)c1cc2c(c(C3CCCC3)c1Cc1ccc(C(F)(F)F)cc1)C(=O)CC(C)(C)O2
Agent: N[C@@H]1c2ccccc2C[C@@H]1O
Solvent: C1CCOC1
Solvent: CO
Product: CC(C)c1cc2c(c(C3CCCC3)c1Cc1ccc(C(F)(F)F)cc1)[C@@H](O)CC(C)(C)O2
Reaction time: 0.5 h

Procedure:
40 μl (210 μmol) of borane/N,N-diethylaniline complex are added slowly to a solution of 1.2 mg (10 μmol) of (1R,2S)-1-aminoindan-2-ol in 1.5 ml of tetrahydrofuran, and the mixture is stirred for 30 min. A solution of 23 mg (50 μmol) of 5-cyclopentyl-7-isopropyl-2,2-dimethyl-6-[4-(trifluoromethyl)benzyl]-2,3-dihydro-4H-chromen-4-one (Example 39A) in 1.5 ml of tetrahydrofuran is then added very slowly dropwise, and the mixture is stirred for 2 h. Methanol is then added, and the mixture is concentrated under reduced pressure. The residue is taken up in ethyl acetate and washed in each case twice with 1 M hydrochloric acid and saturated sodium bicarbonate solution and once with saturated sodium chloride solution. The organic phase is dried over sodium sulfate and then concentrated under reduced pressure. Purification of the residue by preparative HPLC (method 1) gives the target product.
Reaction SMILES: [NH2:1][C:2]1[N:10]=[C:9]([O:11][CH2:12][CH2:13][CH2:14][CH3:15])[N:8]=[C:7]2[C:3]=1[N:4]=[C:5]([O:35][CH3:36])[N:6]2[CH2:16][CH2:17][CH2:18][CH:19]1[CH2:24][CH2:23][CH2:22][CH2:21][N:20]1[C:25]([O:27][CH2:28][C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1)=[O:26].F[C:38](F)(F)C(O)=O.C(OC1N=C2C(N=C(OC)N2)=C(N)N=1)CCC.BrCCCCC1CCCN(C(OCC2C=CC=CC=2)=O)C1>>[NH2:1][C:2]1[N:10]=[C:9]([O:11][CH2:12][CH2:13][CH2:14][CH3:15])[N:8]=[C:7]2[C:3]=1[N:4]=[C:5]([O:35][CH3:36])[N:6]2[CH2:16][CH2:17][CH2:18][CH2:19][CH:24]1[CH2:23][CH2:22][CH2:21][N:20]([C:25]([O:27][CH2:28][C:29]2[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=2)=[O:26])[CH2:38]1
Reactant: O=C(O)C(F)(F)F
Reactant: CCCCOc1nc(N)c2nc(OC)n(CCCC3CCCCN3C(=O)OCc3ccccc3)c2n1
Agent: CCCCOc1nc(N)c2nc(OC)[nH]c2n1
Agent: O=C(OCc1ccccc1)N1CCCC(CCCCBr)C1
Product: CCCCOc1nc(N)c2nc(OC)n(CCCCC3CCCN(C(=O)OCc4ccccc4)C3)c2n1

Procedure:
Prepared similarly to Intermediate 31 from 2-(butyloxy)-8-(methyloxy)-9H-purin-6-amine trifluoroacetate and phenylmethyl 3-(4-bromobutyl)-1-piperidinecarboxylate. LCMS (System B): tRET=3.08 min; MH+ 511
Reaction SMILES: Br[C:2]1[CH:3]=[CH:4][C:5]2[O:9][C:8]3([CH3:16])[CH:10]4[CH2:14][C:13]([CH3:15])([C:7]3([CH3:17])[C:6]=2[CH:18]=1)[CH2:12][CH2:11]4.[Mg].II.[O:22]1CCC[CH2:23]1>>[CH3:15][C:13]12[CH2:14][CH:10]([C:8]3([CH3:16])[C:7]1([CH3:17])[C:6]1[CH:18]=[C:2]([CH:23]=[O:22])[CH:3]=[CH:4][C:5]=1[O:9]3)[CH2:11][CH2:12]2
Reactant: C1CCOC1
Reactant: CC12CCC(C1)C1(C)Oc3ccc(Br)cc3C21C
Agent: II
Agent: [Mg]
Product: CC12CCC(C1)C1(C)Oc3ccc(C=O)cc3C21C
Yield: 74 %

Procedure:
13.76 g (44.8 mmol) of 8-bromo-THTMDBF obtained in Example 2 were added dropwise into a three-necked flask under nitrogen containing 1.31 g of magnesium and an iodine crystal in 5 ml of tetrahydrofuran, and the mixture was maintained under reflux for 2 h, 30 min. After the magnesium was filtered off, the reaction medium was poured into ice-cold water, acidified to pH 1 with concentrated hydrochloric acid and extracted with ether. The organic phase was washed with water, dried over magnesium sulfate, filtered and evaporated to yield 8.47 g (74%) of the expected compound, melting at 144.7° C.; αD =-7° (c=1, chloroform).
Reaction SMILES: [H-].[Na+:2].[CH3:3][O-].[Na+].[C:6]([O:10][C:11]([NH:13][C@@H:14]([CH2:18][OH:19])[C:15]([OH:17])=[O:16])=[O:12])([CH3:9])([CH3:8])[CH3:7].CI>C1COCC1.CO>[CH3:6][O-:10].[Na+:2].[C:6]([O:10][C:11]([NH:13][C@@H:14]([CH2:18][O:19][CH3:3])[C:15]([OH:17])=[O:16])=[O:12])([CH3:9])([CH3:8])[CH3:7]
Reactant: CC(C)(C)OC(=O)N[C@@H](CO)C(=O)O
Agent: C[O-]
Agent: [H-]
Agent: [Na+]
Solvent: CO
Solvent: C1CCOC1
Solvent: CI
Product: COC[C@H](NC(=O)OC(C)(C)C)C(=O)O
Temperature: 25 °C
Reaction time: 2 h

Procedure:
A sodium methanolate (NaOMe) solution was prepared by slowly adding MeOH (50 mL) to a suspension of sodium hydride (60% in mineral oil, 28 g, 0.71 mol) in dry THF (1.2 L) at 0° C. The resulting mixture was stirred at RT for 2 h. A portion of the NaOMe solution (320 mL) was added to (S)-2-(tert-butoxycarbonylamino)-3-hydroxypropanoic acid (36 g, 175 mmol) in dry THF (1.6 L), and the mixture was stirred at RT for 1 h. Methyl iodine (16 mL) was then added and the mixture was stirred at RT for 1 h. Another aliquot of NaOMe solution (540 mL) was added and the reaction mixture stirred at RT for 1 h. Additional methyl iodine (38 mL) in THF (200 mL) was added and the reaction mixture was stirred at RT for 36 h. Following reaction, the mixture was concentrated and the residue was dissolved in water and washed with diethyl ether (2×100 mL). The aqueous layer was acidified to pH 2 by the addition of solid citric acid and was extracted with EtOAc (3×200 mL) and dried over Na2SO4. The organic phase was concentrated, and the residue was dissolved in water and extracted with DCM (4×150 mL). The organic layers were combined and concentrated to give the title compound as an oil, which was used without further purification (10.9 g, 28%).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5]2[C:6](=[C:16]3[CH2:22][CH:21]4[N:23]([C:24](=[O:29])[C:25]([F:28])([F:27])[F:26])[CH:18]([CH2:19][CH2:20]4)[CH2:17]3)[C:7]3[C:12]([O:13][C:14]=2[CH:15]=1)=[CH:11][CH:10]=[CH:9][CH:8]=3.C(N(CC)C(C1C=CC2C(=C3CC4NC(CC4)C3)C3C(OC=2C=1)=CC=CC=3)=O)C.CCOC(C)=O>CCCCCCC>[Br:1][C:2]1[CH:3]=[CH:4][C:5]2[CH:6]([CH:16]3[CH2:22][CH:21]4[N:23]([C:24](=[O:29])[C:25]([F:26])([F:28])[F:27])[CH:18]([CH2:19][CH2:20]4)[CH2:17]3)[C:7]3[C:12]([O:13][C:14]=2[CH:15]=1)=[CH:11][CH:10]=[CH:9][CH:8]=3
Reactant: O=C(N1C2CCC1CC(=C1c3ccccc3Oc3cc(Br)ccc31)C2)C(F)(F)F
Agent: CCN(CC)C(=O)c1ccc2c(c1)Oc1ccccc1C2=C1CC2CCC(C1)N2
Solvent: CCOC(C)=O
Solvent: CCCCCCC
Product: O=C(N1C2CCC1CC(C1c3ccccc3Oc3cc(Br)ccc31)C2)C(F)(F)F

Procedure:
Using an adaptation of the method described in Procedure 9, substituting 1-[3-(3-bromoxanthen-9-ylidene)-8-aza-bicyclo[3.2.1]oct-8-yl]-2,2,2-trifluoro-ethanone, 1j for 9-(8-aza-bicyclo[3.2.1]oct-3-ylidene)-9H-xanthene-3-carboxylic acid diethylamide, 8a, the title compound 1-[3-(3-bromo-9H-xanthen-9-yl)-8-aza-bicyclo[3.2.1]oct-8-yl]-2,2,2-trifluoro-ethanone, 2j was obtained after puirification via flash column chromatography (eluent gradient: 5% to 25% EtOAc in heptane). MS m/z (MH+) 465.8.
Reaction SMILES: [Cl:1][C:2]1[S:6][C:5]([CH2:7][OH:8])=[C:4]([C:9]2[CH:14]=[CH:13][C:12]([CH2:15][CH3:16])=[CH:11][CH:10]=2)[CH:3]=1.O[C:18]1[CH:23]=[CH:22][C:21]([CH2:24][CH2:25][C:26]([O:28]CC)=[O:27])=[C:20]([F:31])[C:19]=1[F:32].ClC1SC(COC2C=CC(CCC(OCC)=O)=C(F)C=2F)=C(C2C=CC(Cl)=CC=2)C=1>>[Cl:1][C:2]1[S:6][C:5]([CH2:7][O:8][C:18]2[CH:23]=[CH:22][C:21]([CH2:24][CH2:25][C:26]([OH:28])=[O:27])=[C:20]([F:31])[C:19]=2[F:32])=[C:4]([C:9]2[CH:14]=[CH:13][C:12]([CH2:15][CH3:16])=[CH:11][CH:10]=2)[CH:3]=1
Reactant: CCOC(=O)CCc1ccc(O)c(F)c1F
Reactant: CCc1ccc(-c2cc(Cl)sc2CO)cc1
Agent: CCOC(=O)CCc1ccc(OCc2sc(Cl)cc2-c2ccc(Cl)cc2)c(F)c1F
Product: CCc1ccc(-c2cc(Cl)sc2COc2ccc(CCC(=O)O)c(F)c2F)cc1

Procedure:
The title compound was prepared according to the procedure described in Example 196 by coupling of [5-chloro-3-(4-ethylphenyl)thiophen-2-yl]methanol and ethyl 3-(4-hydroxy-2,3-difluorophenyl)propanoate followed by hydrolysis of ethyl 3-(4-((5-chloro-3-(4-chlorophenyl)thiophen-2-yl)methoxy)-2,3-difluorophenyl)propanoate to afford the desired product as an off-white solid. 1H NMR (400 MHz, CDCl3) 7.26-7.33 (m, 4H), 6.95 (s, 2H), 6.85 (t, J=8.8 Hz, 2H), 6.59-6.64 (t, J=8.4 Hz, 1H), 6.62 (t, J=8.4 Hz, 1H), 5.13 (s, 2H), 2.96 (t, J=7.8 Hz, 2H), 2.67-2.74 (m, 4H), 1.29 (t, J=7.6 Hz, 3H). Mass spectrum (ESI, m/z): Calcd. for C22H19ClF2O3S, 435.1 (M−H). found 435.1.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]([S:10]([CH3:13])(=[O:12])=[O:11])=[C:6]([CH:9]=1)[C:7]#[N:8].N>C(O)C.CO.[Co]>[ClH:1].[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([S:10]([CH3:13])(=[O:12])=[O:11])=[C:6]([CH2:7][NH2:8])[CH:9]=1
Reactant: CS(=O)(=O)c1ccc(Cl)cc1C#N
Agent: [Co]
Agent: N
Solvent: CCO
Solvent: CO
Product: CS(=O)(=O)c1ccc(Cl)cc1CN
Product: Cl
Temperature: 25 °C
Reaction time: 8 h
Yield: 159.5 %

Procedure:
(Step 3) To a solution of 5-chloro-2-(methylsulfonyl)benzonitrile obtained in Step 2 (3.8 g) in ethanol (25 ml) was added an 8N solution of ammonia in methanol (5 ml) and Raney cobalt (19 g, wet). The resulting mixture was stirred overnight at room temperature under a hydrogen atmosphere. The reaction mixture was filtered through celite, and the filtrate was concentrated under reduced pressure. To the residue were added ethanol (10 ml) and a 2 M hydrogen chloride-methanol solution (10 ml). The resulting mixture was concentrated under reduced pressure, and the residual solid was collected by filtration and washed with ethyl acetate to give 1-[5-chloro-2-(methylsulfonyl)phenyl]methanamine hydrochloride (3.6 g) as a white solid.
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C:9]([C:11]1[CH:28]=[CH:27][C:14]([O:15][CH2:16][CH2:17][CH2:18][N:19]2[CH2:24][CH2:23][NH:22][C:21](=[O:25])[C:20]2=[O:26])=[CH:13][CH:12]=1)=[NH:10])=[O:7])([CH3:4])([CH3:3])[CH3:2].[N:29]1[CH:34]=[CH:33][CH:32]=[C:31]([CH:35]=[CH:36][C:37]([O:39][CH:40]([C:47]2[CH:52]=[CH:51][CH:50]=[CH:49][CH:48]=2)[C:41]2[CH:46]=[CH:45][CH:44]=[CH:43][CH:42]=2)=[O:38])[CH:30]=1.N12CCCN=C1CCCCC2>CN(C)C=O>[C:1]([O:5][C:6]([NH:8][C:9]([C:11]1[CH:28]=[CH:27][C:14]([O:15][CH2:16][CH2:17][CH2:18][N:19]2[CH2:24][CH2:23][N:22]([CH:35]([C:31]3[CH:30]=[N:29][CH:34]=[CH:33][CH:32]=3)[CH2:36][C:37]([O:39][CH:40]([C:41]3[CH:42]=[CH:43][CH:44]=[CH:45][CH:46]=3)[C:47]3[CH:48]=[CH:49][CH:50]=[CH:51][CH:52]=3)=[O:38])[C:21](=[O:25])[C:20]2=[O:26])=[CH:13][CH:12]=1)=[NH:10])=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)NC(=N)c1ccc(OCCCN2CCNC(=O)C2=O)cc1
Reactant: O=C(C=Cc1cccnc1)OC(c1ccccc1)c1ccccc1
Solvent: CN(C)C=O
Solvent: C1CCC2=NCCCN2CC1
Product: CC(C)(C)OC(=O)NC(=N)c1ccc(OCCCN2CCN(C(CC(=O)OC(c3ccccc3)c3ccccc3)c3cccnc3)C(=O)C2=O)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 51.8 %

Procedure:
In 7.5 ml of N,N-dimethylformamide was dissolved 2.5 g of 4-[3-(4-tert-butoxycarbonylamidinophenoxy) propyl]-2,3-dioxopiperazine, and to the solution were added 6.1 g of diphenylmethyl 3-(3-pyridyl)acrylate and 0.48 ml of 1,8-diazabicyclo[5.4.0]undec-7-ene. The resulting mixture was stirred overnight at room temperature and distilled under reduced pressure to remove the solvent. To the resulting residue were added 80 ml of ethyl acetate and 60 ml of water and the pH was adjusted to 7 with 2N hydrochloric acid. The organic layer was separated, washed with water and then a saturated aqueous sodium chloride solution, and then distilled under reduced pressure to remove the solvent. The resulting residue was purified by a silica gel column chromatography (eluent; chloroform: methanol=20:1) to obtain 2.34 g of diphenylmethyl 3-[4-[3-(4-tert -butoxycarbonylamidinophenoxy)propyl]-2,3-dioxopiperazin-1-yl]-3-(pyridin-3-yl)propionate as a colorless oil.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([F:20])[C:5]([C:9]([O:12][C:13]2[CH:18]=[CH:17][C:16](Br)=[CH:15][CH:14]=2)([F:11])[F:10])=[C:6]([F:8])[CH:7]=1.[CH2:21]([OH:27])[CH2:22][CH2:23][CH2:24][C:25]#[CH:26].[OH2:28].Cl>C(N(CC)CC)C.C1(C)C=CC=CC=1.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>[F:10][C:9]([F:11])([O:12][C:13]1[CH:18]=[CH:17][C:16]([C:3]#[C:2][CH2:7][CH2:6][CH2:5][CH2:4][OH:28])=[CH:15][CH:14]=1)[C:5]1[C:4]([F:20])=[CH:3][C:2]([C:26]#[C:25][CH2:24][CH2:23][CH2:22][CH2:21][OH:27])=[CH:7][C:6]=1[F:8]
Reactant: C#CCCCCO
Reactant: Fc1cc(Br)cc(F)c1C(F)(F)Oc1ccc(Br)cc1
Reactant: O
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Cu]I
Agent: Cl
Solvent: Cc1ccccc1
Solvent: CCN(CC)CC
Product: OCCCCC#Cc1ccc(OC(F)(F)c2c(F)cc(C#CCCCCO)cc2F)cc1

Procedure:
10.7 g (25.8 mmol) of 5-bromo-2-[(4-bromophenoxy)difluoromethyl]-1,3-difluorobenzene and 8.00 g (81.5 mmol) of hex-5-yn-1-ol are initially introduced in 11.3 ml of triethylamine and 500 ml of toluene, 1.50 g (2 mmol) of bis(triphenylphosphine)palladium(II) chloride and 0.700 g (3.68 mmol) of copper(I) iodide are added, and the mixture is heated under reflux overnight. The batch is subsequently added to water, neutralised using 2 N hydrochloric acid and extracted three times with toluene. The combined org. phases are dried over sodium sulfate, the solvent is removed in vacuo, and the residue is chromatographed on silica gel firstly with toluene and then with toluene/ethyl acetate (4:1), giving 6-(4-{difluoro[4-(6-hydroxyhex-1-ynyl)phenoxy]methyl}-3,5-difluorophenyl)hex-5-yn-1-ol as a colourless solid.
Reaction SMILES: [F:1][CH:2](F)[CH2:3]I.[NH:6]1[CH2:10][CH2:9][C@H:8]([NH:11][C:12](=[O:18])[O:13][C:14]([CH3:17])([CH3:16])[CH3:15])[CH2:7]1.N1CC[C@@H](NC(=O)OC(C)(C)C)C1>>[F:1][CH2:2][CH2:3][N:6]1[CH2:10][CH2:9][C@H:8]([NH:11][C:12](=[O:18])[O:13][C:14]([CH3:16])([CH3:15])[CH3:17])[CH2:7]1
Reactant: CC(C)(C)OC(=O)N[C@H]1CCNC1
Reactant: FC(F)CI
Agent: CC(C)(C)OC(=O)N[C@@H]1CCNC1
Product: CC(C)(C)OC(=O)N[C@H]1CCN(CCF)C1

Procedure:
The title compound was prepared by substituting 1-fluoro-2-iodoethane for 1,1-difluoro-2-iodoethane and (S)-tert-butyl pyrrolidin-3-ylcarbamate for (R)-tert-butyl pyrrolidin-3-ylcarbamate in EXAMPLE 180A.
Reaction SMILES: [Cl:1][C:2]1[CH:31]=[CH:30][C:5]([C:6]([C:8]2[CH:29]=[CH:28][C:11]([CH2:12][N:13]3[C:17]4[N:18]=[C:19](SC)[N:20]([CH2:23][CH3:24])[C:21](=[O:22])[C:16]=4[C:15]([CH3:27])=[CH:14]3)=[CH:10][CH:9]=2)=[O:7])=[CH:4][CH:3]=1.C(O)(=O)C>COCCOC.C(O)C.[Ni]>[Cl:1][C:2]1[CH:31]=[CH:30][C:5]([C:6]([C:8]2[CH:29]=[CH:28][C:11]([CH2:12][N:13]3[C:17]4[N:18]=[CH:19][N:20]([CH2:23][CH3:24])[C:21](=[O:22])[C:16]=4[C:15]([CH3:27])=[CH:14]3)=[CH:10][CH:9]=2)=[O:7])=[CH:4][CH:3]=1
Reactant: CCn1c(SC)nc2c(c(C)cn2Cc2ccc(C(=O)c3ccc(Cl)cc3)cc2)c1=O
Agent: [Ni]
Solvent: CCO
Solvent: COCCOC
Solvent: CC(=O)O
Product: CCn1cnc2c(c(C)cn2Cc2ccc(C(=O)c3ccc(Cl)cc3)cc2)c1=O
Temperature: 40 °C
Yield: 82.4 %

Procedure:
In a mixture of DME (65 ml) and ethanol (6 ml) was dissolved 7-[4-(4-chlorobenzoyl)benzyl]-3-ethyl-5-methyl-2-methylthio-7H-pyrrolo[2,3-d]pyrimidin-4(3H)-one (500 mg) followed by addition of acetic acid (336 mg), and the mixture was warmed to 40° C. Then, Raney nickel was added until disappearance of the starting compound had been verified by TLC. The catalyst was then filtered off and the solvent was distilled off under reduced pressure. The residue was dissolved in ethyl acetate, washed with saturated aqueous NaHCO3 solution and saturated aqueous NaCl solution in that order, and dried over anhydrous magnesium sulfate. The solvent was then distilled off under reduced pressure and the residue was allowed to stand, whereupon crystals separated out. This crystal crop was harvested by filtration, rinsed with ethanol and hexane, and dried to provide the title compound (370 mg).
Reaction SMILES: [N+:1]([O-:4])(O)=[O:2].[Br:5][C:6]1[CH:11]=[CH:10][C:9]([OH:12])=[C:8]([C:13]([CH3:16])([CH3:15])[CH3:14])[CH:7]=1.CCOCC>CCCCCC>[Br:5][C:6]1[CH:11]=[C:10]([N+:1]([O-:4])=[O:2])[C:9]([OH:12])=[C:8]([C:13]([CH3:16])([CH3:15])[CH3:14])[CH:7]=1
Reactant: O=[N+]([O-])O
Reactant: CC(C)(C)c1cc(Br)ccc1O
Solvent: CCOCC
Solvent: CCCCCC
Product: CC(C)(C)c1cc(Br)cc([N+](=O)[O-])c1O
Reaction time: 2 h

Procedure:
Concentrated nitric acid (112 ml) was gradually added dropwise to a solution of 4-bromo-2-(tert-butyl)phenol (485 g) in hexane (3000 ml) while cooling on ice. After stirring for 2 hours at below 20° C., ether (2000 ml) was added and the reaction mixture was washed with water. The organic layer was dried over anhydrous magnesium sulfate and the solvent was distilled off under reduced pressure. Hexane was added to the residue and the precipitated crystals were filtered to yield the title compound (418 g) as yellow crystals.
Reaction SMILES: C[Si](C)(C)[N-][Si](C)(C)C.[K+].C1(C)C=CC=CC=1.[F:18][C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][C:20]=1[C:25]1[C:29]2=[N:30][C:31](=[O:38])[C:32]3[C:37]([N:28]2[NH:27][N:26]=1)=[CH:36][CH:35]=[CH:34][CH:33]=3.[CH3:39][N:40]1[C:44]([CH2:45]Cl)=[N:43][CH:42]=[N:41]1>CN(C=O)C.O>[F:18][C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][C:20]=1[C:25]1[N:26]=[N:27][N:28]2[C:37]3[C:32](=[CH:33][CH:34]=[CH:35][CH:36]=3)[C:31]([O:38][CH2:45][C:44]3[N:40]([CH3:39])[N:41]=[CH:42][N:43]=3)=[N:30][C:29]=12
Reactant: O=c1nc2c(-c3ccccc3F)n[nH]n2c2ccccc12
Reactant: Cn1ncnc1CCl
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [K+]
Solvent: CN(C)C=O
Solvent: Cc1ccccc1
Solvent: O
Product: Cn1ncnc1COc1nc2c(-c3ccccc3F)nnn2c2ccccc12
Reaction time: 0.17 h
Yield: 47.2 %

Procedure:
A solution of potassium hexamethyldisilazide in toluene (0.5 M, 4 ml, 2.0 mmol) was added at room temperature under nitrogen to a stirred solution of 3-(2-fluorophenyl)-1,2,3-triazolo[1,5-α]quinazolin-5-one (0.56 g, 2.0 mmol) in dry DMF (10 ml). The dark brown solution was stirred for 10 min followed by addition of a solution of 2-methyl-3-chloromethyl-1,2,4-triazole (0.35 g, 2.65 mmol) in dry DMF (3 ml). The red solution was stirred at room temperature for 3 days, then poured into water (120 ml) and the yellow precipitate collected. The material was dissolved in dichloromethane (50 ml), dried (Na2SO4), filtered and concentrated. Flash column chromatography on silica gel, eluting with 5% methanol-dichloromethane, partly removed unreacted starting material. The crude product was hot-filtered and recrystallised from ethyl acetate to give 3-(2-fluorophenyl)-5-(2-methyl-2H-1,2,4-triazol-3-ylmethoxy)-1,2,3-triazolo[1,5-α]quinazoline (0.354 g, 47%) as a very pale yellow solid, m.p. 195-197° C. Found: C, 60.14; H, 3.61; N, 25.86. C19H14FN7O.0.25(H2O) requires C, 60.08; H, 3.85; N, 25.81%. δH (360 MHz; DMSO) 3.94 (3H, s), 5.82 (2H, s), 7.37-7.43 (2H, m), 7.46-7.58 (1H, m), 7.82 (1H, dd, J=7 and 7), 7.97 (1H, s), 8.01 (1H, ddd, J=7, 7 and 1), 8.16 (1H, ddd, J=8, 8 and 1), 8.29 (1H, d, J=8) and 8.61 (1H, d, J=8); m/z (ES+) 376 (M+H+).
Reaction SMILES: [NH4+:1].[Cl-].C[Al](C)C.[Cl:7][C:8]1[C:13]([Cl:14])=[CH:12][CH:11]=[CH:10][C:9]=1[CH2:15][C:16]#[N:17]>C1(C)C=CC=CC=1>[ClH:7].[Cl:7][C:8]1[C:13]([Cl:14])=[CH:12][CH:11]=[CH:10][C:9]=1[CH2:15][C:16]([NH2:1])=[NH:17]
Reactant: N#CCc1cccc(Cl)c1Cl
Reactant: [NH4+]
Agent: C[Al](C)C
Agent: [Cl-]
Solvent: Cc1ccccc1
Product: Cl
Product: N=C(N)Cc1cccc(Cl)c1Cl
Temperature: 25 °C
Reaction time: 2 h
Yield: 156.2 %

Procedure:
To a stirred suspension of NH4Cl (4.29 g, 80.21 mmol) in dry toluene (120 mL) was added trimethyl aluminium (2M in toluene, 41 mL, 80.21 mmol) at 5° C. The mixture was then warmed to room temperature and stirred for 2 h. A solution of (2,3-dichlorophenyl)-acetonitrile (128) (5 g, 26.73 mmol) in toluene (25 mL) was added to the mixture and stirred for 14 h at 80° C. After completion of the reaction, it was quenched with a suspension of silica gel in chloroform and the reaction mixture was stirred for half an hour at room temperature and filtered through a sintered funnel. The silica gel was washed with methanol and the combined filtrate was concentrated under reduced pressure to get 2-(2,3-dichlorophenyl)-acetamidine hydrochloride salt (129) (5 g, 78%) as an off-white solid.
Reaction SMILES: [NH2:1][C:2]1[S:3][CH:4]=[C:5]([C:7]([O:9][CH2:10][CH3:11])=[O:8])[N:6]=1.[Cl:12]N1C(=O)CCC1=O>C(#N)C.CCOC(C)=O>[NH2:1][C:2]1[S:3][C:4]([Cl:12])=[C:5]([C:7]([O:9][CH2:10][CH3:11])=[O:8])[N:6]=1
Reactant: CCOC(=O)c1csc(N)n1
Reactant: O=C1CCC(=O)N1Cl
Solvent: CC#N
Solvent: CCOC(C)=O
Product: CCOC(=O)c1nc(N)sc1Cl
Temperature: 25 °C
Yield: 98.4 %

Procedure:
Ethyl 2-aminothiazole-4-carboxylate (4.72 g, 27.4 mmol) was combined with N-chlorosuccinimide (4.0 g, 30 mmol) and dissolved in acetonitrile (50 mL). The mixture was heated at mild reflux (>81.5° C.) for 5 hours. Subsequently, the flask was cooled to rt and decolorizing carbon was added to the mixture which was further diluted with EtOAc. The resulting slurry was filtered through a pad of silica and concentrated under reduced pressure to provide 5.57 g (98%) of the desired product ethyl 2-amino-5-chlorothiazole-4-carboxylate (1H). The analytical data on this compound corresponded to that previously reported (see. South. M. S. J. Heterocyclic Chem. 1991, 28, 1003).
Reaction SMILES: [CH3:1][CH2:2][N:3]([CH2:6][CH2:7][NH:8][C:9]([C:11]1[C:12]([CH3:29])=[C:13](/[CH:17]=[C:18]2/[C:19]3[CH:20]=[C:21]([F:28])[CH:22]=[CH:23][C:24]=3[NH:25][C:26]/2=[O:27])[NH:14][C:15]=1[CH3:16])=[O:10])[CH2:4][CH3:5].[C:30](O)(=O)[C:31]([OH:33])=[O:32].[CH3:36][OH:37]>ClCCl>[CH3:1][CH2:2][N:3]([CH2:6][CH2:7][NH:8][C:9]([C:11]1[C:12]([CH3:29])=[C:13](/[CH:17]=[C:18]2/[C:19]3[CH:20]=[C:21]([F:28])[CH:22]=[CH:23][C:24]=3[NH:25][C:26]/2=[O:27])[NH:14][C:15]=1[CH3:16])=[O:10])[CH2:4][CH3:5].[C:31]([O-:33])(=[O:32])[CH2:30][C:36]([O-:10])=[O:37]
Reactant: O=C(O)C(=O)O
Reactant: CO
Agent: CCN(CC)CCNC(=O)c1c(C)[nH]c(/C=C2\C(=O)Nc3ccc(F)cc32)c1C
Solvent: ClCCl
Product: O=C([O-])CC(=O)[O-]
Temperature: 27.5 °C
Reaction time: 1 h

Procedure:
Sunitinib (1.0 g) was suspended in 10% methanol in dichloromethane (30mL) at 25° C. , followed by addition of oxalic acid (0.22 g) .The reaction mass was maintained under stirring at 25-30° C. for 60 minutes. The solids obtained were filtered, suck dried and dried under vacuum for a period of 10 hrs at 60° C. to obtain sunitinib malonate. (0.9 g; yield: 75%)
Reaction SMILES: Cl[C:2]1[C:11]([Cl:12])=[N:10][C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[N:3]=1.[CH2:13]([NH2:16])[C:14]#[CH:15].C(N(CC)CC)C>C(O)C>[Cl:12][C:11]1[C:2]([NH:16][CH2:13][C:14]#[CH:15])=[N:3][C:4]2[C:9](=[CH:8][CH:7]=[CH:6][CH:5]=2)[N:10]=1
Reactant: C#CCN
Reactant: Clc1nc2ccccc2nc1Cl
Solvent: CCO
Solvent: CCN(CC)CC
Product: C#CCNc1nc2ccccc2nc1Cl

Procedure:
A mixture of 10 g of 2,3-dichloroquinoxaline, 4.5 ml of propargylamine, 10.5 ml of triethylamine in 50 ml of ethanol is refluxed for 4 h. After evaporating under vacuum the resulting mixture, the residue is chromatographed on SiO2 (eluent: CH2Cl2) thereby obtaining 7.0 g of 2-chloro-3-(propargylamino)quinoxaline (IR (KBr): 3441, 3282, 1518 cm-1). This product is then added with 10 ml of concentrated sulphuric acid and the resulting mixture is stirred at 90° C. for 1 h. After cooling down and cautiously neutralizing with aqueous NaOH, the resulting precipitate is filtered under vacuum, washed, dried, decolorized and recrystallized from dimethylformamide, thereby obtaining 2.4 g of 1-methylimidazo[1,2-a]quinoxaline-4(5H)-one (m.p. >300° C.).