Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C:2]1[C:6]([C:7]([O:9][CH2:10][CH:11]=[CH2:12])=[O:8])=[C:5]([NH2:13])[NH:4][N:3]=1.CO[CH:16](OC)[CH:17]([CH:21](OC)OC)[CH2:18][C:19]#[N:20].NC1C(C(ON2C3C=CC=CC=3N=N2)=O)=C2N=CC(CC#N)=CN2N=1.C([O-])(O)=O.[Na+]>CS(C)=O.O.CCOC(C)=O>[NH2:13][C:5]1[C:6]([C:7]([O:9][CH2:10][CH:11]=[CH2:12])=[O:8])=[C:2]2[N:1]=[CH:16][C:17]([CH2:18][C:19]#[N:20])=[CH:21][N:3]2[N:4]=1
Reactant: C=CCOC(=O)c1c(N)n[nH]c1N
Reactant: COC(OC)C(CC#N)C(OC)OC
Agent: N#CCc1cnc2c(C(=O)On3nnc4ccccc43)c(N)nn2c1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CS(C)=O
Solvent: CCOC(C)=O
Solvent: O
Product: C=CCOC(=O)c1c(N)nn2cc(CC#N)cnc12
Temperature: 85 °C
Reaction time: 8 h
Yield: 62.4 %

Procedure:
To a suspension of allyl 3,5-diamino-1H-pyrazole-4-carboxylate 3 (63.49 g, 348.5 mmol) in a mixture of DMSO (340 mL) and water (340 mL), was added 3-(dimethoxymethyl)-4,4-dimethoxy-butanenitrile (Scheme 3, below) (85 g, 418.2 mmol), followed by para-toluene Sulfonic acid hydrate (1) (11.27 g, 59.24 mmol). The reaction mixture was heated to 85° C. and stirred overnight. The reaction mixture was cooled with an ice bath. The mixture was diluted with EtOAc (680 mL) and a saturated aqueous solution of NaHCO3 (1.36 L). The precipitate was filtered and rinsed with water, then with a mixture of water and EtOAc. The brown solid was dried under vacuum to give allyl 2-amino-6-(cyanomethyl)-pyrazolo[1,5-a]pyrimidine-3-carboxylate 4c as a brown solid (55.94 g, 62% yield).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[CH:8]1[S:13][CH2:12][CH2:11][CH2:10][S:9]1.[Li]CCCC.Cl.Cl.Cl[CH2:22][C:23]1[N:28]=[C:27]2[S:29][C:30]([NH:32][CH:33]([CH3:35])[CH3:34])=[N:31][C:26]2=[CH:25][CH:24]=1.C([O-])(O)=O.[Na+]>C1COCC1.CCOC(C)=O>[F:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1([CH2:22][C:23]2[N:28]=[C:27]3[S:29][C:30]([NH:32][CH:33]([CH3:35])[CH3:34])=[N:31][C:26]3=[CH:25][CH:24]=2)[S:9][CH2:10][CH2:11][CH2:12][S:13]1
Reactant: Fc1ccccc1C1SCCCS1
Reactant: CC(C)Nc1nc2ccc(CCl)nc2s1
Agent: Cl
Agent: O=C([O-])O
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: CC(C)Nc1nc2ccc(CC3(c4ccccc4F)SCCCS3)nc2s1
Reaction time: 0.5 h
Yield: 79.2 %

Procedure:
To a solution of 2-(2-fluorophenyl)-1,3-dithiane (2.72 g, 12.7 mmol, 4.4 eq.) in THF (65 mL) under nitrogen at 0° C. was added n-BuLi (1.6M/hexane; 7.4 mL, 11.8 mmol, 4.1 eq.) over 0.5 hr. After another 0.5 hr, the 0° C. bath was removed and replaced by a −78° C. bath. 5-(Chloromethyl)-N-isopropylthiazolo[5,4-b]pyridin-2-amine dihydrochloride (0.90 g, 2.86 mmol, 1.0 eq.) was added in portions after 15 min., and the reaction was stirred for 1.5 hr. Ice, EtOAc and saturated aqueous NaHCO3 were added, and the −78° C. bath was removed. After stirring to room temperature, the layers were separated, and the organic layer was dried over Na2SO4, filtered, and concentrated in vacuo. Silica gel chromatography using CH2Cl2 followed by CH2Cl2:MeOH (40:1) as eluent afforded 5-((2-(2-fluorophenyl)-1,3-dithian-2-yl)methyl)-N-isopropylthiazolo[5,4-b]pyridin-2-amine as a yellow solid (0.95 g, 79% yield).
Reaction SMILES: C(O)(=O)/C=C\C(O)=O.[C:9]([C:12]1[S:21][C:20]2[CH2:19][CH2:18][CH2:17][N:16]([CH2:22][CH2:23][CH2:24][CH2:25][N:26]3[CH2:31][CH2:30][N:29]([C:32]4[N:37]=[CH:36][CH:35]=[CH:34][N:33]=4)[CH2:28][CH2:27]3)[C:15](=[O:38])[C:14]=2[CH:13]=1)(=O)[CH3:10].Cl.[OH:40][NH2:41].C(=O)([O-])O.[Na+]>C(O)C>[OH:40][N:41]=[C:9]([C:12]1[S:21][C:20]2[CH2:19][CH2:18][CH2:17][N:16]([CH2:22][CH2:23][CH2:24][CH2:25][N:26]3[CH2:31][CH2:30][N:29]([C:32]4[N:37]=[CH:36][CH:35]=[CH:34][N:33]=4)[CH2:28][CH2:27]3)[C:15](=[O:38])[C:14]=2[CH:13]=1)[CH3:10]
Reactant: NO
Reactant: CC(=O)c1cc2c(s1)CCCN(CCCCN1CCN(c3ncccn3)CC1)C2=O
Agent: Cl
Agent: O=C(O)/C=C\C(=O)O
Agent: O=C([O-])O
Solvent: CCO
Product: CC(=NO)c1cc2c(s1)CCCN(CCCCN1CCN(c3ncccn3)CC1)C2=O
Yield: 101.3 %

Procedure:
To a suspension of 6.0 g of 2-acetyl-5,6,7,8-tetrahydro-5-[4-(4-(2-pyrimidinyl)-1-piperazinyl)butyl]-4H-thieno[3,2-c]azepin-4-one maleate in 100 ml of ethanol were added 0.92 g of hydroxyamine hydrochloride and 4.0 g of sodium hydrogencarbonate with stirring and the mixture was refluxed for 5 hours. After cooling, the mixture was concentrated under reduced pressure, to the residue was added water and the solution was extracted with chloroform. The extract was washed with water, dried and concentrated in vacuo. The resulting crystals were recrystallized from a mixed solvent of ethanol and isopropyl ether to give 4.95 g of 5,6,7,8-tetrahydro-2-(1-(hydroxyimino)ethyl)-5-[4-(4-(2-pyrimidinyl)-1-piperazinyl)butyl]-4H-thieno[3,2-c]azepin-4-one as white crystals, melting at 144°-146° C.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([Cl:8])[C:5]([O:9][CH:10]([CH3:12])[CH3:11])=[CH:4][C:3]=1[N:13]1[C:17](=[O:18])[NH:16][C:15]([CH:19]([F:21])[F:20])=[N:14]1.[C:22](=O)([O-])[O-].[K+].[K+].CI>CC(C)=O>[Cl:1][C:2]1[CH:7]=[C:6]([Cl:8])[C:5]([O:9][CH:10]([CH3:12])[CH3:11])=[CH:4][C:3]=1[N:13]1[C:17](=[O:18])[N:16]([CH3:22])[C:15]([CH:19]([F:20])[F:21])=[N:14]1
Reactant: O=C([O-])[O-]
Reactant: CC(C)Oc1cc(-n2nc(C(F)F)[nH]c2=O)c(Cl)cc1Cl
Agent: [K+]
Solvent: CC(C)=O
Solvent: CI
Product: CC(C)Oc1cc(-n2nc(C(F)F)n(C)c2=O)c(Cl)cc1Cl
Temperature: 50 °C
Reaction time: 1 h
Yield: 61.5 %

Procedure:
A stirred mixture of 4.0 g (0.012 mole) of 1-[2,4-dichloro-5-(1-methylethoxy)phenyl]-3-difluoromethyl-4,5-dihydro-1,2,4-triazol-5(1H)-one and 4.1 g (0.03 mole) of potassium carbonate in 160 mL of acetone was heated at reflux for 0.5 hours then cooled to about 50° C. Methyl iodide, 8.4 g (0.06 mole), was added and the mixture stirred at 45° for one hour then at reflux for one hour. The mixture was cooled to room temperature and evaporated under reduced pressure to leave an oil. This oil was partitioned between methylene chloride and water. The organic phase was washed with a 10% aqueous sodium hydroxide solution and then dried over anhydrous magnesium sulfate. The mixture was filtered and the filtrate evaporated under reduced pressure to leave an oil. This oil solidified when stirred with petroleum ether and upon filtration provided 2.6 g of 1-[2,4-dichloro-5-(1-methylethoxy)phenyl]-3-difluoromethyl-4,5-dihydro-4-methyl-1,2,4 -triazol-5-(1H)-one (mp 95°-97° C).
Reaction SMILES: [H-].[Al+3].[Li+].[H-].[H-].[H-].[Cl-].[Al+3].[Cl-].[Cl-].[NH:11]1[C:17]2=[C:18]3[C:23](=[N:24][C:25]4[CH2:26][CH2:27][CH2:28][CH:15]([C:16]=42)[S:14][CH2:13][C:12]1=O)[CH:22]=[CH:21][CH:20]=[CH:19]3.[OH-].[Na+]>O1CCCC1>[NH:11]1[C:17]2=[C:18]3[C:23](=[N:24][C:25]4[CH2:26][CH2:27][CH2:28][CH:15]([C:16]=42)[S:14][CH2:13][CH2:12]1)[CH:22]=[CH:21][CH:20]=[CH:19]3
Reactant: O=C1CSC2CCCc3nc4ccccc4c(c32)N1
Agent: [Al+3]
Agent: [Cl-]
Agent: [H-]
Solvent: C1CCOC1
Product: c1ccc2c3c4c(nc2c1)CCCC4SCCN3
Reaction time: 0.5 h
Yield: 47.6 %

Procedure:
To a solution of lithium aluminum hydride (30 ml of a 1M solution in tetrahydrofuran diluted to 130 ml with tetrahydrofuran) was added aluminum chloride (3.94 g). The mixture was stirred for 30 mins and then 1,3,4a,5,6,7-hexahydro-2H-quino[4,3,2-ef][1,4]benzthiazepin-2-one (6.65 g) was added. The reaction mixture was stirred for 1 hr and then poured into 60 ml of 10% sodium hydroxide solution. The aqueous phase was extracted with ethyl acetate and the combined organic extracts were washed with water, saturated sodium chloride, dried over anhydrous magnesium sulfate, and filtered. The filtrate was preadsorbed on silica and purified by flash chromatography (2% triethylamine/ethyl acetate) to give 3.0 g (48%) of product, mp 171°-175° C. Recrystallization from methanol/water gave the analytical sample, mp 175°-177° C.
Reaction SMILES: [CH2:1]([N:8]([CH2:10][C:11]1[C:12]([C:43]([OH:45])=O)=[C:13]([N:28]([CH2:34][C:35]2[C:40]([F:41])=[CH:39][CH:38]=[CH:37][C:36]=2[F:42])[C:29](OCC)=[O:30])[S:14][C:15]=1[C:16]1[CH:21]=[CH:20][C:19]([NH:22][C:23]([NH:25][O:26][CH3:27])=[O:24])=[CH:18][CH:17]=1)[CH3:9])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.P(C#N)(OCC)(OCC)=O.[OH:56][C:57]([C:60]1[CH:66]=[CH:65][C:63]([NH2:64])=[CH:62][CH:61]=1)([CH3:59])[CH3:58].C(N(C(C)C)C(C)C)C.[O-]CC.[Na+]>C(O)C>[CH2:1]([N:8]([CH2:10][C:11]1[C:12]2[C:43](=[O:45])[N:64]([C:63]3[CH:62]=[CH:61][C:60]([C:57]([OH:56])([CH3:58])[CH3:59])=[CH:66][CH:65]=3)[C:29](=[O:30])[N:28]([CH2:34][C:35]3[C:36]([F:42])=[CH:37][CH:38]=[CH:39][C:40]=3[F:41])[C:13]=2[S:14][C:15]=1[C:16]1[CH:21]=[CH:20][C:19]([NH:22][C:23]([NH:25][O:26][CH3:27])=[O:24])=[CH:18][CH:17]=1)[CH3:9])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CC(C)(O)c1ccc(N)cc1
Reactant: CCOC(=O)N(Cc1c(F)cccc1F)c1sc(-c2ccc(NC(=O)NOC)cc2)c(CN(C)Cc2ccccc2)c1C(=O)O
Agent: CCOP(=O)(C#N)OCC
Agent: CC[O-]
Agent: [Na+]
Solvent: CCN(C(C)C)C(C)C
Solvent: CCO
Product: CONC(=O)Nc1ccc(-c2sc3c(c2CN(C)Cc2ccccc2)c(=O)n(-c2ccc(C(C)(C)O)cc2)c(=O)n3Cc2c(F)cccc2F)cc1
Yield: 21.2 %

Procedure:
The similar reaction as described in Example 40 by using 4-(N-benzyl-N-methylaminomethyl)-2-[N-(2,6-difluorobenzyl)-N-ethoxycarbonylamino]-5-[4-(3-methoxyureido)phenyl]thiophene-3-carboxylic acid (470 mg), diethyl cyanophosphate (167 μl), 4-(1-hydroxy-1-methylethyl)aniline (166 mg) and N-ethyldiisopropylamine (209 μl) gave a crude amide (422 mg). Furthermore, the similar reaction by using ethanol (25.5 ml) and sodium ethoxide (70 mg) gave the title compound (113 mg).
Reaction SMILES: CS(C)=O.C(Cl)(=O)C(Cl)=O.[C:11]([O:15][C:16](=[O:27])[NH:17][C@H:18]([C:20](=[O:26])[NH:21][CH2:22][CH:23]([OH:25])[CH3:24])[CH3:19])([CH3:14])([CH3:13])[CH3:12].C(N(CC)CC)C>C(Cl)Cl>[C:11]([O:15][C:16](=[O:27])[NH:17][C@H:18]([C:20](=[O:26])[NH:21][CH2:22][C:23](=[O:25])[CH3:24])[CH3:19])([CH3:12])([CH3:13])[CH3:14]
Reactant: CC(O)CNC(=O)[C@H](C)NC(=O)OC(C)(C)C
Agent: O=C(Cl)C(=O)Cl
Solvent: CS(C)=O
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CC(=O)CNC(=O)[C@H](C)NC(=O)OC(C)(C)C
Yield: 60.2 %

Procedure:
Dimethylsulfoxide (7.16 ml, 100.8 mmol) is added to a solution of oxalyl chloride (4.41 ml, 50.4 mmol) in 126 mL of methylene chloride at −78° C. The mixture is left to stir for fifteen minutes, and a solution of (2RS, 1S)-[1-(2-hydroxy-propylcarbamyl)-ethyl]-carbamic acid tert-butyl ester (9.92 g, 40.32 mmol) in 100 mL of CH2Cl2 is added dropwise. After stirring for 15 minutes at −78° C., the reaction is quenched with triethylamine (28 mL, 381 mmol), and the temperature is allowed to rise to room temperature. The volatile solvents are removed, and the residue is purified by flash column (SiO2, 60% EtOAc/Hexane). The product (1S)-[1-(2-oxo-propylcarbamoyl)-ethyl]-carbamic acid tertbutyl ester (5.93 g, 60%) is isolated as a white solid. MS C11H20N2O4 MS m/z: 245.
Reaction SMILES: [CH2:1]([C:5]1[NH:6][C:7]([C:14]([O:16][CH2:17][CH3:18])=[O:15])=[C:8]([C:10]([OH:13])([CH3:12])[CH3:11])[N:9]=1)[CH2:2][CH2:3][CH3:4].[H-].[Na+].[C:21]([N:40]1[C:44]([C:45]2[CH:50]=[CH:49][CH:48]=[CH:47][C:46]=2[C:51]2[CH:58]=[CH:57][C:54]([CH2:55]Br)=[CH:53][CH:52]=2)=[N:43][N:42]=[N:41]1)([C:34]1[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=1)([C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1)[C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1>>[CH2:1]([C:5]1[N:6]([CH2:55][C:54]2[CH:53]=[CH:52][C:51]([C:46]3[CH:47]=[CH:48][CH:49]=[CH:50][C:45]=3[C:44]3[N:40]([C:21]([C:34]4[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=4)([C:28]4[CH:29]=[CH:30][CH:31]=[CH:32][CH:33]=4)[C:22]4[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=4)[N:41]=[N:42][N:43]=3)=[CH:58][CH:57]=2)[C:7]([C:14]([O:16][CH2:17][CH3:18])=[O:15])=[C:8]([C:10]([OH:13])([CH3:11])[CH3:12])[N:9]=1)[CH2:2][CH2:3][CH3:4]
Reactant: BrCc1ccc(-c2ccccc2-c2nnnn2C(c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Reactant: CCCCc1nc(C(C)(C)O)c(C(=O)OCC)[nH]1
Agent: [H-]
Agent: [Na+]
Product: CCCCc1nc(C(C)(C)O)c(C(=O)OCC)n1Cc1ccc(-c2ccccc2-c2nnnn2C(c2ccccc2)(c2ccccc2)c2ccccc2)cc1

Procedure:
Following a procedure similar to that described in Example 18(a), but using 0.26 g of ethyl 2-butyl-4-(1-hydroxy-1-methylethyl)imidazole-5-carboxylate (prepared as described in Preparation 8), 45.5 mg of sodium hydride (as a 55% w/w dispersion in mineral oil) and 0.63 g of 4-[2-(trityltetrazol-5-yl)phenyl]benzyl bromide, 0.2 8 g of the title compound were obtained as an oil.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[C:3]([C:7]([NH:9][C:10]2[C:15]3[S:16][C:17]([C:19]([OH:21])=O)=[CH:18][C:14]=3[CH:13]=[CH:12][CH:11]=2)=[O:8])[CH:2]=1.[NH2:22][C:23]1[C:24]([O:38][CH3:39])=[C:25]([NH:33][S:34]([CH3:37])(=[O:36])=[O:35])[CH:26]=[C:27]([C:29]([CH3:32])([CH3:31])[CH3:30])[CH:28]=1.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.C1C=CC2N(O)N=NC=2C=1.C(NC(C)C)(C)C>CN(C=O)C.CCOC(C)=O>[C:29]([C:27]1[CH:26]=[C:25]([NH:33][S:34]([CH3:37])(=[O:36])=[O:35])[C:24]([O:38][CH3:39])=[C:23]([NH:22][C:19]([C:17]2[S:16][C:15]3[C:10]([NH:9][C:7](=[O:8])[C:3]4[CH:4]=[CH:5][CH:6]=[N:1][CH:2]=4)=[CH:11][CH:12]=[CH:13][C:14]=3[CH:18]=2)=[O:21])[CH:28]=1)([CH3:32])([CH3:30])[CH3:31]
Reactant: O=C(Nc1cccc2cc(C(=O)O)sc12)c1cccnc1
Reactant: COc1c(N)cc(C(C)(C)C)cc1NS(C)(=O)=O
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Agent: On1nnc2ccccc21
Solvent: CCOC(C)=O
Solvent: CC(C)NC(C)C
Solvent: CN(C)C=O
Product: COc1c(NC(=O)c2cc3cccc(NC(=O)c4cccnc4)c3s2)cc(C(C)(C)C)cc1NS(C)(=O)=O
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 56.7 %

Procedure:
The above carboxylic acid (100 mg, 0.335 mmol) and N-(3-amino-5-tert-butyl-2-methoxyphenyl)-methanesulfonamide (91 mg, 0.335 mmol) were dissolved in 2 mL DMF and stirred at room temperature. After about 10 min, HATU (127 mg, 0.335 mmol) and HOBt (45 mg, 0.335 mmol) were added followed by diisopropylamine (87 mg, 0.670 mmol, 120 uL) and the solution was stirred at room temperature. After stirring for eight days, the entire reaction was partitioned between EtOAc (75 mL) and water (50 mL). The layers were separated and the organic portion was washed with water (2×25 mL), brine (25 mL), dried (MgSO4), filtered and the solvent was removed to afford a tan solid. Column chromatography (EtOAc, silica gel) afforded the title compound as a colorless solid (105 mg, 57%).
Reaction SMILES: [NH3:1].Cl[C:3]1[N:8]=[C:7]([NH:9][C@H:10]([C:12]2[N:17]=[C:16]3[CH:18]=[CH:19][N:20]([CH3:21])[C:15]3=[CH:14][C:13]=2[C:22]2[N:26]([CH3:27])[N:25]=[CH:24][CH:23]=2)[CH3:11])[C:6]([Cl:28])=[CH:5][N:4]=1.[OH-].[NH4+]>CO>[Cl:28][C:6]1[C:7]([NH:9][C@H:10]([C:12]2[N:17]=[C:16]3[CH:18]=[CH:19][N:20]([CH3:21])[C:15]3=[CH:14][C:13]=2[C:22]2[N:26]([CH3:27])[N:25]=[CH:24][CH:23]=2)[CH3:11])=[N:8][C:3]([NH2:1])=[N:4][CH:5]=1
Reactant: N
Reactant: C[C@H](Nc1nc(Cl)ncc1Cl)c1nc2ccn(C)c2cc1-c1ccnn1C
Agent: [NH4+]
Agent: [OH-]
Solvent: CO
Product: C[C@H](Nc1nc(N)ncc1Cl)c1nc2ccn(C)c2cc1-c1ccnn1C
Temperature: 25 °C
Reaction time: 1 h
Yield: 71.6 %

Procedure:
A 7 N solution of ammonia (1 mL, 7.00 mmol) in MeOH was added to (S)-2,5-dichloro-N-(1-(1-methyl-6-(1-methyl-1H-pyrazol-5-yl)-1H-pyrrolo[3,2-b]pyridin-5-yl)ethyl)pyrimidin-4-amine (20 mg, 0.050 mmol) while stirring at room temperature. The reaction mixture was stirred at room temperature for 1 hour and then at 100° C. in a microwave reactor for 1 hour. The mixture was concentrated, dissolved in dioxane (1 mL), and treated with ammonium hydroxide (1 mL, 7.19 mmol). The mixture was heated at 100° C. in a microwave reactor for 12 hours. The reaction was concentrated and purified by preparative HPLC (basic mode, 25% to 50% ACN/water gradient) to give the title compound as an off-white solid (13.7 mg, 72.0%). 1H NMR (500 MHz, CD3OD) δ ppm 1.42 (d, J=6.35 Hz, 3 H), 3.66 (s, 3 H), 3.90 (s, 3 H), 5.46 (q, J=6.51 Hz, 1 H), 6.45-6.49 (m, 1 H), 6.69-6.72 (m, 1 H), 7.65 (d, J=2.93 Hz, 2 H), 7.69 (s, 1 H), 7.84 (s, 1 H); ESI-MS m/z [M+H]+ calc'd for C18H19ClN8, 383.14; found 383.3.
Reaction SMILES: Br[C:2]1[N:7]=[CH:6][CH:5]=[CH:4][N:3]=1.[Br:8][C:9]1[CH:14]=[CH:13][C:12](B(O)O)=[C:11]([F:18])[C:10]=1[F:19].C(=O)([O-])[O-].[K+].[K+].C(O)C>C1(C)C=CC=CC=1.O.C(OCC)(=O)C.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>[Br:8][C:9]1[CH:14]=[CH:13][C:12]([C:2]2[N:7]=[CH:6][CH:5]=[CH:4][N:3]=2)=[C:11]([F:18])[C:10]=1[F:19]
Reactant: Brc1ncccn1
Reactant: OB(O)c1ccc(Br)c(F)c1F
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CCO
Solvent: CCOC(C)=O
Product: Fc1c(Br)ccc(-c2ncccn2)c1F
Temperature: 90 °C
Reaction time: 8 h

Procedure:
A mixture of 2-bromopyrimidine (2.0 g, 12.7 mmol), 4-bromo-2,3-difluorobenzeneboronic acid (1.0 g, 4.22 mmol), potassium carbonate (2.93 g, 21.1 mmol) in a mixture of toluene (30 ml)/ethanol (30 ml)/water (15 ml) were purged with nitrogen for 15 min. Tetrakis(triphenylphosphine)palladium(0) (488 mg, 0.42 mmol) was added and the mixture was stirred at 90° C. in a sealed-tube for overnight. The mixture was cooled to r.t. and was diluted with water and ethyl acetate. Layers were separated. The separated organic layer was dried (MgSO4), filtered and solvents were removed in vacuum. Column purification [Hexanes-Ethyl acetate, 2:1 (v/v)] gave bromide 3AC (0.97 g, 85%) as white solid.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]2[S:10][CH:11]=[CH:12][C:13]=2[CH3:14])=[CH:5][N:4]=1.[Li]CCCC.[S:20](Cl)([Cl:23])(=[O:22])=[O:21]>C1COCC1.C(OCC)C.C(OCC)C.C(Cl)Cl>[CH3:1][O:2][C:3]1[N:4]=[CH:5][C:6]([C:9]2[S:10][C:11]([S:20]([Cl:23])(=[O:22])=[O:21])=[CH:12][C:13]=2[CH3:14])=[CH:7][CH:8]=1
Reactant: O=S(=O)(Cl)Cl
Reactant: COc1ccc(-c2sccc2C)cn1
Agent: [Li]CCCC
Solvent: ClCCl
Solvent: C1CCOC1
Solvent: CCOCC
Product: COc1ccc(-c2sc(S(=O)(=O)Cl)cc2C)cn1
Temperature: -70 °C
Reaction time: 8 h

Procedure:
2-Methoxy-5-(3-methyl-thiophen-2-yl)-pyridine (0.32 g, 1.6 mmol) was dissolved in THF/diethyl ether (10 ml, 1:1 v/v) and cooled to −70° C. BuLi (1.6M hexanes, 1 ml, 1.6 ml) was added dropwise and after a further 15 min at −70° C. the reaction mixture was added via canula to a condensed solution of SO2 (5 ml) in diethyl ether (10 ml). The yellow colored reaction mixture was slowly warmed to room temperature and stirred overnight. The reaction mixture was concentrated under reduced pressure and the residue washed with diethyl ether and dried. The crude solid (0.31 g) was suspended in dry n-hexane (7 ml), cooled using an ice bath to 0° C. and treated with a solution of sulfuryl chloride (1 M, 1.2 ml, 1.2 mmol) in CH2Cl2. The reaction mixture was slowly warmed to room temperature and analyzed (TLC) showing no starting material. Solvent was removed under reduced pressure and the crude product was purified over silica gel (n-heptane/tert.butylmethyl ether 1:9 to 1:4 v/v) to yield a white solid: 0.19 g (38%), MS: m/e 304.0 (MH+).
Reaction SMILES: [NH2:1][CH2:2][CH2:3][CH2:4][CH2:5][NH2:6].[C:7]([C@:10]1([OH:21])C(=O)[O:14][C:12](=[O:13])[C@:11]1(C(=O)C)[OH:17])(=[O:9])C>O1CCCC1>[NH2:1][CH2:2][CH2:3][CH2:4][CH2:5][NH:6][C:7](=[O:9])[CH:10]([CH:11]([C:12]([OH:14])=[O:13])[OH:17])[OH:21]
Reactant: CC(=O)[C@]1(O)C(=O)OC(=O)[C@@]1(O)C(C)=O
Reactant: NCCCCN
Solvent: C1CCOC1
Product: NCCCCNC(=O)C(O)C(O)C(=O)O
Reaction time: 2 h

Procedure:
13.225 Grams (150 mmoles) of putrescine (VI) was dissolved in 75 ml of tetrahydrofuran (THF), and a solution of 10.8 g (50 mmoles) of diacetyl-L-tartaric acid anhydride (VIII) in 50 ml of THF was gradually added dropwise thereto while cooling with ice under stirring. After addition, stirring was continued for 2 hours at room temperature, and after completion of the reaction, the solvent was removed by evaporation under reduced pressure. Thereafter, 50 ml of water was added, and the reaction solution was adjusted to pH 13 with 2N NaOH and stirred at room temperature for 2 hours to effect the hydrolysis of the acetyl group.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]=[C:7]([CH:12]=[CH:13][C:14]1[N:15]=[C:16]([CH3:19])[S:17][CH:18]=1)[N:6]([C:20]1[C:21]([CH3:26])=[N:22][CH:23]=[CH:24][CH:25]=1)[C:5]2=[O:27].C([O-])=O.[NH4+]>[Pd].CO>[F:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]=[C:7]([CH2:12][CH2:13][C:14]1[N:15]=[C:16]([CH3:19])[S:17][CH:18]=1)[N:6]([C:20]1[C:21]([CH3:26])=[N:22][CH:23]=[CH:24][CH:25]=1)[C:5]2=[O:27]
Reactant: Cc1nc(C=Cc2nc3ccc(F)cc3c(=O)n2-c2cccnc2C)cs1
Agent: [Pd]
Agent: O=C[O-]
Agent: [NH4+]
Solvent: CO
Product: Cc1nc(CCc2nc3ccc(F)cc3c(=O)n2-c2cccnc2C)cs1
Yield: 46.5 %

Procedure:
To a slurry of 10% palladium on carbon (0.15 g) in methanol(12 mL) were added 6-fluoro-3-(2-methyl-pyridin-3-yl)-2-[2-(2-methyl-thiazol-4-yl)-vinyl]-3 H-quinazolin-4-one (0.075 g, 0.198 mmol) and ammonium formate (1.2 g, 19 mmol). The mixture was refluxed overnight, cooled and filtered through celite. The pad was washed with methanol. The filtrate was concentrated. The residue was partitioned between chloroform and water. The phases were separated and the aqueous layer was extracted with chloroform. The combined organic phase was washed with water and brine, dried over magnesium sulfate, and concentrated to afford 0.035 g (47%) of 6-fluoro-3-(2-methyl-pyridin-3-yl)-2-[2-(2-methyl-thiazol-4-yl)-ethyl]-3H-quinazolin-4-one as a white solid.
Reaction SMILES: [CH3:1][N:2]1[CH2:15][CH2:14][C:5]2[NH:6][C:7]3[CH:8]=[CH:9][C:10]([CH3:13])=[CH:11][C:12]=3[C:4]=2[CH2:3]1.N1CCC[C@H]1C(O)=O.P([O-])([O-])([O-])=O.[K+].[K+].[K+].Br[CH:33]=[C:34]([C:36]1[CH:41]=[CH:40][C:39]([Cl:42])=[CH:38][CH:37]=1)[CH3:35]>CN(C=O)C.[Cu]I>[Cl:42][C:39]1[CH:40]=[CH:41][C:36](/[C:34](/[CH3:35])=[CH:33]/[N:6]2[C:7]3[CH:8]=[CH:9][C:10]([CH3:13])=[CH:11][C:12]=3[C:4]3[CH2:3][N:2]([CH3:1])[CH2:15][CH2:14][C:5]2=3)=[CH:37][CH:38]=1
Reactant: Cc1ccc2[nH]c3c(c2c1)CN(C)CC3
Reactant: CC(=CBr)c1ccc(Cl)cc1
Agent: [Cu]I
Agent: O=C(O)[C@@H]1CCCN1
Agent: O=P([O-])([O-])[O-]
Solvent: CN(C)C=O
Product: C/C(=C\n1c2c(c3cc(C)ccc31)CN(C)CC2)c1ccc(Cl)cc1
Temperature: 80 °C

Procedure:
2,8-Dimethyl-2,3,4,5-tetrahydro-1H-pyrido[4,3-b]indole (36 mg, 0.181 mmol) was dissolved in DMF (4 mL). Copper (I) iodide (4 mg, 0.0181 mmol), L-proline (4 mg, 0.0362 mmol) and potassium phosphate (77 mg, 0.362 mmol) were added and the reaction mixture was stirred for min. at RT. 1-(1-Bromoprop-1-en-2-yl)-4-chlorobenzene (50 mg, 0.2183 mmol) was added dropwise and the reaction mixture was purged with nitrogen. The reaction mixture was heated overnight at 80° C. (prolonged heating in some cases was required). DMF was evaporated under reduced pressure, the residue was diluted with water and the solid was filtered. The solid material was purified by silica gel chromatography (100-200 mesh). Yield: 90 mg
Reaction SMILES: [CH3:1][N:2]1[C:9]([CH3:10])=[C:8]([N+:11]([O-:13])=[O:12])[C:6](=[O:7])[N:5]([CH3:14])[C:3]1=[O:4].CO[CH:17](OC)[N:18]([CH3:20])[CH3:19].C(OCC)C>CN(C)C=O>[CH3:1][N:2]1[C:9]([CH:10]=[CH:17][N:18]([CH3:20])[CH3:19])=[C:8]([N+:11]([O-:13])=[O:12])[C:6](=[O:7])[N:5]([CH3:14])[C:3]1=[O:4]
Reactant: Cc1c([N+](=O)[O-])c(=O)n(C)c(=O)n1C
Reactant: COC(OC)N(C)C
Solvent: CN(C)C=O
Solvent: CCOCC
Product: CN(C)C=Cc1c([N+](=O)[O-])c(=O)n(C)c(=O)n1C
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a solution of Step 1 intermediate, 1,3,6-Trimethyl-5-nitrouracil (0.60 g, 3.012 mmol) in dry N,N-dimethylformamide (5.0 mL) was added N,N-dimethylformamide dimethyl acetal (0.53 g, 4.447 mmol) and the reaction mixture was stirred at room temperature for 2 h. After this time, diethyl ether was added to the reaction mixture and the precipitate was collected by filtration and washed with diethyl ether to give 0.45 g of the product as brownish solid; 1H NMR (δ ppm, 300 MHz, DMSO-d6) 2.98 (s, 6H), 3.16 (s, 3H), 3.40 (s, 3H), 4.78 (d, J=12.6 Hz, 1H), 7.05 (d, J=12.6 Hz, 1H); APCI-MS (m/z) 255.11 (M+H)+.