Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][CH2:9][C:10]2[N:11]=[C:12]([NH:15][C:16](=[O:18])[CH3:17])[S:13][CH:14]=2)=[CH:4][CH:3]=1.Cl.C(=O)([O-])O.[Na+].[N:25]#[C:26][NH2:27]>C(O)C.C(OCC)(=O)C>[NH2:27][C:26]([NH:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][CH2:9][C:10]2[N:11]=[C:12]([NH:15][C:16](=[O:18])[CH3:17])[S:13][CH:14]=2)=[CH:4][CH:3]=1)=[NH:25]
Reactant: CC(=O)Nc1nc(CCc2ccc(N)cc2)cs1
Reactant: N#CN
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CCO
Product: CC(=O)Nc1nc(CCc2ccc(NC(=N)N)cc2)cs1
Temperature: 25 °C
Yield: 59.6 %

Procedure:
To a suspension of N-(4-(2-(4-aminophenyl)ethyl)-1,3-thiazol-2-yl)acetamide (26 g) in ethanol (500 ml) was added 4N hydrogen chloride in ethyl acetate (25 ml) and cyanamide (6.3 g). The mixture was refluxed for 26 hours. The reaction mixture was cooled to ambient temperature and poured into a mixture of ethyl acetate (500 ml) and saturated sodium hydrogen carbonate solution (500 ml). The resulted precipitate was collected by filtration and washed with water (300 ml) and ethanol (300 ml) to give N-{4-[2-(4-{[amino(imino)methyl]-amino}phenyl)ethyl]-1,3-thiazol-2-yl}acetamide (18 g) as white crystals.
Reaction SMILES: [CH:1]([NH:4][C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1)([CH3:3])[CH3:2].C(N(CC)CC)C.[Br:18][CH2:19][C:20](Br)=[O:21]>C(Cl)Cl.Cl>[Br:18][CH2:19][C:20]([N:4]([CH:1]([CH3:3])[CH3:2])[C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1)=[O:21]
Reactant: O=C(Br)CBr
Reactant: CC(C)Nc1ccccc1
Agent: Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CC(C)N(C(=O)CBr)c1ccccc1
Temperature: 0 °C
Reaction time: 24 h
Yield: 54.8 %

Procedure:
To a solution of N-isopropylaniline (21.58 g, 180 mmol) in CH2Cl2 (350 mL) was added triethylamine (26.7 mL, 190 mmol). The solution was cooled to 0° C. and bromoacetyl bromide (14.0 mL, 160 mmol) was added slowly over 1 hour. The reaction was warmed to room temperature and was stirred for 24 hours. The reaction was diluted with 5% aqueous HCl. The organic solution was washed with 5% aqueous HCl (2×), aqueous NaHCO3 (1×), and brine (1×). The organic solution was filtered through a silica gel pad, eluting with CH2Cl2. Recrystallization from hexanes (60 mL) provided 22.47 g of 2-bromo-N-isopropyl-N-phenyl-acetamide. 1H NMR (CD2Cl2) δ 7.45 (m, 3H), 7.21 (m, 2H), 4.89 (m, 1H), 3.52 (s, 2H), 1.05 (d, 6H); MS 256.2 (M+1).
Reaction SMILES: O[N:2]=[C:3]([C:9]([C:11]1[CH:16]=[CH:15][C:14]([CH3:17])=[CH:13][CH:12]=1)=O)[C:4]([O:6][CH2:7][CH3:8])=[O:5].[N+:18]([C:21]1[CH:28]=[CH:27][C:24]([CH2:25][NH2:26])=[CH:23][CH:22]=1)([O-:20])=[O:19]>>[CH3:17][C:14]1[CH:15]=[CH:16][C:11]([C:9]2[NH:26][C:25]([C:24]3[CH:23]=[CH:22][C:21]([N+:18]([O-:20])=[O:19])=[CH:28][CH:27]=3)=[N:2][C:3]=2[C:4]([O:6][CH2:7][CH3:8])=[O:5])=[CH:12][CH:13]=1
Reactant: CCOC(=O)C(=NO)C(=O)c1ccc(C)cc1
Reactant: NCc1ccc([N+](=O)[O-])cc1
Product: CCOC(=O)c1nc(-c2ccc([N+](=O)[O-])cc2)[nH]c1-c1ccc(C)cc1
Yield: 77.7 %

Procedure:
Ethyl 2-hydroxyimino-3-(4-methylphenyl)-3-oxopropionate (50.0 g) and 4-nitrobenzylamine (50.0 g) were reacted and treated in the same manner as in Starting Material Synthetic Example 1 to give ethyl 5-(4-methylphenyl)-2-(4-nitrophenyl)imidazole-4-carboxylate (58.0 g), which was dissolved in ethyl alcohol (1200 ml). Thereto was added 1 M sodium hydroxide solution (300 ml) and the mixture was reacted and treated in the same manner as in Starting Material Synthetic Example 2 to give 5-(4-methylphenyl)-2-(4-nitrophenyl)imidazole-4-carboxyic acid (37.6 g), melting point 212° C. (decomposition).
Reaction SMILES: [Cl:1][C:2]1[C:9]([O:10][C:11]2[C:19]3[N:18]=[N:17][N:16]([CH2:20][C:21]4[C:29]5[C:24](=[N:25][C:26]([NH:30]CC6C=CC(OC)=CC=6)=[CH:27][CH:28]=5)[N:23](CC5C=CC(OC)=CC=5)[N:22]=4)[C:15]=3[CH:14]=[CH:13][C:12]=2[Cl:49])=[CH:8][C:7]([Cl:50])=[CH:6][C:3]=1[C:4]#[N:5]>C(O)(C(F)(F)F)=O>[NH2:30][C:26]1[N:25]=[C:24]2[NH:23][N:22]=[C:21]([CH2:20][N:16]3[C:15]4[CH:14]=[CH:13][C:12]([Cl:49])=[C:11]([O:10][C:9]5[C:2]([Cl:1])=[C:3]([CH:6]=[C:7]([Cl:50])[CH:8]=5)[C:4]#[N:5])[C:19]=4[N:18]=[N:17]3)[C:29]2=[CH:28][CH:27]=1
Reactant: COc1ccc(CNc2ccc3c(Cn4nnc5c(Oc6cc(Cl)cc(C#N)c6Cl)c(Cl)ccc54)nn(Cc4ccc(OC)cc4)c3n2)cc1
Solvent: O=C(O)C(F)(F)F
Product: N#Cc1cc(Cl)cc(Oc2c(Cl)ccc3c2nnn3Cc2n[nH]c3nc(N)ccc23)c1Cl
Temperature: 75 °C
Reaction time: 1 h

Procedure:
2,5-dichloro-3-{[5-chloro-1-({1-(4-methoxybenzyl)-6-[(4-methoxybenzyl)amino]-1H-pyrazolo[3,4-b]pyridin-3-yl}methyl)-1H-1,2,3-benzotriazol-4-yl]oxy}benzonitrile (60 mg, 0.083 mmol) was dissolved in TFA and heated to 75° C. After 1 hour, the reaction mixture was concentrated under reduced pressure and re-constituted in EtOAc (15 mL). The reconstituted mixture was then washed with saturated aqueous sodium carbonate (5 mL) and then with water (5 mL). The combined aqueous layers were back-extracted with EtOAc (15 μL). The combined organic fractions were dried (MgSO4), filtered and solvent removed under reduced pressure. The resulting residue was purified by column chromatography on silica gel (4 g) eluting with 0-10% MeOH/CH2Cl2 to yield the title compound. 1H NMR (DMSO-d6) δ 12.70 (s, 1H), 8.04 (d, J=2.3 Hz, 1H), 7.81 (d, J=8.9 Hz, 1H), 7.76 (d, J=8.9 Hz, 1H), 7.53 (d, J=8.6 Hz, 1H), 7.41 (d, J=2.3 Hz, 1H), 6.36 (s, 2H), 6.29 (d, J=8.7 Hz, 1H), 6.15 (s, 2H), 5.75 (s, 1H). HRMS (M+1)=485.0193.
Reaction SMILES: [Cl:1][C:2]1[CH:23]=[C:22]([Cl:24])[C:21]([O:25][CH3:26])=[CH:20][C:3]=1[NH:4][C:5]1[C:14]2[C:9](=[CH:10][C:11](F)=[C:12]([O:15][CH3:16])[CH:13]=2)[N:8]=[CH:7][C:6]=1[C:18]#[N:19].[N:27]1([CH:32]2[CH2:37][CH2:36][NH:35][CH2:34][CH2:33]2)[CH2:31][CH2:30][CH2:29][CH2:28]1>CN1CCCC1=O>[Cl:1][C:2]1[CH:23]=[C:22]([Cl:24])[C:21]([O:25][CH3:26])=[CH:20][C:3]=1[NH:4][C:5]1[C:14]2[C:9](=[CH:10][C:11]([N:35]3[CH2:36][CH2:37][CH:32]([N:27]4[CH2:31][CH2:30][CH2:29][CH2:28]4)[CH2:33][CH2:34]3)=[C:12]([O:15][CH3:16])[CH:13]=2)[N:8]=[CH:7][C:6]=1[C:18]#[N:19]
Reactant: C1CCN(C2CCNCC2)C1
Reactant: COc1cc2c(Nc3cc(OC)c(Cl)cc3Cl)c(C#N)cnc2cc1F
Solvent: CN1CCCC1=O
Product: COc1cc(Nc2c(C#N)cnc3cc(N4CCC(N5CCCC5)CC4)c(OC)cc23)c(Cl)cc1Cl
Temperature: 105 °C
Yield: 43.4 %

Procedure:
Following the procedure of Example 11, a mixture of 200.0 mg (0.51 mmol) of 4-(2,4-dichloro-5-methoxyanilino)-7-fluoro-6-methoxy-3-quinolinecarbonitrile and 472.0 mg (3.06 mmol) of 4-(1-pyrrolidinyl)piperidine in 1.0 mL of 1-methyl-2-pyrrolidinone is heated in a sealed tube at 105° C. for 15 hours to yield the crude product. Purification by preparative thin layer chromatography (eluting with 4:1 dichloromethane/methanol) provides 116.5 mg of the pure product as a yellow solid, mp 225-227° C.
Reaction SMILES: [F:1][C@H:2]1[C@H:8]([NH:9]C(=O)OC(C)(C)C)[CH2:7][CH2:6][C@@H:5]([C:17]2[N:21]([CH3:22])[N:20]=[CH:19][C:18]=2[N+:23]([O-])=O)[O:4][CH2:3]1.[F:26][C:27]1[CH:32]=[CH:31][CH:30]=[C:29]([F:33])[C:28]=1[C:34]1[N:39]=[C:38]([C:40](O)=[O:41])[CH:37]=[CH:36][C:35]=1[F:43]>>[NH2:9][C@H:8]1[C@H:2]([F:1])[CH2:3][O:4][C@H:5]([C:17]2[N:21]([CH3:22])[N:20]=[CH:19][C:18]=2[NH:23][C:40](=[O:41])[C:38]2[CH:37]=[CH:36][C:35]([F:43])=[C:34]([C:28]3[C:27]([F:26])=[CH:32][CH:31]=[CH:30][C:29]=3[F:33])[N:39]=2)[CH2:6][CH2:7]1
Reactant: O=C(O)c1ccc(F)c(-c2c(F)cccc2F)n1
Reactant: Cn1ncc([N+](=O)[O-])c1[C@@H]1CC[C@@H](NC(=O)OC(C)(C)C)[C@H](F)CO1
Product: Cn1ncc(NC(=O)c2ccc(F)c(-c3c(F)cccc3F)n2)c1[C@@H]1CC[C@@H](N)[C@H](F)CO1

Procedure:
Following the procedure for Example 111 starting from tert-butyl ((3S,4R,7S)-3-fluoro-7-(1-methyl-4-nitro-1H-pyrazol-5-yl)oxepan-4-yl)carbamate (Intermediate 80), and replacing 5-((tert-butoxycarbonyl)amino)-2-(2,6-difluorophenyl)thiazole-4-carboxylic acid with 6-(2,6-difluorophenyl)-5-fluoropicolinic acid (see US2012/225061) gave 195. 1H NMR (400 MHz, DMSO-d6) δ 10.20 (s, 1H), 8.30 (dd, J=8.7, 4.0 Hz, 1H), 8.15 (t, J=8.9 Hz, 1H), 7.91 (s, 1H), 7.72-7.59 (m, 1H), 7.30 (t, J=8.4 Hz, 2H), 4.86-4.78 (m, 1H), 4.31-4.05 (m, 1H), 4.02-3.83 (m, 2H), 3.75 (s, 3H), 3.11-2.97 (m, 1H), 2.11-2.00 (m, 1H), 1.82-1.50 (m, 5H). LCMS (ES+) m/z 464 (M+1).
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][N:5]=[CH:4][N:3]=1.CO[CH:10](OC)[N:11]([CH3:13])[CH3:12]>CN(C=O)C>[CH3:10][N:11]([CH3:13])/[CH:12]=[CH:1]/[C:2]1[CH:7]=[CH:6][N:5]=[CH:4][N:3]=1
Reactant: Cc1ccncn1
Reactant: COC(OC)N(C)C
Solvent: CN(C)C=O
Product: CN(C)/C=C/c1ccncn1
Temperature: 140 °C
Reaction time: 24 h
Yield: 95.1 %

Procedure:
A mixture of 10 g of 4-methylpyrimidine, 38 g of N,N-dimethylformamide dimethylacetal (DMFDMA) and 46.6 g of DMF was stirred in a sealed tube at 140° C. for 24 hours. The reaction solution was cooled and the solvent was distilled off under reduced pressure to provide 15.08 g (yield: 95%) of the title compound as brown crystal.
Reaction SMILES: [F:1][C:2]1([F:30])[CH2:7][CH2:6][N:5]([C:8]([C:10]2[NH:11][C:12]3[C:17]([CH:18]=2)=[CH:16][C:15]([C:19]([N:21]2[CH2:26][CH2:25][N:24]([CH:27]([CH3:29])[CH3:28])[CH2:23][CH2:22]2)=[O:20])=[CH:14][CH:13]=3)=[O:9])[CH2:4][CH2:3]1.[C:31]([C:33]1[CH:34]=[C:35](B(O)O)[CH:36]=[CH:37][CH:38]=1)#[N:32].N1C=CC=CC=1>ClCCl.C([O-])(=O)C.[Cu+2].C([O-])(=O)C>[F:30][C:2]1([F:1])[CH2:7][CH2:6][N:5]([C:8]([C:10]2[N:11]([C:37]3[CH:38]=[C:33]([CH:34]=[CH:35][CH:36]=3)[C:31]#[N:32])[C:12]3[C:17]([CH:18]=2)=[CH:16][C:15]([C:19]([N:21]2[CH2:22][CH2:23][N:24]([CH:27]([CH3:28])[CH3:29])[CH2:25][CH2:26]2)=[O:20])=[CH:14][CH:13]=3)=[O:9])[CH2:4][CH2:3]1
Reactant: CC(C)N1CCN(C(=O)c2ccc3[nH]c(C(=O)N4CCC(F)(F)CC4)cc3c2)CC1
Reactant: N#Cc1cccc(B(O)O)c1
Agent: [Cu+2]
Agent: CC(=O)[O-]
Solvent: c1ccncc1
Solvent: ClCCl
Product: CC(C)N1CCN(C(=O)c2ccc3c(c2)cc(C(=O)N2CCC(F)(F)CC2)n3-c2cccc(C#N)c2)CC1
Yield: 77 %

Procedure:
The title compound was synthesized in analogy to example 66, from (4,4-difluoro-piperidin-1-yl)-[5-(4-isopropyl-piperazine-1-carbonyl)-1H-indol-2-yl]-methanone (example 32), 3-cyanophenylboronic acid, copper(II) acetate and pyridine in dichloromethane, to give the desired product as a colorless foam (77%).
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:14]=[CH:13][C:12]([OH:15])=[CH:11][CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.CC(C)([O-])C.[K+].Cl[C:23]1[CH:28]=[CH:27][C:26]([O:29][CH2:30][CH3:31])=[CH:25][C:24]=1[N+:32]([O-:34])=[O:33].O>CN(C)C=O>[CH2:1]([O:8][C:9]1[CH:10]=[CH:11][C:12]([O:15][C:23]2[CH:28]=[CH:27][C:26]([O:29][CH2:30][CH3:31])=[CH:25][C:24]=2[N+:32]([O-:34])=[O:33])=[CH:13][CH:14]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CCOc1ccc(Cl)c([N+](=O)[O-])c1
Reactant: Oc1ccc(OCc2ccccc2)cc1
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: CCOc1ccc(Oc2ccc(OCc3ccccc3)cc2)c([N+](=O)[O-])c1
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 69.2 %

Procedure:
To a solution of 4-(benzyloxy)phenol (5.68 g, 28.4 mmol) in N,N-dimethylformamide (100 ml) was added potassium tert-butoxide (3.50 g, 31.2 mmol), and after stirring for 10 minutes, 1-chloro-4-ethoxy-2-nitrobenzene (5.73 g, 28.4 mmol) was added to the reaction solution, followed by stirring at 150° C. for 2 hours. The reaction solution was cooled to room temperature, poured into water and extracted with ethyl acetate. The organic layer was washed with water and a saturated aqueous sodium chloride solution, and after drying, the solvent was evaporated under reduced pressure. The resulting crude crystals were recrystallized from methanol to give 4-[4-(benzyloxy)phenoxy]-3-nitrophenetole (7.18 g).
Reaction SMILES: [CH:1]1([CH2:4][NH:5][C:6]2[C:7]([O:25][CH3:26])=[N:8][N:9]3[C:14]([C:15]4[C:20]([CH3:21])=[CH:19][C:18]([CH3:22])=[CH:17][C:16]=4[O:23][CH3:24])=[CH:13][CH:12]=[CH:11][C:10]=23)[CH2:3][CH2:2]1.[O:27]1[CH2:32][CH2:31][CH:30]([CH:33]=O)[CH2:29][CH2:28]1.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].C(=O)([O-])O.[Na+]>O1CCCC1.C(OCC)(=O)C>[CH:1]1([CH2:4][N:5]([C:6]2[C:7]([O:25][CH3:26])=[N:8][N:9]3[C:14]([C:15]4[C:20]([CH3:21])=[CH:19][C:18]([CH3:22])=[CH:17][C:16]=4[O:23][CH3:24])=[CH:13][CH:12]=[CH:11][C:10]=23)[CH2:33][CH:30]2[CH2:31][CH2:32][O:27][CH2:28][CH2:29]2)[CH2:2][CH2:3]1
Reactant: COc1cc(C)cc(C)c1-c1cccc2c(NCC3CC3)c(OC)nn12
Reactant: O=CC1CCOCC1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: COc1cc(C)cc(C)c1-c1cccc2c(N(CC3CCOCC3)CC3CC3)c(OC)nn12
Temperature: 25 °C
Reaction time: 1 h
Yield: 70 %

Procedure:
After dissolving N-cyclopropylmethyl-N-[2-methoxy-7-(2-methoxy-4,6-dimethylphenyl)pyrazolo[1,5-a]pyridin-3-yl]amine (134 mg) in tetrahydrofuran (10 mL), tetrahydro-2H-4-pyrancarbaldehyde (131 mg) and sodium triacetoxyborohydride (243 mg) were added, and the mixture was stirred at room temperature for 1 hour. Saturated aqueous sodium hydrogencarbonate was added to the obtained reaction mixture, extraction was performed with ethyl acetate, and the extract washed with brine. After drying over anhydrous magnesium sulfate and filtration, the solvent was concentrated under reduced pressure, the residue was purified by silica gel column chromatography, and the title compound (120 mg) was obtained from the n-hexane:ethyl acetate (4:1) fraction as a yellow amorphous.
Reaction SMILES: C1([C:4]2[CH:11]=[CH:10][C:7]([CH:8]=[O:9])=[CH:6][CH:5]=2)CC1.BrC1C=CC2[O:17][C:18]([CH3:21])([CH3:20])[O:19]C=2C=1.[Li]CCCC.CCCCCC.CN(C=O)C>>[CH3:20][C:18]1([CH3:21])[O:19][C:4]2[CH:5]=[CH:6][C:7]([CH:8]=[O:9])=[CH:10][C:11]=2[O:17]1
Reactant: O=Cc1ccc(C2CC2)cc1
Reactant: CC1(C)Oc2ccc(Br)cc2O1
Agent: [Li]CCCC
Solvent: CN(C)C=O
Solvent: CCCCCC
Product: CC1(C)Oc2ccc(C=O)cc2O1
Yield: 83 %

Procedure:
The title compound was synthesized in analogy to 4-cyclopropyl benzaldehyde (described in example S53) using 420 mg of 5-bromo-2,2-dimethyl-benzo[1,3]dioxole [CAS 73790-19-9] (1.83 mmol), 1.38 ml of a 1.6 molar solution of n-BuLi in hexane (2.20 mmol) and 712 μl of DMF (9.17 mmol). The isolated residue was purified by flash column chromatography (1:9 ether/pentane) to give 270 mg of 2,2-dimethyl-benzo[1,3]dioxole-5-carbaldehyde (83%) as a light yellow liquid. 1H NMR (CDCl3, 300 MHz): δ 1.72 (s, 6H), 6.84 (d, J=7.8 Hz, 1H), 7.26 (s, 1H), 7.87 (dd, J=8.0 and 1.7 Hz, 1H), 9.97 (s, 1H).
Reaction SMILES: Cl.[CH3:2][O:3][C:4]1[CH:5]=[C:6]([CH:10]=[CH:11][N:12]=1)[C:7]([OH:9])=O.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CN1CCOCC1.[CH3:44][O:45][C:46]1[C:47]2[N:60]=[C:59]([NH2:61])[S:58][C:48]=2[C:49]([N:52]2[CH2:57][CH2:56][O:55][CH2:54][CH2:53]2)=[N:50][CH:51]=1>C1COCC1>[CH3:2][O:3][C:4]1[CH:5]=[C:6]([CH:10]=[CH:11][N:12]=1)[C:7]([NH:61][C:59]1[S:58][C:48]2[C:49]([N:52]3[CH2:57][CH2:56][O:55][CH2:54][CH2:53]3)=[N:50][CH:51]=[C:46]([O:45][CH3:44])[C:47]=2[N:60]=1)=[O:9]
Reactant: COc1cc(C(=O)O)ccn1
Reactant: COc1cnc(N2CCOCC2)c2sc(N)nc12
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: C1CCOC1
Solvent: CN1CCOCC1
Product: COc1cc(C(=O)Nc2nc3c(OC)cnc(N4CCOCC4)c3s2)ccn1

Procedure:
From 2-methoxy-isonicotinic acid hydrochloride, HATU and N-methylmorpholine in THF, then treatment with 7-methoxy-4-morpholin-4-yl-thiazolo[5,4-c]pyridin-2-ylamine. ES-MS m/e (%): 402 (M+H+, 100).
Reaction SMILES: [N:1]([C:4]1[C:5]([F:15])=[CH:6][C:7]2[O:12][CH2:11][C:10](=[O:13])[NH:9][C:8]=2[CH:14]=1)=[C:2]=[O:3].C([O:18][C:19]([N:21]1[CH2:26][CH2:25][CH2:24][CH2:23][NH:22]1)=O)C>C(N(CC)CC)C.O1CCOCC1>[F:15][C:5]1[C:4]([N:1]2[C:19](=[O:18])[N:21]3[CH2:26][CH2:25][CH2:24][CH2:23][N:22]3[C:2]2=[O:3])=[CH:14][C:8]2[NH:9][C:10](=[O:13])[CH2:11][O:12][C:7]=2[CH:6]=1
Reactant: CCOC(=O)N1CCCCN1
Reactant: O=C=Nc1cc2c(cc1F)OCC(=O)N2
Solvent: CCN(CC)CC
Solvent: C1COCCO1
Product: O=C1COc2cc(F)c(-n3c(=O)n4n(c3=O)CCCC4)cc2N1
Temperature: 25 °C
Reaction time: 2 h
Yield: 74.7 %

Procedure:
A mixture composed of 6-isocyanato-7-fluoro-2H-1,4-benzoxazin-3(4H)-one (2.14 g), 1-ethoxycarbonylhexahydropyridazine (1.62 g) and dioxane (30 ml) is treated with a few drops of triethylamine, stirred at an ambient temperature for 2 hours, and left overnight. The reaction mixture is made free from dioxane by evaporation in vacuo, mixed with methanol (30 ml) containing a catalytic amount of sodium, and refluxed for 2 hours. After removal of methanol by evaporation in vacuo, the resultant solid is collected, and washed with water to obtain an end product 2-[7-fluoro-2H-1,4-benzoxazin-3(4H)-on-6-yl]-hexahydro-1H-(1,2,4)-triazolo (1,2-a) pyridazine-1,3-dione (2.45 g).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2([C:11]3[C:20]4[C:15](=[CH:16][CH:17]=[C:18]([O:21][CH2:22][CH2:23][NH:24][S:25]([C:28]5[CH:29]=N[N:31]([CH3:33])[CH:32]=5)(=[O:27])=[O:26])[CH:19]=4)[CH2:14][CH2:13][N:12]=3)[CH2:10][CH2:9]2)=[CH:4][CH:3]=1.[BH4-].[Na+].[CH3:36]O>O>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2([CH:11]3[C:20]4[C:15](=[CH:16][CH:17]=[C:18]([O:21][CH2:22][CH2:23][NH:24][S:25]([C:28]5[CH:32]=[N:31][CH:33]=[CH:36][CH:29]=5)(=[O:27])=[O:26])[CH:19]=4)[CH2:14][CH2:13][NH:12]3)[CH2:10][CH2:9]2)=[CH:6][CH:7]=1
Reactant: Cn1cc(S(=O)(=O)NCCOc2ccc3c(c2)C(C2(c4ccc(Cl)cc4)CC2)=NCC3)cn1
Reactant: CO
Agent: [BH4-]
Agent: [Na+]
Solvent: O
Product: O=S(=O)(NCCOc1ccc2c(c1)C(C1(c3ccc(Cl)cc3)CC1)NCC2)c1cccnc1

Procedure:
A solution of N-[2-({1-[1-(4-chlorophenyl)cyclopropyl]-3,4-dihydroisoquinolin-7-yl}oxy)ethyl]-1-methyl-1H-pyrazole-4-sulfonamide (46 mg, 0.09 mmol), sodium borohydrid (7.2 mg, 0.19 mmol) in water (0.25 ml) and methanol (2 ml) was stirred for 3 days at room temperature. The solvent was removed, the residue dissolved in methylenehloride and extracted with water. The methylenehloride was evaporated and the remaining solid purified by chromatography. Yield: 20 mg (0.04 mmol, 43%)
Reaction SMILES: [CH3:1][O:2][C:3]1[C:11]([O:12][CH3:13])=[CH:10][C:9]([CH:14]=O)=[C:8]2[C:4]=1[CH2:5][CH2:6][CH2:7]2.C([O-])(=O)C.[NH4+].[CH3:21][N+:22]([O-:24])=[O:23]>C(O)(=O)C>[CH3:1][O:2][C:3]1[C:11]([O:12][CH3:13])=[CH:10][C:9]([CH:14]=[CH:21][N+:22]([O-:24])=[O:23])=[C:8]2[C:4]=1[CH2:5][CH2:6][CH2:7]2
Reactant: C[N+](=O)[O-]
Reactant: COc1cc(C=O)c2c(c1OC)CCC2
Agent: CC(=O)[O-]
Agent: [NH4+]
Solvent: CC(=O)O
Product: COc1cc(C=C[N+](=O)[O-])c2c(c1OC)CCC2
Temperature: 112 °C
Yield: 9.1 %

Procedure:
To a 100 ml 3-necked round bottom flask fitted with a condenser and thermometer and magnetically stirred, was added 12.97 g (0.063 mole) of 4,5-dimethoxy-7-indanaldehyde, 3.00 g (0.039 mole) of ammonium acetate, 13.0 ml (0.292 mole) of CH3NO2 and 40 ml of glacial acetic acid. This mixture was heated for 1 to 2 hours at 112°C. As the reaction solution began to cool the entire solution solidified. After cooling in an ice bath and removing the solvent by filtration, the solid 4,5-dimethoxy-7-nitrovinylindane was washed with a small volume of acetic acid giving fine yellow needles (9.55 g) after thorough drying. The filtrate was poured into 300 ml of ice and water from which precipitated a slightly gummy, yellow-brown solid. This gave an additional 1.43 g of crystalline solid after drying and crystallizing from methanol giving a total yield of 10.98 g (70%). An analytical sample melted at 128°-130°C. Anal. Calcd. For C13H15NO4 : C, 62.64; H, 6.06; N, 5.62. Found: C, 62.79; H, 6.12; N, 5.52.
Reaction SMILES: [C:1]1(=[O:9])[CH2:8][CH2:7][CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[C:10](OC(C)=C)(=[O:12])[CH3:11]>C1(C)C=CC(S(O)(=O)=O)=CC=1.C(=O)([O-])[O-].[Na+].[Na+]>[C:10]([O:9][C:1]1[CH2:8][CH2:7][CH2:6][CH2:5][CH2:4][CH2:3][CH:2]=1)(=[O:12])[CH3:11]
Reactant: O=C1CCCCCCC1
Reactant: C=C(C)OC(C)=O
Agent: Cc1ccc(S(=O)(=O)O)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Product: CC(=O)OC1=CCCCCCC1
Reaction time: 8 h
Yield: 89.2 %

Procedure:
In the presence of 0.6 g of para-toluenesulfonic acid, 50 g (0.4 mol) of cyclooctanone and 100 ml (0.9 mol) of isopropenyl acetate were refluxed for 11 hours. The reaction mixture was cooled, stirred with 0.6 g of anhydrous sodium carbonate at room temperature for one hour, left standing overnight, and filtered. The filtrate was distilled under reduced pressure to afford 60 g (91% in yield) of 1-cyclooctenyl acetate having a boiling point of 71° to 73° C./3 mmHg.
Reaction SMILES: [C:1]([C:5]1[CH:10]=[C:9](Cl)[N:8]=[CH:7][N:6]=1)([CH3:4])([CH3:3])[CH3:2].[CH3:12][C:13]1[CH:14]=[C:15](B(O)O)[CH:16]=[C:17]([CH3:19])[CH:18]=1.C(=O)([O-])[O-].[Na+].[Na+].O>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.CN(C=O)C>[C:1]([C:5]1[CH:10]=[C:9]([C:15]2[CH:16]=[C:17]([CH3:19])[CH:18]=[C:13]([CH3:12])[CH:14]=2)[N:8]=[CH:7][N:6]=1)([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)c1cc(Cl)ncn1
Reactant: Cc1cc(C)cc(B(O)O)c1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: Cc1cc(C)cc(-c2cc(C(C)(C)C)ncn2)c1
Yield: 96 %

Procedure:
Next, 2.01 g of 4-tert-butyl-6-chloropyrimidine obtained in Step 2, 3.63 g of 3,5-dimethylphenylboronic acid, 2.48 g of sodium carbonate, 0.10 g of bis(triphenylphosphine)palladium(II) dichloride (Pd(PPh3)2Cl2), 20 mL of water, and 20 mL of DMF were put into a recovery flask equipped with a reflux pipe, and the mixture was bubbled with argon for 15 minutes. This reaction container was subjected to irradiation with microwaves (2.45 GHz, 100 W) for 60 minutes to be heated. Here, into the flask were further put 0.90 g of 3,5-dimethylphenylboronic acid, 0.64 g of sodium carbonate, and 0.025 g of Pd(PPh3)2Cl2, and the mixture was bubbled with argon for 15 minutes. This reaction container was subjected to irradiation with microwaves (2.45 GHz, 100 W) again for 60 minutes to be heated. Then, water was added to this solution and the organic layer was extracted with dichloromethane. The obtained organic layer was washed with water and saturated brine, and was dried with magnesium sulfate. After the drying, the solution was filtered. The solvent of this solution was distilled off, and the obtained residue was purified by silica gel column chromatography using dichloromethane and ethyl acetate as a developing solvent in a ratio of 10:1, so that HtBudmppm (abbreviation), which was the pyrimidine derivative to be produced, was obtained as a pale yellow oil in a yield of 96%. Note that the irradiation with microwaves was performed using a microwave synthesis system (Discover, manufactured by CEM Corporation). A synthesis scheme of Step 3 is shown in (k-3).
Reaction SMILES: [OH:1][CH2:2][CH2:3][O:4][CH2:5][CH2:6][NH:7][C:8](=[O:14])[O:9][C:10]([CH3:13])([CH3:12])[CH3:11].C(N(CC)CC)C.[CH3:22][S:23](Cl)(=[O:25])=[O:24].C(=O)(O)[O-].[Na+]>ClCCl>[CH3:22][S:23]([O:1][CH2:2][CH2:3][O:4][CH2:5][CH2:6][NH:7][C:8]([O:9][C:10]([CH3:11])([CH3:13])[CH3:12])=[O:14])(=[O:25])=[O:24]
Reactant: CS(=O)(=O)Cl
Reactant: CC(C)(C)OC(=O)NCCOCCO
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CC(C)(C)OC(=O)NCCOCCOS(C)(=O)=O
Temperature: 25 °C
Reaction time: 8 h
Yield: 96.9 %

Procedure:
Under a nitrogen atmosphere, a solution of tert-butyl 2-(2-hydroxyethoxy)ethylcarbamate (89.0 g, 434 mmol) in dichloromethane (1.5 L) was cooled to 0° C.; triethylamine (90.7 mL, 650 mmol) was added dropwise. Methanesulfonyl chloride (36.9 mL, 477 mmol) was then added over a period of 45 minutes. A precipitate formed, and the reaction became yellow. The reaction was allowed to warm to room temperature and stirred overnight. Saturated aqueous sodium bicarbonate (750 mL) was added. The organic layer was then sequentially washed with water (3×500 mL) and brine (250 mL), dried over magnesium sulfate, filtered, and concentrated under reduced pressure to provide 119.2 g of 2-{2-[(tert-butoxycarbonyl)amino]ethoxy}ethyl methanesulfonate as a light orange oil.