Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([N:4](C(OC(C)(C)C)=O)[CH2:5][CH2:6][CH2:7][N:8](C(OC(C)(C)C)=O)[CH2:9]/[CH:10]=[CH:11]/[CH2:12][N:13](C(OC(C)(C)C)=O)[CH2:14][CH2:15][CH2:16][N:17]([CH2:25][C:26]#[CH:27])C(OC(C)(C)C)=O)[C:2]#[CH:3].[ClH:49]>>[ClH:49].[ClH:49].[ClH:49].[ClH:49].[CH2:25]([NH:17][CH2:16][CH2:15][CH2:14][NH:13][CH2:12]/[CH:11]=[CH:10]/[CH2:9][NH:8][CH2:7][CH2:6][CH2:5][NH:4][CH2:1][C:2]#[CH:3])[C:26]#[CH:27]
Reactant: C#CCN(CCCN(C/C=C/CN(CCCN(CC#C)C(=O)OC(C)(C)C)C(=O)OC(C)(C)C)C(=O)OC(C)(C)C)C(=O)OC(C)(C)C
Agent: Cl
Product: C#CCNCCCNC/C=C/CNCCCNCC#C

Procedure:
0.97 g (1.43 mmol) of (E)-1,14-di-propargyl-1,5,10,14-tetra-BOC-1,5,10,14-tetraazatetradec-7-ene and 15 ml of 3N methanolic hydrochloric acid are reacted analogously to Example 1. Recrystallisation of the crude product from methanol/water yields the title compound, m.p. >260° C. 1H-NMR (D2O): δ2.07-2.19(m,4H); 3.01(t,2H); 3.15-3.30(m,8H); 3.77(d,4H); 3.96(d,4H); 6.05-6.07(m,2H).
Reaction SMILES: [CH3:1][N:2]1[C:15]2[CH:14]=[C:13]([CH:16]([CH2:22][CH:23]3[CH2:28][CH2:27][O:26][CH2:25][CH2:24]3)[C:17]([O:19]CC)=[O:18])[CH:12]=[CH:11][C:10]=2[S:9](=[O:30])(=[O:29])[C:8]2[C:3]1=[CH:4][CH:5]=[CH:6][CH:7]=2.[OH-].[Na+]>CO>[CH3:1][N:2]1[C:15]2[CH:14]=[C:13]([CH:16]([CH2:22][CH:23]3[CH2:28][CH2:27][O:26][CH2:25][CH2:24]3)[C:17]([OH:19])=[O:18])[CH:12]=[CH:11][C:10]=2[S:9](=[O:30])(=[O:29])[C:8]2[C:3]1=[CH:4][CH:5]=[CH:6][CH:7]=2
Reactant: CCOC(=O)C(CC1CCOCC1)c1ccc2c(c1)N(C)c1ccccc1S2(=O)=O
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: CN1c2ccccc2S(=O)(=O)c2ccc(C(CC3CCOCC3)C(=O)O)cc21
Temperature: 80 °C
Reaction time: 1 h

Procedure:
2.0 g of ethyl 2-(10-methyl-5,5-dioxo-5,10-dihydrophenothiazin-2-yl)-3-(tetrahydropyran-4-yl)propionate are suspended in 100 ml of methanol, and 32.1 ml of a 2M NaOH solution are added. The reaction mixture is stirred at 80° C. for one hour. The methanol is removed under reduced pressure and the reaction mixture is adjusted to pH 4 by addition of concentrated hydrochloric acid. The mixture is extracted three times with in each case 100 ml of ethyl acetate. The combined organic phases are dried over MgSO4 and then concentrated under reduced pressure. This gives 1.85 g of 2-(10-methyl-5,5-dioxo-5,10-dihydrophenothiazin-2-yl)-3-(tetrahydropyran-4-yl)propionic acid as a solid.
Reaction SMILES: Br[C:2]1[C:7]([F:8])=[CH:6][C:5]([O:9][CH3:10])=[CH:4][C:3]=1[F:11].[Li]CCCC.[N:17]([C:26]([O:28][C:29]([CH3:32])([CH3:31])[CH3:30])=[O:27])=[N:18][C:19]([O:21][C:22]([CH3:25])([CH3:24])[CH3:23])=[O:20].N#N>C1COCC1>[F:11][C:3]1[CH:4]=[C:5]([O:9][CH3:10])[CH:6]=[C:7]([F:8])[C:2]=1[N:17]([C:26]([O:28][C:29]([CH3:32])([CH3:31])[CH3:30])=[O:27])[NH:18][C:19]([O:21][C:22]([CH3:23])([CH3:24])[CH3:25])=[O:20]
Reactant: CC(C)(C)OC(=O)N=NC(=O)OC(C)(C)C
Reactant: COc1cc(F)c(Br)c(F)c1
Agent: N#N
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: COc1cc(F)c(N(NC(=O)OC(C)(C)C)C(=O)OC(C)(C)C)c(F)c1
Temperature: 25 °C
Reaction time: 0.08 h
Yield: 103.5 %

Procedure:
In an oven-dried, N2-purged round bottom, 4-bromo-3,5-difluoroanisole (500 mg, 2.24 mmol) was dissolved in anhydrous THF (11 mL) and brought to −78° C. nBuLi (0.96 mL, 2.44 M in THF, 2.35 mmol) was added over 2 min. This was stirred for 5 min and then a solution di-tert-butyl azodicarboxylate (542 mg, 2.35 mmol) in anhydrous THF (3 mL) in an oven-dried, N2-purged pear flask was added in one portion via syringe. The reaction was removed from the ice bath and allowed to warm to room temperature over 30 min. The reaction, a clear solution, was quenched by the addition of aq. sat. NH4Cl. The material was extracted with two portions of ethyl acetate and the combined organics were dried over MgSO4 and concentrated in vacuo. Purification by silica gel flash chromatography (ethyl acetate in heptane) gave di-tert-butyl 1-(2,6-difluoro-4-methoxyphenyl)hydrazine-1,2-dicarboxylate (0.868 g, impure with ethyl acetate) as a clear oil. 1H NMR (400 MHz, CDCl3, δ): 6.48 (d, J=10.1 Hz, 2H) 3.73-3.85 (m, 3H) 1.36-1.60 (m, 18H).
Reaction SMILES: [O:1]=[C:2]1[N:6]2[C:7]3[CH:26]=[CH:25][C:24]([Cl:27])=[N:23][C:8]=3[C:9]([C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=3[Cl:22])=[N:10][CH:11]([O:12]C(=O)C)[C:5]2=[N:4][NH:3]1.C(O)CC.[OH-].[K+].C(O)(=O)C>O>[O:1]=[C:2]1[N:6]2[C:7]3[CH:26]=[CH:25][C:24]([Cl:27])=[N:23][C:8]=3[C:9]([C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=3[Cl:22])=[N:10][CH:11]([OH:12])[C:5]2=[N:4][NH:3]1
Reactant: CC(=O)OC1N=C(c2ccccc2Cl)c2nc(Cl)ccc2-n2c1n[nH]c2=O
Agent: [K+]
Agent: [OH-]
Solvent: CCCO
Solvent: CC(=O)O
Solvent: O
Product: O=c1[nH]nc2n1-c1ccc(Cl)nc1C(c1ccccc1Cl)=NC2O
Temperature: 25 °C
Reaction time: 0.25 h

Procedure:
9 grams of 1-keto-4-acetoxy-6-(o-chlorophenyl)-8-chloro-1,2-dihydro-4H-s-triazolo-(4,3-a)-pyrido-(2,3-f)-(1,4)-diazepine were stirred with 60 ml. of n-propanol and a mixture of 10 grams of powdered potassium hydroxide and 100 ml. of n-propanol added. The mixture was stirred for 15 minutes at room temperature. Then it was acidified with glacial acetic acid and 600 ml. of water added. The reaction product crystallized out. It was filtered off with suction and then washed with water. The product can be recrystallized from dimethylformamide-ether whereupon it is subsequently boiled with ethanol for 30 minutes for the complete removal of the dimethyl formamide. Yield 5 grams; M.P. 260°-262° C.
Reaction SMILES: NC(N)=O.S(=NC(N)=O)(=O)=O.[NH2:12][C:13]1[N:18]=[CH:17][C:16]([N:19]2[C:24](=[O:25])[C:23]3[CH:26]=[C:27]([F:32])[C:28]([NH:30][CH3:31])=[CH:29][C:22]=3[O:21][CH2:20]2)=[CH:15][C:14]=1[CH3:33].C([O:36][C:37](=O)[NH:38][S:39]([C:42]1[S:43][C:44]([Cl:47])=[CH:45][CH:46]=1)(=[O:41])=[O:40])C>>[Cl:47][C:44]1[S:43][C:42]([S:39]([NH:38][C:37]([NH:12][C:13]2[C:14]([CH3:33])=[CH:15][C:16]([N:19]3[C:24](=[O:25])[C:23]4[CH:26]=[C:27]([F:32])[C:28]([NH:30][CH3:31])=[CH:29][C:22]=4[O:21][CH2:20]3)=[CH:17][N:18]=2)=[O:36])(=[O:41])=[O:40])=[CH:46][CH:45]=1
Reactant: CCOC(=O)NS(=O)(=O)c1ccc(Cl)s1
Reactant: CNc1cc2c(cc1F)C(=O)N(c1cnc(N)c(C)c1)CO2
Agent: NC(=O)N=S(=O)=O
Agent: NC(N)=O
Product: CNc1cc2c(cc1F)C(=O)N(c1cnc(NC(=O)NS(=O)(=O)c3ccc(Cl)s3)c(C)c1)CO2
Yield: 89.5 %

Procedure:
Analogous to the sulfonylurea urea formation described in Ex 5, 3-(6-amino-5-methylpyridin-3-yl)-6-fluoro-7-(methylamino)-2,3-dihydrobenzo[e][1,3]oxazin-4-one (0.010 g, 0.034 mmol) and (5-Chloro-thiophene-2-sulfonyl)-carbamic acid ethyl ester (0.048 g, 0.166 mmol) were coupled to give 1-(5-chlorothiophen-2-ylsulfonyl)-3-(5-(6-fluoro-7-(methylamino)-4-oxo-2H-benzo[e][1,3]oxazin-3(4H)-yl)-3-methylpyridin-2-yl)urea (0.016 g, 85%). RP-HPLC: 2.7 min; ES-MS (M+H)+=526.0; 1H-NMR (DMSO-d6) δ (ppm): 2.2 (s, 3), 2.8 (s, 3), 5.6 (s, 2), 6.2 (d, 1), 6.8 (bs, 1), 7.2 (s, 1), 7.4 (d, 1), 7.6 (s, 1), 7.8 (d, 1), 8.2 (d, 1), 9.6 (bs, 1).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:7]=[CH:8][C:9]=1[C:10]([F:13])([F:12])[F:11])[CH2:5]Br.[Br:14][C:15]1[C:20]([F:21])=[CH:19][C:18]([OH:22])=[C:17]([F:23])[CH:16]=1.C(=O)([O-])[O-].[K+].[K+]>CC(C)=O>[Br:14][C:15]1[CH:16]=[C:17]([F:23])[C:18]([O:22][CH2:5][C:4]2[CH:7]=[CH:8][C:9]([C:10]([F:13])([F:12])[F:11])=[C:2]([Cl:1])[CH:3]=2)=[CH:19][C:20]=1[F:21]
Reactant: FC(F)(F)c1ccc(CBr)cc1Cl
Reactant: Oc1cc(F)c(Br)cc1F
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: Fc1cc(OCc2ccc(C(F)(F)F)c(Cl)c2)c(F)cc1Br
Temperature: 25 °C
Yield: 98.5 %

Procedure:
To solution of 3-chloro-4-(trifluoromethyl)benzyl bromide (300 mg, 1.097 mmol) in acetone (15 mL) was added 4-bromo-2,5-difluorophenol (1.097 mmol) followed by potassium carbonate (303 mg, 2.194 mmol). The reaction mixture was heated at reflux for 3.5 hours and then allowed to cool to room temperature. The solvent was removed under reduced pressure to yield a white solid, which was partitioned with water/EtOAc mixture (1:1, 50 mL). The organic layer was separated and the aqueous was extracted with EtOAc (3×30 mL). The combined organics were washed with brine (50 mL), dried over sodium sulphate, filtered and concentrated in vacuo to give the title compound as a white solid (434 mg, 99%).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:23])[CH2:4][C:5]1[C:6](=[O:22])[N:7]([CH2:11][C:12]2[CH:17]=[CH:16][C:15]([O:18][CH3:19])=[CH:14][C:13]=2[O:20][CH3:21])[CH2:8][CH2:9][CH:10]=1>CO.[Pd]>[CH3:1][O:2][C:3](=[O:23])[CH2:4][CH:5]1[CH2:10][CH2:9][CH2:8][N:7]([CH2:11][C:12]2[CH:17]=[CH:16][C:15]([O:18][CH3:19])=[CH:14][C:13]=2[O:20][CH3:21])[C:6]1=[O:22]
Reactant: COC(=O)CC1=CCCN(Cc2ccc(OC)cc2OC)C1=O
Agent: [Pd]
Solvent: CO
Product: COC(=O)CC1CCCN(Cc2ccc(OC)cc2OC)C1=O
Temperature: 25 °C
Reaction time: 5 h
Yield: 95.6 %

Procedure:
26 mg of [1-(2,4-dimethoxy-benzyl)-2-oxo-1,2,5,6-tetrahydro-pyridin-3-yl]-acetic acid methyl ester (o) (0.08 mM) was dissolved in methanol solution under Ar atmosphere. 1.7 mg of 10% Pd—C was added thereto and the mixture was hydrogenated under a hydrogen balloon. The reaction mixture was stirred for 5 hrs at room temperature, filtered and concentrated in vacuo. The resulting compound was purified with Silica gel column chromatography to give 25 mg of [1-(2,4-dimethoxy-benzyl)-2-oxo-piperidine-3-yl]acetic acid methyl ester (r) (yield: 99%).
Reaction SMILES: [C:1]1([N:7]2[C:20]3[C:15](=[CH:16][CH:17]=[CH:18][CH:19]=3)[C:9]3([CH2:14][CH2:13][NH:12][CH2:11][CH2:10]3)[CH2:8]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[C:21](Cl)(=[O:28])[C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1>>[C:21]([N:12]1[CH2:11][CH2:10][C:9]2([C:15]3[C:20](=[CH:19][CH:18]=[CH:17][CH:16]=3)[N:7]([C:1]3[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=3)[CH2:8]2)[CH2:14][CH2:13]1)(=[O:28])[C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1
Reactant: c1ccc(N2CC3(CCNCC3)c3ccccc32)cc1
Reactant: O=C(Cl)c1ccccc1
Product: O=C(c1ccccc1)N1CCC2(CC1)CN(c1ccccc1)c1ccccc12

Procedure:
A mixture of 1-phenylspiro[indoline-3,4'-piperidine] (Example 11), propionyl chloride and sodium bicarbonate in chloroform is stirred at reflux. The mixture is permitted to cool, filtered, and the filtrate concentrated, leaving 1-phenyl-1'-propionylspiro[indoline-3,4'-piperidine]. In a similar fashion, 1-phenylspiro[indoline-3,4'-piperidine] is treated with benzoylchloride to provide 1'-benzoyl-1-phenylspiro[indoline-3,4'-piperidine].
Reaction SMILES: [OH:1][C@@H:2]1[C@H:15]2[C@@H:6]([CH2:7][CH2:8][C:9]3[C@:14]2([CH3:16])[CH2:13][CH:12]([CH:17]=O)[C:11](=O)[CH:10]=3)[C@@H:5]2[CH2:20][CH2:21][C@:22]3([C:26]4([CH2:30][O:29][CH2:28][O:27]4)[O:25][CH2:24][O:23]3)[C@@:4]2([CH3:31])[CH2:3]1.[F:32][C:33]1[CH:34]=[C:35]([NH:40][NH2:41])[CH:36]=[CH:37][C:38]=1[F:39]>>[F:32][C:33]1[CH:34]=[C:35]([N:40]2[C:11]3[CH:10]=[C:9]4[CH2:8][CH2:7][C@H:6]5[C@H:15]([C@:14]4([CH3:16])[CH2:13][C:12]=3[CH:17]=[N:41]2)[C@H:2]([OH:1])[CH2:3][C@@:4]2([CH3:31])[C@@:22]3([CH2:21][CH2:20][C@H:5]52)[C:26]2([CH2:30][O:29][CH2:28][O:27]2)[O:25][CH2:24][O:23]3)[CH:36]=[CH:37][C:38]=1[F:39]
Reactant: C[C@]12CC(C=O)C(=O)C=C1CC[C@@H]1[C@@H]2[C@@H](O)C[C@@]2(C)[C@H]1CC[C@@]21OCOC12COCO2
Reactant: NNc1ccc(F)c(F)c1
Product: C[C@@]12Cc3cnn(-c4ccc(F)c(F)c4)c3C=C1CC[C@H]1[C@H]2[C@H](O)C[C@]2(C)[C@@H]1CC[C@]21OCOC12COCO2

Procedure:
The compound was prepared from (8S,9S,10R,11S,13S,14S,17R)-11-hydroxy-10,13-dimethyl-3-oxo-1,2,3,6,7,8,9,10,11,12,13,14,15,16-tetradecahydrodispiro[cyclopenta[a]phenanthrene-17,4′-[1,3]dioxolane-5′,4″-[1,3]dioxolane]-2-carbaldehyde and (3,4-difluorophenyl)hydrazine according to the procedure for Intermediate 50. APCI-MS m/z: 541 [MH+].
Reaction SMILES: FC1C=C(OC)C=C(F)C=1C[NH2:5].C(N(CC)C(C)C)(C)C.C(N1C=CN=C1)(N1C=CN=C1)=O.C(N(CC)CC)C.[F:41][C:42]1[CH:71]=[C:70]([O:72][CH3:73])[CH:69]=[C:68]([F:74])[C:43]=1[CH2:44][N:45]1[C:50]2[N:51]=[CH:52][CH:53]=[CH:54][C:49]=2[S:48](=[O:56])(=[O:55])[N:47]([C:57]2[CH:62]=C[C:60]([O:63][CH3:64])=[C:59]([O:65][CH3:66])[CH:58]=2)[C:46]1=[O:67]>CN(C=O)C>[F:41][C:42]1[CH:71]=[C:70]([O:72][CH3:73])[CH:69]=[C:68]([F:74])[C:43]=1[CH2:44][N:45]1[C:50]2[N:51]=[CH:52][CH:53]=[CH:54][C:49]=2[S:48](=[O:56])(=[O:55])[N:47]([C:57]2[CH:62]=[N:5][C:60]([O:63][CH3:64])=[C:59]([O:65][CH3:66])[CH:58]=2)[C:46]1=[O:67]
Reactant: COc1cc(F)c(CN2C(=O)N(c3ccc(OC)c(OC)c3)S(=O)(=O)c3cccnc32)c(F)c1
Reactant: COc1cc(F)c(CN)c(F)c1
Agent: O=C(n1ccnc1)n1ccnc1
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: COc1cc(F)c(CN2C(=O)N(c3cnc(OC)c(OC)c3)S(=O)(=O)c3cccnc32)c(F)c1

Procedure:
The title compound (134 mg, 0.27 mmol) was prepared in two steps from (IntC4) (165 mg, 0.5 mmol), 2,6-difluoro-4-methoxybenzylamine (90 uL, 0.6 mmol) and N,N-diisopropylethylamine (180 uL, 1.0 mmol); followed by 1,1′-carbonyldiimidazole (331 mg, 2.04 mmol), triethylamine (0.14 mL, 1.00 mmol) in DMF (1.5 mL) using the methods of (95).
Reaction SMILES: C(OCCCC)CCC.[C:10]1([Li])[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1.C(OCC)C.[CH3:22][C:23]1[CH:28]=[N:27][CH:26]=[CH:25][N:24]=1>O>[CH3:22][C:23]1[C:28]([C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)=[N:27][CH:26]=[CH:25][N:24]=1
Reactant: [Li]c1ccccc1
Reactant: Cc1cnccn1
Solvent: CCOCC
Solvent: CCCCOCCCC
Solvent: O
Product: Cc1nccnc1-c1ccccc1
Temperature: 25 °C
Reaction time: 3 h
Yield: 22 %

Procedure:
First, in a nitrogen atmosphere, 50 mL of a dibutyl ether solution containing phenyl lithium (produced by Wako Pure Chemical Industries, Ltd, 2.1 mol/L) and 250 mL of diethylether were mixed. Then, 8.98 g of 2-methylpyrazine (produced by Tokyo Chemical Industries Co., Ltd) was dropped into this solution while the solution was being cooled with ice, and stirred at a room temperature for three hours. Water was added into the reacted solution and an organic layer was extracted with diethylether. The obtained organic layer was washed with water and dried with magnesium sulfate. After the solvent was distilled off, the obtained residue was purified by column chromatography using dichloromethane as a developing solvent, thereby obtaining a pyrazine derivative Hmppr (yellow oily matter, yield: 22%). A synthesis scheme of Step 1 is shown by the following (a-1).
Reaction SMILES: BrC1C(N[C:18]([C:20]2[N:24]([CH3:25])[N:23]=[CH:22][C:21]=2[C:26]([OH:28])=[O:27])=[O:19])=CC2N(C=C(C3C=CC=CC=3)N=2)C=1.[N:29]1([C:35]2[N:40]3[CH:41]=[C:42]([C:44]4[CH:49]=[CH:48][CH:47]=[CH:46][CH:45]=4)[N:43]=[C:39]3[CH:38]=[C:37]([NH2:50])[N:36]=2)[CH2:34][CH2:33][O:32][CH2:31][CH2:30]1>>[CH3:25][N:24]1[C:20]([C:18](=[O:19])[NH:50][C:37]2[N:36]=[C:35]([N:29]3[CH2:34][CH2:33][O:32][CH2:31][CH2:30]3)[N:40]3[CH:41]=[C:42]([C:44]4[CH:49]=[CH:48][CH:47]=[CH:46][CH:45]=4)[N:43]=[C:39]3[CH:38]=2)=[C:21]([C:26]([OH:28])=[O:27])[CH:22]=[N:23]1
Reactant: Cn1ncc(C(=O)O)c1C(=O)Nc1cc2nc(-c3ccccc3)cn2cc1Br
Reactant: Nc1cc2nc(-c3ccccc3)cn2c(N2CCOCC2)n1
Product: Cn1ncc(C(=O)O)c1C(=O)Nc1cc2nc(-c3ccccc3)cn2c(N2CCOCC2)n1

Procedure:
The title compound was prepared in analogy to 5-(6-bromo-2-phenyl-imidazo[1,2-a]pyridin-7-ylcarbamoyl)-1-methyl-1H-pyrazole-4-carboxylic acid (Example 67, Step 4-6), using 5-morpholin-4-yl-2-phenyl-imidazo[1,2-c]pyrimidin-7-ylamine (as prepared in Example 63, Step 1) in Step 4. MS (m/e)=448.3 [M+H+].
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([CH:11]2[CH2:16][CH2:15][NH:14][CH2:13][CH2:12]2)(=[O:10])=[O:9])=[CH:4][CH:3]=1.Cl[C:18]1[C:23]([F:24])=[CH:22][CH:21]=[CH:20][N:19]=1.CCN(C(C)C)C(C)C>O1CCOCC1>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([S:8]([CH:11]2[CH2:16][CH2:15][N:14]([C:18]3[C:23]([F:24])=[CH:22][CH:21]=[CH:20][N:19]=3)[CH2:13][CH2:12]2)(=[O:9])=[O:10])=[CH:6][CH:7]=1
Reactant: Fc1cccnc1Cl
Reactant: O=S(=O)(c1ccc(Cl)cc1)C1CCNCC1
Solvent: C1COCCO1
Solvent: CCN(C(C)C)C(C)C
Product: O=S(=O)(c1ccc(Cl)cc1)C1CCN(c2ncccc2F)CC1
Yield: 13.3 %

Procedure:
Using the procedure from Example 7A, 4-[(4-chlorophenyl)sulfonyl]piperidine (100 mg, 0.38 mmol) was reacted with 2-chloro-3-fluoropyridine (78 μl, 0.76 mmol), DIEA (0.27 ml, 1.52) and 1,4-dioxane (0.3 ml) at 190° C. to afford the title compound (18 mg), a white solid, in 13% yield.
Reaction SMILES: C(=O)([O-])O.[Na+:5].[C:6]([C:8]1[CH:13]=[CH:12][C:11]([S:14](Cl)(=[O:16])=[O:15])=[CH:10][CH:9]=1)#[N:7]>S([O-])([O-])=O.[Na+].[Na+]>[C:6]([C:8]1[CH:9]=[CH:10][C:11]([S:14]([O-:16])=[O:15])=[CH:12][CH:13]=1)#[N:7].[Na+:5]
Reactant: N#Cc1ccc(S(=O)(=O)Cl)cc1
Agent: O=C([O-])O
Agent: O=S([O-])[O-]
Agent: [Na+]
Product: N#Cc1ccc(S(=O)[O-])cc1
Temperature: 70 °C
Reaction time: 4 h
Yield: 120.2 %

Procedure:
[Step 1] To an aqueous solution (180 ml) of sodium sulfite (9.7 g) and sodium hydrogen carbonate (11.8 g) was added 4-cyanobenzenesulfonyl chloride (14.1 g) at room temperature and the mixture was stirred at 70° C. for 4 hrs. The solvent was evaporated under reduced pressure and the obtained residue was purified by medium pressure preparative liquid chromatography (MCI GEL, CHP20P (75-150μ), eluant=water) to give sodium 4-cyanobenzenesulfinate (15.9 g, 99%).
Reaction SMILES: [C:1]([O:5][C:6](=[O:28])[N:7]([C@H:12]1[CH2:16][C@@H:15]([N:17]2[CH:25]=[N:24][C:23]3[C:18]2=[N:19][C:20]([Cl:27])=[N:21][C:22]=3Cl)[CH:14]=[CH:13]1)[C:8](=[O:11])[CH2:9][CH3:10])([CH3:4])([CH3:3])[CH3:2].[CH3:29][CH2:30][CH:31]([NH2:34])[CH2:32][CH3:33]>C1COCC1>[C:1]([O:5][C:6](=[O:28])[N:7]([C@H:12]1[CH2:16][C@@H:15]([N:17]2[CH:25]=[N:24][C:23]3[C:18]2=[N:19][C:20]([Cl:27])=[N:21][C:22]=3[NH:34][CH:31]([CH2:32][CH3:33])[CH2:30][CH3:29])[CH:14]=[CH:13]1)[C:8](=[O:11])[CH2:9][CH3:10])([CH3:3])([CH3:4])[CH3:2]
Reactant: CCC(=O)N(C(=O)OC(C)(C)C)[C@@H]1C=C[C@H](n2cnc3c(Cl)nc(Cl)nc32)C1
Reactant: CCC(N)CC
Solvent: C1CCOC1
Product: CCC(=O)N(C(=O)OC(C)(C)C)[C@@H]1C=C[C@H](n2cnc3c(NC(CC)CC)nc(Cl)nc32)C1
Temperature: 50 °C
Reaction time: 18 h

Procedure:
[(1S,4R)-4-(2,6-Dichloro-purin-9-yl)-cyclopent-2-enyl]-propionyl-carbamic acid tert-butyl ester (700 mg, 1.64 mmol) is dissolved in THF (15 ml) under an atmosphere of argon. 3-Pentyl-amine (315 mg, 3.61 mmol) is added and the reaction mixture is stirred at 50° C. The reaction is shown to be complete by LCMS after 18 hours. The reaction mixture is partitioned between dichloromethane (50 ml) and 0.1M HCl (50 ml). The organic layer is washed with water (20 ml) and brine (20 ml), dried over MgSO4, filtered and the solvent is removed in vacuo to give the title compound. 1H nmr (CDCl3, 400 MHz); 8.10(s, 1H), 6.00(m, 1H), 5.70(m, 1H), 5.60(m, 2H), 5.45(m, 1H), 4.20(m, 1H), 3.65(m, 1H), 3.00(m, 1H), 2.65(m, 3H), 1.95(m, 1H), 1.60(m, 3H), 1.45(s, 9H), 1.10(m, 4H), 0.85(t, 6H), MS (ES+) m/e 477 (MH+).
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([NH2:8])=[CH:4][C:3]=1[N:9]1[CH2:14][CH2:13][N:12]([CH3:15])[CH2:11][CH2:10]1.[CH:16]1[C:25]2[C:20](=[CH:21][CH:22]=[CH:23][CH:24]=2)[CH:19]=[CH:18][C:17]=1[S:26](Cl)(=[O:28])=[O:27]>>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][S:26]([C:17]2[CH:18]=[CH:19][C:20]3[C:25](=[CH:24][CH:23]=[CH:22][CH:21]=3)[CH:16]=2)(=[O:28])=[O:27])=[CH:4][C:3]=1[N:9]1[CH2:10][CH2:11][N:12]([CH3:15])[CH2:13][CH2:14]1
Reactant: O=S(=O)(Cl)c1ccc2ccccc2c1
Reactant: CN1CCN(c2cc(N)ccc2Br)CC1
Product: CN1CCN(c2cc(NS(=O)(=O)c3ccc4ccccc4c3)ccc2Br)CC1

Procedure:
The title compound (E120) was prepared from 4-bromo-3-(4-methylpiperazin-1-yl)benzenamine (EP 0533267A, intermediate 61) (600 mg, 2.23 mmol) and naphthalene-2-sulfonyl chloride (504 mg, 2.23 mmol) using the method of Example 1 (939 mg, 92%) MH+=460/462.
Reaction SMILES: [Br:1][C:2]1[CH:11]=[C:10]2[C:5]([CH2:6][CH2:7][NH:8][C:9]2=[O:12])=[CH:4][CH:3]=1.[F:13][C:14]1[CH:19]=[CH:18][C:17](I)=[CH:16][CH:15]=1.C(=O)([O-])[O-].[K+].[K+]>CN(C=O)C.[Cu]I>[Br:1][C:2]1[CH:11]=[C:10]2[C:5]([CH2:6][CH2:7][N:8]([C:17]3[CH:18]=[CH:19][C:14]([F:13])=[CH:15][CH:16]=3)[C:9]2=[O:12])=[CH:4][CH:3]=1
Reactant: O=C1NCCc2ccc(Br)cc21
Reactant: Fc1ccc(I)cc1
Agent: [Cu]I
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: O=C1c2cc(Br)ccc2CCN1c1ccc(F)cc1
Temperature: 130 °C
Yield: 47.1 %

Procedure:
A mixture of 7-bromo-3,4-dihydroisoquinolin-1(2H)-one (Intermediate 23-1, 60 mg, 0.265 mmol), 1-fluoro-4-iodobenzene (118 mg, 0.531 mmol), potassium carbonate (36.7 mg, 0.265 mmol) and copper (I) iodide (10.11 mg, 0.053 mmol) in DMF (1.000 mL) was heated at 130° C. for 5 h. The mixture was cooled to rt and filtered through a Celite pad, and the solids were washed with EtOAc. The filtrate was washed with water and brine, dried and concentrated. The residue was purified by column chromatography (eluting with a gradient from 90:10 to 60:40 hexane-EtOAc) to give 7-bromo-2-(4-fluorophenyl)-3,4-dihydroisoquinolin-1(2H)-one (40 mg, 47%). 1H NMR (400 MHz, chloroform-d) δ 7.15-7.27 (4 H, m), 7.04-7.13 (2 H, m), 6.48 (1 H, d, J=1.94 Hz), 2.96-3.08 (2 H, m), 2.73-2.84 (2 H, m). Mass spectrum m/z 320, 322 (M+H)+.
Reaction SMILES: [NH2:1][C:2]1[N:6]([C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][C:8]=2[O:13][CH3:14])[N:5]=[CH:4][C:3]=1[C:15]#[N:16].[OH:17]O>[OH-].[NH4+]>[NH2:1][C:2]1[N:6]([C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][C:8]=2[O:13][CH3:14])[N:5]=[CH:4][C:3]=1[C:15]([NH2:16])=[O:17]
Reactant: OO
Reactant: COc1ccccc1-n1ncc(C#N)c1N
Agent: [NH4+]
Agent: [OH-]
Product: COc1ccccc1-n1ncc(C(N)=O)c1N
Temperature: 25 °C
Reaction time: 18 h
Yield: 84 %

Procedure:
To a solution of 5-amino-1-(2-methoxyphenyl)-1H-pyrazole-4-carbonitrile (1.53 g) in saturated ammonium hydroxide (30 mL) was added 30% hydrogen peroxide solution (6 mL). The reaction stirred for 18 h at ambient temperature and was slowly quenched with 60 mL of a saturated sodium sulfate solution. The aqueous layer was extracted with ethyl acetate, dried with magnesium sulfate, filtered and concentrated. MPLC Biotage chromatography eluting with 2-6% methanol/methylene chloride provided the title compound 1.38 g (84%). 400 MHz 1H NMR (DMSO) δ 7.79 (s, 1 H), 7.42 (m, 1H), 7.25 (d, J=7.5 Hz, 2H), 7.19 (d, J=8.3 Hz, 2 H), 7.03 (t, J=6.2 Hz, 1H), 5.83 (s,2H), 3.76 (s, 3 H); MS: (M+H m/z=233.2).
Reaction SMILES: COC(=O)C[CH:5]([C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1)[CH2:6][O:7][C:8](=[O:10])[CH3:9]>O1CCOCC1.S(=O)(=O)(O)O>[C:11]1([CH:5]2[CH2:6][O:7][C:8](=[O:10])[CH2:9]2)[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1
Reactant: COC(=O)CC(COC(C)=O)c1ccccc1
Agent: O=S(=O)(O)O
Solvent: C1COCCO1
Product: O=C1CC(c2ccccc2)CO1
Temperature: 45 °C

Procedure:
A solution of 4-acetoxy-3-phenyl-butyric acid methyl ester, (4.5 g, 19.2 mmol) in 1,4-dioxane (29 mL) and sulfuric acid (29 mL) is stirred at room temperature for one hour then heated at 45° C. for 18 h. Volatile solvents are evaporated and the residue is extracted with toluene. The combined organic extracts are extracted with water and brine, filtered, and concentrated to yield the title compound, 2.2 g (71%), as a colorless liquid.
Reaction SMILES: [NH2:1][C:2]1[N:7]=[C:6]([NH:8][CH2:9][CH2:10][OH:11])[C:5]([N+:12]([O-])=O)=[CH:4][N:3]=1.[CH2:15](OCC)C>CO.[Ni]>[NH2:1][C:2]1[N:7]=[C:6]2[C:5]([N:12]=[CH:15][N:8]2[CH2:9][CH2:10][OH:11])=[CH:4][N:3]=1
Reactant: Nc1ncc([N+](=O)[O-])c(NCCO)n1
Reactant: CCOCC
Agent: [Ni]
Solvent: CO
Product: Nc1ncc2ncn(CCO)c2n1
Temperature: 35 °C
Reaction time: 3 h
Yield: 75 %

Procedure:
19.92 g (0.1 mole) of 2-amino-4-(2-hydroxyethylamino)-5-nitropyrimidine was suspended in 400 ml of methanol, to which 10 g of wet Raney nickel was then added. The mixture was stirred at a temperature of 30-40° C. for 3 hours. After completion of the reaction, the reaction product was filtered through nitrocellulose, followed by washing. The filtrate was concentrated under reduced pressure. To the remaining concentrate, 100 ml of triethylorthoformate and 10 ml of concentrated hydrochloric acid were added, and the mixture was stirred under reflux for 9 hours at a temperature of 80-90° C. After completion of the reaction, the product was cooled to room temperature, and 200 ml of ethylether was then added thereto. The resulting crystal was filtered, washed and dried, thereby giving 13.44 g (75% yield) of yellowish brown-colored 2-amino-9-(2-hydroxyethyl)purine.