Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:8]=[C:7]([O:9][C:10]2[C:19]3[C:14](=[CH:15][C:16]([O:22][CH3:23])=[C:17]([O:20][CH3:21])[CH:18]=3)[N:13]=[CH:12][N:11]=2)[CH:6]=[CH:5][C:3]=1[NH2:4].C(N(CC)CC)C.ClC(Cl)(O[C:35](=[O:41])OC(Cl)(Cl)Cl)Cl.[CH2:43]([N:45]([C:49]1[CH:54]=[CH:53][CH:52]=[C:51]([CH3:55])[CH:50]=1)[CH2:46][CH2:47][NH2:48])[CH3:44]>C(Cl)(Cl)Cl.O>[Cl:1][C:2]1[CH:8]=[C:7]([O:9][C:10]2[C:19]3[C:14](=[CH:15][C:16]([O:22][CH3:23])=[C:17]([O:20][CH3:21])[CH:18]=3)[N:13]=[CH:12][N:11]=2)[CH:6]=[CH:5][C:3]=1[NH:4][C:35]([NH:48][CH2:47][CH2:46][N:45]([CH2:43][CH3:44])[C:49]1[CH:54]=[CH:53][CH:52]=[C:51]([CH3:55])[CH:50]=1)=[O:41]
Reactant: COc1cc2ncnc(Oc3ccc(N)c(Cl)c3)c2cc1OC
Reactant: O=C(OC(Cl)(Cl)Cl)OC(Cl)(Cl)Cl
Reactant: CCN(CCN)c1cccc(C)c1
Solvent: CCN(CC)CC
Solvent: O
Solvent: ClC(Cl)Cl
Product: CCN(CCNC(=O)Nc1ccc(Oc2ncnc3cc(OC)c(OC)cc23)cc1Cl)c1cccc(C)c1
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 90.4 %

Procedure:
2-Chloro-4-[(6,7-dimethoxy-4-quinazolinyl)oxy]-aniline (100 mg) was dissolved in chloroform (10 ml) and triethylamine (1 ml) to prepare a solution. A solution of triphosgene (134 mg) in chloroform was then added to the solution, and the mixture was stirred at room temperature for 10 min. Next, N1-ethyl-N1-(3-methylphenyl)-1,2-ethanediamine (80 mg) was added thereto, and the mixture was further stirred at room temperature for one hr. Water was added to stop the reaction, and the reaction solution was then extracted with chloroform, followed by concentration. The residue was purified on a column using chloroform/methanol to give the title compound (146 mg, yield 91%).
Reaction SMILES: [C:1]([C:3]1[CH:10]=[CH:9][C:6]([CH2:7]Br)=[CH:5][CH:4]=1)#[N:2].[N-:11]=[N+]=[N-].[Na+].[Cl:15][Sn]Cl>CN(C)C=O.CCOCC.CO>[ClH:15].[C:1]([C:3]1[CH:10]=[CH:9][C:6]([CH2:7][NH2:11])=[CH:5][CH:4]=1)#[N:2]
Reactant: Cl[Sn]Cl
Reactant: [N-]=[N+]=[N-]
Reactant: N#Cc1ccc(CBr)cc1
Agent: [Na+]
Solvent: CCOCC
Solvent: CN(C)C=O
Solvent: CO
Product: Cl
Product: N#Cc1ccc(CN)cc1
Temperature: 60 °C
Reaction time: 1 h

Procedure:
4-Cyanobenzyl bromide (5.0 g, 26 mmol) was dissolved in dimethylformamide. Sodium azide (3.3 g, 50 mmol) was added and the reaction mixture was stirred at 60° C. for 1 h. The mixture was diluted with ether and washed with 1 N sodium bicarbonate, water and brine. The solution was then dried over MgSO4 and concentrated. This azide intermediate was dissolved in methanol and added to a slurry of SnCl2 (7.4 g, 39 mmol) in methanol at 0° C. After warming to rt and stirring for 0.5 h, the reaction mixture was concentrated. Cold 1 N NaOH was added and the mixture was extracted with CH2Cl2. The combined organic layers were dried over Na2SO4 and concentrated to afford the title compound. 1H-NMR (300 MHz, CD3OD) δ4.11 (s, 2 H), 7.63 (d, J=8, 2 H), 7.82 (d, J=8, 2 H).
Reaction SMILES: [C:1](Cl)(Cl)=[S:2].[CH2:5]([NH:12][C@H:13]([C:16]([OH:18])=[O:17])[CH2:14][OH:15])[C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1.[CH2:19](N(CC)CC)C.[K+].[Br-]>C1COCC1.C(Cl)Cl>[CH3:19][O:17][C:16]([C@@H:13]1[CH2:14][O:15][C:1](=[S:2])[N:12]1[CH2:5][C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1)=[O:18]
Reactant: CCN(CC)CC
Reactant: O=C(O)[C@H](CO)NCc1ccccc1
Reactant: S=C(Cl)Cl
Agent: [Br-]
Agent: [K+]
Solvent: ClCCl
Solvent: C1CCOC1
Product: COC(=O)[C@@H]1COC(=S)N1Cc1ccccc1
Reaction time: 3 h

Procedure:
Thiophosgene (23.8 g, 207 mmol) in dry THF (200 mL) was slowly added to a solution of N-benzyl-L-serine (43.4 g, 207 mmol), triethylamine (41.9 g, 414 mmol) in dry THF (600 mL) at 60° C. under nitrogen. The mixture was stirred for 3 hours, and was stirred at room temperature for 12 hours. Triethylamine hydrochloride was removed by filtration and the solvent was evaporated in vacuo. The residue was purified by silica gel column chromatography eluted with ethyl acetate/n-hexane (1/1=v/v). Recrystallization from a mixed solvent [THF/n-hexane (2/1=v/v)] gave BnSL (40.1 g, 77%) as a white powder. [α]D25=35.0° (c=0.1 g/dL, in CH2Cl2). m.p.=101.3–101.8° C. 1H NMR (CD2Cl2): δ=3.70 (s, 3H, —OCH3), 4.32–4.37 (m, 1H, —CH2—), 4.54–4.59 (3H, —CH<, —CH2—, and —CH2—C6H5), 5.31–5.42 (m, 1H, —CH2—C6H5), 7.33–7.38 (5H, —C6H5) ppm. 13C NMR (CD2Cl2): δ=51.47 (—CH2—C6H5), 53.06 (—OCH3), 59.90 (—CH<), 65.55 (—CH2—), 128.98, 129.04, 129.48, 135.09 (—C6H5), 169.55 (—COOCH3), 189.39 (—OCSNH—) ppm. IR (KBr): 1743 (—COOCH3), 1481 (C═S), 1450, 1357, 1304, 1211, 971, 701 cm−1. C12H13NO3S: Calcd. C 57.35, H 5.21, N 5.57, S 12.76; Found C 57.54; H 5.19; N 5.64, S 12.72.
Reaction SMILES: [O:1]=[C:2]1[CH:10]2[CH:5]([CH2:6][C:7](O[Si](C)(C)C)=[C:8](O[Si](C)(C)C)[CH2:9]2)[C:4](=[O:21])[NH:3]1.[Cl:22][C:23]1[CH:28]=[CH:27][C:26]([NH:29][NH2:30])=[CH:25][CH:24]=1>CO.C(O)(=O)C>[Cl:22][C:23]1[CH:28]=[CH:27][C:26]([N:29]=[N:30][C:7]2[CH2:6][CH:5]3[CH:10]([CH2:9][C:8]=2[NH:30][NH:29][C:26]2[CH:27]=[CH:28][C:23]([Cl:22])=[CH:24][CH:25]=2)[C:2](=[O:1])[NH:3][C:4]3=[O:21])=[CH:25][CH:24]=1
Reactant: NNc1ccc(Cl)cc1
Reactant: C[Si](C)(C)OC1=C(O[Si](C)(C)C)CC2C(=O)NC(=O)C2C1
Solvent: CC(=O)O
Solvent: CO
Product: O=C1NC(=O)C2CC(NNc3ccc(Cl)cc3)=C(N=Nc3ccc(Cl)cc3)CC12

Procedure:
8 g (24.4 mmole) 1,3,3a,4,7,7a-hexahydro-1,3-dioxo-5,6-bis(trimethylsiloxy)-isoindole and 11.4 g (80 mmole) 4-chlorophenyl hydrazine are boiled under reflux for 16 hours in 50 ml methanol and 50 ml glacial acetic acid. The crystals precipitated out after cooling are filtered off, after-washed several times with methanol, and dried. One obtains 5-[(4-chlorophenyl)-azo]-6-[N'-(4-chlorophenyl)-hydrazino]-1,3,3a,4,7,7a-hexahydro-1,3-dioxoisoindole in the form of yellow-green crystals.
Reaction SMILES: [CH3:1][NH:2][C:3](=O)[CH:4]([OH:22])[CH:5]([C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1)[O:6][C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][C:8]=1[N+:13]([O-:15])=[O:14].B#B.CO.[ClH:28]>C1COCC1.C(OCC)C>[ClH:28].[CH3:1][NH:2][CH2:3][CH:4]([OH:22])[CH:5]([O:6][C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][C:8]=1[N+:13]([O-:15])=[O:14])[C:16]1[CH:17]=[CH:18][CH:19]=[CH:20][CH:21]=1
Reactant: CNC(=O)C(O)C(Oc1ccccc1[N+](=O)[O-])c1ccccc1
Agent: B#B
Agent: Cl
Solvent: C1CCOC1
Solvent: CCOCC
Solvent: CO
Product: CNCC(O)C(Oc1ccccc1[N+](=O)[O-])c1ccccc1
Temperature: 25 °C
Reaction time: 16 h
Yield: 94 %

Procedure:
50.3 g of N-methyl-2-hydroxy-3-phenyl-3-(2-nitro-phenoxy)-propionamide dissolved in 1000 ml of anhydrous THF was reduced to amine by slowly adding at 8° C. 340 ml of a molar solution of diborane in THF. The whole was refluxed for 4 hours, cooled to room temperature, the excess of diborane was decomposed with MeOH and then, again at room temperature, dropwise addition was made of 400 ml of an ethereal solution of HCl. The whole was left to stand for 16 hours and then evaporated to dryness at reduced pressure, taken up with CH2Cl2 and washed once with an aqueous solution of sodium bicarbonate. The organic phase was then washed several times with a saturated aqueous solution of NaCl, dried with sodium sulphate and evaporated to dryness. The dark oil forming the residue was dissolved in 800 ml of ethyl ether and alcoholic hydrochloric acid (18% solution in ETOH) was added; there was obtained 50.9 g of N-methyl-2-hydroxy-3-(2-nitro-phenoxy)-3-phenyl-propylamine, hydrochloride, m.p. 197°-203° C. (yield 94%).
Reaction SMILES: CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.[B-](F)(F)(F)F.[Cl:23][C:24]1[CH:25]=[N:26][C:27]2[N:28]([N:30]=[C:31]([C:33]([OH:35])=O)[CH:32]=2)[CH:29]=1.Cl.[CH3:37][C:38]1[S:39][C:40]2[CH2:46][CH2:45][NH:44][CH2:43][CH2:42][C:41]=2[N:47]=1>CN(C=O)C>[Cl:23][C:24]1[CH:25]=[N:26][C:27]2[N:28]([N:30]=[C:31]([C:33]([N:44]3[CH2:45][CH2:46][C:40]4[S:39][C:38]([CH3:37])=[N:47][C:41]=4[CH2:42][CH2:43]3)=[O:35])[CH:32]=2)[CH:29]=1
Reactant: Cc1nc2c(s1)CCNCC2
Reactant: O=C(O)c1cc2ncc(Cl)cn2n1
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: Cl
Agent: F[B-](F)(F)F
Solvent: CN(C)C=O
Product: Cc1nc2c(s1)CCN(C(=O)c1cc3ncc(Cl)cn3n1)CC2
Temperature: 25 °C
Reaction time: 8 h

Procedure:
0.72 g (2.23 mmol) TBTU was added to 0.40 g (2.03 mmol) 6-Chloro-pyrazolo[1,5-a]pyrimidine-2-carboxylic acid, 0.41 g (2.03 mmol) 2-Methyl-5,6,7,8-tetrahydro-4H-thiazolo[4,5-d]azepine hydrochloride and 0.88 mL (6.28 mmol) TEA in 8.0 mL DMF and stirred at RT overnight. The reaction mixture was purified by HPLC chromatography and lyophilized. Yield: 0.18 g (25% of theory). ESI-MS: m/z=348 (M+H)+; Rt(HPLC): 1.01 min. (Method J).
Reaction SMILES: OC(C(F)(F)F)=O.[F:8][C:9]1[CH:26]=[CH:25][C:12]([CH2:13][C:14]2[C:23]3[C:18](=[CH:19][CH:20]=[CH:21][CH:22]=3)[C:17](=[O:24])[NH:16][N:15]=2)=[CH:11][C:10]=1[C:27]([N:29]1[CH2:34][CH2:33][NH:32][CH2:31][CH2:30]1)=[O:28].[O:35]=[C:36]([CH3:40])[C:37](O)=[O:38].CCN(C(C)C)C(C)C.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F>CN(C=O)C>[F:8][C:9]1[CH:26]=[CH:25][C:12]([CH2:13][C:14]2[C:23]3[C:18](=[CH:19][CH:20]=[CH:21][CH:22]=3)[C:17](=[O:24])[NH:16][N:15]=2)=[CH:11][C:10]=1[C:27]([N:29]1[CH2:34][CH2:33][N:32]([C:37](=[O:38])[C:36](=[O:35])[CH3:40])[CH2:31][CH2:30]1)=[O:28]
Reactant: CC(=O)C(=O)O
Reactant: O=C(c1cc(Cc2n[nH]c(=O)c3ccccc23)ccc1F)N1CCNCC1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: O=C(O)C(F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: CC(=O)C(=O)N1CCN(C(=O)c2cc(Cc3n[nH]c(=O)c4ccccc34)ccc2F)CC1
Temperature: 25 °C
Reaction time: 60 h
Yield: 13.5 %

Procedure:
4-(4-fluoro-3-(piperazine-1-carbonyl)benzyl)phthalazin-1(2H)-one TFA salt (157.5 mg, 0.34 mmol), 2-oxopropanoic acid (0.15 ml (d=1.26), 2.15 mmol), DIPEA (0.5 ml, 3 mmol), and HATU (258.6 mg, 0.68 mmol) were mixed in DMF (20 ml), the resulting reaction mixture was stirred at room temperature for 60 h until the reaction finished (monitored by TLC). The reaction mixture was then partitioned between DCM and water (50 ml each, the water phase was extracted with DCM (50 ml). The combined organic phase was washed with water, sat. aqueous sodium bicarbonate, and brine, dried over sodium sulphate, filtered, and concentrated to yield the crude product. Then the crude product was purified by column chromatography on silica gel (Petroleum ether: Ethyl Acetate=1:2) to afford the desired product (20 mg, 13.5%) as a light yellow solid.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[C:12]3[CH:13]=[N:14][CH:15]=[C:16]([C:17]([NH:19][CH:20]([C:23]4[O:24][C:25]([CH3:31])=[C:26]([C:28](O)=[O:29])[N:27]=4)[CH2:21][CH3:22])=[O:18])[C:11]=3[CH:10]=[N:9]2)=[CH:4][CH:3]=1.CN(C(O[N:40]1N=[N:47][C:42]2C=CC=N[C:41]1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C.NCC(OC)=[O:68].Cl>CN(C=O)C>[C:41]([CH2:42][NH:47][C:28]([C:26]1[N:27]=[C:23]([CH:20]([NH:19][C:17]([C:16]2[C:11]3[CH:10]=[N:9][N:8]([C:5]4[CH:4]=[CH:3][C:2]([F:1])=[CH:7][CH:6]=4)[C:12]=3[CH:13]=[N:14][CH:15]=2)=[O:18])[CH2:21][CH3:22])[O:24][C:25]=1[CH3:31])=[O:29])(=[O:68])[NH2:40]
Reactant: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Reactant: COC(=O)CN
Reactant: CCC(NC(=O)c1cncc2c1cnn2-c1ccc(F)cc1)c1nc(C(=O)O)c(C)o1
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: CCC(NC(=O)c1cncc2c1cnn2-c1ccc(F)cc1)c1nc(C(=O)NCC(N)=O)c(C)o1
Reaction time: 0.17 h

Procedure:
To a solution of 2-(1-{[1-(4-Fluorophenyl)-1H-pyrazolo[3,4-c]pyridine-4-carbonyl]amino}-propyl)-5-methyl-oxazole-4-carboxylic acid (0.130 g, 0.307 mmol) in DMF (3 mL) was added HATU (0.140 g, 0.368 mmol). After 10 minutes, DIPEA (215 μL, 1.22 mmol) and Gly-OMe.HCl (46.2 mg, 0.368 mmol) was added. After 18 hours, the mixture was concentrated in vacuo. The residue was dissolved in ethyl acetate (30 mL) and washed with 2 N sodium hydroxide (3×10 mL), saturated aqueous ammonium chloride (2×10 mL), saturated aqueous sodium bicarbonate (10 mL) and brine (10 mL). The organic layer was dried over MgSO4, filtered and concentrated. The resulting residue was purified by silica gel chromatography eluting with a gradient of 0-4% methanol in ethyl acetate to afford the title compound. MS m/z 495.71 (MH+).
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][C:6]([C:10]3[N:11]([CH2:23][C:24]4[C:29]([F:30])=[CH:28][C:27]([F:31])=[CH:26][C:25]=4[F:32])[N:12]=[C:13]4[C:18]=3[CH:17]=[CH:16][CH:15]=[C:14]4[C:19]([F:22])([F:21])[F:20])=[CH:7][CH:8]=2)[CH:3]=[CH:2]1.[H-].[Na+].[Cl:35][C:36]1[CH:43]=[C:42]([Cl:44])[CH:41]=[CH:40][C:37]=1[CH2:38]Br>CN(C=O)C>[Cl:35][C:36]1[CH:43]=[C:42]([Cl:44])[CH:41]=[CH:40][C:37]=1[CH2:38][N:1]1[C:9]2[C:4](=[CH:5][C:6]([C:10]3[N:11]([CH2:23][C:24]4[C:25]([F:32])=[CH:26][C:27]([F:31])=[CH:28][C:29]=4[F:30])[N:12]=[C:13]4[C:18]=3[CH:17]=[CH:16][CH:15]=[C:14]4[C:19]([F:22])([F:21])[F:20])=[CH:7][CH:8]=2)[CH:3]=[CH:2]1
Reactant: Clc1ccc(CBr)c(Cl)c1
Reactant: Fc1cc(F)c(Cn2nc3c(C(F)(F)F)cccc3c2-c2ccc3[nH]ccc3c2)c(F)c1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: Fc1cc(F)c(Cn2nc3c(C(F)(F)F)cccc3c2-c2ccc3c(ccn3Cc3ccc(Cl)cc3Cl)c2)c(F)c1
Reaction time: 8 h

Procedure:
A solution of 3-(1H-indol-5-yl)-2-(2,4,6-trifluorobenzyl)-7-(trifluoromethyl)-2H-indazole (0.025 g, 0.056 mmol) and sodium hydride (60% in oil, 0.003 g, 0.07 mmol) in 1 mL DMF was stirred at ambient temperature under nitrogen for 20 minutes. 2,4-dichlorobenzyl bromide (0.081 g, 0.42 mmol) was added to the reaction mixture, which was stirred overnight and then partitioned between EtOAc and H2O. The organic phase was concentrated and purified by normal phase HPLC (silica, hexane-EtOAc, 4:1) to provide the title compound.
Reaction SMILES: [OH:1][C:2]1[CH:10]=[CH:9][C:8]([C:11]2[N:12]([C:27]([O:29][C:30]([CH3:33])([CH3:32])[CH3:31])=[O:28])[C:13]3[C:18]([CH:19]=2)=[CH:17][C:16]([CH2:20][N:21]2[CH2:26][CH2:25][CH2:24][CH2:23][CH2:22]2)=[CH:15][CH:14]=3)=[C:7]2[C:3]=1[CH2:4][NH:5][C:6]2=[O:34].C(N(CC)CC)C.[Cl:42][C:43]1[CH:44]=[C:45]([S:50](Cl)(=[O:52])=[O:51])[CH:46]=[CH:47][C:48]=1[CH3:49]>C(#N)C>[CH3:49][C:48]1[CH:47]=[CH:46][C:45]([S:50]([O:1][C:2]2[CH:10]=[CH:9][C:8]([C:11]3[N:12]([C:27]([O:29][C:30]([CH3:31])([CH3:33])[CH3:32])=[O:28])[C:13]4[C:18]([CH:19]=3)=[CH:17][C:16]([CH2:20][N:21]3[CH2:26][CH2:25][CH2:24][CH2:23][CH2:22]3)=[CH:15][CH:14]=4)=[C:7]3[C:3]=2[CH2:4][NH:5][C:6]3=[O:34])(=[O:51])=[O:52])=[CH:44][C:43]=1[Cl:42]
Reactant: CC(C)(C)OC(=O)n1c(-c2ccc(O)c3c2C(=O)NC3)cc2cc(CN3CCCCC3)ccc21
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1Cl
Solvent: CCN(CC)CC
Solvent: CC#N
Product: Cc1ccc(S(=O)(=O)Oc2ccc(-c3cc4cc(CN5CCCCC5)ccc4n3C(=O)OC(C)(C)C)c3c2CNC3=O)cc1Cl
Yield: 47.3 %

Procedure:
In a similar manner to Step 1 of Example 233, 4-hydroxy-7-[1-(tert-butoxycarbonyl)-5-(piperidinomethyl)indol-2-yl]isoindolinone (0.0300 g, 0.0650 mmol) was dissolved in acetonitrile (0.650 mL), and the solution was treated with triethylamine (0.0540 mL, 0.390 mmol) and 3-chloro-4-methylbenzenesulfonyl chloride (0.0440 g, 0.195 mmol) to obtain 4-(4-methyl-3-chlorobenzenesulfonyloxy)-7-[1-(tert-butoxycarbonyl)-5-(piperidinomethyl)indol-2-yl]isoindolinone (0.0200 g, yield 47%).
Reaction SMILES: [CH:1]([C:9]1[CH:14]=[CH:13][C:12](S([O-])(=O)=O)=[CH:11][CH:10]=1)=[CH:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.[Na+].[NH2-:20].[Na+].N>>[NH2:20][C:12]1[CH:13]=[CH:14][C:9]([CH:1]=[CH:2][C:3]2[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=2)=[CH:10][CH:11]=1
Reactant: O=S(=O)([O-])c1ccc(C=Cc2ccccc2)cc1
Reactant: [NH2-]
Agent: N
Agent: [Na+]
Product: Nc1ccc(C=Cc2ccccc2)cc1
Yield: 101.6 %

Procedure:
In a 200-ml autoclave were placed 18.6 grams (0.06 mole) of anhydrous sodium p-styrylbenzene sulfonate, 5.2 grams (0.13 mole) of sodium amide and 50 ml of liquid ammonia in the same manner as in Example 1. The resultant mixture was heated at 120° C for 6 hours. The reaction pressure in the autoclave was 90 atm. during the reaction. After the ammonia was removed, 10 ml of water was added to the reaction mixture for hydrolysis. The product was extracted with ether and the ether was distilled off to produce crude 4-aminostilbene. The recrystallization thereof from ethanol gave 11.9 grams of 4-aminostilbene having a melting point of 151° to 152° C. Yield was 88.5%.
Reaction SMILES: [S:1]1[C:5]([NH:6][C:7]2[CH:12]=[C:11](Cl)[N:10]=[C:9]([S:14][C:15]3[CH:20]=[CH:19][C:18]([NH:21][C:22]([CH:24]4[CH2:26][CH2:25]4)=[O:23])=[CH:17][CH:16]=3)[N:8]=2)=[N:4][CH:3]=[N:2]1.Cl.[CH:28]1([C:31]2([F:35])[CH2:34][NH:33][CH2:32]2)[CH2:30][CH2:29]1.CCN(C(C)C)C(C)C>O1CCOCC1>[S:1]1[C:5]([NH:6][C:7]2[CH:12]=[C:11]([N:33]3[CH2:34][C:31]([CH:28]4[CH2:30][CH2:29]4)([F:35])[CH2:32]3)[N:10]=[C:9]([S:14][C:15]3[CH:20]=[CH:19][C:18]([NH:21][C:22]([CH:24]4[CH2:26][CH2:25]4)=[O:23])=[CH:17][CH:16]=3)[N:8]=2)=[N:4][CH:3]=[N:2]1
Reactant: FC1(C2CC2)CNC1
Reactant: O=C(Nc1ccc(Sc2nc(Cl)cc(Nc3ncns3)n2)cc1)C1CC1
Agent: Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: C1COCCO1
Product: O=C(Nc1ccc(Sc2nc(Nc3ncns3)cc(N3CC(F)(C4CC4)C3)n2)cc1)C1CC1
Temperature: 130 °C
Yield: 3.6 %

Procedure:
A mixture of crude N-(4-(4-(1,2,4-Thiadiazol-5-ylamino)-6-chloropyrimidin-2-ylthio)phenyl)cyclopropanecarboxamide (780 mg, 1.93 mmol), 3-cyclopropyl -3-fluoroazetidine hydrochloride (818 mg, 5.4 mmol), DiPEA (0.7 mL, 4.6 mmol) in 1,4-dioxane (20 mL) was heated in the microwave to 130° C. for 20 minutes. The mixture was concentrated and purified by preparative HPLC to yield 34 mg of N-(4-(4-(1,2,4-Thiadiazol-5-ylamino)-6-(3-cyclopropyl-3-fluoroazetidin-1-yl)pyrimidin-2-ylthio)phenyl)cyclopropanecarboxamide with a purity of 95+% (HPLC method A, Rf=8.573 minutes).
Reaction SMILES: Cl[C:2]1[C:7]([C:8]2[N:13]=[C:12]([CH3:14])[N:11]=[C:10]([NH2:15])[N:9]=2)=[CH:6][C:5]([F:16])=[CH:4][N:3]=1.[NH2:17][C:18]1[CH:19]=[N:20][CH:21]=[C:22]([F:24])[CH:23]=1.[Li+].C[Si]([N-][Si](C)(C)C)(C)C>C1COCC1>[F:16][C:5]1[CH:6]=[C:7]([C:8]2[N:13]=[C:12]([CH3:14])[N:11]=[C:10]([NH2:15])[N:9]=2)[C:2]([NH:17][C:18]2[CH:19]=[N:20][CH:21]=[C:22]([F:24])[CH:23]=2)=[N:3][CH:4]=1
Reactant: Nc1cncc(F)c1
Reactant: Cc1nc(N)nc(-c2cc(F)cnc2Cl)n1
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Li+]
Solvent: C1CCOC1
Product: Cc1nc(N)nc(-c2cc(F)cnc2Nc2cncc(F)c2)n1
Reaction time: 0.08 h
Yield: 16.1 %

Procedure:
A solution of 4-(2-chloro-5-fluoropyridin-3-yl)-6-methyl-1,3,5-triazin-2-amine (85 mg, 0.355 mmol) and 3-amino-5-fluoropyridine (118 mg, 1.053 mmol) in THF (3 mL) was cooled in an ice bath under nitrogen. After 5 min, a solution of LiHMDS (1 M in THF, 2500 μL, 2.500 mmol) was added. After 10 min, the cooling bath was removed. After 2 h, HCl (5 N, 0.5 mL) was added. EtOAc (10 mL) and saturated NH4Cl (10 mL) were added. The mixture was vigorously stirred for 15 min. The resulting emulsion was filtered through a glass frit. The collected solid was dissolved in warm DMSO and purified by prep HPLC (30-75% MeCN/water/w 0.1% TFA over 20 min). The collected product fractions were concentrated to dryness. Saturated NaHCO3 (10 mL) was added. The mixture was neutralized with HCl (5N) and filtered. The filtrate was extracted with iPrOH (5%) in CHCl3 (3×5 mL). The combined organic layers were dried over Na2SO4 and concentrated to a yellow solid which was filtered as a suspension in ether to give the product as a yellow powder (18 mg). LCMS (ES, pos.): calcd for C14H11F2N7: 315.1. found: 316.1 (M+H)+. 1H NMR (400 MHz, d6-DMSO) δ 12.18 (s, 1H); 8.82 (s, 1H); 8.62 (dd, J=9.78, 3.13 Hz, 1H); 8.44-8.53 (m, 2H); 8.18 (d, J=2.54 Hz, 1H); 8.04 (br. s., 1H); 7.90 (br. s., 1H); 2.46 (s, 3H). 19F NMR (377 MHz, d6-DMSO) δ −139.21 (s, 1F); −127.41 (s, 1F).
Reaction SMILES: C([N-][CH:5]([CH3:7])[CH3:6])(C)C.[Li+].C([Li])CCC.C(NC(C)C)(C)C.CC(C)C=NC(C)(C)C.Br[CH2:31][CH2:32][C:33]1([CH3:38])[O:37][CH2:36][CH2:35][O:34]1.C(O)(=O)[C:40](O)=[O:41]>O1CCCC1>[CH3:6][C:5]([CH3:7])([CH2:31][CH2:32][C:33]1([CH3:38])[O:37][CH2:36][CH2:35][O:34]1)[CH:40]=[O:41]
Reactant: CC1(CCBr)OCCO1
Reactant: O=C(O)C(=O)O
Reactant: CC(C)[N-]C(C)C
Agent: CC(C)C=NC(C)(C)C
Agent: [Li+]
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: CC(C)NC(C)C
Product: CC(C)(C=O)CCC1(C)OCCO1
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 23 %

Procedure:
A freshly prepared solution of lithium diisopropylamide, was generated by the addition of n-butyllithium (16.2 mL, 25.9 mmol, 1.6 M in hexane) to a solution of diisopropylamine (6.6 mL, 47.0 mmol) in tetrahydrofuran (20 mL) at −20° C., and allowed to warm to 0° C. and stir for 30 minutes. N-(2-methylpropylidene)-2-methyl-2-propanamine (3.0 g, 23.5 mmol) in tetrahydrofuran (10 mL) was added dropwise over 10 minutes. After stirring at 0° C. for 2 hours, 2-bromoethyl-2-methyl-1,3-dioxolane (5.0 g, 25.9 mmol) in tetrahydrofuran (10 mL) was added over 15 minutes. The reaction was allowed to warm to ambient temperature and stirring was continued for 16 hours. After cooling in an ice bath, an aqueous solution of oxalic acid (100 mL, 10 wgt %) was added and reaction stirred for 1 hour. The layers were separated and the aqueous was extracted with ether (100 mL). The combined organic layers were washed with brine (50 mL), saturated sodium bicarbonate/water (50 mL), brine (50 mL), dried (magnesium sulfate), concentrated in vacuo and chromatographed (silica gel, ethyl acetate/hexane, 1:9) to afford the title compound (1.0 g, 23%) as a clear liquid;
Reaction SMILES: N1(C2N=CC(C[C:13](O)=[O:14])=CC=2)C=NN=N1.[N:16]1([C:21]2[CH:22]=[CH:23][C:24]([CH2:27][C:28]([OH:30])=[O:29])=[N:25][CH:26]=2)[CH:20]=[N:19][N:18]=[N:17]1.ClC1C(OC)=CC([N+]([O-])=O)=CN=1>>[CH3:13][O:14][C:23]1[C:24]([CH2:27][C:28]([OH:30])=[O:29])=[N:25][CH:26]=[C:21]([N:16]2[CH:20]=[N:19][N:18]=[N:17]2)[CH:22]=1
Reactant: O=C(O)Cc1ccc(-n2cnnn2)cn1
Reactant: O=C(O)Cc1ccc(-n2cnnn2)nc1
Agent: COc1cc([N+](=O)[O-])cnc1Cl
Product: COc1cc(-n2cnnn2)cnc1CC(=O)O

Procedure:
The title compound was prepared in an analagous fashion to that described for the syntheses of [6-(1H-tetrazol-1-yl)pyridin-3-yl]acetic acid (Method 1, Steps B-F and [5-(1H-tetrazol-1-yl)pyridin-2-yl]acetic acid (Steps A-E) starting from 2-chloro-3-methoxy-5-nitropyridine. LC/MS: [(M+1-28)]+=208.2.
Reaction SMILES: [CH3:1][CH:2]1[C:10]2[CH:11]=[CH:12][CH:13]=[CH:14][C:9]=2[C:8]2[N:7]([CH2:15][CH2:16][NH:17][C:18](=O)[CH3:19])[CH:6]=[CH:5][C:4]=2[CH2:3]1.P(Cl)(Cl)(Cl)=O.[OH-].[Na+].[C:28]([OH:35])(=[O:34])/[CH:29]=[CH:30]/[C:31]([OH:33])=[O:32]>C(O)C>[C:28]([OH:35])(=[O:34])/[CH:29]=[CH:30]/[C:31]([OH:33])=[O:32].[CH3:1][CH:2]1[C:10]2[CH:11]=[CH:12][CH:13]=[CH:14][C:9]=2[C:8]2[N:7]3[CH2:15][CH2:16][N:17]=[C:18]([CH3:19])[C:6]3=[CH:5][C:4]=2[CH2:3]1
Reactant: CC(=O)NCCn1ccc2c1-c1ccccc1C(C)C2
Agent: O=C(O)/C=C/C(=O)O
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Solvent: O=P(Cl)(Cl)Cl
Product: CC1=NCCn2c1cc1c2-c2ccccc2C(C)C1
Temperature: 100 °C
Reaction time: 0.5 h
Yield: 43 %

Procedure:
N-[2-(4,5-Dihydro-5-methyl-1H-benzo[g]indol-1-yl)ethyl]acetamide (5.0 g) was treated with 20 ml of phosphorus oxychloride under argon and the mixture was stirred at 100° C. for 30 minutes. The cooled mixture was added to 2000 ml of ice-water and treated with 200 ml of 28% sodium hydroxide solution. The mixture was extracted once with 300 ml of methylene chloride and twice with 100 ml of methylene chloride each time, the organic phases were combined, dried with MgSO4 and freed from solvent. 4.6 g of residue were chromatographed on 200 g of silica gel with methylene chloride/methanol mixtures (49:1 to 9:1) as the eluent. Of the crude product, 3.9 g of brown oil, 1.9 g were dissolved in a 20-fold amount of ethanol and treated with 1.1 equivalents of a saturated solution of fumaric acid in ethanol. After concentration to 10 ml and addition of 10 ml of ethanol and 70 ml of ethyl acetate there separated ochre-yellow crystals which were recrystallized from an ethanol/ethyl acetate mixture (1:2, 30-fold amount). There were obtained 1.7 g (43%) of 5,6,10,11-tetrahydro-5,8-dimethylbenzo[g]pyrazino[1,2-a]indole fumarate (2:3); m.pt.: 156°-157° C. (dec.).