Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: S1(CCCC1)(=O)=O.P(Cl)(Cl)([Cl:10])=O.C(N(CC)CC)C.O=[C:21]1[NH:26][CH:25]=[N:24][C:23]2[S:27][C:28]3[CH2:33][N:32]([C:34]([O:36][C:37]([CH3:40])([CH3:39])[CH3:38])=[O:35])[CH2:31][CH2:30][C:29]=3[C:22]1=2>[Cl-].[Na+]>[Cl:10][C:21]1[C:22]2[C:29]3[CH2:30][CH2:31][N:32]([C:34]([O:36][C:37]([CH3:40])([CH3:39])[CH3:38])=[O:35])[CH2:33][C:28]=3[S:27][C:23]=2[N:24]=[CH:25][N:26]=1
Reactant: CC(C)(C)OC(=O)N1CCc2c(sc3nc[nH]c(=O)c23)C1
Reactant: O=P(Cl)(Cl)Cl
Agent: [Cl-]
Agent: [Na+]
Solvent: CCN(CC)CC
Solvent: O=S1(=O)CCCC1
Product: CC(C)(C)OC(=O)N1CCc2c(sc3ncnc(Cl)c23)C1
Temperature: 70 °C
Reaction time: 2 h
Yield: 93 %

Procedure:
To sulfolane (3.19 L) was added phosphoryl chloride (785 g, 5.12 mol) at rt. Triethylamine (518 g, 5.12 mol) was added dropwise with water-bath cooling. tert-Butyl 4-oxo-3,5,6,8-tetrahydropyrido[4′,3′:4,5]thieno[2,3-d]pyrimidine-7(4H)-carboxylate from Example 10A (525.5 g, 1.706 mol) and additional sulfolane (1.34 L) were added, and the mixture was heated to 70° C. for 2.5 h. The mixture was cooled to it, and triethylamine (967 g, 9.56 mol) was added. A semi-saturated aqueous sodium chloride solution (10 L) was added during which the mixture was cooled with an ice-bath. After stirring at rt for 2 h, the precipitate was collected by suction filtration and washed three times with water (1.5 L). The residue was dried to yield 517 g (93%) of the title compound.
Reaction SMILES: [CH:1](O)=[O:2].CCN(C([C@@H]1C=[C:25]2[C@@H:14](CC3C4[C:21]2=[CH:22][CH:23]=[CH:24]C=4NC=3)[N:13]([CH3:27])[CH2:12]1)=O)CC.[OH2:28]>C(#N)C>[CH3:1][O:2][C:24](=[O:28])[CH2:23][CH2:22][CH2:21][CH2:25][CH2:14][N:13]([CH3:12])[CH3:27]
Reactant: CCN(CC)C(=O)[C@@H]1C=C2c3cccc4[nH]cc(c34)C[C@H]2N(C)C1
Reactant: O
Reactant: O=CO
Solvent: CC#N
Product: COC(=O)CCCCCN(C)C

Procedure:
[2-Diethoxy-phosphoryloxy)-ethyl]-(5-methoxycarbonyl-pentyl)-dimethylammonium trifluoroacetate. The methyl ester (1.73 g, 10 mmol) was dissolved in dry acetonitrile (15 mL) and K2CO3 (1.38 g, 10 mmol) was added. This suspension was refluxed under nitrogen gas for 36 h. After cooling to room temperature water was added and the pH was adjusted to 2 by adding TFA. The solution was purified by rp HPLC (Supelco Discovery C18, 21.2 mm×15 cm, 5 μm, A: 5% IPA, 95% H2O, 0.1% TFA, B: 90% IPA, 10% H2O, 0.1% TFA, 0 to 15% B over 14 min, tR=11.8 min) and lyophilized to give the TFA salt of the quaternary amine as light yellow oil (1.06 g, 3.0 mmol, 30%). LC-MS (Phenomenex Gemini, C18, 5 μm, 150×3.0 mm, A: 0.1% formic acid in water, B: 0.1% formic acid in acetonitrile, 10-50% B over 10 min) tR=6.4 min (LSD signal), m/z=354.2 for [M+H]+. 1H NMR (CD3OD, 400 MHz) δ=1.41-1.50 (m, 8H, 2×OCH2CH3 and CH2); 1.77 (m, 2H, CH2); 1.90 (m, 2H, CH2); 2.44 (t, 2H, CH2, 3J=7.2 Hz); 3.25 (s, 6H, N(CH3)2); 3.48 (m, 2H, CH2); 3.72 (s, 3H, COOCH3) 3.82 (m, 2H, CH2); 4.26 (dq, 4H, 2×CH2CH3, 3J(H,H)=6.8 Hz, 3J(H,P)=8.0 Hz); 4.58 (brs, 2H, CH2). 13C NMR (CD3OD, 100.5 MHz) δ=16.4 (d, 2×OCH2CH3, 3J=6.1 Hz); 23.3 (CH2); 25.3 (CH2); 26.7 (CH2); 34.4 (CH2); 52.0 (CH3); 52.2 (CH3); 62.1 (d, CH2, 2J=5.3 Hz); 64.8 (CH2); 66.1 (d, CH2, 2J=6.1 Hz); 66.7 (CH2); 175.5 (CO).
Reaction SMILES: [N:1]1([CH2:7][CH2:8][O:9][C:10](=[O:40])[NH:11][C:12]2[C:13]([CH3:39])=[C:14]3[C:19]([NH:20][C:21]4[CH:26]=[CH:25][C:24]([O:27][C:28]5[CH:33]=[CH:32][CH:31]=[CH:30][C:29]=5[O:34][CH3:35])=[CH:23][CH:22]=4)=[C:18]([C:36]#[N:37])[CH:17]=[N:16][N:15]3[CH:38]=2)[CH2:6][CH2:5][O:4][CH2:3][CH2:2]1.CI.[H-].[Na+].[CH3:45]CO>C1COCC1>[N:1]1([CH2:7][CH2:8][O:9][C:10](=[O:40])[N:11]([C:12]2[C:13]([CH3:39])=[C:14]3[C:19]([NH:20][C:21]4[CH:22]=[CH:23][C:24]([O:27][C:28]5[CH:33]=[CH:32][CH:31]=[CH:30][C:29]=5[O:34][CH3:35])=[CH:25][CH:26]=4)=[C:18]([C:36]#[N:37])[CH:17]=[N:16][N:15]3[CH:38]=2)[CH3:45])[CH2:2][CH2:3][O:4][CH2:5][CH2:6]1
Reactant: COc1ccccc1Oc1ccc(Nc2c(C#N)cnn3cc(NC(=O)OCCN4CCOCC4)c(C)c23)cc1
Reactant: CCO
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CI
Product: COc1ccccc1Oc1ccc(Nc2c(C#N)cnn3cc(N(C)C(=O)OCCN4CCOCC4)c(C)c23)cc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 62 %

Procedure:
To a mixture of 432A (27 mg, 0.050 mmol) and CH3I (3.1 μl, 0.05 mmol) in THF (1 ml) was added NaH (1.5 mg, 0.06 mmol). The resulting mixture was stirred at rt for 2 h under argon. A drop of EtOH was added to quench the reaction. Removal of the solvent under reduced pressure followed by flash chromatography of the residue on silica gel (5/30/65 MeOH/EtOAc/CH2Cl2) gave 432 (17.1 mg, 62%) as a yellow oil. It has a retention time of 5.70 min (standard LC1 method, 8 min run). MS Found: (M+H)+=557.1
Reaction SMILES: [CH2:1]([NH:5][C:6]([CH:8]1[O:25][C:12]2([CH2:17][CH2:16][N:15]([C:18]([O:20][C:21]([CH3:24])([CH3:23])[CH3:22])=[O:19])[CH2:14][CH2:13]2)[CH2:11][N:10]([CH2:26][C:27]([F:30])([F:29])[F:28])[CH2:9]1)=O)[C:2]([CH3:4])=O.COC1C=CC(P2(SP(C3C=CC(OC)=CC=3)(=S)S2)=[S:40])=CC=1>C1COCC1>[CH3:4][C:2]1[S:40][C:6]([CH:8]2[O:25][C:12]3([CH2:17][CH2:16][N:15]([C:18]([O:20][C:21]([CH3:24])([CH3:23])[CH3:22])=[O:19])[CH2:14][CH2:13]3)[CH2:11][N:10]([CH2:26][C:27]([F:30])([F:29])[F:28])[CH2:9]2)=[N:5][CH:1]=1
Reactant: COc1ccc(P2(=S)SP(=S)(c3ccc(OC)cc3)S2)cc1
Reactant: CC(=O)CNC(=O)C1CN(CC(F)(F)F)CC2(CCN(C(=O)OC(C)(C)C)CC2)O1
Solvent: C1CCOC1
Product: Cc1cnc(C2CN(CC(F)(F)F)CC3(CCN(C(=O)OC(C)(C)C)CC3)O2)s1
Temperature: 70 °C
Yield: 121.2 %

Procedure:
Tert-butyl 10-(acetonylcarbamoyl)-8-(2,2,2-trifluoroethyl)-11-oxa-3,8-diazaspiro[5.5]undecane-3-carboxylate (80 mg, 0.18 mmol) was dissolved in anhydrous THF (1.5 mL) followed by the addition of Lawesson's reagent (114 mg, 0.27 mmol) and the reaction mixture was heated at 70° C. for 1 hour under an atmosphere of nitrogen. The reaction mixture was cooled to room temperature and the solvent was removed under reduced pressure. The residue was purified by silica gel column chromatography using 0-10% EtOAc in DCM as eluent to yield tert-butyl 10-(5-methylthiazol-2-yl)-8-(2,2,2-trifluoroethyl)-11-oxa-3,8-diazaspiro[5.5]undecane-3-carboxylate (95 mg, 100%). ESI-MS m/z calc. 435.5. Found 436.5 (M+1)+; Retention time: 1.67 minutes (3 min run); 1H NMR (400 MHz, CDCl3) δ 7.54 (s, 1H), 5.20 (dd, J=9.4, 0.8 Hz, 1H), 3.82-3.76 (m, 2H), 3.43 (d, J=10.1 Hz, 1H), 3.31-3.21 (m, 1H), 3.09-2.94 (m, 3H), 2.72 (dd, J=11.4, 0.5 Hz, 1H), 2.50 (s, 1H), 2.46 (s, 3H), 2.45-2.38 (m, 2H), 1.79-1.67 (m, 1H), 1.65-1.57 (m, 1H), 1.53 (dd, J=11.2, 4.8 Hz, 1H), 1.45 (s, 9H).
Reaction SMILES: [C:1]1([O:7][S:8]([C:11]2[CH:16]=[C:15]([S:17](=[O:20])(=[O:19])[NH2:18])[C:14]([N:21]([CH3:28])[C:22]3[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=3)=[CH:13][C:12]=2Cl)(=[O:10])=[O:9])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[S:30]1[CH:34]=[CH:33][CH:32]=[C:31]1[CH2:35][NH2:36]>>[C:1]1([O:7][S:8]([C:11]2[CH:16]=[C:15]([S:17](=[O:20])(=[O:19])[NH2:18])[C:14]([N:21]([CH3:28])[C:22]3[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=3)=[CH:13][C:12]=2[NH:36][CH2:35][C:31]2[S:30][CH:34]=[CH:33][CH:32]=2)(=[O:10])=[O:9])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: CN(c1ccccc1)c1cc(Cl)c(S(=O)(=O)Oc2ccccc2)cc1S(N)(=O)=O
Reactant: NCc1cccs1
Product: CN(c1ccccc1)c1cc(NCc2cccs2)c(S(=O)(=O)Oc2ccccc2)cc1S(N)(=O)=O
Yield: 94 %

Procedure:
182 g of 2-chloro-4-(N-methylanilino)-5-sulfamoylbenzene sulfonic acid phenyl ester (0.4 mol) are reacted with 0.5 liter of 2-thienylmethyl amine according to Example 1. Working up in the manner described in Example 1 gives 200 g of 2-(thienylmethylamino)-4-(N-methylanilino)-5-sulfamoylbenzene sulfonic acid phenyl ester in chromatographically pure form. Yield: 94% of the theory. The product sinters at a temperature above 90° C.
Reaction SMILES: Cl[CH2:2][C:3](=[O:10])[CH2:4][C:5]([O:7][CH2:8][CH3:9])=[O:6].[CH3:11][C:12]([SH:15])([CH3:14])[CH3:13].C(N(CC)CC)C>[Br-].C([N+](CCCC)(CCCC)CCCC)CCC.C1COCC1>[CH2:8]([O:7][C:5](=[O:6])[CH2:4][C:3](=[O:10])[CH2:2][S:15][C:12]([CH3:14])([CH3:13])[CH3:11])[CH3:9]
Reactant: CCOC(=O)CC(=O)CCl
Reactant: CC(C)(C)S
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [Br-]
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: CCOC(=O)CC(=O)CSC(C)(C)C
Temperature: 25 °C
Reaction time: 8 h

Procedure:
Ethyl 4-chloroacetoacetate (7.5 mL, 51.9 mmol), 2-methyl-2-propanethiol (5.6 mL, 49.7 mmol), triethylamine (10.8 mL, 77.4 mmol), and catalytic tetrabutylammonium bromide were dissolved in THF (250 mL) and stirred at room temperature overnight. Silica gel was added, and the mixture was concentrated and filtered over a plug of silica gel to obtain the desired product (B-1), which was used without further purification.
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C:9]1([C:12]([OH:14])=O)[CH2:11][CH2:10]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].CC(OC(OC(OC(C)(C)C)=O)=O)(C)C.C(=O)(O)[O-].[NH4+].[N:35]1C=CC=CC=1>C(#N)C>[C:1]([O:5][C:6](=[O:7])[NH:8][C:9]1([C:12](=[O:14])[NH2:35])[CH2:11][CH2:10]1)([CH3:4])([CH3:3])[CH3:2]
Reactant: c1ccncc1
Reactant: CC(C)(C)OC(=O)NC1(C(=O)O)CC1
Agent: CC(C)(C)OC(=O)OC(=O)OC(C)(C)C
Agent: O=C([O-])O
Agent: [NH4+]
Solvent: CC#N
Product: CC(C)(C)OC(=O)NC1(C(N)=O)CC1
Temperature: 25 °C
Reaction time: 16 h
Yield: 150.8 %

Procedure:
To a mixture of 1-tert-butoxycarbonylamino-cyclopropanecarboxylic acid (2.00 g, 9.94 mmol), Boc anhydride (2.82 g, 12.9 mmol), ammonium bicarbonate (0.982 g, 12.4 mmol) in 30 mL of acetonitrile at room temperature was added pyridine (0.482 mL, 5.96 mmol). The cloudy, colorless reaction mixture was stirred at room temperature for 16 h and then concentrated under reduced pressure. The residue was partitioned between 100 mL of ethyl acetate and 30 mL of 1 M HCl. The organic phase was washed with 30 mL of saturated. NaHCO3 solution and brine, dried over Na2SO4, filtered, and concentrated in vacuo to give 1.80 g (90%) of (1-carbamoyl-cyclopropyl)-carbamic acid tert-butyl ester as a white solid.
Reaction SMILES: [Cl:1][C:2]1[C:11]2[C:6](=[C:7]([O:12][CH3:13])[CH:8]=[CH:9][CH:10]=2)[N:5]=[C:4]([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[CH:3]=1.[CH2:20]([CH2:22][NH2:23])[OH:21]>>[ClH:1].[CH3:13][O:12][C:7]1[CH:8]=[CH:9][CH:10]=[C:11]2[C:6]=1[N:5]=[C:4]([C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)[CH:3]=[C:2]2[NH:23][CH2:22][CH2:20][OH:21]
Reactant: COc1cccc2c(Cl)cc(-c3ccccc3)nc12
Reactant: NCCO
Product: COc1cccc2c(NCCO)cc(-c3ccccc3)nc12
Product: Cl

Procedure:
The title compound, m.p. 205-209° C., and MS: m/e=295.3 (M+H+), was prepared from 4-chloro-8-methoxy-2-phenyl-quinoline and ethanolamine.
Reaction SMILES: C1(C)C=CC(S(O[CH2:11][C@@H:12]2[O:26][C:16]3=[C:17]4[C:21](=[C:22]([F:24])[CH:23]=[C:15]3[O:14][CH2:13]2)[NH:20][C:19](=[O:25])[CH2:18]4)(=O)=O)=CC=1.[NH:28]1[C:36]2[C:31](=[CH:32][CH:33]=[CH:34][CH:35]=2)[C:30]([CH:37]2[CH2:42][CH2:41][NH:40][CH2:39][CH2:38]2)=[CH:29]1>CS(C)=O.C(OCC)(=O)C.CCCCCC>[NH:28]1[C:36]2[C:31](=[CH:32][CH:33]=[CH:34][CH:35]=2)[C:30]([CH:37]2[CH2:42][CH2:41][N:40]([CH2:11][CH:12]3[O:26][C:16]4=[C:17]5[C:21](=[C:22]([F:24])[CH:23]=[C:15]4[O:14][CH2:13]3)[NH:20][C:19](=[O:25])[CH2:18]5)[CH2:39][CH2:38]2)=[CH:29]1
Reactant: c1ccc2c(C3CCNCC3)c[nH]c2c1
Reactant: Cc1ccc(S(=O)(=O)OC[C@H]2COc3cc(F)c4c(c3O2)CC(=O)N4)cc1
Solvent: CS(C)=O
Solvent: CCOC(C)=O
Solvent: CCCCCC
Product: O=C1Cc2c(c(F)cc3c2OC(CN2CCC(c4c[nH]c5ccccc45)CC2)CO3)N1
Temperature: 25 °C

Procedure:
(R)-2-(Toluene-4-sulfonyloxymethyl)-6-fluoro-2,3,8,9-tetrahydro-7H-1,4-dioxino[2,3-e]indol-8-one (1.0 g, 2.5 mmole) and 4-(1H-indol-3-yl)piperidine (2.0 g, 10 mmole) are combined in 30 ml of dry DMSO and heated at 80°-90° C. for 4 hours under an argon atmosphere. After cooling to room temperature, the mixture is diluted with 500 ml of 1:1 ethyl acetate/hexane and washed with 250 ml of saturated aqueous sodium bicarbonate and with two 250 ml portions of water, dried over sodium sulfate, filtered and concentrated in vacuum. The residue is column chromatographed on silica gel using 0.5% methanol/CHCl3 as eluant to give the free base of the title compound. The product is crystallized from ethanol with the addition of one equivalent of fumaric acid to give the (S) enantiomer of the title compound as a fumarate salt.
Reaction SMILES: [Mg].[CH2:2](Br)[CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9]/[CH:10]=[CH:11]\[CH2:12]/[CH:13]=[CH:14]\[CH2:15][CH2:16][CH2:17][CH2:18][CH3:19].[CH2:21]([O:39][CH:40]1[CH2:44][CH2:43][O:42][C:41]1=[O:45])[CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28]/[CH:29]=[CH:30]\[CH2:31]/[CH:32]=[CH:33]\[CH2:34][CH2:35][CH2:36][CH2:37][CH3:38].C(O[CH2:49][CH3:50])C>>[CH2:2]([C:41]([OH:45])([CH2:18][CH2:17][CH2:16][CH2:15][CH2:14][CH2:13][CH2:12][CH2:11][CH2:10]/[CH:9]=[CH:8]\[CH2:7]/[CH:6]=[CH:5]\[CH2:4][CH2:3][CH2:2][CH2:49][CH3:50])[CH:40]([O:39][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28]/[CH:29]=[CH:30]\[CH2:31]/[CH:32]=[CH:33]\[CH2:34][CH2:35][CH2:36][CH2:37][CH3:38])[CH2:44][CH2:43][OH:42])[CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9]/[CH:10]=[CH:11]\[CH2:12]/[CH:13]=[CH:14]\[CH2:15][CH2:16][CH2:17][CH2:18][CH3:19]
Reactant: CCOCC
Reactant: CCCCC/C=C\C/C=C\CCCCCCCCOC1CCOC1=O
Reactant: CCCCC/C=C\C/C=C\CCCCCCCCBr
Agent: [Mg]
Product: CCCCC/C=C\C/C=C\CCCCCCCCCC(O)(CCCCCCCC/C=C\C/C=C\CCCCC)C(CCO)OCCCCCCCC/C=C\C/C=C\CCCCC
Temperature: 25 °C
Reaction time: 0.33 h
Yield: 56 %

Procedure:
A 100 mL round bottom flask charged with magnesium turnings (250 mg) and a stir bar was dried with a heat gun for 5 minutes then cooled under nitrogen. The flask was charged with dry THF (10 mL) and a small grain of iodine. A solution of linoleyl bromide (3 g, 9.1 mmol) in diethyl ether was added slowly and the mixture was stirred at room temperature. The Grignard did not initiate so the solution was concentrated to ˜5 mL then stirred for 2 minutes until the solution turned opaque and the iodine color disappeared. After 20 minutes, a colorless solid precipitated so the reaction was diluted with THF (15 mL) and stirred overnight. The next day 3-((9Z,12Z)-octadeca-9,12-dienyloxy)dihydrofuran-2(3H)-one (1.3 g, 3.6 mmol) was added and the solution was stirred for 3 hours. The reaction was diluted with ether (100 mL) and washed with 5% HCl (50 mL). The ether layer was dried on magnesium sulfate, filtered and concentrated in vacuo to dryness. The residue was purified by column chromatography on silica gel 60 (eluted with 10% ether in hexanes) to afford (14Z,17Z)-4-((9Z,12Z)-octadeca-9,12-dienyl)-3-((9Z,12Z)-octadeca-9,12-dienyloxy)tricosa-14,17-diene-1,4-diol as a colorless oil (1.75 g, 56%).
Reaction SMILES: [C:1]1([P:7]([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[Br:20][CH2:21][CH2:22][CH2:23][CH2:24][C:25]([O:27][CH2:28][CH3:29])=[O:26]>>[Br-:20].[C:14]1([P+:7]([C:1]2[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=2)([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)[CH2:21][CH2:22][CH2:23][CH2:24][C:25]([O:27][CH2:28][CH3:29])=[O:26])[CH:15]=[CH:16][CH:17]=[CH:18][CH:19]=1
Reactant: CCOC(=O)CCCCBr
Reactant: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Product: CCOC(=O)CCCC[P+](c1ccccc1)(c1ccccc1)c1ccccc1
Product: [Br-]
Yield: 74 %

Procedure:
The title compound was prepared from triphenylphosphine and ethyl 5-bromovalerate as described in Example 1 in a yield of 74%.
Reaction SMILES: [Cl:1][C:2]1[C:10]([Cl:11])=[C:9]2[C:5]([CH2:6][C:7]([CH:14]3[CH2:18][CH2:17][CH2:16][CH2:15]3)([CH3:13])[C:8]2=[O:12])=[CH:4][C:3]=1[OH:19].C(=O)([O-])[O-].[K+].[K+].Br[CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][C:33]([O:35][CH2:36][CH3:37])=[O:34].O>CN(C)C=O>[Cl:1][C:2]1[C:10]([Cl:11])=[C:9]2[C:5]([CH2:6][C:7]([CH:14]3[CH2:18][CH2:17][CH2:16][CH2:15]3)([CH3:13])[C:8]2=[O:12])=[CH:4][C:3]=1[O:19][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][C:33]([O:35][CH2:36][CH3:37])=[O:34]
Reactant: CC1(C2CCCC2)Cc2cc(O)c(Cl)c(Cl)c2C1=O
Reactant: CCOC(=O)CCCCCCBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: CCOC(=O)CCCCCCOc1cc2c(c(Cl)c1Cl)C(=O)C(C)(C1CCCC1)C2
Temperature: -70 °C

Procedure:
6,7-Dichloro-2-cyclopentyl-2,3-dihydro-5-hydroxy-2-methyl-1H-inden-1-one (12 g., 0.04 mole) is dissolved in dimethylformamide (30 ml.), and potassium carbonate (5.5 g., 0.04 mole) is added and the mixture stirred and heated on a steam bath for 30 minutes. Ethyl 7-bromoheptanoate is added dropwise over 10 minutes with stirring and heating on a steam bath for two hours. The mixture is poured into a mixture of ice and water (300 g., total) and then extracted with ether. The ether extract is dried over Na2SO4, filtered and the ether removed at reduced pressure. The residue is dissolved in petroleum ether and cooled to -70° C. to obtain ethyl 7-[(6,7-dichloro-2-cyclopentyl-2,3-dihydro-2-methyl-1-oxo-1H-inden-5-yl)oxy]heptanoate, 17.7 g., m.p. 47°-50° C.
Reaction SMILES: C(O[C:6](=[O:21])[N:7]([CH2:13][C:14]1[CH:19]=[CH:18][C:17]([Cl:20])=[CH:16][CH:15]=1)[N:8]1[CH:12]=[CH:11][CH:10]=[CH:9]1)(C)(C)C.[CH2:22]([O:24][C:25](=[O:37])[CH:26](C(OCC)=O)[C:27](OCC)=[O:28])[CH3:23]>>[CH2:22]([O:24][C:25]([C:26]1[C:6](=[O:21])[N:7]([CH2:13][C:14]2[CH:15]=[CH:16][C:17]([Cl:20])=[CH:18][CH:19]=2)[N:8]2[CH:9]=[CH:10][CH:11]=[C:12]2[C:27]=1[OH:28])=[O:37])[CH3:23]
Reactant: CCOC(=O)C(C(=O)OCC)C(=O)OCC
Reactant: CC(C)(C)OC(=O)N(Cc1ccc(Cl)cc1)n1cccc1
Product: CCOC(=O)c1c(O)c2cccn2n(Cc2ccc(Cl)cc2)c1=O

Procedure:
Prepared according to the thermal cyclization condition used in Example 1 step c) from (4-chloro-benzyl)-pyrrol-1-yl-carbamic acid tert-butyl ester (1.0 eq.) and 2-ethoxycarbonyl-malonic acid diethyl ester (3.0 eq.). ESI (m/z): 347 (M+H)+.
Reaction SMILES: C(OC(=O)C)(=O)C.[CH:8]([OH:10])=O.[Br:11][C:12]1[N:17]=[C:16]([O:18][CH3:19])[C:15]([NH2:20])=[CH:14][CH:13]=1>C1COCC1>[Br:11][C:12]1[N:17]=[C:16]([O:18][CH3:19])[C:15]([NH:20][CH:8]=[O:10])=[CH:14][CH:13]=1
Reactant: COc1nc(Br)ccc1N
Reactant: O=CO
Solvent: C1CCOC1
Solvent: CC(=O)OC(C)=O
Product: COc1nc(Br)ccc1NC=O
Temperature: 25 °C
Reaction time: 0.67 h
Yield: 100 %

Procedure:
A mixture of acetic anhydride (8.54 mL, 24.63 mmol) and formic acid (12.8 mL, 24.63 mmol) was stirred at room temperature for 40 min. To this mixture 6-bromo-2-methoxypyridin-3-amine (5.000 g, 24.63 mmol) in 30 mL of THF was added dropwise. The resulting solution was heated at 60° C. with stirring for 16 h. Upon cooling, the reaction mixture was poured into icewater. The resulting precipitate was filtered to give N-(6-bromo-2-methoxypyridin-3-yl)formamide (5.690 g, 24.63 mmol, 100% yield) as light brown solid. LC-MS (M+Na)+=231.0.
Reaction SMILES: N[C@H:2]([C:7](O)=O)[CH2:3][C:4](=O)O.N[C@H:11]([C:17]([OH:19])=[O:18])[CH2:12][CH2:13][C:14](=O)[OH:15].CC([O:24]C(N[C@H](C(O)=O)CC(OCC1C2C(=CC=CC=2)C2C1=CC=CC=2)=O)=O)(C)C.CC(OC(N[C@H](C(O)=O)CCC(OCC1C2C(=CC=CC=2)C2C1=CC=CC=2)=O)=O)(C)C>>[CH:2]1[CH:7]=[C:13]2[C:14]([C:17]([OH:19])([OH:18])[C:11](=[O:24])[C:12]2=[CH:4][CH:3]=1)=[O:15]
Reactant: CC(C)(C)OC(=O)N[C@@H](CC(=O)OCC1c2ccccc2-c2ccccc21)C(=O)O
Reactant: N[C@@H](CCC(=O)O)C(=O)O
Reactant: N[C@@H](CC(=O)O)C(=O)O
Agent: CC(C)(C)OC(=O)N[C@@H](CCC(=O)OCC1c2ccccc2-c2ccccc21)C(=O)O
Product: O=C1c2ccccc2C(=O)C1(O)O

Procedure:
This methodology uses Nα -Boc-amino acids together with OFm side-chain protection for Asp and Glu. Asp and Glu were introduced with Boc-Asp(OFm)-OH and Boc-Glu(OFm)-OH. After coupling the last amino acid, the OFm protecting groups were selectively removed by treating the peptide resin in 50% piperidine in DMF (Dimethylformamide) for 1 h. The peptide resin was washed with DMF (3×40 mL), DCM (dicholoromethane) (3×40 mL), suspended in 15 mL of DMF, and mixed with a 6-fold excess of BOP reagent in the presence of an 8-fold excess of diisopropylamine (DIEA) for 5 h. The coupling was repeated until the resin gave the negative ninhydrin test.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[N:4][C:5]2[N:6]([N:8]=[C:9]([C:11]([OH:13])=O)[CH:10]=2)[CH:7]=1.[F:14][C:15]1[C:20]([C:21]2[CH:22]=[C:23]3[C:28](=[CH:29][CH:30]=2)[CH:27]([CH3:31])[NH:26][CH2:25][CH2:24]3)=[CH:19][CH:18]=[CH:17][N:16]=1>>[Br:1][C:2]1[CH:3]=[N:4][C:5]2[N:6]([N:8]=[C:9]([C:11]([N:26]3[CH2:25][CH2:24][C:23]4[C:28](=[CH:29][CH:30]=[C:21]([C:20]5[C:15]([F:14])=[N:16][CH:17]=[CH:18][CH:19]=5)[CH:22]=4)[CH:27]3[CH3:31])=[O:13])[CH:10]=2)[CH:7]=1
Reactant: O=C(O)c1cc2ncc(Br)cn2n1
Reactant: CC1NCCc2cc(-c3cccnc3F)ccc21
Product: CC1c2ccc(-c3cccnc3F)cc2CCN1C(=O)c1cc2ncc(Br)cn2n1

Procedure:
In close analogy to the procedure described in Example 1, 6-bromo-pyrazolo[1,5-a]pyrimidine-2-carboxylic acid is reacted with 6-(2-Fluoro-pyridin-3-yl)-1-methyl-1,2,3,4-tetrahydro-isoquinoline to provide the title compound in moderate yield.
Reaction SMILES: [Cl:1][C:2]1[N:7]=[C:6]([C:8]([OH:10])=[O:9])[CH:5]=[CH:4][CH:3]=1.[CH3:11]N(C=O)C.C(Cl)(=O)C(Cl)=O.CO>C(Cl)Cl>[Cl:1][C:2]1[N:7]=[C:6]([C:8]([O:10][CH3:11])=[O:9])[CH:5]=[CH:4][CH:3]=1
Reactant: CN(C)C=O
Reactant: O=C(O)c1cccc(Cl)n1
Agent: O=C(Cl)C(=O)Cl
Solvent: CO
Solvent: ClCCl
Product: COC(=O)c1cccc(Cl)n1
Reaction time: 1 h
Yield: 100 %

Procedure:
6-Chloropyridine-2-carboxylic acid (15.0 g, 0.11 mol) was dissolved in DCM (300 mL) and DMF (1.5 mL) and oxalyl chloride (27.4 g, 0.22 mol) was added dropwise over 10 min. The reaction mixture was stirred for 1 h, MeOH (50 mL) was added dropwise over 5 min and the reaction mixture was stirred for 1.5 h. The solvents were removed in vacuo and the residue azeotroped with DCM (2×150 mL) to give the crude title compound (16.5 g, 100%) as a green solid. LCMS (ES+): 154.5 [MH]+.
Reaction SMILES: [F:1][C:2]1[CH:3]=[CH:4][C:5]([CH:8]([OH:15])C2C=CC=CC=2)=[N:6][CH:7]=1.Cl[C:17]1[CH:22]=[CH:21][N+:20]([O-:23])=[CH:19][CH:18]=1>>[F:1][C:2]1[CH:3]=[CH:4][C:5]([CH2:8][O:15][C:17]2[CH:22]=[CH:21][N+:20]([O-:23])=[CH:19][CH:18]=2)=[N:6][CH:7]=1
Reactant: OC(c1ccccc1)c1ccc(F)cn1
Reactant: [O-][n+]1ccc(Cl)cc1
Product: [O-][n+]1ccc(OCc2ccc(F)cn2)cc1
Yield: 50.9 %

Procedure:
5-Fluoro-2-pyridylbenzylalcohol (3.00 g, 23.6 mmol) and 4-chloropyridine-N-oxide (2.03 g, 15.7 mmol) were reacted according to Example 34 (step a) to provide the title compound (1.76 g, 50%) as a tan solid: 1H NMR (300 MHz, CDCl3) δ 8.48 (s, 1H), 8.12 (d, J=7.7 Hz, 2H), 7.48-7.46 (m, 2H), 6.90 (d, J=7.7 Hz, 2H), 5.20 (s, 2H).
Reaction SMILES: [CH2:1]([N:8]1[CH2:26][CH2:25][C:11]2([N:15]([C:16]3[CH:21]=[CH:20][C:19]([F:22])=[CH:18][CH:17]=3)[C:14](=[O:23])[NH:13][C:12]2=[O:24])[CH2:10][CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[H-].[Na+].[CH2:29](Br)[C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1.C(O)(=O)CC(CC(O)=O)(C(O)=O)O>CN(C=O)C>[CH2:29]([N:13]1[C:12](=[O:24])[C:11]2([CH2:25][CH2:26][N:8]([CH2:1][C:2]3[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=3)[CH2:9][CH2:10]2)[N:15]([C:16]2[CH:21]=[CH:20][C:19]([F:22])=[CH:18][CH:17]=2)[C:14]1=[O:23])[C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1
Reactant: O=C1NC(=O)C2(CCN(Cc3ccccc3)CC2)N1c1ccc(F)cc1
Reactant: BrCc1ccccc1
Agent: O=C(O)CC(O)(CC(=O)O)C(=O)O
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: O=C1N(Cc2ccccc2)C(=O)C2(CCN(Cc3ccccc3)CC2)N1c1ccc(F)cc1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
Combine 8-benzyl-1-(4-fluoro-phenyl)-1,3,8-triaza-spiro[4.5]decane-2,4-dione (12 mmol) and DMF (20 mL). Cool in an ice bath. Add NaH (18 mmol) in several portions. After the addition is complete, add benzyl bromide (18 mmol). Allow the reaction mixture to warm to ambient temperature. After 3 h, cool the reaction vessel using an ice bath and cautiously add 10% aqueous citric acid (20 mL). When gas evolution has ceased, pour into an additional 20 mL of 10% aqueous citric acid and extract using ethyl acetate (3×60 mL). Extract the combined organics with saturated aqueous NaCl, dry over Na2SO4, filter, and concentrate in vacuo to obtain a residue. Purify to obtain the title compound.