Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([O:5][C:6](=[O:18])[NH:7][C:8]1([C:11]2[CH:16]=[CH:15][C:14](I)=[CH:13][N:12]=2)[CH2:10][CH2:9]1)([CH3:4])([CH3:3])[CH3:2].C([Sn](CCCC)(CCCC)[C:24]([O:26]CC)=[CH2:25])CCC.C1(C)C=CC(S([O-])(=O)=O)=CC=1.[NH+]1C=CC=CC=1.O>CN(C=O)C.C(O)(=O)CC(CC(O)=O)(C(O)=O)O>[C:1]([O:5][C:6](=[O:18])[NH:7][C:8]1([C:11]2[CH:16]=[CH:15][C:14]([C:24](=[O:26])[CH3:25])=[CH:13][N:12]=2)[CH2:10][CH2:9]1)([CH3:4])([CH3:3])[CH3:2]
Reactant: C=C(OCC)[Sn](CCCC)(CCCC)CCCC
Reactant: CC(C)(C)OC(=O)NC1(c2ccc(I)cn2)CC1
Agent: Cc1ccc(S(=O)(=O)[O-])cc1
Agent: O=C(O)CC(O)(CC(=O)O)C(=O)O
Agent: c1cc[nH+]cc1
Solvent: O
Solvent: CN(C)C=O
Product: CC(=O)c1ccc(C2(NC(=O)OC(C)(C)C)CC2)nc1
Temperature: 100 °C
Reaction time: 16 h
Yield: 97.2 %

Procedure:
To a solution of [1-(5-Iodo-pyridin-2-yl)-cyclopropyl]-carbamic acid tert-butyl ester (100 mg, 0.278 mmol) in anhydrous DMF (1 mL) was added tributyl-(1-ethoxy-vinyl)-stannane (0.103 mL, 0.305 mmol) followed by tetrakis(triphenylphosphane)palladium (0) (32.1 mg, 0.028 mmol). The mixture was stirred at 100° C. under an atmosphere of argon. After 16 h, pyridinium p-toluenesulfonate (77.0 mg, 0.306 mmol) was added along with 0.5 mL of water and the mixture was stirred at rt for 1 h. The reaction was diluted with 10 mL of 10% citric acid and was extracted with EtOAc (3×30 mL). The combined organic layers were washed with brine, dried over MgSO4, filtered, and concentrated in vacuo. The product was purified by column chromatography (10 g biotage SNAP column, 5-40% EtOAc in hexanes) to give the title compound as a yellow solid (74.7 mg, 97%).
Reaction SMILES: [NH2:1][C:2]1[N:6]=[CH:5][NH:4][N:3]=1.[H-].[Na+].[CH2:9]([O:11][C:12](=[O:15])[CH2:13]I)[CH3:10]>CN(C=O)C.O>[CH2:9]([O:11][C:12](=[O:15])[CH2:13][N:4]1[CH:5]=[N:6][C:2]([NH2:1])=[N:3]1)[CH3:10]
Reactant: Nc1nc[nH]n1
Reactant: CCOC(=O)CI
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: CCOC(=O)Cn1cnc(N)n1
Temperature: 0 °C
Reaction time: 1 h

Procedure:
61.1 To a stirred mixture of 2.8 g 3-amino-1,2,4-triazole in 50 ml DMF, 1.57 g NaH were slowly added at 0° C. under an argon atmosphere. After 1 hr stirring at 0° C., 3.31 ml ethyliodoacetate were added. The reaction mixture was stirred at r.t. over night. The mixture was diluted with water and extracted with EtOAc and CH2Cl2/MeOH 9:1. The organic phase was dried (MgSO4), filtered and concentrated. The crude product was purified by chromatography on silica, using a gradient from CH2Cl2 to CH2Cl2/MeOH 9:1 and then crystallization from cyclohexane/EtOAc to give 750 mg (3-amino-[1,2,4]triazol-1-yl)-acetic acid ethyl ester as a white solid.
Reaction SMILES: [C:1]([C:3]1[C:8]([C:9]#[N:10])=[N:7][C:6]([NH:11][CH2:12][CH3:13])=[C:5](Cl)[N:4]=1)#[N:2].[C:15]1([OH:21])[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1.[OH-].[K+].O>O1CCCC1>[C:1]([C:3]1[C:8]([C:9]#[N:10])=[N:7][C:6]([NH:11][CH2:12][CH3:13])=[C:5]([O:21][C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)[N:4]=1)#[N:2]
Reactant: CCNc1nc(C#N)c(C#N)nc1Cl
Reactant: Oc1ccccc1
Agent: [K+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Product: CCNc1nc(C#N)c(C#N)nc1Oc1ccccc1
Yield: 83.7 %

Procedure:
2,3-Dicyano-5-ethylamino-6-chloropyrazine (2.07 g; 0.01 mole) was dissolved in 40 ml of tetrahydrofuran. The solution was cooled to 0° to 5° C., and with stirring, a solution prepared from 0.94 g (0.01 mole) of phenol, 0.56 g (0.01 mole) of potassium hydroxide, 5 ml of water and 20 ml of tetrahydrofuran was added dropwise over the period of 10 minutes. Then, the mixture was stirred at 0° to 5° C. for 1 hour. After the reaction, the precipitate was separated by filtration. The filtrate was concentrated under reduced pressure, and the residue was poured into 80 ml of water. The precipitated crystals were collected by filtration, and recrystallized from benzene to afford 2.22 g (yield 84%) of 2,3-dicyano-5-ethylamino-6-phenoxypyrazine.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[C:13](=[O:14])[C:12]([O:15][C:16]3[CH:21]=[CH:20][C:19]([C:22]4[CH:27]=[CH:26][C:25]([F:28])=[CH:24][CH:23]=4)=[CH:18][CH:17]=3)=[C:11]([N:29]3[CH2:34][CH2:33][CH:32](O)[CH2:31][CH2:30]3)[CH:10]=[N:9]2)=[CH:4][CH:3]=1.S(Cl)([Cl:38])=O>>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([N:8]2[C:13](=[O:14])[C:12]([O:15][C:16]3[CH:21]=[CH:20][C:19]([C:22]4[CH:23]=[CH:24][C:25]([F:28])=[CH:26][CH:27]=4)=[CH:18][CH:17]=3)=[C:11]([N:29]3[CH2:34][CH2:33][CH:32]([Cl:38])[CH2:31][CH2:30]3)[CH:10]=[N:9]2)=[CH:6][CH:7]=1
Reactant: O=S(Cl)Cl
Reactant: O=c1c(Oc2ccc(-c3ccc(F)cc3)cc2)c(N2CCC(O)CC2)cnn1-c1ccc(Cl)cc1
Product: O=c1c(Oc2ccc(-c3ccc(F)cc3)cc2)c(N2CCC(Cl)CC2)cnn1-c1ccc(Cl)cc1

Procedure:
A suspension of 150 mg (0.305 mmol) of 2-(4-chlorophenyl)-4-(4′-fluorobiphenyl-4-yloxy)-5-(4-hydroxypiperidin-1-yl)-2H-pyridazin-3-one (obtainable in analogy to Example 15) is heated under reflux with 4 ml of thionyl chloride for 60 min. After cooling, the reaction solution is concentrated under high vacuum, the residue is partitioned between 50 ml of ethyl acetate and 20 ml of saturated sodium bicarbonate solution, the organic phase is separated off, and the aqueous phase is extracted three times with ethyl acetate. The combined organic phases are dried over sodium sulfate, and the solvent is removed in vacuo. The product is purified by chromatography on silica gel with toluene/ethyl acetate from 9:1 to 8:2 as mobile phase.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([C:8](=[C:16]2[CH2:21][CH2:20][CH2:19][CH2:18][CH2:17]2)[C:9]2[CH:14]=[CH:13][C:12]([OH:15])=[CH:11][CH:10]=2)=[C:4]([F:22])[CH:3]=1.[C:23]([O:27][C:28]([CH3:31])([CH3:30])[CH3:29])(=[O:26])[CH:24]=[CH2:25].CC1C=CC=CC=1P(C1C=CC=CC=1C)C1C=CC=CC=1C.CCN(CC)CC>O>[C:16]1(=[C:8]([C:9]2[CH:14]=[CH:13][C:12]([OH:15])=[CH:11][CH:10]=2)[C:5]2[CH:6]=[CH:7][C:2](/[CH:25]=[CH:24]/[C:23]([O:27][C:28]([CH3:31])([CH3:30])[CH3:29])=[O:26])=[CH:3][C:4]=2[F:22])[CH2:21][CH2:20][CH2:19][CH2:18][CH2:17]1
Reactant: C=CC(=O)OC(C)(C)C
Reactant: Oc1ccc(C(=C2CCCCC2)c2ccc(Br)cc2F)cc1
Agent: Cc1ccccc1P(c1ccccc1C)c1ccccc1C
Solvent: O
Solvent: CCN(CC)CC
Product: CC(C)(C)OC(=O)/C=C/c1ccc(C(=C2CCCCC2)c2ccc(O)cc2)c(F)c1
Temperature: 140 °C
Yield: 62.3 %

Procedure:
A mixture of 77 (312 mg, 0.864 mmol), tert-butyl acrylate (0.369 mL, 2.55 mmol), P(OAc)2 (15.0 mg, 0.067 mmol), P(o-tolyl)3 (40.0 mg, 0.131 mmol), and Et3N (0.520 mL, 3.73 mmol) were heated under microwave irradiation at 140° C. for 30 min. Water (30 mL) was added and the mixture was extracted with Et2O (3×20 mL). The combined ethereal extracts were washed with water (30 mL), brine (30 mL), and dried over MgSO4. Concentration followed by flash chromatography (20:1 to 5:1 hexanes:EtOAc) afforded 220 mg (62%) of compound 78. 1H NMR (400 MHz, CDCl3): δ 1.52 (s, 9H), 1.58 (m, 6H), 2.07 (br s, 2H), 2.25 (br s, 2H), 4.78 (s, 1H), 6.30 (d, J=16.0 Hz, 1H), 6.74 (d, J=8.6 Hz, 2H), 7.01 (d, J=8.4 Hz, 2H), 7.08 (t, J=7.6 Hz, 1H), 7.13-7.18 (m, 2H), 7.49 (d, J=16.0 Hz, 1H).
Reaction SMILES: [C:1]([O:5][C:6](=[O:23])[NH:7][CH2:8][CH2:9][C:10]1[CH:15]=[CH:14][C:13]([C:16]2[CH:21]=[CH:20][CH:19]=[C:18]([OH:22])[CH:17]=2)=[CH:12][CH:11]=1)([CH3:4])([CH3:3])[CH3:2].[Cl:24][C:25]1[N:30]=[C:29](Cl)[CH:28]=[CH:27][N:26]=1.C(=O)([O-])[O-].[K+].[K+]>CN(C=O)C>[C:1]([O:5][C:6](=[O:23])[NH:7][CH2:8][CH2:9][C:10]1[CH:15]=[CH:14][C:13]([C:16]2[CH:21]=[CH:20][CH:19]=[C:18]([O:22][C:27]3[CH:28]=[CH:29][N:30]=[C:25]([Cl:24])[N:26]=3)[CH:17]=2)=[CH:12][CH:11]=1)([CH3:4])([CH3:2])[CH3:3]
Reactant: Clc1ccnc(Cl)n1
Reactant: CC(C)(C)OC(=O)NCCc1ccc(-c2cccc(O)c2)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)NCCc1ccc(-c2cccc(Oc3ccnc(Cl)n3)c2)cc1
Temperature: 25 °C
Reaction time: 20 h

Procedure:
A mixture of [2-(3′-hydroxy-biphenyl-4-yl)-ethyl]-carbamic acid tert -butyl ester (552 mg), 2,4-dichloropyrimidine (189 mg) and potassium carbonate (252 mg) in DMF (10 ml) is stirred at rt for 20 h. This mixture is quenched with brine and extracted twice with EtOAc. The combined organic phases are dried over sodium sulfate, the solvent is evaporated and the resulting crude product is purified on silica (60 g) with cyclohexane/EtOAc 80/20 to afford pure {2-[3′-(2-chloro-pyrimidin-4-yloxy)-biphenyl-4-yl]-ethyl}carbamic acid tert-butyl ester.
Reaction SMILES: [C:1]([O:5][C:6](=[O:19])[NH:7][CH:8]([CH2:17][OH:18])[CH2:9][C:10]1[CH:15]=[CH:14][C:13]([Br:16])=[CH:12][CH:11]=1)([CH3:4])([CH3:3])[CH3:2].[H-].[Na+].Br[CH2:23][C:24]1[CH:33]=[CH:32][CH:31]=[CH:30][C:25]=1[C:26]([O:28][CH3:29])=[O:27].CC(=O)OCC>C1COCC1>[Br:16][C:13]1[CH:12]=[CH:11][C:10]([CH2:9][CH:8]([NH:7][C:6]([O:5][C:1]([CH3:3])([CH3:2])[CH3:4])=[O:19])[CH2:17][O:18][CH2:23][C:24]2[CH:33]=[CH:32][CH:31]=[CH:30][C:25]=2[C:26]([O:28][CH3:29])=[O:27])=[CH:15][CH:14]=1
Reactant: COC(=O)c1ccccc1CBr
Reactant: CC(C)(C)OC(=O)NC(CO)Cc1ccc(Br)cc1
Agent: [H-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: COC(=O)c1ccccc1COCC(Cc1ccc(Br)cc1)NC(=O)OC(C)(C)C
Reaction time: 1 h
Yield: 33.4 %

Procedure:
To a solution of compound 3f (6.6 g, 20 mmol) in dry THF (100 mL) was added NaH (60%, 960 mg, 24 mmol) in small portions at 0° C. and stirred for 1 hr. Then compound 3b (5 g, 22 mmol) in THF (50 mL) was added dropwise, and the reaction mixture was allowed to stir at rt overnight. The reaction was quenched with water and extracted with EA (2×100 mL). The combined organic extracts were dried over anhydrous Na2SO4 and concentrated under reduced pressure. The residue was purified by CC eluting with PE:EA=9:1 to give 3g as a white solid (3.2 g, 34% yield).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:9]2[N:13]([C:14]3[CH:19]=[CH:18][N:17]=[C:16]([CH3:20])[CH:15]=3)[N:12]=[C:11]([C:21]([OH:23])=O)[CH:10]=2)[CH:5]=[C:6]([F:8])[CH:7]=1.ClC1C=C(C2N(C3C=NC=CC=3)N=C(C([N:45]3[CH2:50][CH2:49][NH:48][C:47](=[O:51])[CH2:46]3)=O)C=2)C=C(F)C=1.O=C1CNCCN1>>[Cl:1][C:2]1[CH:3]=[C:4]([C:9]2[N:13]([C:14]3[CH:19]=[CH:18][N:17]=[C:16]([CH3:20])[CH:15]=3)[N:12]=[C:11]([C:21]([N:45]3[CH2:50][CH2:49][NH:48][C:47](=[O:51])[CH2:46]3)=[O:23])[CH:10]=2)[CH:5]=[C:6]([F:8])[CH:7]=1
Reactant: Cc1cc(-n2nc(C(=O)O)cc2-c2cc(F)cc(Cl)c2)ccn1
Reactant: O=C1CN(C(=O)c2cc(-c3cc(F)cc(Cl)c3)n(-c3cccnc3)n2)CCN1
Agent: O=C1CNCCN1
Product: Cc1cc(-n2nc(C(=O)N3CCNC(=O)C3)cc2-c2cc(F)cc(Cl)c2)ccn1

Procedure:
75 mg (0.23 mmol) of the compound of Example 30A is reacted analogously to the synthesis of the compound of Example 4 with 24 mg (0.24 mmol) of 2-oxopiperazine. 77 mg (82% of theory) of the title compound is obtained.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:22]=[C:23]([O:27][CH3:28])[C:24]=1[O:25][CH3:26])[C:6]([N:8]1[CH2:12][CH2:11][C:10]([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][N:17]=2)([CH2:13][CH:14]=O)[CH2:9]1)=[O:7].[CH2:29]([O:31][CH2:32][CH2:33][N:34]1[C:38]2[CH:39]=[CH:40][CH:41]=[CH:42][C:37]=2[N:36]=[C:35]1[NH:43][CH:44]1[CH2:49][CH2:48][NH:47][CH2:46][CH2:45]1)[CH3:30].C([BH3-])#N.[Na+].[OH-].[Na+]>CO.ClCCl>[CH3:28][O:27][C:23]1[CH:22]=[C:5]([CH:4]=[C:3]([O:2][CH3:1])[C:24]=1[O:25][CH3:26])[C:6]([N:8]1[CH2:12][CH2:11][C:10]([CH2:13][CH2:14][N:47]2[CH2:46][CH2:45][CH:44]([NH:43][C:35]3[N:34]([CH2:33][CH2:32][O:31][CH2:29][CH3:30])[C:38]4[CH:39]=[CH:40][CH:41]=[CH:42][C:37]=4[N:36]=3)[CH2:49][CH2:48]2)([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][N:17]=2)[CH2:9]1)=[O:7]
Reactant: COc1cc(C(=O)N2CCC(CC=O)(c3ccccn3)C2)cc(OC)c1OC
Reactant: CCOCCn1c(NC2CCNCC2)nc2ccccc21
Agent: [BH3-]C#N
Agent: [Na+]
Agent: [OH-]
Solvent: ClCCl
Solvent: CO
Product: CCOCCn1c(NC2CCN(CCC3(c4ccccn4)CCN(C(=O)c4cc(OC)c(OC)c(OC)c4)C3)CC2)nc2ccccc21
Reaction time: 6 h

Procedure:
Combine 1-(3,4,5-trimethoxybenzoyl)-3-(pyrid-2-yl)-3-(2-oxoethyl)pyrrolidine and (0.24 mmol), (1-(2-ethyloxyethyl)-1H-benzimidazol-2-yl)(piperidin-4-yl)amine (0.28 mmol), and 3 Å molecular sieves (about 12 g) in methanol (5 mL). After 6 hours, add sodium cyanoborohydride (0.15 g, 2.4 mmol) and stir under an inert atmosphere. After 18 hours, add a solution of 2 M sodium hydroxide and dichloromethane. After 1 hour, filter, separate the layers in the filtrate, dry the organic layer over Na2SO4, filter, and evaporate in vacuo to give the title compound.
Reaction SMILES: [CH2:1]([CH:8]1[CH2:13][CH2:12][N:11]([CH2:14][CH2:15][CH2:16][N:17]([C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=2)[C:18]([CH:20]2[CH2:25][CH2:24][NH:23][CH2:22][CH2:21]2)=[O:19])[CH2:10][CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(N(CC)CC)C.[CH3:39][S:40](Cl)(=[O:42])=[O:41].C(=O)([O-])O.[Na+]>C1COCC1>[CH2:1]([CH:8]1[CH2:13][CH2:12][N:11]([CH2:14][CH2:15][CH2:16][N:17]([C:26]2[CH:27]=[CH:28][CH:29]=[CH:30][CH:31]=2)[C:18]([CH:20]2[CH2:25][CH2:24][N:23]([S:40]([CH3:39])(=[O:42])=[O:41])[CH2:22][CH2:21]2)=[O:19])[CH2:10][CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CS(=O)(=O)Cl
Reactant: O=C(C1CCNCC1)N(CCCN1CCC(Cc2ccccc2)CC1)c1ccccc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: CS(=O)(=O)N1CCC(C(=O)N(CCCN2CCC(Cc3ccccc3)CC2)c2ccccc2)CC1
Reaction time: 1 h
Yield: 37 %

Procedure:
The compound obtained in Example 2 (252 mg, 0.60 mmol) and triethylamine (0.201 ml) were dissolved in THF (5 ml), and under ice cooling, to the solution was added methanesulfonyl chloride (0.093 ml). The mixture was stirred at the same temperature for 1 hour. The compound obtained in Example 2 (252 mg, 0.60 mmol) and triethylamine (0.201 ml) were dissolved in THF (5 ml). To the solution was added methanesulfonyl chloride (0.093 ml) under ice cooling with stirring, and the mixture was stirred at the same temperature for 1 hour. To the mixture was added a saturated aqueous solution of sodium hydrogencarbonate (15 ml) under ice cooling, and the mixture was extracted with ethyl acetate (15 ml×3). The organic layer was dried over magnesium sulfate and concentrated under reduced pressure. The concentrate was subjected to column chromatography (silica gel 10 g, ethyl acetate/methanol=1/0 to 9/1), and the desired fraction was concentrated under reduced pressure. To the concentrate was added diisopropyl ether (10 ml), and the resulting precipitates were collected by filtration. The precipitates were washed with diisopropyl ether, and dried under reduced pressure to give the titled compound,(110 mg, 0.22 mmol, Yield 37%) as white crystals.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:12]=[CH:11][NH:10][N:9]=2)=[CH:4][CH:3]=1.[Cl:13]Cl>C(O)(=O)C>[Cl:13][C:12]1[C:8]([C:5]2[CH:4]=[CH:3][C:2]([Cl:1])=[CH:7][CH:6]=2)=[N:9][NH:10][CH:11]=1
Reactant: Clc1ccc(-c2cc[nH]n2)cc1
Reactant: ClCl
Solvent: CC(=O)O
Product: Clc1ccc(-c2n[nH]cc2Cl)cc1
Yield: 33.3 %

Procedure:
1.0 g (0.006 mol) of 3-(4-chlorophenyl)-1H-pyrazole are dissolved, at room temperature and with stirring, in 20 ml of acetic acid. 0.5 g (0.007 mol) of chlorine is then introduced into the reaction mixture. The white precipitate formed is filtered, washed with water and heptane and then chromatographed on a silica column (eluent 70/30 heptane/ethyl acetate). 0.7 g (0.002 mol) (yield: 58%, melting point: 158° C.) of 4-chloro-3-(4-chlorophenyl)-1H-pyrazole is obtained.
Reaction SMILES: C(N(CC)CC)C.[CH2:8]([C:11]1([CH2:18][CH:19]=[CH2:20])[CH2:15][NH:14][C@@H:13]([CH2:16][OH:17])[CH2:12]1)[CH:9]=[CH2:10].[S:21](Cl)(Cl)(=[O:23])=[O:22]>C(Cl)Cl>[CH2:18]([C:11]1([CH2:8][CH:9]=[CH2:10])[CH2:15][N:14]2[S:21](=[O:23])(=[O:22])[O:17][CH2:16][C@H:13]2[CH2:12]1)[CH:19]=[CH2:20]
Reactant: C=CCC1(CC=C)CN[C@@H](CO)C1
Reactant: O=S(=O)(Cl)Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: C=CCC1(CC=C)C[C@@H]2COS(=O)(=O)N2C1
Temperature: 25 °C
Reaction time: 8 h
Yield: 30.7 %

Procedure:
A solution of triethylamine (2.460 ml, 17.65 mmol) and (R)-(4,4-diallylpyrrolidin-2-yl)methanol (1.60 g, 8.83 mmol) in DCM (44.1 ml) was cooled to −78° C. To this mixture was added sulfuryl chloride (0.859 ml, 10.59 mmol) in DCM (44 mL) dropwise in 1 h. The reaction was maintained at this temperature for 3 h, then allowed to warm to room temperature and stirred overnight. The mixture washed with aq. 1 N HCl (30 ml×2), brine (30 ml), dried, filtered and concentrated. The crude material was absorbed onto a plug of silica gel and purified by chromatography through a REDISEP™ pre-packed silica gel column (40 g), eluting with a gradient of 0% to 30% EtOAc in hexane, to provide (R)-5,5-diallyltetrahydro-3H-pyrrolo[1,2-c][1,2,3]oxathiazole 1,1-dioxide (0.66 g, 2.71 mmol, 30.7% yield) as light-yellow oil. 1H NMR (400 MHz, CDCl3) δ 5.71-5.86 (m, 2H), 5.10-5.20 (m, 4H), 4.57 (dd, J=6.63, 8.76 Hz, 1H), 4.24-4.36 (m, 1H), 4.19 (dd, J=4.66, 8.76 Hz, 1H), 3.21-3.32 (m, 2H), 2.19-2.29 (m, 4H), 2.03-2.18 (m, 1H), 1.57-1.63 (m, 1H).
Reaction SMILES: [Br:1][C:2]1[N:7]=[CH:6][C:5]([CH:8]=[O:9])=[CH:4][CH:3]=1.[CH3:10][CH2:11]OCC.C1(C)C=CC=CC=1.C([Mg]Cl)C>C1COCC1.[Cl-].[NH4+]>[Br:1][C:2]1[N:7]=[CH:6][C:5]([CH:8]([OH:9])[CH2:10][CH3:11])=[CH:4][CH:3]=1
Reactant: O=Cc1ccc(Br)nc1
Reactant: CCOCC
Agent: CC[Mg]Cl
Agent: [Cl-]
Agent: [NH4+]
Solvent: C1CCOC1
Solvent: Cc1ccccc1
Product: CCC(O)c1ccc(Br)nc1
Reaction time: 4 h

Procedure:
To a chilled (ice bath) solution of 6-bromo-pyridine-3-carbaldehyde (15.0 g, 80.64 mmol) in a 1:1 mixture of ether:toluene (400 mL) was added a 2 M solution of ethylmagnesium chloride (40.0 mL, 80.0 mmol) in THF over a 15 minute period. The reaction was monitored by TLC (ethyl acetate-hexanes 3:7). After 4 hours, the mixture was diluted with saturated aqueous ammonium chloride (300 mL) and the organic phase separated. The aqueous layer was extracted with ethyl acetate (2×100 mL). The combined organic layers were washed with brine (2×50 mL), dried over magnesium sulfate, filtered and concentrated. The crude material was passed through a pad of silica gel eluting with dichloromethane-hexanes (0-100%). The material from the pad was purified by silica gel chromatography eluting with ethyl acetate-hexanes (2:98, then 4:96, then 6:94, then 8:92, then 1:9, then 12:88, then 15:85) to afford 1-(6-bromo-pyridin-3-yl)-propan-1-ol as a clear oil.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([F:8])[C:3]=1[C:9]1[CH:10]=[C:11]2[C:15](=[CH:16][CH:17]=1)[N:14]([CH:18]1[CH2:23][CH2:22][CH2:21][CH2:20][O:19]1)[N:13]=[C:12]2I.C([Sn](CCCC)(CCCC)[C:30]1[N:35]=[C:34]([N:36]2[CH2:41][CH2:40][CH2:39][CH:38]([NH:42][C:43](=[O:49])[O:44][C:45]([CH3:48])([CH3:47])[CH3:46])[CH2:37]2)[CH:33]=[N:32][CH:31]=1)CCC.N#N.O>CN(C=O)C.[Cu]I.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[F:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([F:8])[C:3]=1[C:9]1[CH:10]=[C:11]2[C:15](=[CH:16][CH:17]=1)[N:14]([CH:18]1[CH2:23][CH2:22][CH2:21][CH2:20][O:19]1)[N:13]=[C:12]2[C:30]1[N:35]=[C:34]([N:36]2[CH2:41][CH2:40][CH2:39][CH:38]([NH:42][C:43](=[O:49])[O:44][C:45]([CH3:47])([CH3:46])[CH3:48])[CH2:37]2)[CH:33]=[N:32][CH:31]=1
Reactant: CCCC[Sn](CCCC)(CCCC)c1cncc(N2CCCC(NC(=O)OC(C)(C)C)C2)n1
Reactant: Fc1cccc(F)c1-c1ccc2c(c1)c(I)nn2C1CCCCO1
Agent: [Cu]I
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: N#N
Solvent: CN(C)C=O
Solvent: O
Product: CC(C)(C)OC(=O)NC1CCCN(c2cncc(-c3nn(C4CCCCO4)c4ccc(-c5c(F)cccc5F)cc34)n2)C1
Temperature: 80 °C
Yield: 65.1 %

Procedure:
A solution of 5-(2,6-difluorophenyl)-3-iodo-1-(tetrahydro-2H-pyran-2-yl)-1H-indazole (400 mg, 0.91 mmol) and tert-butyl 1-(6-(tributylstannyl)pyrazin-2-yl)piperidin-3-ylcarbamate (520 mg, 0.91 mmol) in DMF (9.1 mL) was purged with N2 for 15 min and added CuI (225 mg, 1.18 mmol) and Pd(PPh3)4 (105 mg, 0.09 mmol). The reaction mixture was heated at 80° C. for 2 h and cooled to RT. To the reaction mixture was added water and precipitate was formed. The precipitate was collected by filtration, washed with water and dried overnight to give crude product. The crude was purified by chromatography (eluting with 0-10% MeOH and DCM) to obtain the title compound (350 mg, 66% yield). MS (ESI, pos. ion) m/z: 591 (M+1).
Reaction SMILES: [CH3:1][NH:2][CH3:3].[C:4]([NH:8][S:9]([C:12]1[CH:13]=[C:14]([S:18](Cl)(=[O:20])=[O:19])[CH:15]=[CH:16][CH:17]=1)(=[O:11])=[O:10])([CH3:7])([CH3:6])[CH3:5].O>C(OCC)(=O)C>[CH3:1][N:2]([CH3:3])[S:18]([C:14]1[CH:13]=[C:12]([S:9]([NH:8][C:4]([CH3:7])([CH3:6])[CH3:5])(=[O:11])=[O:10])[CH:17]=[CH:16][CH:15]=1)(=[O:20])=[O:19]
Reactant: CNC
Reactant: CC(C)(C)NS(=O)(=O)c1cccc(S(=O)(=O)Cl)c1
Solvent: O
Solvent: CCOC(C)=O
Product: CN(C)S(=O)(=O)c1cccc(S(=O)(=O)NC(C)(C)C)c1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
Dimethylamine gas was allowed to bubble for 3 minutes into a solution of 1.8 grams (7 mmole) of 3-tert-butylsulfamoyl-benzenesulfonyl chloride in ethyl acetate. Water was added and the mixture was stirred at room temperature for 1 hour. The ethyl acetate layer was separated, dried over magnesium sulfate and concentrated in vacuo to a solid which was triturated with hexane/isopropryl ether to give 1.59 grams of the titled compound, m.p. 100-102° C.
Reaction SMILES: Br[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][C:12]([O:14][CH3:15])=[O:13].[I-:16].[Na+]>CC(C)=O>[I:16][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][C:12]([O:14][CH3:15])=[O:13]
Reactant: COC(=O)CCCCCCCCCCBr
Reactant: [I-]
Agent: [Na+]
Solvent: CC(C)=O
Product: COC(=O)CCCCCCCCCCI
Temperature: 22 °C
Reaction time: 19 h
Yield: 95 %

Procedure:
To a solution of commercially available methyl 11-bromoundecanoate (5.80 g, 20.8 mmol) dissolved in dry acetone (70 mL) was added sodium iodide (4.05 g, 27.0 mmol). The reaction mixture was stirred at room temperature (22° C.) for 19 h under an inert nitrogen atmosphere. Afterwards, the acetone was evaporated and the residue transferred into an extraction funnel with diethyl ether (100 mL) and water (40 mL). The organic phase was washed with a thiosulfate solution (5% w/v, 2×20 mL) and with water 3×40 mL. The organic phase was dried, filtered on a short column of celite and celica (1 cm/4 cm) with a mixture of hexanes:acetone as the eluent. Evaporation of the solvent gave the title compound (95%) as an oil, which was used without further purification at the next step.
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:16]=[CH:15][C:12]([CH:13]=O)=[CH:11][C:10]=1[O:17][CH3:18])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH2:19]([NH:23][OH:24])[CH2:20][CH2:21][CH3:22]>>[CH2:1]([O:8][C:9]1[CH:16]=[CH:15][C:12]([CH:13]=[N+:23]([CH2:19][CH2:20][CH2:21][CH3:22])[O-:24])=[CH:11][C:10]=1[O:17][CH3:18])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: COc1cc(C=O)ccc1OCc1ccccc1
Reactant: CCCCNO
Product: CCCC[N+]([O-])=Cc1ccc(OCc2ccccc2)c(OC)c1

Procedure:
The title compound was prepared according to the procedures described in Examples 11 using 4-benzyloxy-3-methoxybenzaldehyde and N-n-butylhydroxylamine. The title compound was isolated in 41.7% yield as a solid, m.p. 81.2° C.
Reaction SMILES: S(OS(C(F)(F)F)(=O)=O)(C(F)(F)F)(=O)=O.[CH3:16][O:17][C:18]1[N:23]=[C:22]([C:24]([NH:26][CH3:27])=O)[CH:21]=[CH:20][C:19]=1[N+:28]([O-:30])=[O:29].[N-:31]=[N+:32]=[N-:33].[Na+].C([O-])(O)=O.[Na+]>CC#N>[CH3:16][O:17][C:18]1[C:19]([N+:28]([O-:30])=[O:29])=[CH:20][CH:21]=[C:22]([C:24]2[N:26]([CH3:27])[N:33]=[N:32][N:31]=2)[N:23]=1
Reactant: [N-]=[N+]=[N-]
Reactant: CNC(=O)c1ccc([N+](=O)[O-])c(OC)n1
Agent: O=C([O-])O
Agent: O=S(=O)(OS(=O)(=O)C(F)(F)F)C(F)(F)F
Agent: [Na+]
Solvent: CC#N
Product: COc1nc(-c2nnnn2C)ccc1[N+](=O)[O-]
Temperature: 25 °C
Yield: 48.6 %

Procedure:
Triflic anhydride (0.29 mL, 1.724 mmol) was added dropwise to a solution of 6-methoxy-N-methyl-5-nitropicolinamide (Preparation 188, 0.182 g, 0.862 mmol) and sodium azide (0.224 g, 3.45 mmol) in MeCN (4.3 mL) at −10° C. The reaction mixture was warmed to room temperature over 3 hours. The reaction mixture was neutralised with saturated aqueous NaHCO3. The mixture was extracted with EtOAc and the organic layer washed with saturated aqueous NaHCO3 and then with brine, dried (Na2SO4), filtered and concentrated in vacuo. The residue was purified by Biotage silica gel column chromatography eluting with cyclohexane/EtOAc 70/30 to 50/50 to afford the title compound as a white solid (99 mg, 49%).