Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([C:8](=O)[CH2:9][N:10]2[CH:14]=[N:13][CH:12]=[N:11]2)=[C:4]([Cl:16])[CH:3]=1.[Cl:17]P(Cl)(Cl)(Cl)Cl.ClCCCl.C(=O)([O-])[O-].[K+].[K+]>O.ClCCl>[Br:1][C:2]1[CH:7]=[CH:6][C:5](/[C:8](/[Cl:17])=[CH:9]\[N:10]2[CH:14]=[N:13][CH:12]=[N:11]2)=[C:4]([Cl:16])[CH:3]=1
Reactant: ClP(Cl)(Cl)(Cl)Cl
Reactant: O=C(Cn1cncn1)c1ccc(Br)cc1Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: ClCCl
Solvent: ClCCCl
Solvent: O
Product: Cl/C(=C/n1cncn1)c1ccc(Br)cc1Cl
Reaction time: 8 h
Yield: 37 %

Procedure:
A mixture of 20 parts of 1-(4-bromo-2-chlorophenyl)-2-(1H-1,2,4-triazol-1-yl)ethanone, 40 parts of pentachlorophosphorane and 300 parts of 1,2-dichloroethane was stirred and relfuxed overnight. 300 Parts of potassium carbonate and 650 parts of dichloromethane were added and water was added dropwise carefully till a volume of about 1500 parts. The aqueous phase was extracted with dichloromethane. The combined organic layers were washed with water, dried, filtered and evaporated. The residue was purified by reversed phase chromatography (HPLC) over LiChroprep RP 18 using a mixture of 75% of methanol containing 0.1% of N-(1-methylethyl)-2-propanamine and 25% of water containing 0.5% of ammonium acetate. The first fraction (E-isomer) was collected and the eluent was evaporated. The residue was crystallized from hexane at 0° C. The product was filtered off and dried in vacuo at 60° C., yielding 7.9 parts (37%) of (E)-1-[2-(4-bromo-2-chlorophenyl)-2 -chloroethenyl]-1H-1,2,4-triazole; mp. 84.0° C. (compound 44). The second fraction (Z-isomer) was collected and the eluent was evaporated. The residue was crystallized from hexane at 0° C. The product was filtered off and dried in vacuo at 60° C., yielding 0.36 parts of (Z)-1-[2-(4-bromo-2-chlorophenyl)-2-chloroethenyl]-1H-1,2,4-triazole; mp. 96.0° C. (compound 45).
Reaction SMILES: [N:1]([CH:4]1[CH:10]([F:11])[CH2:9][CH2:8][N:7]([C:12]2[N:16]([CH3:17])[N:15]=[CH:14][C:13]=2[N+:18]([O-:20])=[O:19])[CH2:6][CH2:5]1)=[N+]=[N-].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>C1COCC1.O>[F:11][CH:10]1[CH2:9][CH2:8][N:7]([C:12]2[N:16]([CH3:17])[N:15]=[CH:14][C:13]=2[N+:18]([O-:20])=[O:19])[CH2:6][CH2:5][CH:4]1[NH2:1]
Reactant: Cn1ncc([N+](=O)[O-])c1N1CCC(F)C(N=[N+]=[N-])CC1
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: O
Solvent: C1CCOC1
Product: Cn1ncc([N+](=O)[O-])c1N1CCC(N)C(F)CC1
Temperature: 60 °C

Procedure:
A solution of 4-azido-5-fluoro-1-(1-methyl-4-nitro-1H-pyrazol-5-yl)azepane (1.4 g, 4.95 mmol) in THF/water (30 mL/6 mL) was treated with triphenylphosphine (1.3 g, 4.95 mmol) and the mixture was heated at 60° C. behind a blast screen for 4 hr. The mixture was partitioned between EtOAc (200 mL) and saturated aqueous NaHCO3 solution (30 mL). The aqueous layer was extracted with EtOAc (50 mL) and the combined organic layers were dried over MgSO4 and concentrated under reduced pressure. The resulting oil was triturated with diethyl ether, the resulting solid was filtered off and the filtrate concentrated under reduced pressure to give 5-fluoro-1-(1-methyl-4-nitro-1H-pyrazol-5-yl)azepan-4-amine contaminated with triphenylphosphine oxide as a yellow oil. To a solution of this oil (1.27 g, 4.95 mmol) in dry DCM (40 mL) at 0° C. was added slowly DIPEA (2.6 mL, 14.8 mmol) followed by trifluoroacetic anhydride (0.83 ml, 5.94 mmol) dropwise. The reaction mixture was allowed to warm to room temperature and stirred for 18 hr. Water (40 mL) was added and the mixture was extracted with DCM (150 mL). The organic layer was separated, dried over MgSO4 and concentrated under reduced pressure. Purification via silica gel column chromatography (40% EtOAc/isohexane) gave 2,2,2-trifluoro-N-(5-fluoro-1-(1-methyl-4-nitro-1H-pyrazol-5-yl)azepan-4-yl)acetamide as a yellow viscous oil (1.4 g). To a solution of this oil (1.4 g, 3.97 mmol) and ammonium formate (2.5 g, 39.7 mmol) in MeOH (40 mL) under nitrogen was added 10% palladium on carbon (140 mg). The mixture was heated at 70° C. for 30 min before being cooled, filtered and concentrated under reduced pressure. The residue was partitioned between water (30 mL) and DCM (75 mL). The aqueous layer was extracted with DCM (2×75 mL) and the combined organic layers were separated, dried over MgSO4 and concentrated under reduced pressure to give N-((4S,5R)-1-(4-amino-1-methyl-1H-pyrazol-5-yl)-5-fluoroazepan-4-yl)-2,2,2-trifluoroacetamide as an orange-yellow glass (1.1 g, 69% over three steps). 1H NMR (400 MHz, CDCl3) δ 7.47 (s, 1H), 7.12 (s, 1H), 5.02-4.85 (m, 1H), 4.69-4.55 (m, 1H), 3.66 (s, 3H), 3.42-3.20 (m, 3H), 3.11 (ddd, J=14.4, 6.7, 3.3 Hz, 1H), 2.36-2.22 (m, 1H), 2.23-1.94 (m, 2H), 1.90-1.82 (m, 1H). NH2 not observed.
Reaction SMILES: Cl.[NH:2]1[CH2:7][CH2:6][C:5](=[CH:8][C:9]2[CH:10]=[C:11]([CH:23]=[CH:24][CH:25]=2)[O:12][C:13]2[CH:18]=[CH:17][C:16]([C:19]([F:22])([F:21])[F:20])=[CH:15][N:14]=2)[CH2:4][CH2:3]1.[CH:26]1([C:29]2[S:33][C:32]([NH:34][C:35](=O)[O:36]C3C=CC=CC=3)=[N:31][N:30]=2)[CH2:28][CH2:27]1.C(N(CC)CC)C.O>CS(C)=O>[CH:26]1([C:29]2[S:33][C:32]([NH:34][C:35]([N:2]3[CH2:7][CH2:6][C:5](=[CH:8][C:9]4[CH:25]=[CH:24][CH:23]=[C:11]([O:12][C:13]5[CH:18]=[CH:17][C:16]([C:19]([F:22])([F:20])[F:21])=[CH:15][N:14]=5)[CH:10]=4)[CH2:4][CH2:3]3)=[O:36])=[N:31][N:30]=2)[CH2:28][CH2:27]1
Reactant: FC(F)(F)c1ccc(Oc2cccc(C=C3CCNCC3)c2)nc1
Reactant: O=C(Nc1nnc(C2CC2)s1)Oc1ccccc1
Agent: Cl
Solvent: O
Solvent: CCN(CC)CC
Solvent: CS(C)=O
Product: O=C(Nc1nnc(C2CC2)s1)N1CCC(=Cc2cccc(Oc3ccc(C(F)(F)F)cn3)c2)CC1
Temperature: 25 °C
Yield: 42 %

Procedure:
A solution of 2-(3-(piperidin-4-ylidenemethyl)phenoxy)-5-(trifluoromethyl)pyridine hydrochloride (0.100 g; Example 1a, Step 5), phenyl 5-cyclopropyl-1,3,4-thiadiazol-2-ylcarbamate (0.085 g, 1.2 equiv), and triethylamine (0.045 mL, 1.2 equiv) in dimethyl sulfoxide (1 mL, 0.3 M) was heated to 65° C. for 2 h. The reaction was cooled to room temperature. Water was added and then the solution was extracted with ethyl acetate (2×). The organic extracts were dried over magnesium sulfate, filtered, and concentrated. The residue was purified on a 12 g silica gel column using 10-30% ethyl acetate/dichloromethane over 30 minutes as the eluent to give the title compound as a white foam. 0.057 g, 42% yield. 1H NMR (400 MHz, CDCl3) δ ppm 0.98-1.07 (2H, m), 1.09-1.18 (2H, m), 2.15-2.25 (1H, m), 2.46 (2H, t, J=5.5 Hz), 2.60 (2H, t, J=5.5 Hz), 3.66 (2H, t, J=5.8 Hz), 3.76 (2H, t, J=5.9 Hz), 6.40 (1H, s), 6.95-7.04 (3H, m), 7.09 (1H, d, J=7.8 Hz), 7.37 (1H, t, J=7.8 Hz), 7.89 (1H, dd, J=8.6, 2.7 Hz), 8.43 (1H, dd, J=1.6, 0.8 Hz).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:12]([CH2:17][C@H:18]2[CH2:38][CH2:37][C:20]3([O:24][C@H:23]([C:25]4[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=4)[C@@H:22]([C:31]4[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=4)[O:21]3)[CH2:19]2)[C:13](=[O:16])[CH:14]=[CH2:15])[CH:5]=[CH:6][C:7]=1[S:8]([CH3:11])(=[O:10])=[O:9].[N:39]1[CH:44]=[CH:43][N:42]=[CH:41][C:40]=1[CH:45]=[O:46].C(N(CC)CC)C>C(O)C.[Cl-].C([N+]1C(C)=C(CCO)SC=1)C1C=CC=CC=1.C(OCC)(=O)C>[Cl:1][C:2]1[CH:3]=[C:4]([CH:12]([CH2:17][C@H:18]2[CH2:38][CH2:37][C:20]3([O:21][C@H:22]([C:31]4[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=4)[C@@H:23]([C:25]4[CH:26]=[CH:27][CH:28]=[CH:29][CH:30]=4)[O:24]3)[CH2:19]2)[C:13](=[O:16])[CH2:14][CH2:15][C:45]([C:40]2[CH:41]=[N:42][CH:43]=[CH:44][N:39]=2)=[O:46])[CH:5]=[CH:6][C:7]=1[S:8]([CH3:11])(=[O:9])=[O:10]
Reactant: O=Cc1cnccn1
Reactant: C=CC(=O)C(C[C@H]1CCC2(C1)O[C@H](c1ccccc1)[C@@H](c1ccccc1)O2)c1ccc(S(C)(=O)=O)c(Cl)c1
Agent: Cc1c(CCO)sc[n+]1Cc1ccccc1
Agent: [Cl-]
Solvent: CCO
Solvent: CCOC(C)=O
Solvent: CCN(CC)CC
Product: CS(=O)(=O)c1ccc(C(C[C@H]2CCC3(C2)O[C@H](c2ccccc2)[C@@H](c2ccccc2)O3)C(=O)CCC(=O)c2cnccn2)cc1Cl
Temperature: 25 °C
Yield: 44 %

Procedure:
To a solution of 4-[3-chloro-4-(methylsulfonyl)phenyl]-5-[(2R,3R,7R)-2,3-diphenyl-1,4-dioxaspiro[4.4]non-7-yl]pent-1-en-3-one (539 mg) in ethanol (5 mL) were added pyrazine-2-carbaldehyde (126 mg), 3-benzyl-5-(2-hydroxyethyl)-4-methyl-1,3-thiazol-3-ium chloride (29.0 mg) and triethylamine (59 μL), and the mixture was stirred with heating under reflux for 1 hr. After cooling to room temperature, the reaction mixture was diluted with ethyl acetate and washed with water. The ethyl acetate layer was dried (MgSO4) and concentrated. The residue was subjected to silica gel column chromatography, and the title compound (284 mg, yield 44%) was obtained as a pale-yellow amorphous solid from a fraction eluted with ethyl acetate-hexane (2:1, volume ratio).
Reaction SMILES: [CH3:1][C:2]1[C:10]2[C:5](=[CH:6][C:7]([NH:11][C:12]3[N:13]=[C:14]([N:21]4[CH2:26][CH2:25][CH:24]([C:27]#[N:28])[CH2:23][CH2:22]4)[C:15]4[O:20][CH:19]=[CH:18][C:16]=4[N:17]=3)=[CH:8][CH:9]=2)[NH:4][N:3]=1.Cl.[NH2:30][OH:31].C([O-])(O)=O.[Na+]>CO>[OH:31][N:30]=[C:27]([CH:24]1[CH2:25][CH2:26][N:21]([C:14]2[C:15]3[O:20][CH:19]=[CH:18][C:16]=3[N:17]=[C:12]([NH:11][C:7]3[CH:6]=[C:5]4[C:10]([C:2]([CH3:1])=[N:3][NH:4]4)=[CH:9][CH:8]=3)[N:13]=2)[CH2:22][CH2:23]1)[NH2:28]
Reactant: NO
Reactant: Cc1n[nH]c2cc(Nc3nc(N4CCC(C#N)CC4)c4occc4n3)ccc12
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CO
Product: Cc1n[nH]c2cc(Nc3nc(N4CCC(C(N)=NO)CC4)c4occc4n3)ccc12
Temperature: 70 °C
Reaction time: 120 h
Yield: 22.4 %

Procedure:
A mixture of 1-(2-(3-methyl-1H-indazol-6-ylamino)furo[3,2-d]pyrimidin-4-yl)piperidine-4-carbonitrile (0.082 g, 0.22 mmol), hydroxylamine hydrochloride (0.061 g, 0.88 mmol) and NaHCO3 (0.15 g, 1.7 mmol) in MeOH (20 mL) was stirred at about 70° C. for about 120 h. The solvent was removed and the residue was purified by preparative HPLC (Table 2, Method p) to give N′-hydroxy-1-(2-(3-methyl-1H-indazol-6-ylamino)furo[3,2-d]pyrimidin-4-yl)piperidine-4-carboximidamide (0.020 g, 22%): LC/MS (Table 2, Method h) Rt=1.66 min; MS m/z: 407 (M+H)+. Syk IC50=B
Reaction SMILES: [NH2:1][C:2]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[NH:4][N:3]=1.Br.[CH3:12][CH:13]([N:17]1[CH2:22][CH2:21][O:20][CH2:19][CH2:18]1)[CH2:14][CH2:15]Br.NC1C2C(=CC=CC=2Cl)NN=1.Br.BrCCCN(CC)CC>>[O:20]1[CH2:21][CH2:22][N:17]([CH:13]([CH3:12])[CH2:14][CH2:15][N:4]2[C:5]3[C:10](=[CH:9][CH:8]=[CH:7][CH:6]=3)[C:2]([NH2:1])=[N:3]2)[CH2:18][CH2:19]1
Reactant: Nc1n[nH]c2ccccc12
Reactant: CC(CCBr)N1CCOCC1
Agent: Br
Agent: CCN(CC)CCCBr
Agent: Nc1n[nH]c2cccc(Cl)c12
Product: CC(CCn1nc(N)c2ccccc21)N1CCOCC1
Yield: 48 %

Procedure:
The same procedures as described in Example 1 were repeated except that 4.50 g of 3-aminoindazole and 5.03 g of (1-methyl-3-bromopropyl)-morpholine hydrobromide were employed instead of the 5.66 g of 3-amino-4-chloroindazole and the 4.83 g of 3-bromopropyldiethylamine hydrobromide, respectively. As a result, 1-(3-morpholinobutyl)-3-aminoindazole having the following analytical values was obtained in a yield of 48%.
Reaction SMILES: [CH2:1]([NH:3][C:4]([NH:6][CH2:7][CH3:8])=[S:5])[CH3:2].[C:9]([C:14](O)=[O:15])#[C:10][C:11]([OH:13])=[O:12]>>[CH2:1]([N:3]1[C:14](=[O:15])[C:9](=[CH:10][C:11]([OH:13])=[O:12])[S:5][C:4]1=[N:6][CH2:7][CH3:8])[CH3:2]
Reactant: O=C(O)C#CC(=O)O
Reactant: CCNC(=S)NCC
Product: CCN=C1SC(=CC(=O)O)C(=O)N1CC
Yield: 82.1 %

Procedure:
Prepared by the method described in Example 1 from N,N'-diethylthiourea (1.0 g, 8 mmoles) and acetylenedicarboxylic acid (1 g, 9 mmoles). Crystallization from hexane gave the product (1.5 g), mp 148°-152° C.
Reaction SMILES: [CH2:1]([P:3]([CH2:10][CH2:11][CH2:12][OH:13])(=[O:9])[O:4][CH2:5][CH2:6]CC)[CH3:2].C(O)C[OH:16]>C([O-])(C([O-])=O)=O.C([O-])(C([O-])=O)=O.O=[Ti+2].[K+].[K+]>[CH2:1]([P:3]([CH2:10][CH2:11][CH2:12][OH:13])(=[O:9])[O:4][CH2:5][CH2:6][OH:16])[CH3:2]
Reactant: OCCO
Reactant: CCCCOP(=O)(CC)CCCO
Agent: O=[Ti+2]
Agent: O=C([O-])C(=O)[O-]
Agent: [K+]
Product: CCP(=O)(CCCO)OCCO
Temperature: 200 °C
Reaction time: 2 h
Yield: 111.9 %

Procedure:
To 416 g (2 mol) of butyl ethyl(3-hydroxypropyl)phosphinate (produced as in Example 9) are added 155 g (2.5 mol) of ethylene glycol and 0.4 g of potassium titanyloxalate, followed by stirring at 200° C. for 2 h. Volatiles are distilled off by gradual evacuation to leave 439 g (98% of theory) of 2-hydroxyethyl ethyl(3-hydroxypropyl)phosphinate.
Reaction SMILES: [NH2:1][C:2]1[CH:24]=[CH:23][C:5]([O:6][C:7]2[CH:12]=[CH:11][N:10]=[C:9]3[CH:13]=[C:14]([C:16]([N:18]4[CH2:22][CH2:21][CH2:20][CH2:19]4)=[O:17])[S:15][C:8]=23)=[C:4]([F:25])[CH:3]=1.C1C=CC2N(O)N=NC=2C=1.C(Cl)CCl.[O:40]=[C:41]([NH:46][C:47]1[CH:52]=[CH:51][CH:50]=[CH:49][CH:48]=1)[CH2:42][C:43](O)=[O:44]>CN(C=O)C.CCOC(C)=O>[F:25][C:4]1[CH:3]=[C:2]([NH:1][C:43](=[O:44])[CH2:42][C:41]([NH:46][C:47]2[CH:48]=[CH:49][CH:50]=[CH:51][CH:52]=2)=[O:40])[CH:24]=[CH:23][C:5]=1[O:6][C:7]1[CH:12]=[CH:11][N:10]=[C:9]2[CH:13]=[C:14]([C:16]([N:18]3[CH2:19][CH2:20][CH2:21][CH2:22]3)=[O:17])[S:15][C:8]=12
Reactant: Nc1ccc(Oc2ccnc3cc(C(=O)N4CCCC4)sc23)c(F)c1
Reactant: O=C(O)CC(=O)Nc1ccccc1
Agent: On1nnc2ccccc21
Solvent: CCOC(C)=O
Solvent: ClCCCl
Solvent: CN(C)C=O
Product: O=C(CC(=O)Nc1ccc(Oc2ccnc3cc(C(=O)N4CCCC4)sc23)c(F)c1)Nc1ccccc1
Reaction time: 24 h
Yield: 51 %

Procedure:
To a solution of 23 (100 mg, 0.28 mmol), HOBT (49 mg, 0.36 mmol) and EDC (80 mg, 0.41 mmol) in DMF (5 mL) was added 3-oxo-3-(phenylamino)propanoic acid (1) (65 mg, 0.36 mmol). The reaction mixture was stirred for 1 day and was diluted with EtOAc. The resultant solution was washed with water and brine, dried over anhydrous sodium sulfate and concentrated to provide a residue, which was purified by column chromatography (eluents MeOH—CH2Cl2, 2:98, 5:95) to produce a solid material, which after trituration with EtOAc/hexane afforded 5f as a white solid (74 mg, 51% yield). MS (m/z): 519.2 (M+H).
Reaction SMILES: [CH2:1]([O:8][C@@H:9]1[C@@H:14]([O:15][CH2:16][C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[C@H:13]([O:23][CH2:24][C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=2)[C:12](=[CH2:31])[O:11][C@H:10]1[C:32]1[CH:37]=[CH:36][C:35]([Cl:38])=[C:34]([CH2:39][C:40]2[CH:45]=[CH:44][C:43]([O:46][CH2:47][CH3:48])=[CH:42][CH:41]=2)[CH:33]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[N+](=[CH:51][C:52]([O:54][CH2:55][CH3:56])=[O:53])=[N-]>ClCCl.O.C([O-])(=O)C.[Rh+3].C([O-])(=O)C.C([O-])(=O)C>[CH2:55]([O:54][C:52]([CH:51]1[C:12]2([C@@H:13]([O:23][CH2:24][C:25]3[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=3)[C@H:14]([O:15][CH2:16][C:17]3[CH:18]=[CH:19][CH:20]=[CH:21][CH:22]=3)[C@@H:9]([O:8][CH2:1][C:2]3[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=3)[C@H:10]([C:32]3[CH:37]=[CH:36][C:35]([Cl:38])=[C:34]([CH2:39][C:40]4[CH:45]=[CH:44][C:43]([O:46][CH2:47][CH3:48])=[CH:42][CH:41]=4)[CH:33]=3)[O:11]2)[CH2:31]1)=[O:53])[CH3:56]
Reactant: C=C1O[C@@H](c2ccc(Cl)c(Cc3ccc(OCC)cc3)c2)[C@H](OCc2ccccc2)[C@@H](OCc2ccccc2)[C@@H]1OCc1ccccc1
Reactant: CCOC(=O)C=[N+]=[N-]
Agent: [Rh+3]
Agent: CC(=O)[O-]
Solvent: O
Solvent: ClCCl
Product: CCOC(=O)C1CC12O[C@@H](c1ccc(Cl)c(Cc3ccc(OCC)cc3)c1)[C@H](OCc1ccccc1)[C@@H](OCc1ccccc1)[C@@H]2OCc1ccccc1
Reaction time: 18 h

Procedure:
To a solution of (2S,3S,4R,5S)-3,4,5-tris-benzyloxy-2-[4-chloro-3-(4-ethoxy-benzyl)-phenyl]-6-methylene-tetrahydro-pyran (See Ex. 1, step III, 100 mg, 0.15 mmole) and rhodium acetate dimmer (0.13 mg, 0.002 mmole) in dry dichloromehane (5 mL), ethyl diazoacetate in dichloromethane (2 mL) was added during 3 hours at room temperature and stirred for 18 hours. The reaction mixture was diluted with water (20 mL) and extracted with DCM (2×30 mL). The crude product was purified by silica gel column chromatography (20% ethyl acetate in hexane) to furnish 50 mg of (5S,6S,7R,8S)-6,7,8-tris-benzyloxy-5-[4-chloro-3-(4-ethoxy-benzyl)-phenyl]-4-oxa-spiro[2.5]octane-1-carboxylic acid ethyl ester.
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:14]=[C:13]([C:15]([C:17]2[CH:26]=[C:25]([CH3:27])[C:20]3[NH:21][C:22](=[O:24])[O:23][C:19]=3[CH:18]=2)=[O:16])[CH:12]=[C:11]([Cl:28])[N:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.I[CH3:30]>CN(C=O)C>[CH2:1]([O:8][C:9]1[CH:14]=[C:13]([C:15]([C:17]2[CH:26]=[C:25]([CH3:27])[C:20]3[N:21]([CH3:30])[C:22](=[O:24])[O:23][C:19]=3[CH:18]=2)=[O:16])[CH:12]=[C:11]([Cl:28])[N:10]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CI
Reactant: Cc1cc(C(=O)c2cc(Cl)nc(OCc3ccccc3)c2)cc2oc(=O)[nH]c12
Solvent: CN(C)C=O
Product: Cc1cc(C(=O)c2cc(Cl)nc(OCc3ccccc3)c2)cc2oc(=O)n(C)c12
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
Under a nitrogen atmosphere and while cooling with ice 220 mg (5.06 mmol) sodium hydride (55%, suspension in mineral oil) were added to 2.00 g (5.07 mmol) 6-(2-benzyloxy-6-chloro-pyridine-4-carbonyl)-4-methyl-3H-benzoxazol-2-one in 10 mL DMF. The reaction mixture was stirred for 30 min at RT. Then 0.312 mL (5.06 mmol) iodomethane were added and the mixture was stirred overnight at RT. The reaction mixture was poured onto water and the precipitated product was suction filtered, washed with water and dried. The residue was stirred with diethyl ether, suction filtered and dried.
Reaction SMILES: [CH2:1]([N:8]1[CH:12]=[CH:11][C:10]([C:17]2[CH:22]=[C:21]([Cl:23])[CH:20]=[C:19]([Cl:24])[CH:18]=2)([C:13]([F:16])([F:15])[F:14])[CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(O)=O.[H][H]>CO.[Pt].C(OCC)(=O)C>[CH2:1]([N:8]1[CH2:12][CH2:11][C:10]([C:17]2[CH:18]=[C:19]([Cl:24])[CH:20]=[C:21]([Cl:23])[CH:22]=2)([C:13]([F:16])([F:15])[F:14])[CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: [H][H]
Reactant: FC(F)(F)C1(c2cc(Cl)cc(Cl)c2)C=CN(Cc2ccccc2)C1
Agent: [Pt]
Solvent: CO
Solvent: CCOC(C)=O
Solvent: O=CO
Product: FC(F)(F)C1(c2cc(Cl)cc(Cl)c2)CCN(Cc2ccccc2)C1
Temperature: 25 °C
Reaction time: 6 h
Yield: 96 %

Procedure:
1-Benzyl-3-(3,5-dichlorophenyl)-3-(trifluoromethyl)-2,3-dihydro-1H-pyrrole (200 mg, 82% purity, 440 μmol) was dissolved in methanol (5 mL) under an argon atmosphere. Formic acid (200 μL, 5.30 mmol) and platinum on charcoal (5 w/w % Pt/C, ˜60% H2O, 42.9 mg, 4.4 μmol) was added and the flask was charged with hydrogen (balloon). The reaction was stirred for six hours at room temperature and then left standing over night. After the addition of platinum on charcoal (0.5 mol %) and formic acid (1 mL) the reaction mixture was warmed to 40-50° C. for six hours and then left standing at room temperature. Refluxing the mixture for three more hours and addition of more platinum on charcoal (1.0 mol %) after one hour led to complete conversion. The reaction mixture was cooled to room temperature, diluted with ethyl acetate (5 mL), filtered over celite, washed with saturated sodium bicarbonate and brine solution. The organic phase was dried over sodium sulfate, filtered and the solvents evaporated. 1-benzyl-3-(3,5-dichlorophenyl)-3-(trifluoromethyl)pyrrolidine was obtained (163 mg, 97% purity, 96% yield).
Reaction SMILES: ClC1C=CC=C(C(OO)=[O:9])C=1.[CH3:12][S:13][C:14]1[N:26]=[CH:25][C:17]2=[CH:18][C:19]3[C:24]([N:16]2[N:15]=1)=[CH:23][CH:22]=[CH:21][CH:20]=3.C([O-])(O)=O.[Na+]>ClCCl.O>[CH3:12][S:13]([C:14]1[N:26]=[CH:25][C:17]2=[CH:18][C:19]3[C:24]([N:16]2[N:15]=1)=[CH:23][CH:22]=[CH:21][CH:20]=3)=[O:9]
Reactant: O=C(OO)c1cccc(Cl)c1
Reactant: CSc1ncc2cc3ccccc3n2n1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Solvent: ClCCl
Product: CS(=O)c1ncc2cc3ccccc3n2n1
Temperature: 25 °C
Reaction time: 1 h
Yield: 98.5 %

Procedure:
261 g) Into a round-bottom flask, m-chloroperbenzoic acid (77% by weight in benzoic acid, 853 mg, 3.80 mmol) was added to a solution of 2-methylsulfanyl-[1,2,4]triazino[1,6-a]indole (780 mg, 3.60 mmol) in dichloromethane (20 mL), at 0° C. The reaction was stirred for 1 hour at room temperature. Saturated NaHCO3 in water was added and the reaction mixture was stirred for 30 minutes. The organic phase was separated, washed with brine, and dried over magnesium sulfate, then filtered. The solvent was removed under vacuum to afford 2-methanesulfinyl-[1,2,4]triazino[1,6-a]indole (820 mg, 98%) as an orange solid, which was used without further purification. 1H-NMR (CDCl3) δ 9.28 (s, 1H), 8.34 (d, J=8.5 Hz, 1H), 7.95 (d, J=8.1 Hz, 1H), 7.60 (m, 1H), 7.52 (m, 1H), 7.21 (s, 1H), 3.06 (s, 3H); LC/MS (ESI+): 254.5 (M+Na).
Reaction SMILES: C([O:3][C:4](=[O:32])[CH2:5][CH:6]1[CH2:11][CH2:10][N:9]([C:12]2[C:17]([NH:18][C:19](=[O:27])[C:20]3[CH:25]=[CH:24][CH:23]=[C:22]([Cl:26])[CH:21]=3)=[CH:16][CH:15]=[C:14]([S:28]([CH3:31])(=[O:30])=[O:29])[N:13]=2)[CH2:8][CH2:7]1)C.O1CCCC1.CO.[OH-].[Li+]>O>[Cl:26][C:22]1[CH:21]=[C:20]([CH:25]=[CH:24][CH:23]=1)[C:19]([NH:18][C:17]1[C:12]([N:9]2[CH2:10][CH2:11][CH:6]([CH2:5][C:4]([OH:32])=[O:3])[CH2:7][CH2:8]2)=[N:13][C:14]([S:28]([CH3:31])(=[O:29])=[O:30])=[CH:15][CH:16]=1)=[O:27]
Reactant: CCOC(=O)CC1CCN(c2nc(S(C)(=O)=O)ccc2NC(=O)c2cccc(Cl)c2)CC1
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: CO
Solvent: C1CCOC1
Product: CS(=O)(=O)c1ccc(NC(=O)c2cccc(Cl)c2)c(N2CCC(CC(=O)O)CC2)n1
Temperature: 25 °C
Reaction time: 8 h
Yield: 46.3 %

Procedure:
To a mixture of 0.055 g (0.11 mmol) of [3′-(3-chloro-benzoylamino)-6′-methanesulfonyl-3,4,5,6-tetrahydro-2H-[1,2′]bipyridinyl-4-yl]-acetic acid ethyl ester in a 2:1 mixture of tetrahydrofuran:methanol (6 mL) is added 0.014 g (0.57 mmol) of lithium hydroxide as a solution in water (1 mL). The mixture is stirred overnight at room temperature then concentrated under reduced pressure. The residue is diluted with water and the pH of the mixture is adjusted to pH 2 by the addition of concentrated hydrochloric acid causing a solid to precipitate from solution. The formed precipitate is collected by filtration and dried to provide 0.023 g (44%) of [3′-(3-chloro-benzoylamino)-6′-methanesulfonyl-3,4,5,6-tetrahydro-2H-[1,2′]bipyridinyl-4-yl]-acetic acid as a yellow solid.
Reaction SMILES: Br[C:2]1[CH:3]=[N:4][CH:5]=[CH:6][CH:7]=1.[CH:8]#[C:9][CH:10]([OH:13])[CH2:11][CH3:12]>C(N(CC)CC)C.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.CSC.[Cu]Br>[N:4]1[CH:5]=[CH:6][CH:7]=[C:2]([C:8]#[C:9][CH:10]([OH:13])[CH2:11][CH3:12])[CH:3]=1
Reactant: C#CC(O)CC
Reactant: Brc1cccnc1
Agent: [Cu]Br
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Solvent: CSC
Solvent: CCN(CC)CC
Product: CCC(O)C#Cc1cccnc1
Temperature: 70 °C
Yield: 100.1 %

Procedure:
To a solution of 3-bromopyridine (12.0 g, 75.6 mmol) and 1-pentyn-3-ol (7.0 mL, 83.2 mmol) in triethylamine (150 mL) were added Pd(PPh3)4 (88 mg, 0.076 mmol) and copper(I) bromide dimethylsulfide (31 mg, 0.15 mmol). The mixture was heated at 70° C. for 5 hr, cooled to room temperature and filtered. The filter cake was washed with EtOAc (30 mL). The combined filtrate was concentrated to give 1-(3-pyridinyl)-1-pentyn-3-ol (12.2 g, 99%) as a dark oil.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([OH:8])=[CH:4][C:3]=1[F:9].[N+:10]([O-])([OH:12])=[O:11].O>C(Cl)Cl>[Br:1][C:2]1[C:3]([F:9])=[CH:4][C:5]([OH:8])=[C:6]([N+:10]([O-:12])=[O:11])[CH:7]=1
Reactant: O=[N+]([O-])O
Reactant: Oc1ccc(Br)c(F)c1
Solvent: O
Solvent: ClCCl
Product: O=[N+]([O-])c1cc(Br)c(F)cc1O
Reaction time: 0.5 h
Yield: 48.6 %

Procedure:
To a 0° C. mixture of 4-bromo-3-fluorophenol (70.0 g, 366 mmol) in DCM (500 mL) was added HNO3 (23.0 g, 366 mmol) carefully and the reaction mixture was stirred 30 min. The reaction mixture was poured into water (1 L) and extracted with DCM (3×500 mL). The combined organic portion was washed with brine (300 mL) and dried over anhydrous Na2SO4, filtered and concentrated in vacuo. The residue was crystallized from EtOH to give 4-bromo-5-fluoro-2-nitrophenol (42.0 g, 49%). 1H NMR (DMSO-d6, 400 MHz): δ 11.72 (brs, 1H), δ 8.30 (d, J=7.2 Hz, 1H), 7.09 (d, J=10.0 Hz, 1H).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][N:6]=[C:5]2[I:11].[CH3:12][N:13]1[CH2:18][CH2:17][O:16][CH:15]([CH2:19][CH2:20]O)[CH2:14]1>>[I:11][C:5]1[C:4]2[C:8](=[CH:9][CH:10]=[C:2]([F:1])[CH:3]=2)[N:7]([CH2:20][CH2:19][CH:15]2[O:16][CH2:17][CH2:18][N:13]([CH3:12])[CH2:14]2)[N:6]=1
Reactant: CN1CCOC(CCO)C1
Reactant: Fc1ccc2[nH]nc(I)c2c1
Product: CN1CCOC(CCn2nc(I)c3cc(F)ccc32)C1
Yield: 80 %

Procedure:
The title compound was prepared from 5-fluoro-3-iodo-indazole and 2-(4-methylmorpholin-2-yl)ethanol in 80% yield according to the general procedure for Preparation 31A. The minor isomer was not isolated or characterized.