Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl-].[O:2]=[C:3]1[N:8]2[C:9]([C:12]([F:15])([F:14])[F:13])=[CH:10][S:11][C:7]2=[N:6][C:5]([CH2:16][P+](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=[CH:4]1.[H-].[Na+].CO[CH2:40][C:41]([CH3:53])([CH3:52])[CH2:42][O:43][C:44]1[CH:51]=[CH:50][CH:49]=[CH:48][C:45]=1[CH:46]=O.C1([CH2:57][O:58]C2C(OC)=CC=CC=2/C=C/C2N=C3SC=CN3C(=O)C=2I)CC1>CS(C)=O>[CH3:57][O:58][C:51]1[C:44]([O:43][CH2:42][C:41]([CH3:40])([CH3:52])[CH3:53])=[C:45](/[CH:46]=[CH:16]/[C:5]2[N:6]=[C:7]3[S:11][CH:10]=[C:9]([C:12]([F:13])([F:14])[F:15])[N:8]3[C:3](=[O:2])[CH:4]=2)[CH:48]=[CH:49][CH:50]=1
Reactant: COc1cccc(/C=C/c2nc3sccn3c(=O)c2I)c1OCC1CC1
Reactant: COCC(C)(C)COc1ccccc1C=O
Reactant: O=c1cc(C[P+](c2ccccc2)(c2ccccc2)c2ccccc2)nc2scc(C(F)(F)F)n12
Agent: [Cl-]
Agent: [H-]
Agent: [Na+]
Solvent: CS(C)=O
Product: COc1cccc(/C=C/c2cc(=O)n3c(C(F)(F)F)csc3n2)c1OCC(C)(C)C

Procedure:
A stirred suspension of Step 3 intermediate (1.0 g, 1.886 mmol) in dry DMSO (10 ml) was treated with NaH (83 mg, 2.075 mmol) and 3-methoxy-2,2-dimethylpropoxy-benzaldehyde (460 mg, 2.075 mmol) according to the procedure described in Step 3, Intermediate 2 to yield a crude solid which was purified by column chromatography using 10% ethyl acetate in petroleum ether to afford 300 mg of the desired compound: 1H NMR (300 MHz, DMSO-d6) δ 1.08 (s, 9H), 3.56 (s, 2H), 3.79 (s, 3H), 6.13 (s, 1H), 7.02-7.18 (m, 3H), 7.32-7.35 (m, 1H), 8.15 (d, J=15.6 Hz 1H), 8.25 (s, 1H); ESI-MS (m/z) 439.11 (M+H)+.
Reaction SMILES: C(N(CC)CC)C.[SH:8][CH2:9][C:10]([NH2:12])=[O:11].[CH2:13](Br)[C:14]([C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1)=O>C(O)C>[C:16]1([C:14]2[NH:12][C:10](=[O:11])[CH2:9][S:8][CH:13]=2)[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1
Reactant: O=C(CBr)c1ccccc1
Reactant: NC(=O)CS
Solvent: CCO
Solvent: CCN(CC)CC
Product: O=C1CSC=C(c2ccccc2)N1
Temperature: 25 °C
Reaction time: 4 h

Procedure:
Triethylamine (4.55 g) is added to a solution of 2-mercaptoacetamide (8.00 g, Reference compound No. 40-1) in ethanol (70 ml), then phenacyl bromide (17.5 g) is added to the mixture, and the whole is stirred for four hours. The reaction mixture is concentrated under reduced pressure, water and 0.1 N hydrochloric acid are added to the resulting residue, and the whole is extracted with ethyl acetate. The extract is washed with saturated brine and dried over anhydrous magnesium sulfate. The extract is concentrated under reduced pressure. The resulting residue is suspended in ethanol (200 ml), p-toluenesulfonic acid monohydrate (catalytic amount) is added to the suspension, and the mixture is refluxed for five days. The reaction mixture is cooled to room temperature to precipitate crystals. The crystals are filtered off and washed with ethanol to give the titled reference compound (11.6 g).
Reaction SMILES: [C:1](Cl)(Cl)=[O:2].[CH2:5]([C:8]1[S:12][C:11]([NH2:13])=[N:10][N:9]=1)[CH:6]=[CH2:7]>C(OCC)(=O)C>[CH2:5]([C:8]1[S:12][C:11]([N:13]=[C:1]=[O:2])=[N:10][N:9]=1)[CH:6]=[CH2:7]
Reactant: O=C(Cl)Cl
Reactant: C=CCc1nnc(N)s1
Solvent: CCOC(C)=O
Product: C=CCc1nnc(N=C=O)s1
Reaction time: 16 h

Procedure:
A saturated solution of phosgene in ethyl acetate (100 ml) is charged into a glass reaction vessel equipped with a mechanical stirrer. A slurry of 5-allyl-2-amino-1,3,4-thiadiazole (40 grams) in ethyl acetate (300 ml) is added to the reaction vessel and the resulting mixture is stirred for a period of about 16 hours, resulting in the formation of a precipitate. The reaction mixture is then purged with nitrogen gas to remove unreacted phosgene. The purged mixture is then filtered to recover the precipitate. The precipitate is then recrystallized to yield the desired product 5-allyl-1,3,4-thiadiazol-2-yl isocyanate dimer.
Reaction SMILES: [I:1]N1C(=O)CCC1=O.[Br:9][C:10]1[CH:11]=[C:12]2[CH:18]=[N:17][NH:16][C:13]2=[N:14][CH:15]=1>ClC(Cl)C.C1COCC1>[Br:9][C:10]1[CH:11]=[C:12]2[C:18]([I:1])=[N:17][NH:16][C:13]2=[N:14][CH:15]=1
Reactant: Brc1cnc2[nH]ncc2c1
Reactant: O=C1CCC(=O)N1I
Solvent: C1CCOC1
Solvent: CC(Cl)Cl
Product: Brc1cnc2[nH]nc(I)c2c1
Temperature: 25 °C
Yield: 74.8 %

Procedure:
N-Iodosuccinimide (8.1 g, 34.1 mmol) was added to a solution of 5-bromo-1H-pyrazolo[3,4-b]pyridine (4.5 g, 22.7 mmol) in dichloroethane (100 mL), and the reaction mixture was heated to reflux overnight. The reaction mixture was cooled to room temperature and diluted with THF (300 mL). The organic layers were washed with saturated Na2S2O3 (100 mL) and brine (100 mL). The organic layers were dried, filtered and concentrated to a solid. The crude product was triturated with DCM and ethyl acetate to give 5-bromo-3-iodo-1H-pyrazolo[3,4-b]pyridine (5.5 g, 75%) as a solid.
Reaction SMILES: [Br:1][C:2]1[C:3]([F:12])=[C:4]2[C:10]([NH2:11])=[CH:9][NH:8][C:5]2=[N:6][CH:7]=1.[CH3:13][N:14]1[CH:18]=[CH:17][C:16]([C:19](O)=[O:20])=[N:15]1.C1N(P(Cl)(N2C(=O)OCC2)=O)C(=O)OC1.[Li+].[OH-]>C(Cl)Cl.O>[Br:1][C:2]1[C:3]([F:12])=[C:4]2[C:10]([NH:11][C:19]([C:16]3[CH:17]=[CH:18][N:14]([CH3:13])[N:15]=3)=[O:20])=[CH:9][NH:8][C:5]2=[N:6][CH:7]=1
Reactant: Nc1c[nH]c2ncc(Br)c(F)c12
Reactant: Cn1ccc(C(=O)O)n1
Agent: O=C1OCCN1P(=O)(Cl)N1CCOC1=O
Agent: [Li+]
Agent: [OH-]
Solvent: ClCCl
Solvent: O
Product: Cn1ccc(C(=O)Nc2c[nH]c3ncc(Br)c(F)c23)n1
Temperature: 25 °C
Reaction time: 1 h
Yield: 5.1 %

Procedure:
TEA (1.21 mL, 8.69 mmol) was added to 5-bromo-4-fluoro-1H-pyrrolo[2,3-b]pyridin-3-amine (400 mg, 1.74 mmol, Example 1, Step H), 1-methyl-1H-pyrazole-3-carboxylic acid (260 mg, 2.09 mmol) and BOP—Cl (60 mg, 2.61 mmol) in DCM (5 mL). The reaction was stirred at room temperature for 1 hour, and then a LiOH solution (3 mL, 2N) was added. The mixture was stirred for 30 minutes, and water (10 mL) was added. The solid formed was collected by filtration, washed with DCM (5 mL) and dried to give N-(5-bromo-4-fluoro-1H-pyrrolo[2,3-b]pyridin-3-yl)-1-methyl-1H-pyrazole-3-carboxamide (30 mg, 66% yield) as a solid.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:9]=[CH:8][CH:7]=[CH:6][C:4]=1[NH2:5].[CH3:10][CH:11]([C:17]([CH3:19])=O)[C:12](OCC)=[O:13].C1(C)C=CC=CC=1>Cl.C1(C)C=CC=CC=1.O>[CH3:19][C:17]1[C:11]([CH3:10])=[C:12]([OH:13])[C:6]2[C:4](=[C:3]([O:2][CH3:1])[CH:9]=[CH:8][CH:7]=2)[N:5]=1
Reactant: CCOC(=O)C(C)C(C)=O
Reactant: COc1ccccc1N
Agent: Cl
Solvent: O
Solvent: Cc1ccccc1
Product: COc1cccc2c(O)c(C)c(C)nc12
Temperature: 200 °C
Reaction time: 8 h
Yield: 10.5 %

Procedure:
12.3 g of 2-methoxyaniline, 14.2 g of ethyl 2-methylacetoacetate and 3 drops of 1N HCl are introduced into a 250 ml three-necked flask fitted with Dean-Stark apparatus and a condenser. The mixture is stirred overnight. 100 ml of toluene are added and the mixture is refluxed until distillation of the toluene/water azeotrope is complete. The toluene is then evaporated off and 100 ml of diphenyl ether are added. The mixture is heated at 200° C. for 1 h. 50 ml of diphenyl ether are evaporated off and the mixture is cooled to room temperature. 20 ml of petroleum ether are added and the product which crystallizes is filtered off. 2.1 g (yield: 10%) of 2,3-dimethyl-4-hydroxy-8-methoxyquinoline are obtained—m.p.: >290° C.
Reaction SMILES: [CH2:1]=O.[OH-].[Na+].[NH2:5][CH2:6][C:7]([OH:9])=[O:8].[P:10]([O-:17])([O:14]CC)[O:11]CC.Cl>O>[P:10]([CH2:1][NH:5][CH2:6][C:7]([OH:9])=[O:8])([OH:17])([OH:14])=[O:11]
Reactant: C=O
Reactant: CCOP([O-])OCC
Reactant: NCC(=O)O
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: O=C(O)CNCP(=O)(O)O
Reaction time: 0.17 h
Yield: 65 %

Procedure:
8.6 g. of 37% formaline (= 0.1 moles of formaldehyde) are added to a stirred solution of 4.0 g. (0.1 moles) of sodium hydroxide and 7.5 g. (0.1 moles) of glycine in 40 ml. of water. After 10 minutes of stirring at 0° to 5° C, 13.8 g. (0.1 moles) of diethyl phosphite are added, and stirring is continued for 2 hours at 90° to 100° C. The mixture is acidified with 60 ml. of concentrated hydrochloric acid, and stirred further for 2 hours at 90° to 100° C. The obtained solution is evaporated to dryness under reduced pressure (80 to 100 mmHg.). The oily residue is treated with 200 ml. of warm 90% ethanol, the mixture is cooled, the product is filtered off, and dissolved in 30 to 35 ml. of hot water. The solution is decolorized, filtered, and the product is precipitated from the filtrate with 45 ml. of acetone. 11.0-11.4 g. (65-67.5%) of N-phosphonomethyl-glycine are obtained; m.p.: 224°-226° C (with decomposition).
Reaction SMILES: [CH:1]1[C:14]2[CH2:13][C:12]3[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=3)[O:6][C:5]=2[CH:4]=[CH:3][CH:2]=1.[OH:15]N1C(=O)C2=CC=CC=C2C1=O>C(#N)C1C=CC=CC=1>[O:15]=[C:13]1[C:12]2[CH:11]=[CH:10][CH:9]=[CH:8][C:7]=2[O:6][C:5]2[C:14]1=[CH:1][CH:2]=[CH:3][CH:4]=2
Reactant: O=C1c2ccccc2C(=O)N1O
Reactant: c1ccc2c(c1)Cc1ccccc1O2
Solvent: N#Cc1ccccc1
Product: O=c1c2ccccc2oc2ccccc12
Temperature: 100 °C
Reaction time: 20 h
Yield: 99 %

Procedure:
A mixture of 2 mmole of xanthene, 10 mole % of N-hydroxyphthalimide relative to xanthene, and 5 ml of benzonitrile was stirred for 20 hours at 100° C. under an oxygen atmosphere. The products in the reaction mixture were analyzed by gas chromatography, and, as a result, 9-oxoxanthene (yield not less than 99%) was formed.
Reaction SMILES: [OH:1][C:2]1[CH:17]=[C:16]([O:18][CH2:19][CH:20]([OH:35])[C:21]2[CH:30]=[CH:29][C:28]3[C:27]([CH3:32])([CH3:31])[CH2:26][CH2:25][C:24]([CH3:34])([CH3:33])[C:23]=3[CH:22]=2)[CH:15]=[CH:14][C:3]=1[C:4]([O:6][CH2:7][C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)=[O:5].C1C[O:39][CH2:38][CH2:37]1.N1C=CC=CC=1.C(Cl)(=O)C>O>[OH:1][C:2]1[CH:17]=[C:16]([O:18][CH2:19][CH:20]([C:21]2[CH:30]=[CH:29][C:28]3[C:27]([CH3:31])([CH3:32])[CH2:26][CH2:25][C:24]([CH3:34])([CH3:33])[C:23]=3[CH:22]=2)[O:35][C:38](=[O:39])[CH3:37])[CH:15]=[CH:14][C:3]=1[C:4]([O:6][CH2:7][C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)=[O:5]
Reactant: C1CCOC1
Reactant: CC1(C)CCC(C)(C)c2cc(C(O)COc3ccc(C(=O)OCc4ccccc4)c(O)c3)ccc21
Solvent: CC(=O)Cl
Solvent: O
Solvent: c1ccncc1
Product: CC(=O)OC(COc1ccc(C(=O)OCc2ccccc2)c(O)c1)c1ccc2c(c1)C(C)(C)CCC2(C)C
Temperature: 25 °C
Reaction time: 8 h

Procedure:
2.2 g (4.6 mmol) of benzyl 2-hydroxy-4-[2-hydroxy-2-(5,6,7,8-tetrahydro-5,5,8,8-tetramethyl-2-naphthyl)ethoxy]benzoate, 50 ml of THF and 380 μl (4.6 mmol) of pyridine are introduced into a flask. 330 μl (4.6 mmol) of acetyl chloride are added dropwise and the reaction mixture is stirred at room temperature for 8 hours. It is poured into water and extracted with ethyl ether, and the organic phase is separated, dried over magnesium sulphate and evaporated-The residue obtained is purified by chromatography on a silica column, eluted with a mixture of hexane and dichloromethane (90:10). After evaporation of the solvents, 1.8 g (77%) of the expected product are collected in the form of a yellow oil.
Reaction SMILES: [Cl:1][C:2]1[CH:17]=[CH:16][C:5]([CH:6]([OH:15])[C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][C:8]=2[CH2:13][OH:14])=[CH:4][CH:3]=1.[Se](=O)=O>C(O)(=O)C>[Cl:1][C:2]1[CH:17]=[CH:16][C:5]([C:6]([C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][C:8]=2[CH:13]=[O:14])=[O:15])=[CH:4][CH:3]=1
Reactant: OCc1ccccc1C(O)c1ccc(Cl)cc1
Agent: O=[Se]=O
Solvent: CC(=O)O
Product: O=Cc1ccccc1C(=O)c1ccc(Cl)cc1

Procedure:
A solution of 18.6 g. of 4'-chloro-2-hydroxymethylbenzhydrol in 100 ml. of acetic acid and 10.4 g. selenium dioxide was refluxed for 2 hours. The mixture was poured on ice and made alkaline and extracted with ether. Concentration of the ether solution and addition of petroleum ether gave pale yellow prisms which after recrystallization from a mixture of ether and petroleum ether gave 2-(p-chlorobenzoyl)-benzaldehyde melting at 112°-113°. Ultraviolet inflexion (2-propanol) at 225 μ (ε = 17,500) and maximum at 259 μ (ε = 22,500), infrared absorption (CHCL3) at 1670 cm-1 and 1705 cm-1.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]2[C:9](=[C:10]([O:12][Si:13]([CH:20]([CH3:22])[CH3:21])([CH:17]([CH3:19])[CH3:18])[CH:14]([CH3:16])[CH3:15])[CH:11]=1)[N:8]=[C:7]([CH:23]=O)[CH:6]=[CH:5]2.[NH:25]([C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][N:28]=1)[NH2:26]>CCO>[F:1][C:2]1[CH:3]=[C:4]2[C:9](=[C:10]([O:12][Si:13]([CH:20]([CH3:22])[CH3:21])([CH:17]([CH3:19])[CH3:18])[CH:14]([CH3:16])[CH3:15])[CH:11]=1)[N:8]=[C:7]([CH:23]=[N:26][NH:25][C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][N:28]=1)[CH:6]=[CH:5]2
Reactant: CC(C)[Si](Oc1cc(F)cc2ccc(C=O)nc12)(C(C)C)C(C)C
Reactant: NNc1ccccn1
Solvent: CCO
Product: CC(C)[Si](Oc1cc(F)cc2ccc(C=NNc3ccccn3)nc12)(C(C)C)C(C)C
Temperature: 25 °C
Yield: 73.8 %

Procedure:
6-Fluoro-8-(triisopropylsilyloxy)quinoline-2-carbaldehyde (15.0 g, 43.2 mmol) and 2-hydrazinylpyridine (4.71 g, 43.2 mmol) were combined in 100 mL of anhydrous EtOH, and stirred at ambient temperature over night. Following over night stirring, the desired product was collected by filtration (washing with cold EtOH), affording 6-fluoro-2-((2-(pyridin-2-yl)hydrazono)methyl)-8-(triisopropylsilyloxy)quinoline (14.0 g, 31.9 mmol, 74% yield) as a yellow-white powder.
Reaction SMILES: [F:1][C:2]1[CH:3]=[CH:4][C:5]2[N:9]=[CH:8][N:7]([CH2:10][C:11]([OH:13])=O)[C:6]=2[C:14]=1[F:15].[NH2:16][CH:17]([C:19]1[CH:24]=[CH:23][C:22]([C:25]2([C:31]#[N:32])[CH2:30][CH2:29][S:28][CH2:27][CH2:26]2)=[CH:21][C:20]=1[CH3:33])[CH3:18].CCN(CC)CC.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F>>[C:31]([C:25]1([C:22]2[CH:23]=[CH:24][C:19]([CH:17]([NH:16][C:11](=[O:13])[CH2:10][N:7]3[C:6]4[C:14]([F:15])=[C:2]([F:1])[CH:3]=[CH:4][C:5]=4[N:9]=[CH:8]3)[CH3:18])=[C:20]([CH3:33])[CH:21]=2)[CH2:26][CH2:27][S:28][CH2:29][CH2:30]1)#[N:32]
Reactant: O=C(O)Cn1cnc2ccc(F)c(F)c21
Reactant: Cc1cc(C2(C#N)CCSCC2)ccc1C(C)N
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(CC)CC
Product: Cc1cc(C2(C#N)CCSCC2)ccc1C(C)NC(=O)Cn1cnc2ccc(F)c(F)c21

Procedure:
The amide is synthesized according to example 1 by mixing (6,7-difluoro-1H-benzimidazol-1-yl)acetic acid (96 mg, 0.45 mmol) prepared according to scheme 2, 4-[4-(1-aminoethyl)-3-methylphenyl]tetrahydro-2H-thiopyran-4-carbonitrile (129 mg, 0.50 mmol) prepared according to scheme 14, Et3N (0.69 μL, 0.50 mmol) and HATU (189 mg, 0.50 mmol) in MECN (3.0 mL). The compound is purified by silica gel column chromatography (10% MeOH in DCM) (121 mg, 59%). 1H NMR (400 MHz, DMSO-D6) δ ppm 1.35 (d, J=7.03 Hz, 3H), 2.05-2.16 (m, 2H), 2.26-2.35 (m, 5H), 2.72-2.81 (m, J=14.06 Hz, 2H), 2.88-2.99 (m, J=12.50, 12.50 Hz, 2H), 5.01-5.11 (m, 3H), 7.16-7.26 (m, 1H), 7.30 (s, 1H), 7.33-7.38 (m, 1H), 7.39-7.48 (m, 2 H), 8.18 (s, 1H), 8.84 (d, J=7.42 Hz, 1H). MS [M+H], calcd: 455.5. found: 455.3.
Reaction SMILES: C([O-])(=O)C.[NH4+:5].C1(C)C(C)=CC=CC=1.[S:14]1[CH:18]=[CH:17][CH:16]=[C:15]1[CH:19]1[C:23](=O)[CH2:22][NH:21][C:20]1=[O:25]>O>[NH2:5][C:23]1[CH2:22][NH:21][C:20](=[O:25])[C:19]=1[C:15]1[S:14][CH:18]=[CH:17][CH:16]=1
Reactant: [NH4+]
Reactant: O=C1CNC(=O)C1c1cccs1
Agent: CC(=O)[O-]
Solvent: O
Solvent: Cc1ccccc1C
Product: NC1=C(c2cccs2)C(=O)NC1
Yield: 99 %

Procedure:
To a round bottom flask with a Dean-Stark distilling receiver, ammonium acetate (20.90 g, 271 mmol) and xylene (215 mL) were charged and kept at 60° C. Then 3-thiophen-2-yl-pyrrolidine-2,4-dione (19.0 g, 105 mmol) was added portionwise. The mixture was heated to reflux until there was no more water collected by the receiver (about 15 mL water) and a sticky gel was formed at the bottom. After cooling, toluene was decanted and the sticky gel was further washed by toluene and water and dried under vacuum at 80° C. Finally, a sticky gel was obtained (18.3 g, yield 99%), which can be used directly for the preparation of various compounds having one or more pyrrolo[3,2-b]pyrrole-2,5(1H,4H)-dione-3,6-diyl units. 1H NMR (d6-DMSO, 500 MHz), δ=7.23 (s, 1H), 7.22 (s, 1H), 7.10 (s, 1H), 7.00 (dd, J=5.0, 4.0 Hz, 1H), 6.77 (s, 2H), 3.82 (s, 2H).
Reaction SMILES: [H-].[Na+].[CH3:3][O:4][C:5]([C:7]1([OH:22])[CH2:11][CH2:10][N:9]([C:12]([O:14][CH2:15][C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)=[O:13])[CH2:8]1)=[O:6].[CH3:23]I.O>CN(C=O)C>[CH3:3][O:4][C:5]([C:7]1([O:22][CH3:23])[CH2:11][CH2:10][N:9]([C:12]([O:14][CH2:15][C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)=[O:13])[CH2:8]1)=[O:6]
Reactant: CI
Reactant: COC(=O)C1(O)CCN(C(=O)OCc2ccccc2)C1
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: COC(=O)C1(OC)CCN(C(=O)OCc2ccccc2)C1
Temperature: 17 °C
Reaction time: 1 h
Yield: 98.5 %

Procedure:
To a suspension of NaH (52 g, 1.3 mol) in 2.2 L of anhydrous DMF at 8° C., was added a solution of 3-Hydroxy-pyrrolidine-1,3-dicarboxylic acid 1-benzyl ester 3-methyl ester 3a (278 g, 1.0 mol) in 700 DMF, keeping the reaction temperature below 11° C. After complete addition (˜20 min), ice bath was removed, stirred at 16-18° C. for 1 h, and then at ambient temperature for 1 h. Cooled back to 15° C., added MeI (81 mL, 1.3 mol) slowly. Reaction mixture was stirred at ambient temperature for 1 overnight. The reaction mixture was then poured in a cold water (4 L) and then extracted with Et2O (6 L) and EtOAc (2 L), washed the organic later with water (5 L), brine (700 mL), dried over magnesium sulfate, filtered and evaporated to give crude 3-Methoxy-pyrrolidine-1,3-dicarboxylic acid 1-benzyl ester 3-methyl ester 4a 289 g (99% crude yield, contains mineral oil) (stirring/separation with pentane wash gave 4a, 268.2 g (92%).
Reaction SMILES: O=C1C2(C3C(=CC4OCCOC=4C=3)OC2)C2C(=CC=CC=2)N1C[C:24]1[C:29]([C:30]([OH:32])=O)=[CH:28][CH:27]=[CH:26][N:25]=1.Cl.CN.O[N:37]1C2C=CC=CC=2N=N1.CN1CCOCC1>O.CN(C)C=O>[N:25]1[CH:26]=[CH:27][CH:28]=[C:29]([C:30]([NH2:37])=[O:32])[CH:24]=1
Reactant: O=C(O)c1cccnc1CN1C(=O)C2(COc3cc4c(cc32)OCCO4)c2ccccc21
Reactant: On1nnc2ccccc21
Agent: CN
Agent: Cl
Solvent: CN1CCOCC1
Solvent: CN(C)C=O
Solvent: O
Product: NC(=O)c1cccnc1
Temperature: 25 °C
Reaction time: 20 h
Yield: 335.7 %

Procedure:
A 50 mL round-bottom flask was charged with 2-[(2′-oxo-2,3-dihydrospiro[furo[2,3-g][1,4]benzodioxine-8,3′-indol]-1′(2′H)-yl)methyl]pyridine-3-carboxylic acid (0.43 g, 1.0 mmol), methylamine hydrochloride (0.14 g, 2.0 mmol), 1-ethyl-3-(3-dimethyllaminopropyl)carbodiimide hydrochloride (0.26 g, 1.4 mmol), 1-hydroxybenzotriazole (0.20 g, 1.5 mmol), N-methylmorpholine (0.4 mL, 3.6 mmol) and N,N-dimethylformamide (7 mL). The reaction mixture was stirred under nitrogen at ambient temperature for 20 h, and poured into water (200 mL). The solid was collected by filtration, washed with water, dried and purified by column chromatography and eluted with a 0% to 50% gradient of ethyl acetate in dichloromethane to afford N-methyl-2-[2′-oxo-2,3-dihydrospiro[furo[2,3-g][1,4]benzodioxine-8,3′-indol]-1′(2′H)-yl)methyl]pyridine-3-carboxamide (0.41 g, 92%) as an off-white solid: 1H NMR (300 MHz, CDCl3) δ 8.43 (d, J=4.8 Hz, 1H), 7.85 (d, J=7.7 Hz, 1H), 7.36 (dd, J=7.5, 5.0 Hz, 1H), 7.20-7.07 (m, 2H), 6.95 (t, J=7.5, 1H), 6.81 (d, J=7.8 Hz, 1H), 6.46 (d, J=1.2 Hz, 1H), 6.43 (d, J=1.2 Hz, 1H), 5.16 (ABq, 2H), 4.70 (ABq, 2H), 4.20-4.05 (m, 4H), 2.77 (s, 3H); 13C NMR (75 MHz, CDCl3) δ 177.3, 167.6, 154.9, 152.7, 150.1, 144.5, 143.3, 138.1, 136.2, 132.5, 131.6, 129.0, 123.7, 123.1, 122.9, 122.2, 112.4, 109.6, 99.0, 79.7, 64.6, 64.1, 57.7, 43.3, 26.5; MS (ES+) m/z 443.9 (M+1).
Reaction SMILES: N[C:2]1[C:10]2[C:5](=[CH:6][C:7]([C:11]#[N:12])=[CH:8][CH:9]=2)[NH:4][N:3]=1.N([O-])=O.[Na+]>CC(O)=O>[NH:4]1[C:5]2[C:10](=[CH:9][CH:8]=[C:7]([C:11]#[N:12])[CH:6]=2)[CH:2]=[N:3]1
Reactant: N#Cc1ccc2c(N)n[nH]c2c1
Agent: O=N[O-]
Agent: [Na+]
Solvent: CC(=O)O
Product: N#Cc1ccc2cn[nH]c2c1
Temperature: 25 °C
Reaction time: 60 h
Yield: 56 %

Procedure:
To a suspension of 3-amino-1H-indazole-6-carbonitrile (345 mg) in AcOH was slowly added an aqueous NaNO2 solution (301 mg) at 0° C. It was stirred at room temperature for 2.5 days, and the residue was collected by filtration, and washed with cool water. To the residue were added 0.1M HCl and DME, followed by stirring at 80° C. for 2 hours. The reaction mixture was neutralized with a saturated aqueous NaHCO3 solution, and extracted with EtOAc. The organic layer was dried over anhydrous MgSO4, and concentrated. The residue was purified by silica gel column chromatography (n-hexane:EtOAc=80:20 to 50:50) to obtain 1H-indazole-6-carbonitrile (175 mg) as a yellow solid.
Reaction SMILES: [BH4-].[Na+].[Si:3]([O:10][C:11]1[CH:16]=[C:15]([O:17][Si:18]([C:21]([CH3:24])([CH3:23])[CH3:22])([CH3:20])[CH3:19])[CH:14]=[CH:13][C:12]=1[CH:25]1[CH2:30][CH2:29][C:28](=[O:31])[CH2:27][CH2:26]1)([C:6]([CH3:9])([CH3:8])[CH3:7])([CH3:5])[CH3:4]>C(O)C>[Si:3]([O:10][C:11]1[CH:16]=[C:15]([O:17][Si:18]([C:21]([CH3:22])([CH3:23])[CH3:24])([CH3:20])[CH3:19])[CH:14]=[CH:13][C:12]=1[C@@H:25]1[CH2:26][CH2:27][C@H:28]([OH:31])[CH2:29][CH2:30]1)([C:6]([CH3:7])([CH3:8])[CH3:9])([CH3:5])[CH3:4]
Reactant: CC(C)(C)[Si](C)(C)Oc1ccc(C2CCC(=O)CC2)c(O[Si](C)(C)C(C)(C)C)c1
Agent: [BH4-]
Agent: [Na+]
Solvent: CCO
Product: CC(C)(C)[Si](C)(C)Oc1ccc([C@H]2CC[C@@H](O)CC2)c(O[Si](C)(C)C(C)(C)C)c1
Reaction time: 18 h

Procedure:
Sodium borohydride (164 mg) was added to a stirred solution of 4-(2,4-bis{(tert-butyl(dimethyl)silyl]oxy}phenyl)cyclohexanone (1.57 g) in ethanol (50 ml) at 0° C. After 18 hr at room temperature, the mixture was partitioned between 2M HCl (20 ml), water (40 ml) and ethyl acetate (50 ml) and the aqueous layer was re-extracted with ethyl acetate (2×50 ml). The combined organic extracts were washed with brine (40 ml), dried over magnesium sulfate and evaporated in vacuo. The residue was purified using flash column chromatography (SiO2, ethyl acetate/petrol, 3:17 v/v) to give the trans-title compound as a white solid (546 mg, 35%), and the cis-title compound as a white solid (83 mg, 5%).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4](/[C:8](/[CH3:13])=[CH:9]/[C:10]([OH:12])=O)[CH:5]=[CH:6][CH:7]=1.C(N(CC)CC)C.C(Cl)(=O)OCC(C)C.[CH:29]1([NH2:32])[CH2:31][CH2:30]1>C1(C)C=CC=CC=1>[CH:29]1([NH:32][C:10](=[O:12])/[CH:9]=[C:8](/[C:4]2[CH:5]=[CH:6][CH:7]=[C:2]([F:1])[CH:3]=2)\[CH3:13])[CH2:31][CH2:30]1
Reactant: NC1CC1
Reactant: C/C(=C\C(=O)O)c1cccc(F)c1
Agent: CC(C)COC(=O)Cl
Solvent: CCN(CC)CC
Solvent: Cc1ccccc1
Product: C/C(=C\C(=O)NC1CC1)c1cccc(F)c1

Procedure:
To a solution of 18.0 g of (E)-3-(3-fluorophenyl)-2-butenoic acid in 200 ml of toluene was added 13.9 ml of triethylamine under cooling and a nitrogen atmosphere with stirring, followed by the addition of 13.0 ml of isobutyl chlorocarbonate, and then the solution was stirred at room temperature for 30 minutes. To the reaction solution cooled on ice was added dropwise 7.6 ml of cyclopropylamine with stirring, and the mixture was stirred at room temperature for 2 hours. Then, following a procedure similar to that of Example 6 to give 14.0 g of (E)-N-cyclopropyl-3-(3-fluorophenyl)-2-butenamide.
Reaction SMILES: ClC1C=CC=C(C(OO)=[O:9])C=1.[Cl:12][C:13]1[C:22]2[C:17](=[C:18]([CH3:25])[C:19]([O:23][CH3:24])=[CH:20][CH:21]=2)[N:16]=[CH:15][CH:14]=1>C(Cl)(Cl)Cl>[Cl:12][C:13]1[C:22]2[C:17](=[C:18]([CH3:25])[C:19]([O:23][CH3:24])=[CH:20][CH:21]=2)[N+:16]([O-:9])=[CH:15][CH:14]=1
Reactant: COc1ccc2c(Cl)ccnc2c1C
Reactant: O=C(OO)c1cccc(Cl)c1
Solvent: ClC(Cl)Cl
Product: COc1ccc2c(Cl)cc[n+]([O-])c2c1C
Yield: 18.3 %

Procedure:
Metachloroperbenzoic acid (90.2 g, 366.0 mmol) was added portion wise over 3 h to a solution of 4-chloro-7-methoxy-8-methylquinoline (13, 15.2 g, 73.2 mmol) in CHCl3 (1 L). Then, the solution was partitioned between ice-cooled NaOH 1N and CH2Cl2 (8 successive extractions). The organic layers were combined, dried (Na2SO4) and evaporated. The residue was purified by column chromatography (gradient of AcOEt/CH2Cl2, 1:2 to 1:0) to give 3.0 g (18.3%) of the title product 14 as a pale yellow powder: m/z=224 (M+H)+.