Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][S:2](=[O:19])([CH:7]([C:9]1[CH:10]=[N:11][C:12]([C:15]([F:18])([F:17])[F:16])=[CH:13][CH:14]=1)[CH3:8])=[N:3][C:4]([NH2:6])=[S:5].Br[CH:21]1[CH2:29][CH2:28][C:24]2=[N:25][O:26][N:27]=[C:23]2[C:22]1=O>CCO>[CH3:1][S:2](=[N:3][C:4]1[S:5][C:29]2[CH2:21][CH2:22][C:23]3[C:24]([C:28]=2[N:6]=1)=[N:25][O:26][N:27]=3)(=[O:19])[CH:7]([C:9]1[CH:10]=[N:11][C:12]([C:15]([F:17])([F:18])[F:16])=[CH:13][CH:14]=1)[CH3:8]
Reactant: O=C1c2nonc2CCC1Br
Reactant: CC(c1ccc(C(F)(F)F)nc1)S(C)(=O)=NC(N)=S
Solvent: CCO
Product: CC(c1ccc(C(F)(F)F)nc1)S(C)(=O)=Nc1nc2c(s1)CCc1nonc1-2
Temperature: 25 °C
Reaction time: 2 h

Procedure:
N-(methyl(oxo){1-[6-(trifluoromethyl)-3-pyridinyl]ethyl}-λ6-sulfanylidene)thiourea (J) (100 mg, 0.321 mmol) and 5-bromo-6,7-dihydrobenzo[c][1,2,5]oxadiazol-4(5H)-one (76.6 mg, 0.353 mmol, 1.1 eq) were suspended in EtOH (1.6 mL). The reaction was stirred at room temperature for 2 h, and then heated to reflux for 1 h. The hot solution was filtered via a 0.45 μm nylon syringe filter and the filtrate was stored at −20° C. over night. 7-[(methyl(oxo){1-[6-(trifluoromethyl)-3-pyridinyl]ethyl}-λ6-sulfanylidene)amino]-4,5-dihydro[1,3]thiazolo[4,5-e][2,1,3]benzoxadiazole (65) was obtained in form of slightly yellow crystals (70 mg, 0.163 mmol, 51%) as a 1:1 mixture of diastereomers (racemate) that were isolated by filtration, washed with a small amount of cold ethanol, and dried in the high vacuum. 1H-NMR (DMSO-d6, 400 MHz): δ=1.87 (d, J=6.9 Hz, 1.5H, CHCH3, diastereomer 1); 1.89 (d, J=6.9 Hz, 1.5H, CHCH3, diastereomer 2); 3.06-3.27 (m, 4H, CH2—CH2, diastereomers 1, 2); 3.42 (s, 1.5H, S—CH3, diastereomer 1); 3.43 (s, 1.5H, S—CH3, diastereomer 2); 5.34 (q, J=6.9 Hz, 1H, CHCH3, diastereomers 1, 2); 7.96 (d, J=7.7 Hz, 0.5H, pyr-C3-H, diastereomer 1), 7.98 (d, J=7.8 Hz, 0.5H, pyr-C3-H, diastereomer 2); 8.21-8.26 (m, 1H, pyr-C4-H, diastereomers 1, 2); 8.85 (d, 0.5H 4J=1.6 Hz, pyr-C6-H, diastereomer 1); 8.86 (d, 0.5H, 4J=1.6 Hz, pyr-C6-H, diastereomer 2). 13C-NMR (DMSO-d6, 100 MHz): δ=13.3, 13.6 (CHCH3, two diastereomers); 17.9 (double peak, CH2, two diastereomers); 20.4 (double peak, CH2, two diastereomers); 36.4, 36.5 (S—CH3, two diastereomers); 60.8, 60.9 (CHCH3, two diastereomers); 119.4, 119.5 (pyr-C, two diastereomers); 120.3 (q, 2J (C—F)=271.5 Hz, CF3, two diastereomers), 131.6, 131.9; (pyr-C, two diastereomers); 132.0, 132.1 (Ar, two diastereomers), 132.4, 132.5 (Ar, two diastereomers); 138.0, 138.1 (pyr-C, two diastereomers); 145.0 (double peak, Ar, two diastereomers); 145.0, 145.1 (Ar, two diastereomers); 149.9 (double peak, pyr-C, two diastereomers); 151.2 (double peak, Ar, two diastereomers); 166.3, 166.6 (thiazole, two diastereomers). UPLC-MS (ESI+): mass calc'd for C16H15F3N5O2S2 (M+H+): 430.1. Found 430.1, UPLC-MS (ESI−) mass calc'd for C16H13F3N5O2S2 (M−H+): 428.1. Found 428.1.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[CH:4][CH:5]=[C:6]2[C:11]=1[NH:10][C:9](=[O:12])[CH:8]=[CH:7]2.Br.[Br:14][CH2:15][CH2:16][NH:17][CH2:18][CH2:19]Br.C(=O)([O-])[O-].[Na+].[Na+]>CN(C=O)C>[BrH:14].[N:1]1([C:2]2[CH:3]=[CH:4][CH:5]=[C:6]3[C:11]=2[NH:10][C:9](=[O:12])[CH:8]=[CH:7]3)[CH2:19][CH2:18][NH:17][CH2:16][CH2:15]1
Reactant: BrCCNCCBr
Reactant: Nc1cccc2ccc(=O)[nH]c12
Agent: Br
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: O=c1ccc2cccc(N3CCNCC3)c2[nH]1
Reaction time: 10 h
Yield: 17 %

Procedure:
8-Aminocarbostyril (15.47 g, 96.6 mmols) and bis(β-bromoethyl)amine hydrobromide (33 g, 106 mmols) were suspended in DMF and the suspension was stirred at 70° to 80° C. for 10 hours. After adding 5.1 g of sodium carbonate the reaction mixture was stirred at the same temperature as above for 7 hours. After distilling off the solvent under reduced pressure, methanol was added to the residue to crystallize. The crude crystals thus obtained were recrystallized from methanol-ether to give 5.1 g of 8-(1-piperazinyl)carbostyril hydrobromide, m.p. above 300° C., colorless scales.
Reaction SMILES: [NH2:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([OH:8])=O)=[C:4]([Cl:11])[C:3]=1[F:12].[C:13]([NH:17][C:18](=[O:32])[C:19]1[CH:24]=[CH:23][CH:22]=[C:21]([CH2:25][N:26]2[CH2:31][CH2:30][NH:29][CH2:28][CH2:27]2)[CH:20]=1)([CH3:16])([CH3:15])[CH3:14].C(N(CC)CC)C.CCCP1(OP(CCC)(=O)OP(CCC)(=O)O1)=O>ClCCl.C(OCC)(=O)C>[NH2:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([N:29]2[CH2:28][CH2:27][N:26]([CH2:25][C:21]3[CH:20]=[C:19]([CH:24]=[CH:23][CH:22]=3)[C:18]([NH:17][C:13]([CH3:15])([CH3:16])[CH3:14])=[O:32])[CH2:31][CH2:30]2)=[O:8])=[C:4]([Cl:11])[C:3]=1[F:12]
Reactant: Nc1ccc(C(=O)O)c(Cl)c1F
Reactant: CC(C)(C)NC(=O)c1cccc(CN2CCNCC2)c1
Agent: CCCP1(=O)OP(=O)(CCC)OP(=O)(CCC)O1
Solvent: CCOC(C)=O
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CC(C)(C)NC(=O)c1cccc(CN2CCN(C(=O)c3ccc(N)c(F)c3Cl)CC2)c1
Reaction time: 2 h
Yield: 28.6 %

Procedure:
To 4-amino-2-chloro-3-fluorobenzoic acid (2.64 mmol, 500 mg) and N-tert-butyl-3-(piperazin-1-ylmethyl)benzamide (2.54 mmol, 700 mg) and triethylamine (10.76 mmol, 1.5 mL, 1089 mg) in dichloromethane (30 mL) was added 1-propanephosphonic acid cyclic anhydride (6.75 mmol, 4 mL, 4296 mg, 50% solution in ethyl acetate). After 2 hours stirring, ethyl acetate was added. The organic mixture was washed with saturated sodium hydrogen carbonate, water, and saturated sodium chloride. The organic mixture was dried sodium sulfate, filtered and concentrated under reduced pressure. The crude residue was purified by silica chromatography (eluting with 5% methanol in dichloromethane) to yield the title compound (325 mg). MS (ESI) m/z 447.1 [M+H]+
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([CH:12]=[CH:13][CH:14]=1)[C:5]([O:7][C:8]([CH3:11])([CH3:10])[CH3:9])=[O:6].[CH3:15][S:16]([O-:18])=[O:17].[Na+].N1CCC[C@H]1C(O)=O.[OH-].[Na+]>[Cu]I>[CH3:15][S:16]([C:2]1[CH:3]=[C:4]([CH:12]=[CH:13][CH:14]=1)[C:5]([O:7][C:8]([CH3:11])([CH3:10])[CH3:9])=[O:6])(=[O:18])=[O:17]
Reactant: CS(=O)[O-]
Reactant: CC(C)(C)OC(=O)c1cccc(Br)c1
Agent: [Cu]I
Agent: O=C(O)[C@@H]1CCCN1
Agent: [Na+]
Product: CC(C)(C)OC(=O)c1cccc(S(C)(=O)=O)c1
Temperature: 80 °C
Reaction time: 18 h
Yield: 72.4 %

Procedure:
The mixture of tert-butyl 3-bromobenzoate (7.0 g, 27.2 mmol), sodium methanesulfinate (4.45 g, 43.6 mmol), copper(I) iodide (0.52 g, 2.72 mmol), L-proline (0.63 g, 5.44 mmol) and sodium hydroxide (0.22 g, 5.44 mmol) was purged with nitrogen and DMSO was added. The mixture was heated to 80° C. After 18 h, the mixture was cooled to ambient temperature. Additional sodium methanesulfinate (2.78 g, 27.2 mmol), copper(I) iodide (0.52 g, 2.72 mmol), L-proline (0.63 g, 5.44 mmol) were added and the mixture was stirred at 80° C. for another 18 h. The mixture was cooled to ambient temperature and filtered with Celite. Lithium chloride (3.0 M in water) was added and the mixture was extracted with ethyl acetate (3×). The combined organic extracts were washed with LiCl (3.0 M in water), brine, dried over sodium sulfate, filtered and concentrated. Purification by silica gel chromatography (100% hexanes→75% hexanes/ethyl acetate) gave the title compound (5.05 g).
Reaction SMILES: [CH:1]([C:3]1[CH:18]=[CH:17][C:6]([O:7][C:8]2[N:9]=[CH:10][C:11]([C:14]([NH2:16])=[O:15])=[N:12][CH:13]=2)=[C:5]([CH3:19])[CH:4]=1)=O.[CH3:20][C:21]([CH3:26])([CH3:25])[CH2:22][CH2:23][NH2:24].[BH4-].[Na+]>CO>[CH3:20][C:21]([CH3:26])([CH3:25])[CH2:22][CH2:23][NH:24][CH2:1][C:3]1[CH:18]=[CH:17][C:6]([O:7][C:8]2[N:9]=[CH:10][C:11]([C:14]([NH2:16])=[O:15])=[N:12][CH:13]=2)=[C:5]([CH3:19])[CH:4]=1
Reactant: Cc1cc(C=O)ccc1Oc1cnc(C(N)=O)cn1
Reactant: CC(C)(C)CCN
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Product: Cc1cc(CNCCC(C)(C)C)ccc1Oc1cnc(C(N)=O)cn1
Reaction time: 8 h
Yield: 41.3 %

Procedure:
Place 5-(4-formyl-2-methylphenoxy)pyrazine-2-carboxamide (Example 404, Part D) (0.200 g, 0.777 mmol), 3,3-dimethylbutylamine (0.100 g, 0.777 mmol) and 3 Å molecular sieves in a vial. Add methanol (3.8 mL), cap and stir overnight. Add NaBH4 (in excess over two portions) and stir until the gasses stop evolving. Load the reaction mixture directly onto a 5 g ISCO® pre-load column. Dry the pre-loaded column in a vacuum oven at room temperature. Purify by eluting through a 10 g ISCO® column with (2.0 M NH3 in methanol), ethyl acetate and hexanes. After concentrating, take the product up in CH2Cl2 (25 mL) and wash with 1.0 N NaOH solution (2× 10 mL). Dry the organic layer over Na2SO4, filter and concentrate to give the title compound (0.110 g, 41.4%): MS ES+ 343.1 (M+H)+, base peak 242.0 (M-C6H14N)+; HPLC [YMC-Pack Pro C-18 (150×4.6 mm, S-5 microm), 0.1% TFA/acetonitrile in 0.1% TFA/water at 1.0 mL/min, 5-95% over 19 min], tR=9.7 min, 94.3% purity.
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]([CH:7]=[CH:8][C:9]=1[OH:10])[CH:5]=[O:6].C([O-])([O-])=O.[K+].[K+].[CH2:17]([O:19][C:20](=[O:23])[CH2:21]Br)[CH3:18].C(O)C>CC(C)=O>[CH:5]([C:4]1[CH:7]=[CH:8][C:9]([O:10][CH2:21][C:20]([O:19][CH2:17][CH3:18])=[O:23])=[C:2]([OH:1])[CH:3]=1)=[O:6]
Reactant: O=Cc1ccc(O)c(O)c1
Reactant: CCOC(=O)CBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Solvent: CCO
Product: CCOC(=O)COc1ccc(C=O)cc1O
Temperature: 25 °C
Reaction time: 20 h
Yield: 14.7 %

Procedure:
The compound was prepared according to general procedure E with 3,4 dihydroxybenzaldehyde (3.7 mmol) in dry acetone (20 ml), anhydrous K2CO3 (2.3 mmol), and ethylbromoacetate (3.4 mmol) at 0°. The mixture was stirred at room temperature for 20 h. Ethanol was added and evaporated by azeotropic distillation with ethylbromoacetate The crude product was purified by silica gel chromatography (eluent dichloromethane). 112 mg of purified compound were obtained (15% yield). 1H NMR (250 MHz, CDCl3): δ 1.31 (t, J=7.1 Hz, 3H), 4.28 (q, J=7.1 Hz, 2H), 4.78 (q, J=6.8 Hz, 1H) 6.95 (d, J=8.8 Hz, 1H), 7.46 (d, J=8.9 Hz, 1H), 7.55 (s, 1H), 9.86 (s, 1H) 13C NMR (63 MHz, CDCl3): δ 15.2, 63.5, 67.1, 113.9, 117.1, 125.3, 132.8, 148.6, 152.4, 170.8, 193.3
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4]([C:14]([OH:16])=O)[C:5]2[CH:10]=[N:9][N:8]([CH:11]([CH3:13])[CH3:12])[C:6]=2[N:7]=1.[NH2:17][CH2:18][C:19]1[C:20](=[O:27])[NH:21][C:22]([CH3:26])=[CH:23][C:24]=1[CH3:25].Cl.ON1C2N=CC=CC=2N=N1.CN1CCOCC1.C(Cl)CCl>CS(C)=O.O>[CH3:25][C:24]1[CH:23]=[C:22]([CH3:26])[NH:21][C:20](=[O:27])[C:19]=1[CH2:18][NH:17][C:14]([C:4]1[C:5]2[CH:10]=[N:9][N:8]([CH:11]([CH3:12])[CH3:13])[C:6]=2[N:7]=[C:2]([CH3:1])[CH:3]=1)=[O:16]
Reactant: Cc1cc(C)c(CN)c(=O)[nH]1
Reactant: Cc1cc(C(=O)O)c2cnn(C(C)C)c2n1
Agent: Cl
Agent: On1nnc2cccnc21
Solvent: ClCCCl
Solvent: CS(C)=O
Solvent: O
Product: Cc1cc(C(=O)NCc2c(C)cc(C)[nH]c2=O)c2cnn(C(C)C)c2n1
Temperature: 25 °C
Reaction time: 48 h
Yield: 68 %

Procedure:
In a 25 mL sealable tube under nitrogen were combined 6-methyl-1-(1-methylethyl)-1H-pyrazolo[3,4-b]pyridine-4-carboxylic acid (60 mg, 0.27 mmol) and 3-(aminomethyl)-4,6-dimethyl-2(1H)-pyridinone.HCl (62 mg, 0.33 mmol) in DMSO (3 mL). 1-hydroxy-7-azabenzotriazole (56 mg, 0.41 mmol) was added and the resulting mixture was degassed with nitrogen for 10 minutes. N-methylmorpholine (0.11 ml, 0.96 mmol) and EDC (79 mg, 0.41 mmol) were added, the vessel was sealed, and the light brown mixture was stirred at room temperature for 2 days. Next added 2 mL of water and the mixture was stirred for 10 min. Solids that precipitated were sonicated, and allowed to stand at room temperature for 10 min. The contents were filtered, washed with water, and dried to afford the title compound (68 mg, 68%) as a light pink solid. LCMS E-S (M+H)=354.3. 1H NMR (400 MHz, DMSO-d6) δ ppm 11.54 (s, 1 H), 8.69 (t, J=4.80 Hz, 1 H), 8.26 (s, 1 H), 7.46 (s, 1 H), 5.89 (s, 1 H), 5.20 (quin, J=6.69 Hz, 1 H), 4.36 (d, J=5.05 Hz, 2 H), 2.63 (s, 3 H), 2.21 (s, 3 H), 2.13 (s, 3 H), 1.48 (d, J=6.57 Hz, 6 H).
Reaction SMILES: [NH2:1][CH2:2][CH:3]([C:5]1[S:6][CH:7]=[CH:8][CH:9]=1)[OH:4].CC1(C)[NH:16][C:15](=[O:17])[C:14]2[CH:18]=[C:19]([O:22][CH2:23][CH2:24]Br)[CH:20]=[CH:21][C:13]=2[O:12]1>C(N(CC)CC)C>[C:15]([C:14]1[CH:18]=[C:19]([CH:20]=[CH:21][C:13]=1[OH:12])[O:22][CH2:23][CH2:24][NH:1][CH2:2][CH:3]([C:5]1[S:6][CH:7]=[CH:8][CH:9]=1)[OH:4])(=[O:17])[NH2:16]
Reactant: CC1(C)NC(=O)c2cc(OCCBr)ccc2O1
Reactant: NCC(O)c1cccs1
Solvent: CCN(CC)CC
Product: NC(=O)c1cc(OCCNCC(O)c2cccs2)ccc1O

Procedure:
A mixture of 2.7 g of α-(aminomethyl)-2-thiophenmethanol and 3.6 g of 2,3-dihydro-2,2-dimethyl-6-(2-bromoethoxy)-4H-1,3-benzoxazin-4-one is stirred together with 2 ml of triethylamine for 1 hour in a bath at 100°-110°. The reaction mixture is partitioned between 100 ml of ethyl acetate and 10 ml of 2N aqueous potassium bicarbonate solution and the organic phase is separated off, dried over magnesium sulfate and evaporated, yielding crude α-[N-[2-(3-carbamoyl-4-hydroxy-phenoxy)-ethyl]-amino-methyl]-2-thiophen-methanol in the form of a crystalline mass which after recrystallisation from a little isopropanol melts at 158°-161°; repeated recrystallisation raises the melting point to 171°-172°.
Reaction SMILES: C([Li])CCC.Br[C:7]1[CH:15]=[CH:14][C:10]([C:11]([OH:13])=[O:12])=[CH:9][C:8]=1[CH3:16].[CH:17]([S:20]SCCC)([CH3:19])[CH3:18].Cl>C1COCC1.[OH-].[Na+]>[CH:17]([S:20][C:7]1[CH:15]=[CH:14][C:10]([C:11]([OH:13])=[O:12])=[CH:9][C:8]=1[CH3:16])([CH3:19])[CH3:18]
Reactant: Cc1cc(C(=O)O)ccc1Br
Reactant: CCCSSC(C)C
Agent: Cl
Agent: [Li]CCCC
Agent: [Na+]
Solvent: C1CCOC1
Product: Cc1cc(C(=O)O)ccc1SC(C)C
Temperature: -78 °C
Reaction time: 0.5 h
Yield: 34.5 %

Procedure:
Butyllithium (16 mL of 1.6 M, 26 mmol) was added drop-wise to a mixture of 4-bromo-3-methyl-benzoic acid (2.5 g, 12 mmol) and THF (63 mL) at −78° C. The mixture was allowed to stir at −78° C. for 30 minutes before a solution of 2-isopropyldisulfanylpropane (1.7 g, 12 mmol) in THF (2 mL) was added drop-wise. The mixture was allowed to stir at −78° C. for 30 min, then 30 min at rt. The reaction mixture was then diluted with 100 mL of 1M aqueous sodium hydroxide. The organic layer was discarded and the aqueous layer was made acidic with 4M aqueous hydrochloric acid. The aqueous layer was then extracted 3 times with ethyl acetate. The combined extracts were dried over sodium sulfate and then evaporated to dryness. The crude material was purified by column chromatography using a gradient of 0-5% MeOH in dichloromethane to give 4-(isopropylthio)-3-methylbenzoic acid (870 mg, 18%). MS m/z calc. 210.3, found 211.2 (M+1)+. Retention time: 2.32 minutes (3 min run).
Reaction SMILES: CC1(C)CO[CH:5]([CH:8]([C@@H:10]2[C@:27]3([CH3:28])[C@H:13]([C@H:14]4[C@H:24]([CH2:25][CH2:26]3)[C@:22]3([CH3:23])[C:17]([CH2:18][C@@H:19]([OH:30])[C@@H:20]5[O:29][C@@H:21]53)=[CH:16][C@H:15]4[O:31][C:32]([O:34][CH3:35])=[O:33])[CH2:12][CH2:11]2)[CH3:9])[O:4]C1.CC1(C)COC(C([C@@H]2[C@]3(C)[C@H]([C@H]4[C@H](CC3)[C@]3(C)C(C[C@@H](O)[C@@H]5O[C@@H]53)=C[C@H]4O)CC2)C)OC1>>[O:29]1[C@H:20]2[C@H:19]([OH:30])[CH2:18][C:17]3[C@:22]([CH3:23])([C@@H:21]12)[C@@H:24]1[C@H:14]([C@H:13]2[C@:27]([CH3:28])([CH2:26][CH2:25]1)[C@@H:10]([CH:8]([CH:5]=[O:4])[CH3:9])[CH2:11][CH2:12]2)[C@H:15]([O:31][C:32]([O:34][CH3:35])=[O:33])[CH:16]=3
Reactant: COC(=O)O[C@@H]1C=C2C[C@@H](O)[C@@H]3O[C@@H]3[C@]2(C)[C@H]2CC[C@]3(C)[C@@H](C(C)C4OCC(C)(C)CO4)CC[C@H]3[C@H]12
Agent: CC(C1OCC(C)(C)CO1)[C@H]1CC[C@H]2[C@@H]3[C@H](O)C=C4C[C@@H](O)[C@@H]5O[C@@H]5[C@]4(C)[C@H]3CC[C@]12C
Product: COC(=O)O[C@@H]1C=C2C[C@@H](O)[C@@H]3O[C@@H]3[C@]2(C)[C@H]2CC[C@]3(C)[C@@H](C(C)C=O)CC[C@H]3[C@H]12
Yield: 62.1 %

Procedure:
The procedure of Example 36 was repeated except that 2.5 mg (0.005 mmole) of 20-(5,5-dimethyl-1,3-dioxan-2-yl)-1α,2α-epoxy-7α-methoxycarbonyloxypregn-5-en-3β-ol was used in lieu of 2.2 mg of 20-(5,5-dimethyl-1,3-dioxan-2-yl)-1α,2α-epoxypregn-5-ene-3β,7α-diol to give 1.3 mg of 1α,2α-epoxy-3β-hydroxy-7α-methoxycarbonyloxypregn-5-ene-20-carbaldehyde (yield: 62%).
Reaction SMILES: Cl.C1COCC1.[Si]([O:14][C@H:15]1[CH2:19][CH2:18][N:17]([CH2:20][CH2:21][O:22][C:23]2[CH:28]=[CH:27][C:26]([N:29]3[CH:34]=[CH:33][C:32]([O:35][CH2:36][C:37]4[CH:42]=[CH:41][C:40]([Cl:43])=[CH:39][N:38]=4)=[CH:31][C:30]3=[O:44])=[CH:25][CH:24]=2)[CH2:16]1)(C(C)(C)C)(C)C.[OH-].[Na+]>C(Cl)(Cl)Cl>[Cl:43][C:40]1[CH:41]=[CH:42][C:37]([CH2:36][O:35][C:32]2[CH:33]=[CH:34][N:29]([C:26]3[CH:25]=[CH:24][C:23]([O:22][CH2:21][CH2:20][N:17]4[CH2:18][CH2:19][C@H:15]([OH:14])[CH2:16]4)=[CH:28][CH:27]=3)[C:30](=[O:44])[CH:31]=2)=[N:38][CH:39]=1
Reactant: CC(C)(C)[Si](C)(C)O[C@H]1CCN(CCOc2ccc(-n3ccc(OCc4ccc(Cl)cn4)cc3=O)cc2)C1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: ClC(Cl)Cl
Product: O=c1cc(OCc2ccc(Cl)cn2)ccn1-c1ccc(OCCN2CC[C@H](O)C2)cc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 94.2 %

Procedure:
5N aqueous hydrochloric acid (2.4 mL, 12 mmols) was added to THF (2.4 mL) solution of 1-(4-{2-[(3S)-3-{[tert-butyl(dimethyl)silyl]oxy}-1-pyrrolidinyl]ethoxy]phenyl}-4-[(5-chloro-2-pyridinyl)methoxy]-1H-pyridin-2-one (264.7 mg, 0.48 mmol), and stirred at room temperature for 2 hours. The reaction liquid was neutralized with 1N aqueous sodium hydroxide, extend with chloroform, washed with saturated brine and dried over anhydrous magnesium sulfate. Concentrating the solvent under reduced pressure, the residue was recrystallized from mixed solvent of ethyl acetate and heptane, to provide the title compound (199.8 mg, 95%).
Reaction SMILES: [N:1]([CH2:4][CH3:5])=[C:2]=[O:3].[CH2:6]([C:8]1[C:16]2[C:11](=[CH:12][C:13]([C:17]3[N:21]([C:22]4[CH:27]=[CH:26][C:25]([S:28]([CH3:31])(=[O:30])=[O:29])=[CH:24][CH:23]=4)[N:20]=[CH:19][CH:18]=3)=[CH:14][CH:15]=2)[NH:10][N:9]=1)[CH3:7].O.C(OCC)(=O)C>N1C=CC=CC=1>[CH2:4]([NH:1][C:2]([N:10]1[C:11]2[C:16](=[CH:15][CH:14]=[C:13]([C:17]3[N:21]([C:22]4[CH:23]=[CH:24][C:25]([S:28]([CH3:31])(=[O:30])=[O:29])=[CH:26][CH:27]=4)[N:20]=[CH:19][CH:18]=3)[CH:12]=2)[C:8]([CH2:6][CH3:7])=[N:9]1)=[O:3])[CH3:5]
Reactant: CCc1n[nH]c2cc(-c3ccnn3-c3ccc(S(C)(=O)=O)cc3)ccc12
Reactant: CCN=C=O
Solvent: O
Solvent: CCOC(C)=O
Solvent: c1ccncc1
Product: CCNC(=O)n1nc(CC)c2ccc(-c3ccnn3-c3ccc(S(C)(=O)=O)cc3)cc21
Temperature: 100 °C
Reaction time: 0.25 h
Yield: 52.2 %

Procedure:
Isocyanatoethane (0.014 mL, 0.18 mmol) was added to a solution of 3-ethyl-6-{1-[4-(methylsulfonyl)phenyl]-1H-pyrazol-5-yl}-1H-indazole (50 mg, 0.14 mmol) in pyridine (2 mL) and the mixture was heated at 100° C. for 16 hours. Upon cooling, water and ethyl acetate were added and the product was washed once with 0.1 N HCl, once with water and once with brine. The combined organics were dried, the solvent was removed, and the reside was purified by column chromatography on silica gel, eluting with 20% ethyl acetate in hexanes for 5 minutes, a linear gradient to 50% ethyl acetate in hexanes over 15 minutes, and then 50% ethyl acetate for an additional 10 minutes, to afford 32 mg (54%) of N,3-diethyl-6-{1-[4-(methylsulfonyl)phenyl]-1H-pyrazol-5-yl}-1H-indazole-1-carboxamide. LC/MS (EI) tR 4.33 (Method C), m/z 438.2 (M++1), 1H NMR (CDCl3) δ 1.0 (t, 3H), 1.4 (t, 3H), 2.9 (t, 2H), 3.0 (s, 3H), 3.4 (m, 2H), 6.5 (s, 1H), 7.0 (d, 1H), 7.1 (s, 1H), 7.4 (d, 2H), 7.5 (m, 1H), 7.8 (s, 1H), 7.9 (d, 2H), 8.4 (s, 1H).
Reaction SMILES: [Cl:1][C:2]1[CH:12]=[CH:11][C:5]([O:6][CH:7]([CH3:10])[CH2:8][OH:9])=[CH:4][CH:3]=1.C(N(CC)CC)C.[CH3:20][S:21](Cl)(=[O:23])=[O:22]>ClCCl>[CH3:20][S:21]([O:9][CH2:8][CH:7]([O:6][C:5]1[CH:11]=[CH:12][C:2]([Cl:1])=[CH:3][CH:4]=1)[CH3:10])(=[O:23])=[O:22]
Reactant: CS(=O)(=O)Cl
Reactant: CC(CO)Oc1ccc(Cl)cc1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CC(COS(C)(=O)=O)Oc1ccc(Cl)cc1
Reaction time: 1 h

Procedure:
A solution of 51.5 g of 2-(p-chlorophenoxy)-1-propanol and 57.5 ml of triethylamine in 680 ml of dichloromethane is chilled to -10° C. To the solution is added dropwise with stirring 25.8 ml of methanesulfonyl chloride in 20 ml of dichloromethane. The mixture is stirred for 1 hour at -7° C. to -10° C. and washed with ice cold water, saturated NaCl, saturated NaHCO3 and dried (MgSO4). The solvent is removed under reduced pressure to give 73 g of product as an oil.
Reaction SMILES: [NH2:1][CH:2]1[N:8]=[C:7]([N:9]2[CH2:14][CH2:13][N:12]([CH3:15])[CH2:11][CH2:10]2)[C:6]2[CH:16]=[CH:17][CH:18]=[CH:19][C:5]=2[N:4]([CH2:20][CH2:21][CH3:22])[C:3]1=[O:23].C([NH:31][C@@H:32]([C:40](O)=[O:41])[CH2:33][C:34]1[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=1)(OC(C)(C)C)=O.ON1C2C=CC=CC=2N=N1.Cl.CN(C)CCCN=C=NCC.C(=O)([O-])O.[Na+].Cl.P(=O)(O)(O)O>CN(C)C=O.ClCCl.CO.N.O.C(N(CC)CC)C.C(#N)C.C(OCC)(=O)C>[NH2:31][CH:32]([CH2:33][C:34]1[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=1)[C:40]([NH:1][CH:2]1[N:8]=[C:7]([N:9]2[CH2:10][CH2:11][N:12]([CH3:15])[CH2:13][CH2:14]2)[C:6]2[CH:16]=[CH:17][CH:18]=[CH:19][C:5]=2[N:4]([CH2:20][CH2:21][CH3:22])[C:3]1=[O:23])=[O:41]
Reactant: CC(C)(C)OC(=O)N[C@H](Cc1ccccc1)C(=O)O
Reactant: CCCN1C(=O)C(N)N=C(N2CCN(C)CC2)c2ccccc21
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: N
Solvent: ClCCl
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: CCCN1C(=O)C(NC(=O)C(N)Cc2ccccc2)N=C(N2CCN(C)CC2)c2ccccc21
Temperature: 25 °C
Reaction time: 0.25 h

Procedure:
To a stirred solution of 3-amino-1,2-dihydro-5-(4-methylpiperazin-1-yl)-1-propyl-3H-1,4-benzodiazepin-2-one (2.96 g) in anhydrous dimethylformamide (30 ml) was added BOC-D-phenylalanine (2.61 g), 1-hydroxybenzotriazole (1.33 g), 1-(3-dimethylaminopropyl)-3-ethyl-carbodiimide hydrochloride (1.89 g) and triethylamine (1.37 ml). After stirring at room temperature for 15 minutes the solution was treated with saturated sodium hydrogen carbonate solution then extracted with ethyl acetate (4×100 ml). The combined organic phases were washed with saturated sodium chloride solution, dried (Na2SO4), evaporated to dryness and the residue purified by column chromatography on silica using 5% methanol/dichloromethane to 10% methanol/dichloromethane. The product obtained (5.28 g) was treated at 0° C. with ethyl acetate (100 ml) saturated with hydrogen chloride gas and stirred at 0° C. for 1 hour. The solution was basified to pH 9 with saturated sodium hydrogen carbonate solution, the organic layer was separated and the aqueous re-extracted with ethyl acetate (4×100 ml). The combined organic phases were dried (Na2SO4) and the more polar (by silica tlc) diastereomer crystallised from methanol/diethyl ether to afford a solid (460 mg. mp 152°-153° C.; Rf 0.50 in dichloromethane/methanol/ammonia (9:1:0.1) on silica plates. HPLC (Spherisorb ODS2 column, 25% acetonitrile/75% of 0.2% triethylamine in water, pH to 3 with orthophosphoric acid): Rt 5.09 minutes, 99.5% pure. δH (360 MHz, DMSO-d6) δ0.68 (3H, t, J=7 Hz), 1.20-1.29 (1H, m), 1.37-1.44 (1H, m), 2.19 (3H, s), 2.25-2.35 (2H, m), 2.40-2,48 (2H, m), 2.59 (1H, dd, J=9 and 13 Hz), 3.00 (1H, dd, J=4 and 13 Hz), 3.10-3.30 (4H, m), 3.47 (1H, dd, J=4 and 9 Hz), 3.60-3.68 (1H, m), 4.19-4.28 (1H, m), 4.97 (1H, d, J=8 Hz), 7.16-7.30 (5H, m), 7.36-7.42 (1H, m), 7.55 (1H, d, J=8 Hz), 7.63-7.66 (2H, m), 8.76 (1H, d, J=8 Hz). (Found: C, 67.62; H, 7.24; N, 18.17. C26H34N6O2 requires 67.51; H, 7.41; N, 18.17%).
Reaction SMILES: [NH2:1][C:2]1[N:7]=[C:6](S(C)=O)[C:5]([C:11]#[N:12])=[C:4]([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][N:14]=2)[N:3]=1.[OH:19][CH2:20][C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][N:22]=1.C1CCN2C(=NCCC2)CC1>COCCOC>[NH2:1][C:2]1[N:3]=[C:4]([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][N:14]=2)[C:5]([C:11]#[N:12])=[C:6]([O:19][CH2:20][C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][N:22]=2)[N:7]=1
Reactant: OCc1ccccn1
Reactant: CS(=O)c1nc(N)nc(-c2ccccn2)c1C#N
Solvent: C1CCC2=NCCCN2CC1
Solvent: COCCOC
Product: N#Cc1c(OCc2ccccn2)nc(N)nc1-c1ccccn1

Procedure:
From 2-amino-4-methanesulfinyl-6-pyridin-2-yl-pyrimidine-5-carbonitrile, 2-(hydroxymethyl)pyridine and DBU in DME. EI-MS m/e (%): 304 (M+, 100), 275 (33), 197 (50), 92 (30), 65 (34).