Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br[CH2:2][CH2:3][CH2:4][CH2:5][O:6][C:7]1[CH:8]=[CH:9][C:10]2[C:14]([C:15]3[CH:20]=[CH:19][C:18]([Br:21])=[CH:17][CH:16]=3)=[C:13]([CH3:22])[S:12][C:11]=2[CH:23]=1.[CH3:24][NH:25][CH3:26]>>[Br:21][C:18]1[CH:19]=[CH:20][C:15]([C:14]2[C:10]3[CH:9]=[CH:8][C:7]([O:6][CH2:5][CH2:4][CH2:3][CH2:2][N:25]([CH3:26])[CH3:24])=[CH:23][C:11]=3[S:12][C:13]=2[CH3:22])=[CH:16][CH:17]=1
Reactant: CNC
Reactant: Cc1sc2cc(OCCCCBr)ccc2c1-c1ccc(Br)cc1
Product: Cc1sc2cc(OCCCCN(C)C)ccc2c1-c1ccc(Br)cc1

Procedure:
According to the method in example 31, 6-(4-Bromo-butoxy)-3-(4-bromo-phenyl)-2-methyl-benzo[b]thiophene and dimethylamine were converted to yield {4-[3-(4-Bromo-phenyl)-2-methyl-benzo[b]thiophen-6-yloxy]-butyl}-dimethyl-amine as yellowish oil, MS: 418 (MH+,1Br).
Reaction SMILES: [NH:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[C:9]([CH2:10][N:11]([CH2:18][C:19]3[C:24]([CH3:25])=[CH:23][CH:22]=[CH:21][N:20]=3)[CH:12]3[CH2:17][CH2:16][NH:15][CH2:14][CH2:13]3)[C:4]=2[N:3]=[CH:2]1.[O:26]([C:33]([NH:35][OH:36])=O)C1C=CC=CC=1>C1COCC1>[OH:36][NH:35][C:33]([N:15]1[CH2:14][CH2:13][CH:12]([N:11]([CH2:10][C:9]2[C:4]3[N:3]=[CH:2][NH:1][C:5]=3[CH:6]=[CH:7][CH:8]=2)[CH2:18][C:19]2[C:24]([CH3:25])=[CH:23][CH:22]=[CH:21][N:20]=2)[CH2:17][CH2:16]1)=[O:26]
Reactant: O=C(NO)Oc1ccccc1
Reactant: Cc1cccnc1CN(Cc1cccc2[nH]cnc12)C1CCNCC1
Solvent: C1CCOC1
Product: Cc1cccnc1CN(Cc1cccc2[nH]cnc12)C1CCN(C(=O)NO)CC1
Temperature: 25 °C
Reaction time: 66 h
Yield: 55 %

Procedure:
To a THF solution (3 mL) of the amine from above (100 mg, 0.300 mmol) was added N-(Phenoxycarbonyl)hydroxylamine (54.8 mg, 0.360 mmol), and the resultant solution was heated to 80° C. for 7 h and stirred at room temperature for 66 h. The solution was concentrated to dryness and the crude material was purified by flash chromatography on silica gel (CH2Cl2/MeOH/NH4OH, 80:10:10) to afford COMPOUND 288 (49 mg, 55%) as a white solid.
Reaction SMILES: [OH:1][C@@H:2]1[C@@H:21]([Br:22])[CH2:20][C@@:19]2([CH3:23])[C@@H:4]([CH2:5][CH2:6][C@@H:7]3[C@@H:18]2[CH2:17][CH2:16][C@@:15]2([CH3:24])[C@H:8]3[CH2:9][CH2:10][C@@H:11]2[C:12](=[O:14])[CH3:13])[CH2:3]1.[C:25](OC(=O)C)(=[O:27])[CH3:26].O>N1C=CC=CC=1>[C:25]([O:1][C@@H:2]1[C@@H:21]([Br:22])[CH2:20][C@@:19]2([CH3:23])[C@@H:4]([CH2:5][CH2:6][C@@H:7]3[C@@H:18]2[CH2:17][CH2:16][C@@:15]2([CH3:24])[C@H:8]3[CH2:9][CH2:10][C@@H:11]2[C:12](=[O:14])[CH3:13])[CH2:3]1)(=[O:27])[CH3:26]
Reactant: CC(=O)[C@H]1CC[C@H]2[C@@H]3CC[C@H]4C[C@H](O)[C@@H](Br)C[C@]4(C)[C@H]3CC[C@]12C
Reactant: CC(=O)OC(C)=O
Solvent: O
Solvent: c1ccncc1
Product: CC(=O)O[C@H]1C[C@@H]2CC[C@@H]3[C@H](CC[C@]4(C)[C@@H](C(C)=O)CC[C@@H]34)[C@@]2(C)C[C@@H]1Br
Reaction time: 8 h

Procedure:
A solution of 3α-hydroxy-2β-bromo-5α-pregnan-20-one (8.5 g.) in pyridine (25 ml.) was treated with acetic anhydride (12.5 ml.), and the mixture was allowed to stand at room temperature overnight. The reaction mixture was poured into water and the product was extracted with methylene chloride. The extract was washed with water, dried (Na2SO4) and evaporated. A portion (582 mg.) of the residue (8.5 g.) was purified by preparative thin layer chromatography and crystallisation from iso-propyl ether to give the title compound (70 mg.), m.p. 142°-146°, [α]D + 120.9°.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([Br:8])=[CH:4][CH:3]=1.C([Li])CCC.CCCCCC.[CH:20](=[O:29])[C:21]1[CH:26]=[CH:25][CH:24]=[C:23]([O:27][CH3:28])[CH:22]=1>O1CCCC1>[Br:8][C:5]1[CH:6]=[CH:7][C:2]([CH:20]([C:21]2[CH:26]=[CH:25][CH:24]=[C:23]([O:27][CH3:28])[CH:22]=2)[OH:29])=[CH:3][CH:4]=1
Reactant: COc1cccc(C=O)c1
Reactant: Brc1ccc(Br)cc1
Agent: [Li]CCCC
Solvent: CCCCCC
Solvent: C1CCOC1
Product: COc1cccc(C(O)c2ccc(Br)cc2)c1
Temperature: -78 °C
Yield: 96.6 %

Procedure:
p-Dibromobenzene (7.08 g, 30.0 mmole) was added to 50 ml of anhydrous tetrahydrofuran under nitrogen and the slurry was cooled to -78° C. A solution of n-butyllithium in hexane (1.67M, 18.0 ml, 30 mmole) was added dropwise over 15 minutes. After stirring for ten minutes at -78° C., 3.8 ml (4.1 g, 30 mmole) of m-anisaldehyde was added dropwise over five minutes. After stirring for 15 minutes, the reaction was quenched with 10 ml of saturated aqueous ammonium chloride solution and was allowed to warm to room temperature. The reaction solution was diluted with 300 ml of diethyl ether and washed with three 50 ml portions of 1.0M aqueous sodium bisulfite, followed by 50 ml of 1.0 M sodium hydroxide, 100 ml of water, and 100 ml of saturated sodium chloride. After drying over magnesium sulfate, the solvent was removed to give 8.5 g (97%) of crude (4-bromophenyl)(3-methoxyphenyl)-methanol.
Reaction SMILES: C([C@@:3]1([C:22]([OH:24])=[O:23])[CH2:8][CH2:7][CH2:6][CH2:5][C@H:4]1[O:9][CH2:10][CH2:11][C:12]1[CH:17]=[CH:16][C:15]([O:18][CH3:19])=[C:14]([O:20][CH3:21])[CH:13]=1)C.[OH-].[Na+]>CCO>[CH3:21][O:20][C:14]1[CH:13]=[C:12]([CH:17]=[CH:16][C:15]=1[O:18][CH3:19])[CH2:11][CH2:10][O:9][C@@H:4]1[CH2:5][CH2:6][CH2:7][CH2:8][C@H:3]1[C:22]([OH:24])=[O:23]
Reactant: CC[C@@]1(C(=O)O)CCCC[C@H]1OCCc1ccc(OC)c(OC)c1
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: COc1ccc(CCO[C@@H]2CCCC[C@H]2C(=O)O)cc1OC
Yield: 74.3 %

Procedure:
A solution of crude (1R,2R)-2-(3,4-dimethoxyphenethoxy)cyclohexane-1-carboxylic acid (167) (3.71 g, 10 mmol) and 4M NaOH aq (10 mL, 40 mmol) in EtOH (25 mL) was stirred at room temperature for 18 hrs. The reaction mixture was then concentrated in vacuo, the residue was re-dissolved in water (25 mL) and the resultant basic aqueous solution was extracted with diethyl ether (2×25 mL). The aqueous layer was collected, acidified to pH1 with 6M HCl aq and extracted with dichloromethane (2×25 mL). The combined organic extracts were dried over anhydrous MgSO4 and concentrated in vacuo to give 2.29 g of (1R,2R)-2-(3,4-dimethoxyphenethoxy)cyclohexane-1-carboxylic acid (168) (74% yield; Rt: 13.48 min (HPLC—method A); 1H-NMR (300 MHz, CDCl3) δ: 7.95 (br s, 1H, CO2H), 6.78-6.69 (m, 3H, Ar), 3.84 (s, 3H, CH3O), 3.82 (s, 3H, CH3O), 3.81 (overlapped dt, J 14 Hz & 7 Hz, 1H, CH2aO), 3.57 (dt, J 14 Hz & 7 Hz, 1H, CH2bO), 3.52-3.42 (m, 1H, CHO), 2.79 (t, J 7 Hz, 2H, CH2), 2.34 (dt, J 14 Hz & 6 Hz, 1H, CHN), 2.13-1.09 (m, 8H, Aliph); MS (ES+) 307.1 [M+H]+.
Reaction SMILES: [O:1]=[C:2]([NH:10][CH2:11][CH2:12][C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1)[CH2:3][CH2:4][CH2:5][CH2:6][C:7](O)=[O:8].Cl.[NH2:20][CH2:21][CH2:22][C:23]1[CH:24]=[CH:25][C:26]([O:34][CH3:35])=[C:27]([NH:29][S:30]([CH3:33])(=[O:32])=[O:31])[CH:28]=1.C(N(CC)CC)C>ClCCl>[CH3:33][S:30]([NH:29][C:27]1[CH:28]=[C:23]([CH2:22][CH2:21][NH:20][C:7](=[O:8])[CH2:6][CH2:5][CH2:4][CH2:3][C:2]([NH:10][CH2:11][CH2:12][C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)=[O:1])[CH:24]=[CH:25][C:26]=1[O:34][CH3:35])(=[O:32])=[O:31]
Reactant: O=C(O)CCCCC(=O)NCCc1ccccc1
Reactant: COc1ccc(CCN)cc1NS(C)(=O)=O
Agent: Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: COc1ccc(CCNC(=O)CCCCC(=O)NCCc2ccccc2)cc1NS(C)(=O)=O
Reaction time: 0.5 h

Procedure:
N,N'-carbonyldiimidazole (3.25 g, 0.02 moles) was added in portions under nitrogen to a suspension of 6-oxo-6-(2-phenylethylamino)hexanoic acid (4.98 g, 0.02 moles) in dry dichloromethane (100 ml). The mixture was stirred for 30 mins, the product from step (b) (5.6 g, 0.02 moles) and triethylamine (2.8 ml, 2.02 g, 0.02 moles) were added, and stirring continued for a further 4 hr. The precipitate was collected and the filtrate washed with dilute hydrochloric acid and aqueous sodium bicarbonate solution and evaporated. The residue and the original precipitate were combined and recrystallised from methanol giving the sub-title compound (6.6 g) as white needles mp 193°-195°.
Reaction SMILES: [C:1]([C:3]1[CH:23]=[CH:22][C:6]([O:7][CH2:8][CH:9]2[CH2:14][CH2:13][N:12]([C:15]([O:17][C:18]([CH3:21])([CH3:20])[CH3:19])=[O:16])[CH2:11][CH2:10]2)=[CH:5][CH:4]=1)#[N:2].Cl.[NH2:25][OH:26].C(N(CC)CC)C>C(O)C>[OH:26][N:25]=[C:1]([C:3]1[CH:4]=[CH:5][C:6]([O:7][CH2:8][CH:9]2[CH2:10][CH2:11][N:12]([C:15]([O:17][C:18]([CH3:19])([CH3:20])[CH3:21])=[O:16])[CH2:13][CH2:14]2)=[CH:22][CH:23]=1)[NH2:2]
Reactant: CC(C)(C)OC(=O)N1CCC(COc2ccc(C#N)cc2)CC1
Reactant: NO
Agent: Cl
Solvent: CCO
Solvent: CCN(CC)CC
Product: CC(C)(C)OC(=O)N1CCC(COc2ccc(C(N)=NO)cc2)CC1
Temperature: 25 °C
Yield: 78.7 %

Procedure:
A solution of tert-butyl 4-[(4-cyanophenoxy)methyl]piperidine-1-carboxylate (Step 1, 1.47 g, 4.22 mmol, purity 91%), hydroxylamine hydrochloride (646 mg, 9.30 mmol) and triethylamine (1.30 mL, 9.30 mmol) in ethanol (24 mL) was stirred and heated at reflux for 1 h. After being cooled to rt, the reaction mixture was evaporated to dryness. The resulting material was treated with ethyl acetate, and the solid was filtered off. The ethyl acetate solution was washed with water and saturated sodium chloride solution, dried with anhydrous magnesium sulfate and filtered. After evaporation of the solvent, the crude product was stirred in tert-butyl methyl ether. The solid was filtered off and dried in vacuo to give the title compound (1.16 g, 78%): 1H NMR (400 MHz, CDCl3) δ 7.53 (d, 2H), 6.89 (d, 2H), 4.82 (s, 2H), 4.22-4.08 (broad m, 2H), 3.81 (d, 2H), 2.81-2.66 (m, 2H), 2.02-1.90 (m, 1H), 1.85-1.78 (d, 2H), 1.46 (s, 9H), 1.35-1.18 (m, 2H); ES-MS m/z 350, HPLC RT (Method D) 1.56 min.
Reaction SMILES: O=[C:2]([C:8]1[C:9]([C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)=[N:10][N:11]2[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=12)[CH2:3][CH2:4][C:5](O)=[O:6].O.[NH2:24][NH2:25]>C(O)C>[O:6]=[C:5]1[CH2:4][CH2:3][C:2]([C:8]2[C:9]([C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=3)=[N:10][N:11]3[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=23)=[N:25][NH:24]1
Reactant: O=C(O)CCC(=O)c1c(-c2ccccc2)nn2ccccc12
Reactant: NN
Solvent: CCO
Solvent: O
Product: O=C1CCC(c2c(-c3ccccc3)nn3ccccc23)=NN1
Yield: 70.5 %

Procedure:
A mixture of 4-oxo-4-(2-phenylpyrazolo[1,5-a]pyridin-3-yl)butyric acid (1.71 g), hydrazine monohydrate (1.46 g) and ethanol (17 ml) was heated under reflux for 1 hour. Ethanol was evaporated in vacuo. Water (20 ml) was added to the residue, acidified with 5% hydrochloric acid and extracted with chloroform (25 ml×3). The combined extract was washed with a saturated aqueous solution of sodium chloride, dried over magnesium sulfate and evaporated in vacuo. The residue was recrystallized from ethanol to give crystals of 3-(3-oxo-2,3,4,5-tetrahydropyridazin-6-yl)-2-phenylpyrazolo[1,5-a]pyridine (1.19 g).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8](=[O:35])[C:9]1[CH:14]=[C:13]([Cl:15])[CH:12]=[CH:11][C:10]=1[N:16]([S:22]([C:25]1[CH:30]=[CH:29][C:28]([O:31][CH3:32])=[C:27]([O:33][CH3:34])[CH:26]=1)(=[O:24])=[O:23])[CH2:17][C:18]([O:20][CH3:21])=[O:19].C1CCN2C(=NCCC2)CC1>C(Cl)Cl>[Cl:15][C:13]1[CH:14]=[C:9]2[C:10](=[CH:11][CH:12]=1)[N:16]([S:22]([C:25]1[CH:30]=[CH:29][C:28]([O:31][CH3:32])=[C:27]([O:33][CH3:34])[CH:26]=1)(=[O:23])=[O:24])[CH:17]([C:18]([O:20][CH3:21])=[O:19])[C:8]2([C:3]1[CH:4]=[CH:5][CH:6]=[CH:7][C:2]=1[Cl:1])[OH:35]
Reactant: COC(=O)CN(c1ccc(Cl)cc1C(=O)c1ccccc1Cl)S(=O)(=O)c1ccc(OC)c(OC)c1
Solvent: ClCCl
Solvent: C1CCC2=NCCCN2CC1
Product: COC(=O)C1N(S(=O)(=O)c2ccc(OC)c(OC)c2)c2ccc(Cl)cc2C1(O)c1ccccc1Cl
Reaction time: 8 h

Procedure:
1.3 g of the compound obtained in step B are dissolved at 0° C. in 13 ml of DCM in the presence of 180 mg of DBU. After stirring overnight, the reaction medium is poured directly on to a silica column prepared in DCM and the mixture of compounds resulting from cyclization is thus separated by elution with DCM. Chromatography is then carried out on alumina using a DCM/isopropyl ether mixture (70/30, v/v) as the eluent. The cis isomer is thus isolated.
Reaction SMILES: CC(C)=[O:3].OS(O)(=O)=O.O=[Cr](=O)=O.[CH3:14][C:15]1[C:20](=[O:21])[C:19]([CH3:22])=[C:18]([CH3:23])[C:17](=[O:24])[C:16]=1[CH:25]([C:33]1[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=1)[CH2:26][CH2:27][CH2:28][C:29]#[C:30][CH2:31][OH:32]>CC(C)=O>[CH3:14][C:15]1[C:20](=[O:21])[C:19]([CH3:22])=[C:18]([CH3:23])[C:17](=[O:24])[C:16]=1[CH:25]([C:33]1[CH:34]=[CH:35][CH:36]=[CH:37][CH:38]=1)[CH2:26][CH2:27][CH2:28][C:29]#[C:30][C:31]([OH:3])=[O:32]
Reactant: CC(C)=O
Reactant: CC1=C(C)C(=O)C(C(CCCC#CCO)c2ccccc2)=C(C)C1=O
Agent: O=[Cr](=O)=O
Agent: O=S(=O)(O)O
Product: CC1=C(C)C(=O)C(C(CCCC#CC(=O)O)c2ccccc2)=C(C)C1=O
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 68 %

Procedure:
Jones' reagent (2.25 ml) was added dropwise to a solution of 7-(3,5,6-trimethyl-1,4-benzoquinon-2-yl)-7-phenyl-2-heptyne-1-ol (1.01 g, 3.0 mmole) in acetone (15 ml) at room temperature over the 15-minutes period. The mixture was stirred at room temperature for another 30 minutes and the acetone was distilled off under reduced pressure. Isopropyl ether and water were added to the residue, and extraction was effected. The isopropyl ether layer was separated out, washed with aqueous sodium chloride solution, dried (magnesium sulfate) and evaporated. The residue was recrystallized from isopropyl ether to give 7-(3,5,6-trimethyl-1,4-benzoquinon-2-yl)-7-phenyl-2-heptynoic acid (0.71 g, 68%).
Reaction SMILES: [C:1]([C:3]1[CH:27]=[CH:26][C:6]([C:7]([NH:9][C:10](=[O:25])[NH:11][C:12]2[CH:24]=[CH:23][C:15]([O:16][CH2:17][C:18]([O:20][CH2:21][CH3:22])=[O:19])=[CH:14][CH:13]=2)=[O:8])=[CH:5][CH:4]=1)#[N:2].N1C=CC=CC=1.[SH2:34]>C(N(CC)CC)C>[C:1]([C:3]1[CH:4]=[CH:5][C:6]([C:7]([NH:9][C:10](=[O:25])[NH:11][C:12]2[CH:24]=[CH:23][C:15]([O:16][CH2:17][C:18]([O:20][CH2:21][CH3:22])=[O:19])=[CH:14][CH:13]=2)=[O:8])=[CH:26][CH:27]=1)(=[S:34])[NH2:2]
Reactant: S
Reactant: CCOC(=O)COc1ccc(NC(=O)NC(=O)c2ccc(C#N)cc2)cc1
Solvent: CCN(CC)CC
Solvent: c1ccncc1
Product: CCOC(=O)COc1ccc(NC(=O)NC(=O)c2ccc(C(N)=S)cc2)cc1

Procedure:
In a similar manner to Example, starting material step 1 (b), the product of step (a) (10.12 g), pyridine (500 ml), triethylamine (80 ml) and H2S gas were reacted to give ethyl 4-[3-(4-thiocarbamoylbenzoyl)ureido]phenoxyacetate (11 g) as a yellow solid: NMR Spectrum (DMSO-d6) 1.21 (3H, t), 4.18 (2H, q), 4.74 (2H, s), 6.93 (2H, d), 7.49 (2H, d), 7.95 (2H, d), 8.03 (2H, d), 9.64 (1H, br s), 10.03 (1H, br s), 10.60 (1H, s), 11.04 (1H, s); Mass Spectrum m/Z 402 (M+H)+.
Reaction SMILES: [NH2:1][C:2]1[C:7]([O:8][CH2:9][C:10]2[CH:17]=[CH:16][CH:15]=[CH:14][C:11]=2[C:12]#[N:13])=[CH:6][C:5](Br)=[CH:4][N:3]=1.CC1(C)C(C)(C)OB([C:27]2[CH:32]=[CH:31][C:30]([NH:33][S:34]([CH3:37])(=[O:36])=[O:35])=[CH:29][CH:28]=2)O1>>[NH2:1][C:2]1[N:3]=[CH:4][C:5]([C:27]2[CH:28]=[CH:29][C:30]([NH:33][S:34]([CH3:37])(=[O:35])=[O:36])=[CH:31][CH:32]=2)=[CH:6][C:7]=1[O:8][CH2:9][C:10]1[CH:17]=[CH:16][CH:15]=[CH:14][C:11]=1[C:12]#[N:13]
Reactant: N#Cc1ccccc1COc1cc(Br)cnc1N
Reactant: CC1(C)OB(c2ccc(NS(C)(=O)=O)cc2)OC1(C)C
Product: CS(=O)(=O)Nc1ccc(-c2cnc(N)c(OCc3ccccc3C#N)c2)cc1

Procedure:
N-{4-[6-Amino-5-(2-cyano-benzyloxy)-pyridin-3-yl]-phenyl}-methanesulfonamide was prepared following procedure 3 from 2-(2-Amino-5-bromo-pyridin-3-yloxymethyl)-benzonitrile and N-[4-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-phenyl]-methanesulfonamide.
Reaction SMILES: Cl[CH2:2][CH2:3][NH:4][C:5]([C:7]1[NH:8][C:9]2[C:14]([CH:15]=1)=[CH:13][CH:12]=[CH:11][C:10]=2[N+:16]([O-:18])=[O:17])=O.COC1C=CC(P2(SP(C3C=CC(OC)=CC=3)(=S)S2)=[S:28])=CC=1>ClC(Cl)C.C1(C)C=CC=CC=1>[S:28]1[CH2:2][CH2:3][N:4]=[C:5]1[C:7]1[NH:8][C:9]2[C:14]([CH:15]=1)=[CH:13][CH:12]=[CH:11][C:10]=2[N+:16]([O-:18])=[O:17]
Reactant: COc1ccc(P2(=S)SP(=S)(c3ccc(OC)cc3)S2)cc1
Reactant: O=C(NCCCl)c1cc2cccc([N+](=O)[O-])c2[nH]1
Solvent: CC(Cl)Cl
Solvent: Cc1ccccc1
Product: O=[N+]([O-])c1cccc2cc(C3=NCCS3)[nH]c12
Yield: 60 %

Procedure:
7-Nitro-1H-indole-2-carboxylic acid (2-chloro-ethyl)-amide (267 mg, 1 mmol) prepared in Step B was dissolved in dichloroethane (10 mL) and toluene (10 mL), and Lawesson's Reagent (1.29 g, 3.2 mmol) was added thereto. The mixture was refluxed for 4 h, and distilled under reduced pressure. Water was added thereto, and the reaction mixture was extracted with ethyl acetate, dried over anhydrous magnesium sulfate, and filtered. The filtrate was distilled under reduced pressure, and the concentrate was purified by column chromatography to give the title compound as a product of the cyclization reaction (148 mg, Yield 60%).
Reaction SMILES: [CH3:1][NH:2][C:3]1[CH:4]=[C:5]([CH:8]=[CH:9][CH:10]=1)[C:6]#[N:7].Br[CH2:12][CH2:13][OH:14].C([O-])([O-])=O.[Ca+2]>O>[OH:14][CH2:13][CH2:12][N:2]([CH3:1])[C:3]1[CH:4]=[C:5]([CH:8]=[CH:9][CH:10]=1)[C:6]#[N:7]
Reactant: CNc1cccc(C#N)c1
Reactant: OCCBr
Agent: O=C([O-])[O-]
Agent: [Ca+2]
Solvent: O
Product: CN(CCO)c1cccc(C#N)c1
Yield: 76.2 %

Procedure:
3-methylaminobenzonitrile (11.36 g, 86 mmol, 1.0 eq), 2-bromoethanol (43.00 g, 344 mmol, 4.0 eq) and CaCO3 (34.40 g, 344 mmol, 4.0 eq) are added into water (150 ml) at room temperature, and the resulting mixture is refluxed with elevated temperature for 13.5 h, then cooled and filtered, and the aqueous solution is extracted with ethyl acetate (100 ml*3). The organic phases are combined, washed with water (20 ml*2), washed with saturated brine twice, dried over anhydrous sodium sulfate, and concentrated to give a light yellow oily crude product (11.55 g, crude yield: 76.2%). The crude product can be used directly in next step without purification.
Reaction SMILES: Br[C:2]1[N:6]=[C:5]([C:7]2[CH:8]=[C:9]([C:13]3[C:14]4[C:21]([C:22]([O:24][CH2:25][CH3:26])=[O:23])=[CH:20][N:19]([CH2:27][O:28][CH2:29][CH2:30][Si:31]([CH3:34])([CH3:33])[CH3:32])[C:15]=4[N:16]=[CH:17][N:18]=3)[CH:10]=[CH:11][CH:12]=2)[S:4][N:3]=1.[CH3:35][N:36](C=O)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.[C-]#N.[Zn+2].[C-]#N>[C:35]([C:2]1[N:6]=[C:5]([C:7]2[CH:8]=[C:9]([C:13]3[C:14]4[C:21]([C:22]([O:24][CH2:25][CH3:26])=[O:23])=[CH:20][N:19]([CH2:27][O:28][CH2:29][CH2:30][Si:31]([CH3:34])([CH3:33])[CH3:32])[C:15]=4[N:16]=[CH:17][N:18]=3)[CH:10]=[CH:11][CH:12]=2)[S:4][N:3]=1)#[N:36]
Reactant: CCOC(=O)c1cn(COCC[Si](C)(C)C)c2ncnc(-c3cccc(-c4nc(Br)ns4)c3)c12
Reactant: CN(C)C=O
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: [C-]#N
Agent: [Zn+2]
Product: CCOC(=O)c1cn(COCC[Si](C)(C)C)c2ncnc(-c3cccc(-c4nc(C#N)ns4)c3)c12
Temperature: 95 °C

Procedure:
A mixture of ethyl 4-(3-(3-bromo-1,2,4-thiadiazol-5-yl)phenyl)-7-((2-(trimethylsilyl)ethoxy)methyl)-7H-pyrrolo[2,3-d]pyrimidine-5-carboxylate (51 mg, 0.092 mmol), tetrakis(triphenylphosphine)palladium(0) (53 mg, 0.046 mmol), and zinc cyanide (107 mg, 0.915 mmol) in DMF (1.0 mL) was heated to 95° C. overnight. The resulting mixture was filtered and concentrated under reduced pressure. Purification by chromatography on silica eluting with 0-50% ethyl acetatehexane gave ethyl 4-(3-(3-cyano-1,2,4-thiadiazol-5-yl)phenyl)-7-((2-(trimethylsilyl)ethoxy)methyl)-7H-pyrrolo[2,3-d]pyrimidine-5-carboxylate. LRMS (ESI) calc'd for C24H27N6O3SSi [M+H]+: 507, found 507.
Reaction SMILES: [C:1]([NH:4][C:5]1[S:6][C:7]2[CH:13]=[CH:12][CH:11]=[C:10]([O:14][C:15]3[N:20]=[CH:19][N:18]=[C:17]([C:21]4[CH:26]=[CH:25][C:24]([C:27]([F:30])([F:29])[F:28])=[CH:23][C:22]=4[NH:31][C:32]([C@:34]4([CH3:39])[CH2:38][CH2:37][CH2:36][NH:35]4)=[O:33])[CH:16]=3)[C:8]=2[N:9]=1)(=[O:3])[CH3:2].[CH3:40][C:41]([CH3:43])=O>>[C:1]([NH:4][C:5]1[S:6][C:7]2[CH:13]=[CH:12][CH:11]=[C:10]([O:14][C:15]3[N:20]=[CH:19][N:18]=[C:17]([C:21]4[CH:26]=[CH:25][C:24]([C:27]([F:29])([F:30])[F:28])=[CH:23][C:22]=4[NH:31][C:32]([C@:34]4([CH3:39])[CH2:38][CH2:37][CH2:36][N:35]4[CH:41]([CH3:43])[CH3:40])=[O:33])[CH:16]=3)[C:8]=2[N:9]=1)(=[O:3])[CH3:2]
Reactant: CC(=O)Nc1nc2c(Oc3cc(-c4ccc(C(F)(F)F)cc4NC(=O)[C@]4(C)CCCN4)ncn3)cccc2s1
Reactant: CC(C)=O
Product: CC(=O)Nc1nc2c(Oc3cc(-c4ccc(C(F)(F)F)cc4NC(=O)[C@]4(C)CCCN4C(C)C)ncn3)cccc2s1

Procedure:
(2S)-N-(2-(6-(2-Acetamidobenzo[d]thiazol-4-yloxy)pyrimidin-4-yl)-5-(trifluoromethyl)phenyl)-2-methylpyrrolidine-2-carboxamide (Example 57) was reacted with acetone under the conditions of Example 3(d) to give the title compound as a white solid. MS (ESI, pos. ion.) m/z: 599 (M+1).
Reaction SMILES: O=[C:2]1[CH2:8][CH2:7][N:6]([C:9]([O:11][C:12]([CH3:15])([CH3:14])[CH3:13])=[O:10])[CH2:5][CH2:4][NH:3]1.P12(SP3(SP(SP(S3)(S1)=S)(=S)S2)=S)=[S:17].ClCCl.C([O-])([O-])=O.[K+].[K+]>CC(C)=O>[S:17]=[C:2]1[CH2:8][CH2:7][N:6]([C:9]([O:11][C:12]([CH3:15])([CH3:14])[CH3:13])=[O:10])[CH2:5][CH2:4][NH:3]1
Reactant: CC(C)(C)OC(=O)N1CCNC(=O)CC1
Reactant: S=P12SP3(=S)SP(=S)(S1)SP(=S)(S2)S3
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: ClCCl
Solvent: CC(C)=O
Product: CC(C)(C)OC(=O)N1CCNC(=S)CC1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
tert-Butyl 5-oxo-1,4-diazepane-1-carboxylate, P4S10 (0.2 eq.), HMDO (2 eq.) and dichloromethane were combined and stirred magnetically at room temperature for 1 hour. The reaction mixture was then cooled to 0° C. and aqueous K2CO3 solution (1.26 mL of 5.3 M/mmol P4S10 taken) was added. A volume of acetone equal to one half of the reaction solvent was added to obtain a stirrable mixture, and the reaction mixture was stirred vigorously for 30 minutes at 0° C. Volatiles were evaporated, water and ethyl acetate were added, layers were separated and the organic phase was washed with water and brine. The organic extract was dried over Na2SO4 and evaporated, to afford the title compound. 1H NMR (300 MHz, CDCl3) δ 8.7 (bs, 1H), 3.68-3.60 (m, 4H), 3.42-3.38 (m, 2H), 3.15-3.09 (m, 2H), 1.43 (s, 9H); MS (ES) C10H18N2O2S requires 230. Found: 231 (M+H+).
Reaction SMILES: O.NN.O=C1C2C(=CC=CC=2)[C:7](=[O:14])[N:6]1[O:15][CH:16]1[CH2:21][CH2:20][N:19]([CH:22]([C:25]2[CH:30]=[CH:29][C:28]([O:31][C:32]([F:35])([F:34])[F:33])=[CH:27][CH:26]=2)[C:23]#[N:24])[CH2:18][CH2:17]1.[F:36][C:37]1[CH:42]=[CH:41][C:40]([N:43]=C=O)=[CH:39][CH:38]=1>C(Cl)Cl>[C:23]([CH:22]([C:25]1[CH:26]=[CH:27][C:28]([O:31][C:32]([F:35])([F:33])[F:34])=[CH:29][CH:30]=1)[N:19]1[CH2:20][CH2:21][CH:16]([O:15][NH:6][C:7]([NH:43][C:40]2[CH:41]=[CH:42][C:37]([F:36])=[CH:38][CH:39]=2)=[O:14])[CH2:17][CH2:18]1)#[N:24]
Reactant: N#CC(c1ccc(OC(F)(F)F)cc1)N1CCC(ON2C(=O)c3ccccc3C2=O)CC1
Reactant: O=C=Nc1ccc(F)cc1
Agent: NN
Solvent: O
Solvent: ClCCl
Product: N#CC(c1ccc(OC(F)(F)F)cc1)N1CCC(ONC(=O)Nc2ccc(F)cc2)CC1
Temperature: 25 °C
Reaction time: 16 h
Yield: 121.6 %

Procedure:
Hydrazine monohydrate (0.063 ml, 1.303 mmol) was added to a solution of 2-(4-(1,3-dioxoisoindolin-2-yloxy)piperidin-1-yl)-2-(4-(trifluoromethoxy)phenyl)acetonitrile (258 mg, 0.434 mmol) in CH2Cl2 (5 ml) and the whole was stirred at room temperature for 16 hours. The resulting solid was filtered off and the filtrate was concentrated in vacuo. The residue was dissolved in tetrahydrofuran (5 ml), treated with 4-fluorophenyl isocyanate (0.023 ml, 0.200 mmol) and stirred at room temperature for 14 hours. The reaction mixture was concentrated in vauo and the residue was purified by column chromatography (ethyl acetate/hexane: 50/50 to 0/100) and the resulting solid was triturated with ethyl acetate/hexane to give 1-(1-(cyano(4-(trifluoromethoxy)phenyl)methyl)piperidin-4-yloxy)-3-(4-fluorophenyl)urea (110 mg, 56%) as a white solid: LCMS: 442 [M+1]+. 1H NMR (DMSO-d6) δ: 1.67 (m, 1H), 1.81 (m, 1H), 1.94 (m, 2H), 2.33 (m, 2H), 2.58 (m, 1H), 2.88 (m, 1H), 3.76 (m, 1H), 5.47 (s, 1H), 7.10 (m, 2H), 7.46-7.60 (m, 6H), 8.62 (s, 1H), 9.43 (s, 1H).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5](Cl)=[N:6][CH:7]=1.[OH:9][CH2:10][CH2:11][NH2:12]>CC(N(C)C)=O>[Br:1][C:2]1[CH:3]=[CH:4][C:5]([NH:12][CH2:11][CH2:10][OH:9])=[N:6][CH:7]=1
Reactant: NCCO
Reactant: Clc1ccc(Br)cn1
Solvent: CC(=O)N(C)C
Product: OCCNc1ccc(Br)cn1
Temperature: 170 °C

Procedure:
A mixture of 5-bromo-2-chloropyridine (Aldrich, Buchs, Switzerland, 1 g, 5.2 mmol) and 2-hydroxyethylamine (1.59 g, 26 mmol) in 3 ml DMA was heated by microwaves at 170° C. for 1 h. Then the RM was quenched with saturated aqueous NaHCO3 (50 ml) and extracted with EtOAc. The organic layers were washed with saturated aqueous NaHCO3 (4×), dried over Na2SO4, filtered and evaporated. The residue was purified by flash chromatography (DCM/MeOH 0 to 5%). The fractions containing product were evaporated together to give the title compound as an off-white solid. (HPLC: tR 1.66 min (Method A); M+H=217, 219 (Br-pattern) MS-ES)