Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: N1C2C(=CC=C([C@H]3[C@@]4(C5C(=CC=CC=5)NC4=O)C3)C=2)C=N1.C([N:29]1[C:37]2[C:32](=[CH:33][C:34]([F:38])=[CH:35][CH:36]=2)[C@:31]2([CH2:40][C@H:39]2[C:41]2[CH:49]=[C:48]3[C:44]([CH:45]=[N:46][N:47]3CC3C=CC=CC=3)=[CH:43][CH:42]=2)[C:30]1=[O:57])C1C=CC=CC=1>>[F:38][C:34]1[CH:33]=[C:32]2[C:37](=[CH:36][CH:35]=1)[NH:29][C:30](=[O:57])[C@:31]12[CH2:40][C@H:39]1[C:41]1[CH:49]=[C:48]2[C:44]([CH:45]=[N:46][NH:47]2)=[CH:43][CH:42]=1
Reactant: O=C1N(Cc2ccccc2)c2ccc(F)cc2[C@]12C[C@H]2c1ccc2cnn(Cc3ccccc3)c2c1
Agent: O=C1Nc2ccccc2[C@]12C[C@H]2c1ccc2cn[nH]c2c1
Product: O=C1Nc2ccc(F)cc2[C@]12C[C@H]2c1ccc2cn[nH]c2c1
Yield: 51.7 %

Procedure:
The title compound was prepared in a manner similar to the method of (1R,2S)-2-(1H-indazol-6-yl)spiro[cyclopropane-1,3′-indolin]-2′-one using (1R,2S)-1′-benzyl-2-(1-benzyl-1H-indazol-6-yl)-5′-fluorospiro[cyclopropane-1,3′-indolin]-2′-one (560 mg, 1.18 mmol). Purification by using silica gel column chromatography with 5-95% EtOAc in hexane to give the title compound as a creamy solid (179 mg, 52%). NMR (400 MHz, CD3OD) δ 8.03 (s, 1H), 7.71 (d, J=8.0 Hz, 1H), 7.62-7.46 (m, 2H), 6.94 (d, J=8.4 Hz, 1H), 6.88 (t, J=4.8 Hz, 1H), 5.69 (d, J=9.2 Hz, 1H), 3.39 (t, J=8.0 Hz, 1H), 2.30-2.71 (m, 1H), 2.23-2.18 (m, 1H); MS ESI 294.1 [M+H]+, calcd for [C17H12FN3O+H]+ 294.10.
Reaction SMILES: [Si:1]([O:8][CH:9](C1C=CN=C(C#N)C=1)[CH3:10])([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2].[C:19]([C:22]1[CH:27]=[C:26](Cl)[CH:25]=[CH:24][N:23]=1)(=[O:21])[CH3:20]>>[C:19]([C:22]1[CH:27]=[C:26]([CH:9]([O:8][Si:1]([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2])[CH3:10])[CH:25]=[CH:24][N:23]=1)(=[O:21])[CH3:20]
Reactant: CC(=O)c1cc(Cl)ccn1
Reactant: CC(O[Si](C)(C)C(C)(C)C)c1ccnc(C#N)c1
Product: CC(=O)c1cc(C(C)O[Si](C)(C)C(C)(C)C)ccn1

Procedure:
The title compound was prepared from 4-[1-(tert-butyldimethylsilyloxy)ethyl]-2-pyridinecarbonitrile according to the procedure for preparing 2-acetyl-4-chloropyridine described Example 33.
Reaction SMILES: C1N=CN([C:6](N2C=NC=C2)=[O:7])C=1.[NH2:13][C:14]1[CH:19]=[CH:18][C:17]([O:20][CH3:21])=[CH:16][C:15]=1[CH2:22][CH2:23][NH:24][CH:25]1[CH2:30][CH2:29][N:28]([CH2:31][C:32]2[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=2)[CH2:27][CH2:26]1>CN(C=O)C>[CH2:31]([N:28]1[CH2:29][CH2:30][CH:25]([N:24]2[CH2:23][CH2:22][C:15]3[CH:16]=[C:17]([O:20][CH3:21])[CH:18]=[CH:19][C:14]=3[NH:13][C:6]2=[O:7])[CH2:26][CH2:27]1)[C:32]1[CH:33]=[CH:34][CH:35]=[CH:36][CH:37]=1
Reactant: O=C(n1ccnc1)n1ccnc1
Reactant: COc1ccc(N)c(CCNC2CCN(Cc3ccccc3)CC2)c1
Solvent: CN(C)C=O
Product: COc1ccc2c(c1)CCN(C1CCN(Cc3ccccc3)CC1)C(=O)N2
Temperature: 100 °C
Reaction time: 2 h
Yield: 84.1 %

Procedure:
35.0 g (216 mmol) N,N-carbonyldiimidazole were added to 23.9 g (70.3 mmol) [2-(2-amino-5-methoxyphenyl)-ethyl]-(1-benzylpiperidin-4-yl)-amine in 175 mL DMF and the mixture was stirred for 2 h at 100° C. The reaction mixture was poured onto approx. 1 kg of ice water and stirred overnight. The precipitated product was suction filtered, washed with 100 mL water and dried at 45° C. in the CAD. The residue was stirred with 150 mL DIPE and suction filtered. The solid product was washed with 50 mL DIPE. After drying in the CAD at 35° C., 21.6 g of the desired product were obtained.
Reaction SMILES: Br.Br[CH2:3][CH2:4][C:5]1[C:10](=[O:11])[N:9]2[C:12]([CH3:15])=[CH:13][S:14][C:8]2=[N:7][C:6]=1[CH3:16].[F:17][C:18]1[CH:23]=[CH:22][C:21]([C:24]2([CH:29]3[CH2:34][CH2:33][NH:32][CH2:31][CH2:30]3)[O:28][CH2:27][CH2:26][O:25]2)=[CH:20][CH:19]=1.C(=O)([O-])[O-].[Na+].[Na+].CC(C)CC(=O)C>O>[F:17][C:18]1[CH:23]=[CH:22][C:21]([C:24]2([CH:29]3[CH2:34][CH2:33][N:32]([CH2:3][CH2:4][C:5]4[C:10](=[O:11])[N:9]5[C:12]([CH3:15])=[CH:13][S:14][C:8]5=[N:7][C:6]=4[CH3:16])[CH2:31][CH2:30]3)[O:28][CH2:27][CH2:26][O:25]2)=[CH:20][CH:19]=1
Reactant: Cc1nc2scc(C)n2c(=O)c1CCBr
Reactant: Fc1ccc(C2(C3CCNCC3)OCCO2)cc1
Agent: Br
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Solvent: CC(=O)CC(C)C
Product: Cc1nc2scc(C)n2c(=O)c1CCN1CCC(C2(c3ccc(F)cc3)OCCO2)CC1
Yield: 35 %

Procedure:
A mixture of 9.3 parts of 6-(2-bromoethyl)-3,7-dimethyl-5H-thiazolo[3,2-a]pyrimidin-5-one monohydrobromide, 6.5 parts of 4-[2-(4-fluorophenyl)-1,3-dioxolan-2-yl]piperidine, 10.2 parts of sodium carbonate and 120 parts of 4-methyl-2-pentanone was stirred and refluxed overnight. The reaction mixture was cooled and water was added. The layers were separated. The organic phase was dried, filtered and evaporated. The residue was purified by column-chromatography over silica gel using a mixture of trichloromethane and methanol (98:2 by volume) as eluent. The pure fractions were collected and the eluent was evaporated. The residue was crystallized from 2,2'-oxybispropane. The product was filtered off and dried, yielding 4 parts (35%) of 6-[2-[4-[2-(4-fluorophenyl)-1,3-dioxolan-2-yl]-1-piperidinyl]ethyl]-3,7-dimethyl-5H-thiazolo[3,2-a]pyrimidin-5-one; mp. 140° C. (compound 35).
Reaction SMILES: [CH2:1]([Li])[CH2:2][CH2:3][CH3:4].[C:6]12(C(=O)C3C[CH:10]1[CH2:11][CH2:12]3)[CH2:9][CH2:8][CH2:7]2>[Br-].C[P+](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.O1CCCC1>[CH2:4]=[C:3]1[C:6]2([CH2:9][CH2:8][CH2:7]2)[CH:10]2[CH2:1][CH:2]1[CH2:12][CH2:11]2
Reactant: [Li]CCCC
Reactant: O=C1C2CCC(C2)C12CCC2
Agent: C[P+](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Br-]
Solvent: C1CCOC1
Product: C=C1C2CCC(C2)C12CCC2
Temperature: -78 °C
Reaction time: 0.5 h
Yield: 75 %

Procedure:
To a suspension of (methyl)triphenylphosphonium bromide (49.9 mmol, 18.2 g) in dry tetrahydrofuran (THF) (100 mL) at −78° C. was added n-butyllithium (46.5 mmol, 18.6 mL of 2.5 M solution in hexanes). The mixture was stirred for 30 min at −78° C. To this mixture was added spiro[bicyclo[2.2.1]heptane-2,1′-cyclobutan]-3-one (5.00 g, 33.3 mmol). The resulting mixture was stirred at ambient temperature for 20 h. Hexanes (300 mL) were added, and the mixture was filtered. The filtrate was concentrated, and the residue was purified on an 80 g silica gel column, eluting with hexanes, to obtain 3-methylenespiro[bicyclo[2.2.1]heptane-2,1′-cyclobutane] (Compound III in Scheme 1) (3.7 g, 75%) as oil. 1H NMR (CDCl3, 400 MHz); δ 4.82 (s, 2H), 2.63 (bra, 1H), 2.22 (bra, 1H), 2.05-1.78 (m, 6H), 1.63-1.52 (m. 1H), 1.48-1.34 (m, 3H), 1.21-1.12 (m, 2H).
Reaction SMILES: O=[C:2]1[CH2:6][S:5][CH2:4][CH:3]1[C:7]#[N:8].[C:9]1([C:15]2[N:20]=[CH:19][C:18]([C:21]3[CH:22]=[N:23][NH:24][C:25]=3[NH2:26])=[CH:17][CH:16]=2)[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1>C1(C)C=CC=CC=1>[C:9]1([C:15]2[N:20]=[CH:19][C:18]([C:21]3[CH:22]=[N:23][N:24]4[C:7]([NH2:8])=[C:3]5[CH2:4][S:5][CH2:6][C:2]5=[N:26][C:25]=34)=[CH:17][CH:16]=2)[CH:10]=[CH:11][CH:12]=[CH:13][CH:14]=1
Reactant: N#CC1CSCC1=O
Reactant: Nc1[nH]ncc1-c1ccc(-c2ccccc2)nc1
Solvent: Cc1ccccc1
Product: Nc1c2c(nc3c(-c4ccc(-c5ccccc5)nc4)cnn13)CSC2
Temperature: 115 °C

Procedure:
A mixture of 4-oxotetrahydrothiophene-3-carbonitrile (77.6 mg, 0.61 mmol) and 4-(6-phenylpyridin-3-yl)-1H-pyrazol-5-amine (144 mg, 0.61 mmol) in toluene (10 mL) was heated at 115° C. overnight. Concentration and purification with prep-LC provided 3-(6-phenylpyridin-3-yl)-5,7-dihydropyrazolo[1,5-a]thieno[3,4-d]pyrimidin-8-amine: LCMS tR=1.48 Min (5 min run, UV254mn), Mass calculated for, M+345.1, observed LC/MS m/z 346.1 (M+H).
Reaction SMILES: [CH2:1]([C:3]1[C:4](=[O:15])[NH:5][C:6]([CH3:14])=[C:7]([C:9]2[O:10][CH:11]=[CH:12][CH:13]=2)[CH:8]=1)[CH3:2].[CH:16](=[O:18])[CH3:17]>>[CH2:1]([C:3]1[C:4](=[O:15])[NH:5][C:6]([CH3:14])=[C:7]([C:9]2[O:10][C:11]([CH:16]([OH:18])[CH3:17])=[CH:12][CH:13]=2)[CH:8]=1)[CH3:2]
Reactant: CCc1cc(-c2ccco2)c(C)[nH]c1=O
Reactant: CC=O
Product: CCc1cc(-c2ccc(C(C)O)o2)c(C)[nH]c1=O

Procedure:
Example 267 is substantially repeated except for utilizing 3-ethyl-6-methyl-5-furan-2-yl-1H-pyridin-2-one prepared in accordance with the procedures of Example 44, Step 2 and acetaldehyde to afford the title compound. MS: m/e=248 (M+H).
Reaction SMILES: [C:1](O)(=O)[CH3:2].C(OC(=O)C)(=O)C.[OH:12][NH:13][C:14]([C:16]1[CH:21]=[CH:20][C:19](=[O:22])[NH:18][N:17]=1)=[NH:15]>N1C=CC=CC=1>[CH3:1][C:2]1[O:12][N:13]=[C:14]([C:16]2[CH:21]=[CH:20][C:19](=[O:22])[NH:18][N:17]=2)[N:15]=1
Reactant: CC(=O)O
Reactant: N=C(NO)c1ccc(=O)[nH]n1
Solvent: c1ccncc1
Solvent: CC(=O)OC(C)=O
Product: Cc1nc(-c2ccc(=O)[nH]n2)no1
Temperature: 90 °C
Reaction time: 15 h

Procedure:
2.8 ml of glacial acetic acid, 2.3 ml of acetic anhydride and 200 μl of pyridine are added to 375 mg (2.43 mmol) of N-hydroxy-6-oxo-1,6-dihydro-pyridazine-3-carboxamidine, and the mixture is stirred at 90° C. for 15 h. During cooling of the reaction mixture, a precipitate forms, which is filtered off with suction, washed with water and dried in vacuo; yield: 253 mg, yellow solid; HPLC: Rt=1.51 min; LC-MS: 179 (M+H).
Reaction SMILES: [Br:1][C:2]1[CH:6]=[N:5][N:4]([CH3:7])[C:3]=1[C:8]1[CH:9]=[C:10]([NH2:24])[CH:11]=[CH:12][C:13]=1[O:14][CH2:15][CH2:16][N:17]1[CH2:23][CH2:22][CH2:21][O:20][CH2:19][CH2:18]1.C(N(CC)C(C)C)(C)C.[F:34][C:35]1[CH:36]=[C:37]([CH:41]=[CH:42][C:43]=1[C:44]([F:47])([F:46])[F:45])[C:38](Cl)=[O:39]>CC(N(C)C)=O.CS(C)=O>[Br:1][C:2]1[CH:6]=[N:5][N:4]([CH3:7])[C:3]=1[C:8]1[CH:9]=[C:10]([NH:24][C:38](=[O:39])[C:37]2[CH:41]=[CH:42][C:43]([C:44]([F:45])([F:46])[F:47])=[C:35]([F:34])[CH:36]=2)[CH:11]=[CH:12][C:13]=1[O:14][CH2:15][CH2:16][N:17]1[CH2:23][CH2:22][CH2:21][O:20][CH2:19][CH2:18]1
Reactant: O=C(Cl)c1ccc(C(F)(F)F)c(F)c1
Reactant: Cn1ncc(Br)c1-c1cc(N)ccc1OCCN1CCCOCC1
Solvent: CC(=O)N(C)C
Solvent: CS(C)=O
Solvent: CCN(C(C)C)C(C)C
Product: Cn1ncc(Br)c1-c1cc(NC(=O)c2ccc(C(F)(F)F)c(F)c2)ccc1OCCN1CCCOCC1
Temperature: 25 °C
Reaction time: 8 h
Yield: 53 %

Procedure:
To a solution of 3-(4-bromo-2-methyl-2H-pyrazol-3-yl)-4-(2-[1,4]oxazepan-4-yl-ethoxy)-phenylamine (0.06 g, 0.152 mmol), and N,N-diisopropylethylamine (0.0529 mL, 0.304 mmol) in 3.0 mL of DMA was added slowly 3-fluoro-4-(trifluoromethyl)benzoyl chloride (0.0278 mL, 0.182 mmol) and the reaction mixture was stirred at ambient temperature overnight. The reaction mixture was diluted to 5.0 mL with DMSO and subjected to purification on a RP-HPLC. The proper fractions were collected and lyophilized to furnish N-[3-(4-Bromo-2-methyl-2H-pyrazol-3-yl)-4-(2-[1,4]oxazepan-4-yl-ethoxy)-phenyl]-3-fluoro-4-trifluoromethyl-benzamide as an off-white semisolid in 53% yield. LCMS m/z (%)=585 (M+H79Br, 100), 587 (M+H81Br, 98). 1H NMR (400 MHz, DMSO-d6) δ: 10.3 (bs, 1H), 8.06 (d, J=11.27 Hz, 1H), 7.95-8.01 (m, 3H), 7.72 (d, J=2.60 Hz, 1H), 7.68 (d, J=2.36 Hz, 1H), 7.31 (d. J=9.48 Hz, 1H), 4.35-4.44 (m, 2H), 3.5-3.9 (m, 10H), 2.51-2.69 (m, 5H).
Reaction SMILES: [NH:1]1[CH:5]=[C:4]([C:6](Cl)=[O:7])[CH:3]=[N:2]1.[CH2:9]([NH2:11])[CH3:10].C(N(CC)CC)C>C(Cl)Cl>[CH2:9]([NH:11][C:6]([C:4]1[CH:3]=[N:2][NH:1][CH:5]=1)=[O:7])[CH3:10]
Reactant: CCN
Reactant: O=C(Cl)c1cn[nH]c1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CCNC(=O)c1cn[nH]c1
Yield: 97 %

Procedure:
Following the same procedure in Example 28 (Step C of Method B), using 1H-pyrazole-4-carbonyl chloride (0.47 g, 3.6 mmol), ethylamine (3.0 mL, 2.0 M in THF, 6.0 mmol) and triethylamine (1.01 g, 1.39 mL, 10 mmol) in CH2Cl2 (15 mL), provided the title compound as a white solid. Yield: 0.49 g (97% yield). 1H NMR (400 MHz, METHANOL-D4) δ 1.18 (t, J=7.23 Hz, 3 H) 3.34 (q, J=7.23 Hz, 2 H) 7.92 (s, 1 H) 8.09 (s, 1 H)
Reaction SMILES: [NH2:1][C:2]1[CH:14]=[CH:13][C:5]([CH2:6][N:7]2[CH2:12][CH2:11][O:10][CH2:9][CH2:8]2)=[CH:4][CH:3]=1.[CH3:15][N:16]1[CH2:21][CH2:20][C:19](=O)[CH2:18][CH2:17]1.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>C(O)(=O)C>[CH3:15][N:16]1[CH2:21][CH2:20][CH:19]([NH:1][C:2]2[CH:14]=[CH:13][C:5]([CH2:6][N:7]3[CH2:12][CH2:11][O:10][CH2:9][CH2:8]3)=[CH:4][CH:3]=2)[CH2:18][CH2:17]1
Reactant: CN1CCC(=O)CC1
Reactant: Nc1ccc(CN2CCOCC2)cc1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: CC(=O)O
Product: CN1CCC(Nc2ccc(CN3CCOCC3)cc2)CC1
Reaction time: 8 h

Procedure:
A flask containing 4-(4-aminobenzyl)morpholine from Preparation No. 22 (0.48 g) is treated with tetrhydrofuran (10 mL) and N-methyl-4-piperidone (0.37 mL) under an argon atmosphere. The solution is treated with acetic acid (0.20 mL) followed by sodium triacetoxyborohydride (0.80 g). After stirring overnight, the mixture is partitioned between diethyl ether and saturated aqueous sodium bicarbonate containing sodium hyroxide. The aqueous is back-extracted with additional portions of dichloromethane. The combined organic layer is washed with brine, dried over sodium sulfate, and concentrated under reduced pressure. The residue is purified by flash column chromatography on silica gel eluting with 2% to 5% methanol saturated with ammonia in dichloromethane to afford 0.52 g of 1-methyl-N-[4-(4-morpholinylmethyl)phenyl]-4-piperidinamine as a tan solid.
Reaction SMILES: C([O:3][C:4]([C:6]1([NH:19][C:20](=[O:32])[C:21]2[CH:26]=[CH:25][CH:24]=[C:23]([CH3:27])[C:22]=2[O:28][CH2:29][CH:30]=[CH2:31])[CH2:17][C:16]2[C:18]3[C:12]([CH:13]=[CH:14][CH:15]=2)=[CH:11][CH:10]=[CH:9][C:8]=3[CH2:7]1)=[O:5])C.[OH-].[K+].O>CCO>[CH2:29]([O:28][C:22]1[C:23]([CH3:27])=[CH:24][CH:25]=[CH:26][C:21]=1[C:20]([NH:19][C:6]1([C:4]([OH:5])=[O:3])[CH2:17][C:16]2[C:18]3[C:12]([CH:13]=[CH:14][CH:15]=2)=[CH:11][CH:10]=[CH:9][C:8]=3[CH2:7]1)=[O:32])[CH:30]=[CH2:31]
Reactant: C=CCOc1c(C)cccc1C(=O)NC1(C(=O)OCC)Cc2cccc3cccc(c23)C1
Agent: [K+]
Agent: [OH-]
Solvent: O
Solvent: CCO
Product: C=CCOc1c(C)cccc1C(=O)NC1(C(=O)O)Cc2cccc3cccc(c23)C1
Temperature: 25 °C
Reaction time: 8 h
Yield: 93.9 %

Procedure:
The mixture of 2-(2-allyloxy-3-methyl-benzoylamino)-2,3-dihydro-1H-phenalene-2-carboxylic acid ethyl ester (23) (107 mg, 0.26 mmol) and KOH (500 mg, 8.9 mmol) is dissolved in EtOH (5 mL) and water (0.5 mL) under a water bath. The water bath is removed when KOH is completely dissolved and the resulting reaction solution is stirred at RT for 8 h. After concentration in vacuo, the residue is dissolved in water (20 mL) and acidified with conc. HCl until no more white precipitate came out from the water. The precipitate is filtered to give a pure product (24) as white solid (98 mg, 94%).
Reaction SMILES: [CH2:1]([O:3][C:4]1[CH:5]=[C:6]([CH:13]=[CH:14][C:15]=1[C:16]([F:19])([F:18])[F:17])[C:7](N(OC)C)=[O:8])[CH3:2].[CH3:20][Mg]Br.Cl>C1COCC1.CC(OC)(C)C>[CH2:1]([O:3][C:4]1[CH:5]=[C:6]([C:7](=[O:8])[CH3:20])[CH:13]=[CH:14][C:15]=1[C:16]([F:17])([F:18])[F:19])[CH3:2]
Reactant: CCOc1cc(C(=O)N(C)OC)ccc1C(F)(F)F
Reactant: C[Mg]Br
Agent: Cl
Solvent: C1CCOC1
Solvent: COC(C)(C)C
Product: CCOc1cc(C(C)=O)ccc1C(F)(F)F
Temperature: 0 °C
Reaction time: 0.25 h

Procedure:
To a solution of 3-ethoxy-N-methoxy-N-methyl-4-trifluoromethyl-benzamide from step 7 (15.96 g, 58 mmol) in THF (182 mL) at −5° C. was added methylmagnesium bromide (3 M in Et2O, 38.37 mL, 115 mmol). The mixture was stirred at 0° C. for 15 min, then warmed up to 23° C., stirring was continued for further 3 h at 23° C. Cooled to 0° C., 1 N HCl (274 mL) was added dropwise, stirring was continued at 23° C. for 15 min, the mixture was diluted with TBME, the phases were separated, the organic layer was washed with water and brine, dried over MgSO4. Removal of the solvent in vacuum left a yellow solid (13.10 g, 98%), which was used without further purification. MS (EI) 232.2 [M].
Reaction SMILES: N([O-])=O.[Na+].N[C:6]1[CH:7]=[C:8]2[C:21](=[CH:22][CH:23]=1)[CH2:20][C@:10]1([C:18]3[C:13](=[N:14][CH:15]=[CH:16][CH:17]=3)[NH:12][C:11]1=[O:19])[CH2:9]2.[OH:24]S(O)(=O)=O>O>[OH:24][C:6]1[CH:7]=[C:8]2[C:21](=[CH:22][CH:23]=1)[CH2:20][C@:10]1([C:18]3[C:13](=[N:14][CH:15]=[CH:16][CH:17]=3)[NH:12][C:11]1=[O:19])[CH2:9]2
Reactant: O=S(=O)(O)O
Reactant: Nc1ccc2c(c1)C[C@@]1(C2)C(=O)Nc2ncccc21
Agent: O=N[O-]
Agent: [Na+]
Solvent: O
Product: O=C1Nc2ncccc2[C@]12Cc1ccc(O)cc1C2
Temperature: 25 °C

Procedure:
A solution of sodium nitrite (275 mg, 3.98 mmol) in water (1.6 mL) was slowly added to a cooled mixture of (R)-5-amino-1,3-dihydrospiro[indene-2,3′-pyrrolo[2,3-b]pyridin]-2′(1′H)-one (1 g, 3.98 mmol, described in Intermediate 3) in of 10% aqueous H2SO4 (8 mL) at 0° C. The ice bath was removed and the reaction allowed to stir at ambient temperature. The reaction mixture was then placed into a 70° C. oil bath and the bath was heated to 100° C. Bubbling was observed and heating was continued until LCMS indicated that the reaction was complete. The reaction was slowly neutralized by addition of 30% NH4OH (ca. 2 mL) and the precipitate was collected by filtration and washed with water. The solid was then air dried and chromatographed by first mixing with silica and dry loading on a silica gel column. The product was eluted. with (10% MeOH/CH2Cl2). Concentration of the product containing fractions gave the title compound. MS: m/z=253 (M+1).
Reaction SMILES: [F:1][C:2]1[CH:9]=[CH:8][CH:7]=[C:6]([O:10][CH2:11][C:12]([F:15])([F:14])[F:13])[C:3]=1[C:4]#N.[H-].C([Al+]CC(C)C)C(C)C.C[OH:27].Cl>C1(C)C=CC=CC=1>[F:1][C:2]1[CH:9]=[CH:8][CH:7]=[C:6]([O:10][CH2:11][C:12]([F:15])([F:14])[F:13])[C:3]=1[CH:4]=[O:27]
Reactant: CO
Reactant: N#Cc1c(F)cccc1OCC(F)(F)F
Agent: CC(C)C[Al+]CC(C)C
Agent: Cl
Agent: [H-]
Solvent: Cc1ccccc1
Product: O=Cc1c(F)cccc1OCC(F)(F)F
Temperature: 25 °C
Reaction time: 16 h
Yield: 94 %

Procedure:
To a suspension of 2-fluoro-6-(2,2,2-trifluoroethoxy)benzonitrile (2.3 g, 11 mmol, J. Hetelocyclic Chem. 1988, 25, 1173-1177) in toluene (40 mL) was added diisobutylaluminium hydride (1.0 M in toluene, 11 mL, 11 mmol) at −78° C. The mixture was warmed to room temperature and stirred for 16 h. Methanol (3.0 mL) was added to the mixture and the mixture was stirred for 10 min, then 2N hydrochloric acid (6.0 mL) was added to the mixture. After being stirred at room temperature for 1 h, the mixture was extracted with ethyl acetate (50 mL×2) and washed with aq. sodium hydrogencarbonate. The combined extracts were dried over magnesium sulfate and concentrated in vacuo to give a solid. The residual solid was purified by silica gel column chromatography (hexane/ethyl acetate 4:1) to afford 2.2 g (94%) of the title compound as a white solid.
Reaction SMILES: [CH3:1][S:2]([N:5]1[CH2:26][CH2:25][C:8]2([C:12](=[O:13])[N:11]([C:14]3[CH:19]=[CH:18][C:17]([O:20][C:21]([F:24])([F:23])[F:22])=[CH:16][CH:15]=3)[CH2:10][CH2:9]2)[CH2:7][CH2:6]1)(=[O:4])=[O:3].[Li]CCCC.[CH:32]1([CH:35]=[O:36])[CH2:34][CH2:33]1>C1COCC1>[CH:32]1([CH:35]([OH:36])[CH2:1][S:2]([N:5]2[CH2:6][CH2:7][C:8]3([C:12](=[O:13])[N:11]([C:14]4[CH:15]=[CH:16][C:17]([O:20][C:21]([F:23])([F:22])[F:24])=[CH:18][CH:19]=4)[CH2:10][CH2:9]3)[CH2:25][CH2:26]2)(=[O:4])=[O:3])[CH2:34][CH2:33]1
Reactant: O=CC1CC1
Reactant: CS(=O)(=O)N1CCC2(CCN(c3ccc(OC(F)(F)F)cc3)C2=O)CC1
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: O=C1N(c2ccc(OC(F)(F)F)cc2)CCC12CCN(S(=O)(=O)CC(O)C1CC1)CC2
Temperature: 0 °C
Reaction time: 0.08 h
Yield: 47.8 %

Procedure:
To a solution of 8-methanesulfonyl-2-(4-trifluoromethoxy-phenyl)-2,8-diaza-spiro[4.5]decan-1-one (76 mg, 0.19 mmol) in THF at −78° C. was added n-BuLi (1.6M, 145 uL, 0.23 mmol) dropwise. The reaction mixture was stirred for 5 min followed by the addition of a solution of cyclopropanecarbaldehyde (54 mg, 0.78 mmol) in THF (500 uL) at −78° C. The dry ice bath was removed and the reaction mixture was warmed to 0° C. and stirring was continued for a further 30 min. The reaction mixture was quenched with AcOH (20 uL) and was then concentrated to dryness under reduced pressure. The crude residue was partitioned between ethyl acetate and water and the organic layer was then washed with brine, dried with Na2SO4, filtered and concentrated in vacuo to give a crude residue which was purified by flash column chromatography to afford 8-(2-cyclopropyl-2-hydroxy-ethanesulfonyl)-2-(4-trifluoromethoxy-phenyl)-2,8-diaza-spiro[4.5]decan-1-one (42 mg, 47%) as a white solid. MS (ESI): 463.2 (MH+)
Reaction SMILES: [F:1][C:2]1[CH:19]=[CH:18][C:17]([C:20]2[CH:25]=[CH:24][CH:23]=[C:22]([F:26])[CH:21]=2)=[CH:16][C:3]=1[C:4]([NH:6][C:7]1[C:12]([F:13])=[CH:11][CH:10]=[C:9]([OH:14])[C:8]=1[CH3:15])=O>C1COCC1>[F:13][C:12]1[CH:11]=[CH:10][C:9]([OH:14])=[C:8]([CH3:15])[C:7]=1[NH:6][CH2:4][C:3]1[CH:16]=[C:17]([C:20]2[CH:25]=[CH:24][CH:23]=[C:22]([F:26])[CH:21]=2)[CH:18]=[CH:19][C:2]=1[F:1]
Reactant: Cc1c(O)ccc(F)c1NC(=O)c1cc(-c2cccc(F)c2)ccc1F
Solvent: C1CCOC1
Product: Cc1c(O)ccc(F)c1NCc1cc(-c2cccc(F)c2)ccc1F
Temperature: 50 °C
Yield: 69.3 %

Procedure:
To a solution of 2-fluoro-N-(6-fluoro-3-hydroxy-2-methyl-phenyl)-5-(3-fluorophenyl)benzamide (300 mg, 0.84 mmol, 1.0 eq) in THF (10 mL) under N2 was added dropwise a solution of BH3 (1M in THF, 4.2 mL, 4.2 mmol, 5.0 eq). The reaction mixture was heated at 50° C. overnight, then cooled and the reaction quenched by addition of 1M HCl. The mixture was extracted with EtOAc and the organic extract was washed with water and brine, dried (Na2SO4), filtered and evaporated in vacuo to give the title product as an oil (200 mg, 69%).
Reaction SMILES: Br[C:2]1[C:6]([C:7]#[C:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH3:14])=[CH:5][S:4][CH:3]=1.C([Li])CCC.CCCCCC.CN(C)[CH:28]=[O:29]>O1CCCC1.CCOCC>[C:7]([C:6]1[C:2]([CH:28]=[O:29])=[CH:3][S:4][CH:5]=1)#[C:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH3:14]
Reactant: CCCCCCC#Cc1cscc1Br
Reactant: CN(C)C=O
Agent: [Li]CCCC
Solvent: CCCCCC
Solvent: C1CCOC1
Solvent: CCOCC
Product: CCCCCCC#Cc1cscc1C=O
Reaction time: 8 h

Procedure:
3-Bromo-4-(1-octynyl)thiophene (2.0 g, 7.38 mM) was dissolved in dry tetrahydrofuran under argon. Butyl lithium (2.85 ml of a 2.6M hexane solution) was added keeping the temperature at -20° C. After 30 min at this temperature, N,N-dimethl formamide (2 ml) was added and the mixture allowed to attain room temperature overnight. Hydrolysis and extraction with ether yielded a yellow oil (1.70 g) which was purified by chromatography on silica eluting with chloroform/hexane (1:1). This gave 550 mg (34%) of the title compound as a yellow oil. νmax (film) 3100, 2225, 1680, 880, 760, 670; δ(CDCl3) 0.93(3H, t, J=6 Hz), 1.3(8H, m), 2.2(2H, t, 6 Hz), 7.25(1H, s), 7.67(1H, s), 9.93(1H, s).
Reaction SMILES: [Cl:1][C:2]1[CH:14]=[N:13][C:5]2[NH:6][C:7]3[CH2:12][CH2:11][NH:10][CH2:9][C:8]=3[C:4]=2[CH:3]=1.CCN(C(C)C)C(C)C.[C:24]([C:26]1[CH:27]=[C:28]([CH:32]=[CH:33][CH:34]=1)[C:29](Cl)=[O:30])#[N:25].Cl.CCOCC>C1COCC1>[ClH:1].[Cl:1][C:2]1[CH:14]=[N:13][C:5]2[NH:6][C:7]3[CH2:12][CH2:11][N:10]([C:29]([C:28]4[CH:27]=[C:26]([CH:34]=[CH:33][CH:32]=4)[C:24]#[N:25])=[O:30])[CH2:9][C:8]=3[C:4]=2[CH:3]=1
Reactant: Clc1cnc2[nH]c3c(c2c1)CNCC3
Reactant: N#Cc1cccc(C(=O)Cl)c1
Agent: Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: CCOCC
Solvent: C1CCOC1
Product: N#Cc1cccc(C(=O)N2CCc3[nH]c4ncc(Cl)cc4c3C2)c1
Temperature: 25 °C
Reaction time: 1 h
Yield: 55.8 %

Procedure:
3-Chloro-6,7,8,9-tetrahydro-5H-dipyrido[2,3-b;3′,4′-d]pyrrole (50 mg, 0.24 mmol) and DIEA (0.05 mL, 0.29 mmol) were dissolved in THF (2 mL). 3-Cyanobenzoyl chloride (48 mg, 0.29 mmol) was added dropwise, and the reaction solution was allowed to stir at room temperature for 1 h. The crude reaction mixture was concentrated, and converted to the HCl salt by dissolving the crude material in MeOH (2 ml) and adding 1 M HCl/ether (2 equiv). The resulting solution was refrigerated overnight. The resulting precipitate was filtered and dried under vacuum to provide 23 (25 mg, 28% yield) as a pale yellow solid. LC-MS (M+H=337, obsd.=337).